Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment. High or standard initial dose of budesonide to control mild-to-moderate asthma? Effect of inhaled budesonide on severe steroid-dependent asthma. Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. Bioequivalent doses of budesonide and prednisone in moderate and severe asthma. Comparison of high and low dose of the inhaled steroid, budesonide, as an initial treatment in newly detected asthma. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide. Salmeterol/fluticasone propionate combination therapy 50/250 microg twice daily is more effective than budesonide 800 microg twice daily in treating moderate to severe asthma. Once-daily dosing with budesonide/formoterol compared with twice-daily budesonide/formoterol and once-daily budesonide in adults with mild to moderate asthma. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Adrenal function in asthmatic children treated with inhaled budesonide. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. Comparison of budesonide and beclomethasone dipropionate for treatment of asthma. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients. Budesonide inhaled via Turbuhaler: a more effective treatment for asthma than beclomethasone dipropionate via Rotahaler. Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study). A randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial of the minimal effective doses of budesonide and fluticasone dry-powder inhalers in adults with mild to moderate asthma. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Budesonide treatment of moderate and severe asthma in children: a dose-response study. Once daily inhalation of budesonide in the treatment of chronic asthma: a clinical comparison. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Dose-related efficacy of budesonide administered via a dry powder inhaler in the treatment of children with moderate to severe persistent asthma. Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group. High-dose inhaled budesonide in treatment of severe steroid-dependent asthma. High-dose inhaled steroids in the management of asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function. Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma. Potency ratio fluticasone propionate (Flixotide Diskus)/budesonide (Pulmicort Turbuhaler). Randomized, controlled trial of inhaled budesonide as an adjunct to oral prednisone in acute asthma. Budesonide/formoterol pressurized metered-dose inhaler versus budesonide: a randomized controlled trial in black patients with asthma. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. High-dose inhaled budesonide may substitute for oral therapy after an acute asthma attack. Therapeutic comparison of a new budesonide/formoterol pMDI with budesonide pMDI and budesonide/formoterol DPI in asthma. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations.
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. 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. Twenty-four patients with severe steroid-dependent asthma participated in a double-blind cross-over study performed in two centers. After a run-in period of 2 weeks when beclomethasone dipropionate (BDP) (400 micrograms/day) was used, the patients were treated for 4 weeks with either a high-dose (1600 micrograms/day) or a low-dose (400 micrograms/day) of budesonide (Pulmicort). Thereafter the doses of budesonide were switched and the treatment continued for a further 4-week period. Patients treated with high-dose budesonide displayed significant improvements in airway functions. In addition, subjective scores for cough, sputum production and dyspnoea were more improved in the high-dose group than in the low-dose group. The need for concomitant beta 2-agonist therapy was also significantly reduced during the high-dose treatment. No significant changes in plasma cortisol levels were detected and no adverse effects of importance were registered. The results indicate that high-dose budesonide treatment improves the clinical status of patients with severe steroid-dependent asthma more than a low-dose therapy but without causing systemic side-effects. The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma.
                The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo.
                This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call.
                A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups.
                In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated. We determined the relative antiasthmatic and systemic glucocorticoid potencies of inhaled budesonide (BUD) versus morning-dose oral prednisone (PRED) in 34 adult patients with asthma over a dose range extending from conventional to high and potentially toxic levels, 3.2 mg of BUD or 40 mg of PRED per day. Changes in symptom frequency and severity, FEV1, and peak expiratory flow rate were measured during a double-blind, double-dummy controlled, crossover protocol. The drugs proved equally effective, provided a sufficient dosage was administered. The dose required to eliminate recurrently disabling asthma relapses in these patients was about 2.0 mg of BUD per day or greater than 40 mg of PRED per day. On the average, BUD doses greater than or equal to 1.84 mg/day/70 kg adult (26.3 micrograms/kg/day) exhibited systemic effects on the 8 AM serum cortisol level and blood eosinophil count equivalent to greater than or equal to 15 mg of PRED per day. The latter doses are known to be associated with steroid-induced complications, such as osteoporosis. However, the level of systemic glucocorticoid activity produced by any particular dose of BUD in these patients was consistently much lower than that produced by the dose of PRED needed to achieve an equivalent level of antiasthmatic response. Thus, the use of high-dose inhaled BUD appears clinically reasonable and ethically acceptable in patients with severe asthma in whom the alternative is their continuing dependency on PRED. 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. Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma.
                After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 microg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or budesonide 1600 microg/day (n=441) for 12 weeks.
                Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1-3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" beta agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated.
                The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone. To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 microgram/d, with those of budesonide (BUD), 800 microgram/d, in children with moderate to severe asthma.
                Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within +/- 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment.
                Baseline peak expiratory flow was similar, FP 236 +/- 72 (SD) L/min and BUD 229 +/- 74, increasing after treatment to 277 +/- 41 and 257 +/- 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P =.002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P =.172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P =.0003).
                FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function. Three hundred and fifty-three asthmatic patients who remained symptomatic despite treatment with budesonide 800-1200 microg day(-1) (or equivalent) were randomized to a new combination therapy comprising salmeterol 50 microg and fluticasone propionate 250 microg (Seretide, Advair, Viani 50/250 microg) twice daily or budesonide 800 microg twice daily for 24 weeks. Patients kept daily records of their morning and evening peak expiratory flow (PEF), daytime and night-time symptom scores and daytime and night-time use of rescue salbutamol. Mean morning PEF increased by 451 min(-1) (baseline 361 l min(-1)) in the salmeterol/fluticasone propionate combination (SFC) group and by 19 l min(-1) (baseline 358 l min(-1)) in the budesonide group over the 24 weeks. The adjusted mean morning PEF over weeks 1 to 24 was significantly greater in the SFC group, despite the > three-fold lower corticosteroid dose (406 vs. 380 l min(-1); P < 0.001). A significantly greater improvement in evening PEF was also seen in the SFC group (adjusted mean 416 vs. 398 l min(-1); P<0.001). SFC also provided significantly better control of daytime symptoms and a significantly greater reduction in the requirement for rescue salbutamol compared with budesonide. These results demonstrate that SFC 50/250 microg twice daily is superior to budesonide 800 microg twice daily in the management of patients with moderate to severe asthma who are symptomatic on their existing dose of corticosteroid. Adherence to maintenance therapy is often poor in patients with asthma. Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity. In this 12-week, randomized, double-blind, double-dummy, parallel-group study, 617 patients with mild to moderate persistent asthma (mean forced expiratory volume in 1s [FEV1] 78.5% predicted) who were not optimally controlled on inhaled corticosteroids (200-500 microg/day) were randomized to once-daily budesonide/formoterol (80/4.5 microg, 2 inhalations in the evening), twice-daily budesonide/formoterol (80/4.5 microg, 1 inhalation), or a corresponding dose of budesonide once-daily (200 microg, 1 inhalation in the evening). All patients received budesonide (100 microg twice daily) during a 2-week run-in. Changes in mean morning peak expiratory flow (PEF) were similar for od budesonide/formoterol (23.4 l/min) and twice-daily budesonide/formoterol (24.1 l/min), and both were greater than with budesonide (5.5 l/min; both P<0.001). Evening PEF, symptom-free days, reliever-free days, and asthma control days were improved with budesonide/formoterol therapy vs. budesonide (P<0.05 vs. budesonide for all variables). All treatments were well tolerated. Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma. Previous guidelines recommend doubling the daily dose of maintenance inhaled corticosteroid to treat or prevent progression of exacerbations of asthma.
                Over a 6 month period a cohort of patients were evaluated prospectively and randomised in a double blind controlled trial to treatment with either a continued maintenance dose (MD) of inhaled corticosteroid or doubling the dose (DD) at the time of an exacerbation.
                A total of 290 patients were randomised (33% male) and 98 (DD, n = 46) experienced evaluable asthma exacerbations during the study period. Mean (SD) baseline characteristics at randomisation (age 33.5 (14.0) years; forced expiratory volume in 1 second (FEV(1)) 2.8 (0.7) l; peak expiratory flow (PEF) 422.9 (110.5) l/min) were similar in both groups. In the DD group 41% of patients were considered treatment failures because they either required systemic steroids (n = 12), had an unscheduled visit to a physician (n = 1), or their asthma did not return to baseline (n = 6). This did not differ from the MD group in which 40% were treatment failures (n = 9, 0, and 12, respectively; p = 0.94).
                In patients who regularly take an inhaled corticosteroid, doubling the maintenance dose may not affect the pattern of the exacerbation. The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7-15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 microgram through 400 microgram to 800 micrograms in three randomized consecutive periods of 8 weeks. The unstimulated diurnal production of cortisol was assessed by measurement of free cortisol in 24-hour urine samples at the end of each period. No significant dose-related suppression was found. The cortisol production did not differ significantly during treatment with 800 microgram budesonide as compared to treatment with 200 microgram budesonide (95% confidence interval: 74%-112%). It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children. In a previous study, we found that two years of treatment with an inhaled corticosteroid, budesonide, was more effective than treatment with an inhaled beta 2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from beta 2-agonist therapy to corticosteroid therapy would have.
                A total of 37 patients treated for two years with inhaled budesonide at a dose of 1200 micrograms per day were randomly assigned to treatment with 400 micrograms of budesonide per day (19 patients) or placebo (18 patients) in a double-blind manner. Another 37 patients, who had received terbutaline during the first two years, were crossed over in an open-label manner to treatment with 1200 micrograms of budesonide per day during the third year.
                Treatment with the reduced dose of budesonide was sufficiently effective in 74 percent of the patients to maintain bronchial responsiveness at a level similar to that achieved with the higher dose. In contrast, improvement was maintained in only 33 percent of the patients receiving placebo, and the differences in pulmonary function between the steroid and placebo groups were significant (for forced expiratory volume in one second, P = 0.007; for bronchial responsiveness to histamine, P = 0.025; and for peak expiratory flow in the morning, P = 0.040). The condition of patients who were crossed over from terbutaline therapy to treatment with 1200 micrograms of budesonide per day improved. However, the degree of improvement in these patients appeared to be less than in those who were treated with budesonide at the beginning of the three-year study.
