Health-related quality of life in moderate asthma: 400 microg hydrofluoroalkane beclomethasone dipropionate vs 800 microg chlorofluorocarbon beclomethasone dipropionate. The Study Group

OBJECTIVE: To compare the effect of hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP; 400 microg/d) with that of chlorofluorocarbon (CFC) BDP (800 microg/d) on asthma health-related quality of life in a 12-week, parallel-group, multicenter study. BACKGROUND: HFA-BDP is a new CFC-free preparation of BDP, which was developed as a result of CFCs being phased out from metered dose inhalers. METHODS: Following 7 to 12 days of prednisone, 30 mg/d, 347 adults with moderate asthma were randomized to receive either 400 microg/d HFA-BDP, 800 microg/d CFC-BDP, or HFA placebo for 12 weeks (all other oral and inhaled steroids were withdrawn). Patients completed the Asthma Quality of Life Questionnaire (AQLQ), and clinical asthma status was measured at the end of a run-in period, at randomization (after oral steroid treatment), and at the end of the study treatment. RESULTS: Sixty-one patients withdrew, 43 due to worsening asthma (33 placebo; 5 HFA-BDP; 5 CFC-BDP). There was a deterioration in the AQLQ score (- 0.81) in the placebo group, and the difference between this and the stability observed in both the HFA-BDP group (+ 0.13) and the CFC-BDP group (- 0.03) was statistically significant (p 相似文献   

Clinically important improvements in asthma-specific quality of life,but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropionate

STUDY OBJECTIVE: Clinical trials of asthma treatments usually use measures of asthma control to assess efficacy. However, it is also important to determine whether patients themselves benefit from interventions. The aim of this study was to evaluate health-related quality of life in patients with asthma switched from conventional chlorofluorocarbon (CFC) beclomethasone dipropionate (BDP) to hydrofluroalkane-134a (HFA) BDP extrafine aerosol at half the daily dose. DESIGN: Open-label, 12-month, parallel-group, randomized trial. SETTING: Fifty-seven centers in four countries (United States, Belgium, the Netherlands, and United Kingdom). PATIENTS: Four hundred seventy-three patients with a > or = 6-month history of asthma, stable symptoms, and maintained on CFC-BDP, 400 to 1,600 microg/d. INTERVENTIONS: HFA-BDP, 200 to 800 microg/d (n = 354), or CFC-BDP, 400 to 1,600 microg/d (n = 119). MEASUREMENTS AND RESULTS: The Asthma Quality of Life Questionnaire (AQLQ) and pulmonary function tests were completed at months 0, 2, 4, 8, and 12. For 1 month before each visit, patients made daily recordings of symptoms, peak expiratory flow, and beta(2)-agonist use. Two hundred ninety-six patients completed the study (HFA-BDP, 83.6%; CFC-BDP, 83.2%). At month 12, improvements in overall AQLQ scores were greater in the HFA-BDP group than in the CFC-BDP group (p = 0.0024). The number of patients who need to be treated with HFA-BDP for one to have a clinically important improvement in overall asthma-specific quality of life compared with CFC-BDP was 7.3. There was no evidence of differences (p > 0.05) between treatment groups for airway caliber, symptoms, or beta(2)-agonist use. CONCLUSION: Clinically important improvements in the AQLQ score were observed at month 12 for HFA-BDP vs CFC-BDP, while conventional clinical indexes of pulmonary function and asthma control were similar in the two groups.     

Efficacy of HFA-beclomethasone dipropionate extra-fine aerosol (800 microg day(-1)) versus HFA-fluticasone propionate (1000 microg day(-1)) in patients with asthma

Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extra-fine aerosol and HFA-fluticasone propionate (HFA-FP) are chlorofluorocarbon-free inhalers. We conducted an 8-week, open study to demonstrate the equivalence of HFA-BDP (800 microg day(-1)) and HFA-FP (1000 microg day(-1)) in moderate to severe asthma. Symptomatic patients on 500-1000 microg day(-1) CFC-BDP (or equivalent) and short-acting beta-agonist, were randomized to HFA-BDP (n = 101) or HFA-FP (n = 97) after 7-14 (+/-2) day run-in. In the intent-to-treat (ITT) population (n = 198), both treatments provided clinically and statistically significant improvements in asthma control, with increases in peak expiratory flow in the morning (AM PEF) and asthma symptoms (within treatment analysis P<0.05). Mean (SE) change in AM PEF from baseline at week 8 was equivalent (defined as 90% CI for the mean difference between treatments within +/-25 l min(-1)) in the two groups: 29.59 (5.19) l min(-1) for HFA-BDP vs. 17.3 (5.45) l min(-1) for HFA-FP (90% CI-0.02, 24.91). For the perprotocol population (n = 121), the mean (SE) change in AM PEF from baseline was not equivalent; AM PEF improved to a significantly greater extent in the HFA-BDP group than HFA-FP group [34.84 (7.08) vs. 20.63 (7.32) l min(-1) P<0.01; 90% CI; 2.66, 31.10]. At week 8 in the ITT population, there were no statistically significant differences in FEV1, beta-agonist use, asthma symptom/sleep disturbance scores, or percentage of days without asthma symptoms/sleep disturbance. There was a significantly greater reduction from baseline in mean eosinophil count for HFA-BDP compared with HFA-FP at weeks 3 and 8 (P<0.01), and eosinophil cationic protein value at week 8 (P<0.01). Both treatments were well tolerated and there were no statistically significant differences in urinary cortisol creatinine parameters. In conclusion, this study showed that, in patients with moderate-to-severe symptomatic asthma, HFA-BDP extra-fine aerosol 800 microg(-1) was at least as effective and equally well tolerated as 1000 microg day(-1) HFA-FP.     

Efficacy and safety of inhaled ciclesonide compared with chlorofluorocarbon beclomethasone dipropionate in adults with moderate to severe persistent asthma

BACKGROUND AND OBJECTIVE: Inhaled corticosteroids are recognized as first-line therapy in the management of asthma; however, their use may be limited by systemic and local side-effects. Ciclesonide, a novel pro-drug inhaled corticosteroid, is activated in the lungs and is expected to have less systemic and local side-effects. This study evaluated the efficacy and safety of ciclesonide in hydrofluoroalkane (HFA) compared with beclomethasone dipropionate (BDP) in a chlorofluorocarbon (CFC) formulation in adult patients with moderate to severe asthma. METHODS: This was a multicentre, randomized, open-label, parallel-group comparative study. The patients were given 800 microg/day of CFC-BDP in the four-week baseline period. After the baseline period, 319 patients were randomly allocated into three groups which, respectively, received HFA-ciclesonide 400 microg/day (without a spacer), HFA-ciclesonide 800 microg/day (without spacer) and CFC-BDP 800 microg/day (with spacer) for the eight-week treatment period. The primary efficacy variable was morning PEF. RESULTS: The morning PEF increased by 16.02 L/min in the 400 microg HFA-ciclesonide group, 23.98 L/min in the 800 microg HFA-ciclesonide group and 5.91 L/min in the 800 microg CFC-BDP group. Better outcomes were achieved by the use of 800 microg/day of HFA-ciclesonide compared with 800 microg/day of CFC-BDP (P = 0.001). There was no difference in adverse events between the groups. CONCLUSION: In adult patients with moderate to severe asthma, 800 microg/day of HFA-ciclesonide was significantly more effective than 800 microg/day of CFC-BDP. Ciclesonide at doses of 400 microg/day and 800 microg/day was safe and well tolerated.     

Comparison of hydrofluoroalkane-beclomethasone dipropionate Autohaler with budesonide Turbuhaler in asthma control.