                Early treatment with inhaled budesonide results in long-lasting control of mild asthma. Maintenance therapy can usually be given at a reduced dose, but discontinuation of treatment is often accompanied by exacerbation of the disease. Beclomethasone dipropionate (BDP) and budesonide (BUD) were each given in a dose of 200 micrograms twice daily by metered dose inhaler to 10 asthmatic children already dependent on treatment with steroids. In a double blind randomised crossover study each course lasted one month. No clinically important differences were found between the two treatments when symptom scores, symptom free days, additional use of salbutamol, and results of lung function tests were considered. Metyrapone mildly reduced the plasma concentration of 11-deoxycortisol in two patients during treatment with budesonide, and in four during treatment with beclomethasone. It is concluded that although they are usually safe, both drugs may cause mild adrenal suppression when given in a dose of 200 micrograms twice daily. We evaluated the efficacy and safety of low-dose budesonide/formoterol, 80 micro g/4.5 micro g, bid in a single inhaler (Symbicort Turbuhaler; AstraZeneca; Lund, Sweden) compared with an increased dose of budesonide, 200 micro g bid, in adult patients with mild-to-moderate asthma not fully controlled on low doses of inhaled corticosteroid alone.
                All patients received budesonide, 100 micro g bid, during a 2-week run-in period. At the end of the run-in phase, 467 patients with a mean FEV(1) of 82% predicted received 12 weeks of treatment with budesonide/formoterol in a single inhaler or budesonide alone in a higher dose. Patients kept daily records of their morning and evening peak expiratory flow (PEF), nighttime and daytime symptom scores, and use of reliever medication.
                The increase in mean morning PEF-the primary efficacy measure-was significantly higher for budesonide/formoterol compared with budesonide alone (16.5 L/min vs 7.3 L/min, p = 0.002). Similarly, evening PEF was significantly greater in the budesonide/formoterol group (p < 0.001). In addition, the percentage of symptom-free days and asthma-control days (p = 0.007 and p = 0.002, respectively) were significantly improved in the budesonide/formoterol group. Budesonide/formoterol decreased the relative risk of an asthma exacerbation by 26% (p = 0.02) compared with budesonide alone. Adverse events were comparable between the two treatment groups.
                This study shows that in adult patients whose mild-to-moderate asthma is not fully controlled on low doses of inhaled corticosteroids, single-inhaler therapy with budesonide and formoterol provides greater improvements in asthma control than increasing the maintenance dose of inhaled corticosteroid. The adjustable-dose budesonide/formoterol dry powder inhaler (DPI) has demonstrated similar or greater asthma control with less inhaled corticosteroid compared with the fixed-dose budesonide/formoterol DPI.
                We sought to evaluate the efficacy, tolerability, and resource use of maintenance therapy with the adjustable-dose budesonide/formoterol pressurized metered-dose inhaler versus the fixed-dose budesonide/formoterol pressurized metered-dose inhaler and the fixed-dose fluticasone propionate/salmeterol DPI.
                This was a randomized, open-label, multicenter study of patients (N = 1225) 12 years and older with moderate-to-severe persistent asthma. After 10 to 14 days of current therapy, patients were randomized 2:1 to fixed-dose budesonide/formoterol (160/4.5 microg x 2 inhalations [320/9 microg] twice daily) or fixed-dose fluticasone propionate/salmeterol (250/50 microg x 1 inhalation twice daily) for 1 month (treatment period 1), after which, the fixed-dose fluticasone propionate/salmeterol group continued therapy and the fixed-dose budesonide/formoterol group was randomized 1:1 to fixed-dose budesonide/formoterol or adjustable-dose budesonide/formoterol (adjustable from 2 inhalations [320/9 microg] twice daily to 2 inhalations [320/9 microg] once daily or 4 inhalations [640/18 microg] twice daily) for 6 months (treatment period 2).
                There were no significant between-group differences in asthma exacerbations (primary variable), asthma symptoms, or lung function during the 7-month treatment period. Less study drug (inhalations per day, P < .001) was used with adjustable-dose versus fixed-dose budesonide/formoterol. All treatments were well tolerated.
                Adjustable-dose and fixed-dose budesonide/formoterol showed no differences in asthma control or tolerability versus fixed-dose fluticasone propionate/salmeterol. Chlorofluorocarbon-propelled metered dose inhalers are facing a worldwide ban. Dry powder inhalers have been developed for the agents used in treatment of asthma.
                Our objective was to compare the effects of two inhaled glucocorticosteroids in dry power inhalers: budesonide (delivered via Turbuhaler) and beclomethasone dipropionate (delivered via Rotahaler).
                A randomized, crossover study with two steroid-treatment periods of 8 weeks. At the end of the study, the treatment with the inhaled steroid was stopped for 4 weeks. Sixteen adult patients with moderately severe asthma participated. Before the study all patients were treated with an inhaled steroid in a median dose of 0.60 mg/day (range 0.15-0.80); during the study they received 0.20 mg twice daily. Peak expiratory flow rate was measured twice daily at home throughout the study, lung function was assessed every fourth week and airway responsiveness was measured before and after each period. Preference concerning efficacy and inhaler type was assessed at the end of the study.
                Twelve patients completed the study. Lung function, airway responsiveness, and symptoms deteriorated significantly in the steroid-free washout period; this period had to be shortened in 5/12 patients. Mean morning peak expiratory flow was significantly higher during budesonide treatment than during beclomethasone dipropionate treatment, the difference being 17 L/min (95% C.I.: 2-32 L/min, P = .026). Airway responsiveness improved 1.1 doubling concentrations after budesonide treatment, but decreased 0.3 doubling concentrations after beclomethasone dipropionate treatment. The difference between the values after budesonide and beclomethasone dipropionate treatment was 1.4 doubling concentrations (95% C.I.: 0.4-2.4 doubling concentrations, P = .033). Forced expiratory flow in one second improved slightly more during budesonide than during beclomethasone treatment. The difference was 4.3% predicted (95% C.I.: -0.7-9.3%). Most patients reported budesonide Turbuhaler to be more effective (10 versus 0) and easier to use (11 versus 1) than beclomethasone dipropionate Rotahaler.
                As a consequence of the difference in local potency of the steroids and the fact that Turbuhaler deposits more drug particles in the lung than Rotahaler, budesonide inhaled via Turbuhaler appeared to be a more effective steroid formulation than beclomethasone dipropionate inhaled via Rotahaler. To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and
                176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks.
                Lung function, the number of exacerbations and growth.
                Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth.
                Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment. Inhaled corticosteroids are established first-line anti-inflammatory treatment for asthma. Clinical trials comparing inhaled corticosteroids must take into consideration that because of their excellent effect at low doses, they typically induce a near-maximal response in asthma patients.
                The aim of the present dose-response study was to estimate the minimal effective doses (MEDs) of budesonide and of fluticasone propionate via dry-powder inhaler in adults with mild to moderate asthma.
                This was a randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial performed in adults to compare these 2 inhaled corticosteroids. After a 4- to 6-week run-in period with beclomethasone dipropionate 2000 pg/d, patients fulfilling defined criteria for asthma control were randomly allocated to treatment with budesonide or fluticasone, both administered BID at a total of 800 pg/d. At 5-week intervals, the dose was reduced to 400 and then 200 pg/d (200 and 100 pg BID) if asthma control was maintained according to further defined criteria. The MED was defined as the last dose level before deterioration of asthma control.
                Subjects were 197 asthmatic patients with a mean age of 40.6 years in the budesonide group and 41.5 years in the fluticasone group. In both groups, baseline mean forced expiratory volume in 1 second (FEV(1)) was 79.4% of the predicted normal volume and baseline mean FEV(1) reversibility was 22.3%. The median MED for both groups was 400 microg/d, with no detectable difference in dis-tributions. The budesonide-to-fluticasone ratio for the geometric mean MED was 123% (95% CI, 99-153 [not significant]). No statistically significant differences regarding lung function, symptom scores, or rescue medication usage were found between the treatment groups during the first treatment period. Adverse-event profiles were similar in both groups, and no unexpected adverse events were considered to be caused by the study drugs.
                This effect-controlled study did not detect a statistically significant difference between the MEDs for budesonide and fluticasone via dry-powder inhaler in adults with mild to moderate asthma. Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma. To evaluate whether prolonged treatment can bring about full recovery, this double-blind, randomized, controlled trial examined the effect of budesonide, 400 micrograms daily for 1 yr, on airway hyperresponsiveness. The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated. Thirty-two stable adult asthmatics, requiring bronchodilators alone, were selected. Before and monthly throughout the study, airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire, daily bronchodilator use, and number of asthma exacerbations. Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo (p less than 0.0005), whose responsiveness remained very stable. Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range. Largest improvements occurred during the first 3 months but, in some, were still progressing slowly at 1 yr. Improvements in responsiveness were accompanied by significant improvements in asthma symptoms, bronchodilator use, and number of asthma exacerbations. The results show that regular, prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness, sometimes with full resolution, and these improvements are accompanied by clinically significant improvements in clinical asthma. The optimal treatment for mild asthma is uncertain. We assessed the effects of adding a long-acting inhaled beta-agonist, formoterol, to low doses of an inhaled corticosteroid, budesonide, for 1 yr in subjects with mild asthma, receiving no or only a small dose of inhaled corticosteroid. The 698 corticosteroid free patients (Group A) were assigned to twice daily treatment with 100 microg budesonide, 100 microg budesonide plus 4.5 microg formoterol, or placebo. The 1,272 corticosteroid-treated patients (Group B) were assigned to twice daily treatment with 100 microg budesonide, 100 microg budesonide plus 4.5 microg formoterol, 200 microg budesonide, or 200 microg budesonide plus 4.5 microg formoterol. The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days. In Group A, budesonide alone reduced the risk for severe exacerbations by 60% and poorly controlled days by 48%; adding formoterol increased lung function with no change in other end points. By contrast, in Group B, adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30%, respectively. Thus, in corticosteroid-free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, and in patients already receiving inhaled corticosteroid, adding formoterol was more effective than doubling the corticosteroid dose. 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. In a short-term, open cross-over clinical efficacy study, inhalation of budesonide 800 micrograms once daily was compared to inhalation of budesonide 400 micrograms twice daily and beclomethasone dipropionate 200 micrograms four times daily in 20 patients with stable steroid-dependent chronic asthma. Budesonide was inhaled through a spacer tube. The drugs were given in 3-week periods. Clinical symptoms, consumption of beta 2-agonists and peak flow were measured. In all but one patient, the reduced frequency of budesonide inhalations to only once daily has not given significantly different results compared with more frequent inhalations. This study was designed to compare the effects of a 6-month treatment with budesonide 100 microg bid (low dose) and 400 microg bid (standard reference dose) in controlling symptoms and lung function in a group of asthmatics with moderate asthma (baseline FEV(1) > or = 50% and < or = 90% of predicted values) previously treated with inhaled beclomethasone dipropionate (500 to 1,000 microg/d). Moreover, we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide.