BACKGROUND: Hydrofluoroalkane-beclomethasone dipropionate Autohaler (HFA-BDP AH) is a breath-actuated chlorofluorocarbon (CFC)-free metered dose inhaler in which BDP is in a solution of HFA propellant. Budesonide Turbuhaler (BUD TH) is a breath-dependent dry powder inhaler. OBJECTIVES: To test the hypothesis that half the daily dose of HFA-BDP AH would provide an equivalent control of asthma symptoms to the BUD TH. METHODS: This was an 8-week open study in patients with symptomatic moderate-to-severe asthma, previously on BUD 500-1,000 microg x day(-1), or an equivalent. After 5-14 days' run-in, patients were randomized to HFA-BDP AH 800 microg x day(-1) or BUD TH 1,600 microg x day(-1). The intent-to-treat population consisted of 111 patients on HFA-BDP AH and 98 patients on BUD TH. RESULTS: Mean change from baseline in PEF in the morning (AM PEF) at week 8 was 23.95 liters x min(-1) for HFA-BDP AH and 24.46 liters x min(-1) for BUD TH. A two-sided equivalence test using the 0.51 liter x min(-1) difference gave 95% confidence intervals within a defined equivalence interval of (-infinity, 25 liters x min(-1)) indicating that the mean change in AM PEF was equivalent for the two groups. There were no significant differences in the mean change from baseline in FEV1 or beta-agonist use. Patients using HFA-BDP AH had a significantly greater mean change from baseline in the percentage of days free from shortness of breath (p = 0.05), chest tightness (p = 0.02) and nights without sleep disturbance (p = 0.04) at week 3, and wheeze (p = 0.01), shortness of breath (p = 0.02), chest tightness (p < 0.01) and daily asthma symptoms (p = 0.03) at week 8. The incidence, type and severity of adverse events were similar in each group. At week 8, the mean change from baseline in corrected urine cortisol/creatinine ratio in a subgroup of patients was -0.36 for HFA-BDP and -4.88 for BUD TH (p < 0.01). CONCLUSIONS: HFA-BDP 800 microg x day(-1) provided control of moderate-to-severe asthma with efficacy and safety at least similar to BUD TH 1,600 microg x day(-1).     

Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma

OBJECTIVE: To assess the therapeutic effects of oral zileuton tablets combined with low-dose beclomethasone compared to doubling the dose of beclomethasone, in improving lung function and reducing asthma symptoms. METHODS: Randomized, active-control, double-blind, parallel, multi-center study of zileuton (400 or 600 mg QID)+200 microg beclomethasone dipropionate (BDP) BID versus placebo+BDP 400 microg BID in asthmatics with baseline FEV(1) percent predicted values between 40% and 80% following a single-blind ICS (BDP 200 microg BID) 2-week run-in. During the 3-month double-blind treatment period, assessments included safety, daytime and nighttime symptoms, acute asthma exacerbations, beta(2)-agonist use, AM and PM peak expiratory flow (PEF) and FEV(1). RESULTS: The addition of a 5-lipoxygenase (5-LO) inhibitor added to a low-dose of BDP showed no significant difference in FEV(1) compared to doubling the dose of BDP. FEV(1) improved in all 3 treatment groups, with mean increases of 10% with zileuton 600 mg QID+BDP 200 microg BID, 12% with zileuton 400mg QID+BDP 200 microg BID, and 11% with BDP 400 microg BID by study end. Within each treatment group, there were significant improvements in asthma symptoms and AM and PM PEF compared to baseline. No significant differences were observed between groups with regards to salbutamol use, acute asthma exacerbations, the requirement for oral/parenteral corticosteroids and adverse clinical events. CONCLUSIONS: The addition of a 5-LO inhibitor added to low-dose beclomethasone may be an alternative to higher-doses of ICS in patients unable to achieve sufficient asthma control on low-dose ICS therapy.     

Equivalent asthma control after dose reduction with HFA-134a beclomethasone solution aerosol. Comparative Inhaled Steroid Investigation Group (CISIG)

AIM: The replacement of chlorofluorocarbon (CFC) by hydrofluoroalkane has the potential to improve airway deposition of BDP. We investigated whether HFA-BDP extra-fine solution aerosol 400 microg day(-1) is as effective as CFC-BDP 1000 micro day(-1) in patients with stable, moderate asthma, having persistent bronchial hyperresponsiveness. PATIENTS AND METHODS: One hundred and fifty patients with moderate asthma from 20 centres, on inhaled steroids for < or = 3 months, entered a 4-week run-in period with 1000 microg day(-1) CFC-BDP. Patients were then allocated to a 10-week study phase, receiving CFC-BDP 1000 microg day(-1) or HFA-BDP 400 microg day(-1). Symptom score and PEF were measured daily and recorded as biweekly means. Spirometry, PC20FEV1, blood eosinophils and serum ECP were determined on days 15, 29, 43 and 71, and compared to the last visit of the run-in period. All group members were trained in a quality control centre. RESULTS: Treating the population of the HFA-BDP group (n = 72) and the CFC-BDP group (n = 78) did not show significant differences in terms of symptoms, lung function, airway hyperresponsiveness and serum markers of inflammation at the end of the run-in period and the end of the study phase. CONCLUSION: Using HFA instead of a CFC metered dose inhaler, containing less than half the daily dose of BDP, allows control of symptoms and lung function parameters, without changes in bronchial hyperresponsiveness.     

Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children

We set out to evaluate lung deposition, systemic availability, and basic pharmacokinetic parameters of beclomethasone dipropionate (BDP) in children with chronic asthma. Plasma levels of BDP, 17 and 21 beclomethasone monopropionate (17-BMP and 21-BMP), and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A) 100 microg HFA-BDP, B) 200 microg HFA-BDP, C) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal (GI) absorption of drug, and D) 400 microg CFC-BDP. A breath-actuated pMDI (Autohaler) was used for HFA inhalations, and a pMDI with a large volume spacer (Volumatic) for CFC inhalations. Treatments A-D were given in a randomized, cross-over design. Fourteen patients aged 10-14 years completed all 5 study days. The mean systemic bioavailabilities in percent of dose leaving the canister valve (ex-valve) were 70% (100 HFA), 74% (200 HFA), 60% (200 HFA + charcoal), and 27% (400 microg CFC). After HFA treatment, 82% of the systemically available dose was absorbed through the lungs, and 18% from the gastrointestinal tract. The estimated bioavailability of BDP from the GI tract was 68%. BDP was metabolized to 17-BMP within minutes. Mean steady-state volume of distribution of 17-BMP was 84 L, and the mean terminal half-life (T((1/2))) after the four inhalations was 2.7 hr (range, 2.2-3.7 hr). Mean T((1/2)) and clearance after i.v. administration were 1.7 hr and 0.9 L/min, respectively. The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer.     

Efficacy and safety of beclomethasone dipropionate extrafine aerosol in childhood asthma: a 12-week,randomized, double-blind,placebo-controlled study

BACKGROUND: 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. OBJECTIVE: To examine the efficacy and safety of HFA-BDP in childhood asthma. DESIGN: 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. SETTING: Hospital outpatient. RESULTS: 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. CONCLUSIONS: HFA-BDP, 80 to 160 micro g/d, is effective and safe in childhood asthma.     

Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma.

Inhaled corticosteroids and long-acting beta2-agonists effectively control asthma symptoms and improve airway function. The effects of beclomethasone were compared with those of salmeterol on markers of eosinophilic inflammation in induced sputum in steroid-naive asthmatic subjects with moderate asthma. Fifteen moderate asthmatics were treated with either beclomethasone dipropionate (500 microg b.i.d.) or salmeterol (50 microg b.i.d.) for 4 weeks, according to a randomised, double-blind, parallel-group study design. All patients underwent spirometry, methacholine test, sputum induction, and blood sampling before and after 2 and 4 weeks of treatment. They also recorded daily symptoms and peak expiratory flow (PEF). Sputum eosinophils, eosinophil cationic protein (ECP) and eosinophil protein X (EPX), and blood eosinophils, as well as the forced expiratory volume in one second (FEV1) and morning PEF, significantly improved after beclomethasone but not after salmeterol. PEF variability, the symptom score and rescue beta2-agonist use significantly improved after both treatments, although the improvement in the symptom score tended to be greater after beclomethasone. After 2 and 4 weeks of beclomethasone treatment, both serum ECP and EPX decreased. With salmeterol, only serum EPX decreased, after 4 weeks. Bronchial hyperresponsiveness to methacholine did not change after either treatment. The authors conclude that beclomethasone, but not salmeterol, substantially improves airway inflammation in asthma. Beclomethasone also had an overall greater clinical effect, although the improvement in symptoms and peak expiratory flow variability was similar after both treatments.     