                After a 2-week run-in period and 1-month treatment with a high dose of budesonide (800 microg bid), 213 patients with moderate asthma were assigned to randomized treatments. Daily treatment included budesonide (bid) plus an additional treatment in case of exacerbation (qid for 7 days). Treatments were as follows: budesonide 400 microg plus placebo (group 1); budesonide 100 microg plus budesonide 200 microg (group 2); and budesonide 100 microg plus placebo (group 3). Symptoms and a peak expiratory flow (PEF) diary were recorded and lung function was measured each month. An exacerbation was defined as a decrease in PEF > 30% below baseline values on 2 consecutive days.
                We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms. Moreover, symptoms were under control in all treatment groups throughout the study period. Similarly, lung function improved and remained stable, and no relevant differences between groups were observed. In each treatment group, the majority of patients had no exacerbations. In patients treated with the standard budesonide dose (group 1), the number of exacerbations and days with exacerbations were significantly lower than in group 3 (intention-to-treat analysis). Additionally, patients treated with low budesonide dose plus budesonide (group 2) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 (per-protocol analysis).
                This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide, a low dose of budesonide (200 microg/d) is as effective as the standard dose (800 microg/d) in the control of symptoms and lung function over a period of several months. Furthermore, results showed that the addition of inhaled budesonide (800 microg/d) at onset of an asthmatic exacerbation has a beneficial clinical effect. Current asthma guidelines recommend that patients are educated to adjust their medication according to their asthma severity using physician-guided self-management plans. However, many patients take a fixed dose of their controller medication and adjust their reliever medication according to asthma symptoms.
                This study examined whether asthma control improved if patients adjusted the maintenance dose of budesonide/formoterol (Symbicort Turbuhaler* 160/4.5 microg) according to asthma severity compared with traditional fixed dosing (FD) regimens.
                Symptomatic patients with asthma (n = 658, mean symptom score 1.5, mean inhaled corticosteroids 735 microg/day, mean forced expiratory volume in 1 second [FEV(1)] 84% predicted) were randomised after 2 weeks' run-in to either: budesonide/formoterol adjustable maintenance dosing (AMD), budesonide/formoterol FD or salmeterol/fluticasone (Seretide Diskus dagger 50/250 microg) FD. In a 4-week double-blind period, both budesonide/formoterol AMD and FD groups received two inhalations twice daily (bid) and salmeterol/fluticasone FD patients received one inhalation bid. In the following 6-month open extension, both FD groups continued with the same treatment. Patients in the AMD group with well-controlled asthma stepped down to one inhalation bid; others continued with two inhalations bid. All AMD patients could increase to four inhalations bid for 7-14 days if symptoms worsened. All patients used terbutaline or salbutamol for symptom relief throughout. The primary variable was the odds of achieving a well-controlled asthma week (WCAW).
                The odds ratio for achieving a WCAW did not differ between the FD regimens; however, during the open period, budesonide/formoterol AMD increased the odds of achieving a WCAW vs. budesonide/formoterol FD (odds ratio 1.335; 95% CI: 1.001, 1.783; p = 0.049) despite a 15% reduction in average study drug use. Budesonide/formoterol AMD patients had a lower exacerbation rate over the study: 40% lower vs. salmeterol/fluticasone FD (p = 0.018); 32% lower vs. budesonide/formoterol FD (NS). During the double-blind period, there were no clinically relevant differences between the budesonide/formoterol FD and salmeterol/fluticasone FD groups. Budesonide/formoterol AMD patients used less reliever medication in the open extension: 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD (p = 0.001) and 0.80 occasions/day for salmeterol/fluticasone FD (p = 0.011).
                Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control by reducing exacerbations and reliever medication usage compared with fixed-dose salmeterol/fluticasone. To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler (Turbuhaler) in children with moderate to severe persistent asthma.
                In our randomized, double-blind, placebo-controlled, parallel-group, multicenter study, a total of 404 children with asthma, who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy, were randomly assigned to receive either 100, 200, or 400 micrograms of budesonide or placebo twice daily for 12 weeks. At baseline, mean forced expiratory volume in 1 second (FEV1) was 74.6% (range, 30.7% to 123.3%) of the predicted normal value.
                Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function (morning peak expiratory flow and FEV1), in asthma symptoms, and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo. Improvements were evident within 2 weeks and were maintained throughout the 12 weeks. Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function, and the incidence of reported adverse events was similar in all treatment groups.
                Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children (6 to 18 years of age) with moderate to severe persistent asthma. To determine the ability of budesonide via an inhaler (Pulmicort Turbuhaler; Astra Draco AB) to replace oral glucocorticosteroids (GCSs) in adult subjects with moderate-to-severe asthma.
                Double-blind, randomized, and placebo-controlled study, with parallel groups.
                Multicenter study in outpatient setting.
                Eighty men and 79 women, aged 20 to 69 years, with moderate-to-severe asthma and a mean FEV1 of 58.3% predicted normal. All subjects were receiving oral GCS treatment and 79% of subjects were also receiving inhaled beclomethasone dipropionate (BDP). The mean daily doses of prednisone at baseline, including converted dose of BDP, for the placebo, budesonide 400 microg, and budesonide 800 microg, respectively, were 19.7 mg, 19.5 mg, and 18.7 mg.
                After a 2-week baseline period, subjects entered a 20-week treatment period, during which the oral dose of prednisone was reduced by forced down-titration at 2-weekly intervals.
                Subjects receiving 400 microg or 800 microg bid of budesonide achieved a significantly greater reduction (82.9% and 79.0% respectively) in oral GCS dose compared with placebo-treated subjects (27%; p<0.001). Two thirds of the subjects receiving budesonide were able to achieve sustained oral corticosteroid cessation, compared with 8% in the placebo group. Additionally, both doses of budesonide resulted in significant improvement in results of pulmonary function tests and asthma symptoms scores, and a significant decrease in the use of bronchodilator therapy. The mean plasma cortisol levels before and after adrenocorticotropic hormone stimulation increased most toward the normal range in the budesonide-treated groups compared with placebo-treated subjects.
                Budesonide administered via Turbuhaler has a significant oral GCS-sparing capacity with maintained or improved asthma control in adult subjects with moderate-to-severe asthma. Forty-five steroid-dependent asthmatic outpatients were treated twice daily for 51 weeks with a new inhalation steroid, budesonide (BUD), using a 750 ml spacer. During the initial 15 weeks the prednisone-sparing effects of a high daily dose (1600 micrograms) and a conventional dose (400 micrograms per day) were compared in a double-blind randomized trial including 50 patients. During the remaining 36 weeks 45 patients were treated openly with 1600 micrograms daily. All patients used other antiasthmatic drugs which were maintained throughout the study, except for inhalations of beta-2 agonists that could be used whenever needed. All patients but 2 were able to reduce the daily dose of oral prednisone. The mean daily dose decreased from 13.9 mg to 5.3 mg. Eighteen patients (40%) were able to discontinue oral prednisone. Adrenal gland function improved considerably as prednisone intake decreased. Oropharyngeal thrush frequency showed no change. No severe side effects were observed. The efficacy of budesonide (800 micrograms b.d.) and beclomethasone dipropionate (750 micrograms b.d.) in controlling the symptoms of asthma, pulmonary function, bronchial responsiveness to histamine, and adrenal function, was assessed in a double-blind, double-dummy cross-over study of 36 adult chronic asthmatic patients. The patients, the majority of whom were assessed to be affected to a severe degree, were insufficiently controlled in their current regimen of inhaled steroids and/or inhaled and oral bronchodilators. A 2 weeks baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups showed improvements from baseline in clinical assessment of lung function carried out after the first 6 weeks of treatment. No significant differences were seen throughout the entire 12 weeks study, when comparing the effects of the treatments on FEV1, FVC, PEF or the histamine PC20. Asthma severity, symptom score and inhaled bronchodilator use showed the same results after both treatments. It is concluded that inhalations of budesonide and beclomethasone dipropionate in high doses are equally potent in the treatment of severe asthma. There is no significant influence on the adrenal function and no significant side effects during a period equal to that of the present study. Patients with moderate persistent asthma (n = 523; mean FEV1 77.4%) not fully controlled with inhaled corticosteroids (ICS; 400-1000 microg/day) were randomized to receive either once-daily budesonide/formoterol (160/4.5 microg, two inhalations); or twice-daily budesonide/formoterol (160/4.5 microg, one inhalation); or budesonide (400 microg) once-daily for 12 weeks. Once-daily dosing was administered in the evening and twice-daily dosing was administered in the morning and evening. All patients received twice-daily budesonide (200 microg) during a 2-week run-in. Compared with budesonide alone, change in mean morning and evening peak expiratory flow was greater in the once-daily budesonide/formoterol group (27 and 171 min(-1), respectively; P < 0.001) and twice-daily budesonide/formoterol group (23 and 24 l min(-1), respectively; P < 0.001). Night awakenings, symptom-free days, reliever-use-free days and asthma-control days were all improved during once-daily budesonide/formoterol therapy vs. budesonide (P < or = 0.05). Similar improvements were also seen with twice-daily budesonide/formoterol (P < or = 0.05). The risk of a mild exacerbation was reduced after once- and twice-daily budesonide/formoterol vs. budesonide (38% and 35%, respectively; P < 0.002). All treatments were well tolerated. Budesonide/formoterol, once- or twice-daily, in a single inhaler improved asthma symptoms and exacerbations compared with budesonide. In the majority of patients with moderate persistent asthma requiring ICS and long-acting beta-agonists, once-daily formoterol/budesonide provided sustained efficacy over 24 h, similar to twice-daily dosing. In the choice of, or switch between, various inhaled corticosteroids (ICS) it is important to know equipotent doses for clinical treatment effects of the alternatives. Various ICS do have different inherent potency. Further, the ICS are delivered from inhalers that may differ markedly in output characteristics and drug delivery to intrapulmonary airways. Therefore, clinical efficacy comparisons must include drug-inhaler comparisons. We estimated the therapeutic potency ratio of the Flixotide Diskus (fluticasone propionate, FP) and the Pulmicort Turbuhaler (budesonide, BUD) in steroid-naive asthma patients, using a dose-reduction technique (FP 500-0 mcg/day, BUD 800-0 mcg/day). The dose defining end point was loss of asthma control in this paper denoted as exacerbation. In total, 282 patients with proven asthma were enrolled in the study, and 103 in the FP group and 98 in the BUD group completed the study per protocol. In total, 80 patients in the FP-group and 79 in the BUD-group experienced a dose defining exacerbation. The exacerbation frequency increased in a dose-dependent way as the dose was titrated down. From these data the potency difference between the present drug inhaler combinations, Flixotide Diskus and Pulmicort Turbuhaler, was calculated to be between 1.50:1 (95% CI 1.10:1-2.05:1) and 1.75:1 (CI 1.26:1-2.43:1) depending on if patients with insufficient steroid-response were excluded from the calculations or not. In these steroid-naïve patients, the potency difference was evident only at low daily doses, below 200 mcg. To compare the clinical effect of nebulized budesonide with placebo in acute pediatric asthma.