Corticosteroid--effects of beclomethasone dipropionate 800 micrograms/day

The effects of beclomethasone dipropionate (BD) 800 micrograms on steroid-dependent adult asthmatics were examined. The study consisted of two groups; 20 patients on 800 micrograms and another 20 patients on 400 micrograms. In addition, 800 micrograms was administered to an additional 12 patients receiving 400 micrograms with insufficient effects. After two weeks of observation period, BD was administered for 12 weeks, and its effects adverse reactions were analyzed on the basis of asthma patients' diary etc. As the results, effects appeared earlier in the 800 micrograms group than in the 400 micrograms group and marked efficacy was seen. The 800 micrograms group was much better than the 400 micrograms group in the achievement of weaning from or of dose reduction of systemic steroid. A significant increase of serum cortisol levels which was considered to be due to the decrease of the systemic steroid usage was noted. Considerable efficacy was also observed in patients whose dosage had been increased from 400 micrograms to 800 micrograms. High dose administration usually increases topical side effects such as hoarseness and stomatitis, however the use of spacers was effective in the prophylaxis and treatment of those symptoms.     

Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone : a cross-over study in healthy volunteers

STUDY OBJECTIVES: To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) with chlorofluorocarbon fluticasone propionate (CFC-FP) and chlorofluorocarbon beclomethasone (CFC-BDP). DESIGN: Six-day, open-label, nonrandomized, crossover study. SETTING: Clinical research laboratory. PARTICIPANTS: Nine healthy, nonsmoking, adult volunteers. INTERVENTIONS: On each study day, participants inhaled one or two puffs of 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. All products delivered 50 micro g per puff ex-valve. Subjects used a respiratory training and monitoring device to meet predefined, standardized inhalation patterns. Immediately after inhalation of radiolabeled study drug, planar gamma camera images were obtained. MEASUREMENTS AND RESULTS: Radiolabeled HFA-BDP had a higher deposition in the lungs (53% ex-actuator) compared with CFC-FP (12 to 13%) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher distribution to the oropharynx (72 to 78%, and 82%, respectively) than HFA-BDP (29%). HFA-BDP was deposited evenly throughout the lungs, while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways. Andersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 micro m, 2.0 micro m, and 3.5 micro m, respectively. CONCLUSIONS: Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP. Deposition values appeared to be related to the particle size distribution of each inhaler, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition.     

Efficacy of budesonide Turbuhaler compared with that of beclomethasone dipropionate pMDI in Japanese patients with moderately persistent asthma

OBJECTIVE: The aim of the study was to compare the efficacy and safety of budesonide Turbuhaler with that of beclomethasone dipropionate (BDP) pMDI. METHODOLOGY: Three hundred and fifty adult asthma patients (mean age 52.7 years, mean baseline morning peak expiratory flow (PEF) 294 L/min (< 80% predicted normal)), taking BDP via pressurized metered-dose inhaler (pMDI), 400 microg daily for at least 2 months, were randomized in an open 6 week study to receive daily doses of either budesonide 100 microg or 400 microg twice daily via Turbuhaler or continued treatment with BDP, 100 microg four times daily. The primary efficacy variable was the mean change in morning PEF from baseline to the end of treatment. Outcome was also assessed using symptom scores and investigators' assessments employed in Japanese clinical trials. RESULTS: At the end of the 6 week treatment period, mean morning PEF improved significantly from baseline in both budesonide groups, 16 L/min and 33 L/min in the 200 microg and 800 microg groups, respectively, but not in the BDP group, 5 L/min. There was no significant difference between 200 microg budesonide and 400 microg BDP treatment in the effect on PEF (P = 0.29), but 800 microg budesonide was significantly superior to BDP (P < 0.001). Final assessment of improvement and usefulness ratings showed that both budesonide treatments were significantly superior to BDP (P < 0.001). All treatments were well tolerated. CONCLUSION: Budesonide Turbuhaler (200 microg) was as effective as 400 microg BDP pMDI. The efficacy of budesonide was improved significantly by increasing the dosage to 800 microg daily. The study design shows the importance of including a higher dose treatment group when comparing two formulations of inhaled corticosteroids in order to determine whether the treatments to be compared are on the steep part of the dose-response curve. Without that information, comparative studies are usually inconclusive.     