                A randomized, controlled, double-blind trial with parallel design was used in the ED of a tertiary care children's hospital. Children aged 6 months to 18 years with a moderate to severe exacerbation of asthma [Pulmonary Index Score (PIS) > or = 5 or < or = 11 after a salbutamol nebulization of 0.15 mg/kg] were eligible. All patients received prednisone 1 mg/kg orally and nebulized salbutamol (0.15 mg/kg) every 30 minutes for 3 doses and then every hour for 4 hours. The intervention was 2 mg (4 mL) of nebulized budesonide or 4 mL of nebulized normal saline.
                Baseline characteristics were comparable in the budesonide group (n = 24) and in the placebo group (n = 20). There were no significant differences in the primary outcome measure (PIS) between the 2 groups. However, the PIS at 1 hour had a tendency to be lower in the budesonide group (median = 5) as compared with the placebo group (median = 6; p = 0.07). Survival analysis of release/discharge from the ED/hospital showed a more rapid rate in the budesonide group as compared with the placebo group (p = 0.02). No adverse effects were seen.
                Although these preliminary results suggest that nebulized budesonide may be an effective adjunct to oral prednisone in the management of moderate to severe asthma exacerbations, a larger trial will be required before the widespread use of inhaled budesonide in acute asthma can be advocated. Concerns exist that responses to long-acting β(2)-adrenergic agonists in black patients may differ from the general population. The efficacy and safety of budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (BUD DPI) were evaluated in adolescent and adult black asthma patients.
                This 12-week, randomized, double-blind, multicenter, phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma, previously receiving medium- to high-dose inhaled corticosteroid. After 2 weeks on BUD 90 μg × 2 inhalations twice daily (bid), symptomatic patients were randomized to BUD/FM 160/4.5 μg × 2 inhalations bid or BUD 180 μg × 2 inhalations bid.
                Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean (primary variable) was greater with BUD/FM versus BUD (0.16 vs. 0.07 L; p = .008); this effect was also observed at weeks 2, 6, and end of treatment (p ≤ .032). Greater improvements (p < .001) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks (morning: 25.34 vs. 7.53 L/minute, respectively; evening: 21.61 vs. 7.67 L/minute, respectively); greater improvements in daily asthma symptom score and rescue medication use were also observed (p ≤ .039). Both treatments were well tolerated, with similar safety profiles.
                In this population of black asthma patients, BUD/FM pMDI resulted in greater improvements in pulmonary function and asthma control versus BUD DPI, with similar safety profiles. This study evaluated the efficacy and safety of a novel asthma management strategy--budesonide/formoterol for both maintenance and symptom relief (Symbicort Single Inhaler Therapy)--compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma.
                This was a 12-month, randomised, double-blind, parallel-group study. Symptomatic patients with asthma (n = 1890; mean age 43 years [range 11 years-80 years], mean baseline forced expiratory volume in 1 s [FEV(1)] 70% of predicted, mean inhaled corticosteroid [ICS] dose 746 microg/day) received either budesonide (160 microg, 2 inhalations twice daily) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol (160/4.5 microg, 2 inhalations once daily) with additional inhalations of budesonide/formoterol 160/4.5 microg as needed. Time to first severe exacerbation (hospitalisation/emergency room [ER] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [PEF] to < or = 70% of baseline on 2 consecutive days) was the primary outcome variable.
                A total of 1890 patients were randomised, of whom 1563 (83%) had severe asthma. The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy (p < 0.001) compared with a higher dose of budesonide. The risk of having a severe exacerbation was 39% lower with budesonide/formoterol single inhaler therapy compared with budesonide (p < 0.001). The number needed to treat to prevent one severe exacerbation per year with budesonide/formoterol compared with budesonide was 5. The budesonide/formoterol group had 45% fewer severe exacerbations requiring medical intervention per patient compared with the budesonide group (p < 0.001). Budesonide/formoterol patients had fewer hospitalisations/ER treatments (15 vs 25 events, respectively [descriptive statistics]) and fewer treatment days with systemic steroids (1776 days vs 3177 days, respectively [descriptive statistics]) compared with budesonide patients. Budesonide/formoterol single inhaler therapy patients used less as-needed medication compared with budesonide patients (0.90 vs 1.42 inhalations/day; p < 0.001). The mean daily ICS dose was lower in the budesonide/formoterol group than in the budesonide group (466 microg/day vs 640 microg/day). Over the 12-month study period, the budesonide/formoterol group achieved asthma control sufficient to not require any additional as-needed medication on 60% of days. Overall, budesonide/formoterol single inhaler therapy gave 31 more asthma control days (a night and day with no asthma symptoms and no as-needed medication use) per patient-year and 12 additional undisturbed nights per patient-year compared with a higher dose of budesonide. Both treatments were well tolerated.
                Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler, demonstrating a high level of efficacy in patients with moderate to severe asthma. Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens. Patients attending the emergency room with acute asthma, participating in a study comparing salbutamol (albuterol in the United States) via a dry powder inhaler (Turbuhaler) with pressurized metered-dose inhaler (pMDI), were included in this 1-week follow-up study with the aim of assessing whether inhaled budesonide via Turbuhaler may be an alternative to prednisolone tablets after an acute asthma attack. Eighty-one patients with a mean age of 38 years and forced expiratory volume in 1 sec (FEV1) of 64% predicted normal value after treatment with salbutamol were randomized in this double-blind, double-dummy, parallel-group study. The doses given were budesonide 1600 microg b.i.d. or prednisolone in daily doses from 40 mg (day 1) decreased to 5 mg (day 7). FEV1 was recorded before and after the 7-day treatments and peak expiratory flow (PEF) morning and evening, clinical symptoms (visual analogue scale 0-100), and doses of rescue medication (terbutaline Turbuhaler 0.25 mg/dose) were recorded daily. The mean increase in FEV1 from baseline to day 7 was 17.3% in the budesonide Turbuhaler group and 17.6% in the prednisolone group. Mean values of morning PEF increased from day 1 to day 7 by 67 L/min in the budesonide Turbuhaler group and by 57 L/min in the prednisolone group (not significant). There were no statistically significant differences between the groups in clinical symptoms and in the number of doses of rescue medication. Because of disease deterioration, five patients in the Turbuhaler group and three in the prednisolone group needed additional symptomatic as well as corticosteroid treatment. Inhaled budesonide in high doses may be a substitute for oral therapy as follow-up treatment after an acute asthma attack. Budesonide/formoterol is an effective treatment for both asthma and chronic obstructive pulmonary disease. This study compared the efficacy and safety of a novel hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI) formulation of budesonide/formoterol with that of budesonide pMDI and budesonide/formoterol dry-powder inhaler (DPI; Turbuhaler).
                This was a 12-week, multinational, randomised, double-blind, double-dummy study involving patients aged > or = 12 years with asthma. All patients had a forced expiratory volume in 1 s of 50-90% predicted normal and were inadequately controlled on inhaled corticosteroids (500-1600 microg/day) alone. Following a 2-week run-in, during which they received their usual medication, patients were randomised (two inhalations twice daily) to budesonide pMDI 200 microg, budesonide/formoterol DPI 160/4.5 microg or budesonide/formoterol pMDI 160/4.5 microg. The primary efficacy end-point was change from baseline in morning peak expiratory flow (PEF).
                In total, 680 patients were randomised, of whom 668 were included in the primary analysis. Therapeutically equivalent increases in morning PEF were observed with budesonide/formoterol pMDI (29.3 l/min) and budesonide/formoterol DPI (32.0 l/min) (95% confidence interval: -10.4 to 4.9; p = 0.48). The increase in morning PEF with budesonide/formoterol pMDI was significantly higher than with budesonide pMDI (+28.7 l/min; p < 0.001). Similar improvements with budesonide/formoterol pMDI vs. budesonide pMDI were seen for all secondary efficacy end-points. Both combination treatments were similarly well tolerated.
                Budesonide/formoterol, administered via the HFA pMDI or DPI, is an effective and well-tolerated treatment for adult and adolescent patients with asthma, with both devices being therapeutically equivalent. This randomised, double-blind, 6-month study compared budesonide/formoterol for maintenance and relief with salmeterol/fluticasone and a fixed maintenance dose of budesonide/formoterol, both with terbutaline for relief. Following a 2-week run-in, 3335 symptomatic adults and adolescents (mean FEV1 73% predicted, mean inhaled corticosteroid dose 745 microg/day) received budesonide/formoterol 160/4.5 microg one inhalation bid plus additional inhalations as needed, salmeterol/fluticasone 25/125 microg two inhalations bid plus as-needed terbutaline or budesonide/formoterol 320/9 microg one inhalation bid plus as-needed terbutaline. Budesonide/formoterol for maintenance and relief prolonged the time to first severe exacerbation requiring hospitalisation, emergency room treatment or oral steroids (primary variable) vs. fixed-dose salmeterol/fluticasone and budesonide/formoterol (p=0.0034 and p=0.023 respectively; log-rank test). Exacerbation rates were 19, 16 and 12 events/100 patients/6 months for salmeterol/fluticasone, fixed-dose budesonide/formoterol and budesonide/formoterol for maintenance and relief, respectively, [rate reduction vs. fixed-dose salmeterol/fluticasone (0.61; 95% CI 0.49-0.76, p<0.001) and vs. fixed-dose budesonide/formoterol (0.72; 95% CI 0.57-0.90, p=0.0048)]. Budesonide/formoterol maintenance and relief patients used less inhaled corticosteroid vs. salmeterol/fluticasone and fixed-dose budesonide/formoterol patients. All treatments provided similar marked improvements in lung function, asthma control days and asthma-related quality of life. Budesonide/formoterol for maintenance and relief reduces asthma exacerbations and maintains similar daily asthma control at a lower overall drug load compared with fixed-dose salmeterol/fluticasone and budesonide/formoterol.
This review strongly supports use of budesonide in chronic asthma. Consensus guidelines for chronic asthma suggest titrating inhaled steroid dose to individual requirements. Evidence from this review of trials does not present a case for routine dose titration above 800 mcg/d.