Treatment of steroid-dependent asthma patients with beclomethasone dipropionate aerosol.

Fifty-two steroid-dependent adults with chronic perennial asthma were transferred to beclomethasone dipropionate aerosol. The tests demonstrated a significant improvement with beclomethasone in terms of the diary score, bronchodilator use, and PEF and FEV1.0 measurements, as compared with the previous period of prednisolone treatment. Before the transfer, 26 of the patients displayed one or more diseases or symptoms which were probably due to systemic steroid medication. Morning cortisol levels, along with the response to tetracosactrin had in all cases returned to normal when tests were carried out 41 days after transfer to beclomethasone dipropionate. In a group of 12 patients with the lowest 11-OHCS basal values, the mean of their 11-OHCS values during prednisolone treatment was as low as 0.14 plus or minus 0.06 mumol/l, but tetracosactrin challenge induced an elevation to a normal level, 0.33 plus or minus 0.13 mumol/l. After 41 days of beclomethasone treatment, the corresponding values were 0.56 plus or minus 0.90 plus or minus 0.28 mumol/l. Thirty-seven patients experienced one or more disturbing symptoms after transfer to beclomethasone. In many cases, the symptoms of allergic rhinitis were troublesome and persistent leading to a sixfold increase in the use of antihistaminic tablets. When the patients had learned to exhale through the nose following beclomethasone inhalation, the use of antihistaminic tablets again diminished to some extent. Moreover, two cases of ulcerative colitis were encountered during the beclomethasone treatment. During a follow-up period of one year, 14 patients were again receiving prednisolone; most often, this was due to worsening of the asthma because of respiratory infections. During the beclomethasone treatment, a continuous significant improvement in PEF was noted after isoprenaline inhalation, suggesting that further benefit may be obtained by the employment of bronchodilator aerosols as an essential part of the treatment.     

A clinical trial of treating asthma of moderate severity with beclomethasone dipropionate aerosol]

In order to investigate the efficacy of steroid inhalation in treating asthma of moderate severity, a single-blind, randomized short-term (3-4 weeks) trial was performed in 25 asthmatics uncontrolled by salbutamol inhalation, oral aminophylline and beta 2-agonist. 22 patients finished the trial. Among them, twelve received beclomethasone dipropionate 300 mcg/day and ten received placebo. There was significant improvement in asthmatic symptoms and pulmonary function (FEV1.0, V50, V25) in the group treated with steroid inhalation at the end of this trial, whereas no significant changes were observed in the placebo group. The results demonstrated that steroid inhalation could effectively control asthma of moderate severity.     

Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma.

A new hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) aerosol markedly increases drug delivery to the airways. Therefore, even low doses of HFA-BDP should be effective, and the present study assesses this. A randomised, double-blind, crossover study was used to compare the effect of placebo, HFA-BDP 50 microg or 100 microg given q.d. (QVAR(TM) Autohaler(TM); 3M Pharmaceuticals, St. Paul, MN, USA) on exercise-induced bronchoconstriction and exhaled nitric oxide (eNO). After a 14-day run-in, 25 children (5-14 yrs old) entered three 4-week treatment periods, separated by a 1-week washout. After each period, the fall in forced expiratory volume in one second (FEV1), after an exercise test, and eNO were measured. Significant treatment effects with no carry-over or period effects were seen for both eNO and maximum fall in FEV1 after exercise. Differences were seen between placebo (fall in FEV1=27.9%; eNO=14.4 parts per billion (ppb)) and either dose of HFA-BDP, but not between the two active doses (50 microg: fall in FEV1=20.8%, eNO=9.3 ppb; 100 microg: fall in FEV1=20.9%, eNO=8.9 ppb). In conclusion, low q.d. doses of hydrofluoroalkane-beclomethasone dipropionate reduced exhaled nitric oxide and exercise-induced bronchoconstriction. Further studies are needed to assess whether q.d. administration of beclomethasone dipropionate is as effective as b.i.d. administration.     

Pharmacokinetics of beclomethasone dipropionate in an hydrofluoroalkane-134a propellant system in Japanese children with bronchial asthma.

BACKGROUND: Hydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma. METHODS: Plasma concentrations of beclomethasone 17-monopropionate (17-BMP),a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 microg as four inhalations from 50 microg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters. RESULTS: The area under the concentration-time curve from time zero to the last quantifiable time (AUC(0-t)) was 1659 +/- 850 pg x h/mL (arithmetic mean +/- standard deviation (SD)), the maximum concentration observed (C(max)) was 825 +/- 453 pg/mL and the apparent elimination half-life (t(1/2)) was 2.1 +/- 0.7 hours. The time to reach Cmax Tmax was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC(0-t), 1.04 for Cmax and 1.4 for t(1/2). The median of Tmax was 0.5 hours in American patients as well as Japanese patients. CONCLUSIONS: The pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested.     

Evaluation of theophylline or pranlukast, a cysteinyl leukotriene receptor 1 antagonist, as add-on therapy in uncontrolled asthmatic patients with a medium dose of inhaled corticosteroids.

A few studies compared the additional effects of oral controller medicines on pulmonary function in asthmatic patients on a moderate dose of inhaled steroids. The aim of this study was to compare the additional effects of two oral asthma controllers, a leukotriene receptor antagonist and a sustained released theophylline (Theo), with a moderate dose of inhaled steroid on peak expiratory flow (PEF) and asthma-related symptoms. A total of 67 adult asthmatic patients with PEF < 80% predicted during a 2-week run-in period with 800 microg/day of beclomethasone dipropionate were randomized to receive either pranlukast, 450 mg/day (n = 33), or sustained released Theo, 200 mg/day (n = 34), for 4 weeks. Pranlukast and Theo did not significantly alter the symptom scores, use of rescue beta2-agonist, and daily PEF variability. However, both agents significantly increased both morning and evening PEF compared with the run-in periods. The effects of both medications were comparable. For asthmatic patients even on a moderate dose of inhaled steroids, the addition of either leukotriene receptor antagonist or sustained released Theo does not improve asthma-related symptoms but significantly and equally increases PEF.     

Initial improvements in lung function and bronchial hyperresponsiveness are maintained during 5 years of treatment with inhaled beclomethasone dipropionate and terbutaline.

OBJECTIVES: Treatment with inhaled corticosteroids reduces bronchial hyperresponsiveness and relieves airways obstruction in patients with asthma. Up to now, it is unknown whether initial improvements are maintained over a long period of time. Therefore, we assessed whether initial improvements in FEV(1), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)), and peak expiratory flow (PEF) persist with a constant dose of inhaled corticosteroids. Furthermore, we investigated whether FEV(1), PC(20), PEF indexes, and symptom scores improve after increasing the dose of inhaled corticosteroids in patients who did not respond sufficiently to treatment with beclomethasone dipropionate (BDP), 800 microg/d. METHODS: Sixty-eight patients with bronchial hyperresponsiveness and airways obstruction completed a previous study on 3 years of treatment with terbutaline, 500 microg qid, and BDP, 200 microg qid. Fifty-eight of these patients participated in the current extension of another 2.5 years of follow-up. Every 6 months, FEV(1) and PC(20) were measured. Five patients dropped out of the study, one for pulmonary reasons. Forty-four patients continued treatment with BDP, 800 microg/d (BDP-800 group), and 9 patients received a higher dose of BDP (500 microg tid; BDP-1,500 group) after the first 3 years because of a rapid decline in FEV(1) (> 50 mL/yr) despite BDP treatment during the previous study period. RESULTS: After the initial improvement, the mean slope of individual regression lines for FEV(1), PC(20), and morning PEF were - 28 mL/yr, - 0.01 doubling concentrations per year, and 0.6 L/min/yr, respectively, in the BDP-800 group. In the BDP-1,500 group, there were no statistically significant improvements in FEV(1), PC(20), PEF indexes, and symptom scores after increasing the dose of BDP. CONCLUSIONS: We conclude that initial improvements in FEV(1), PC(20), and PEF are well preserved over 5 years in patients with obstructive airways diseases who are treated with terbutaline and BDP. In the patients who responded sufficiently to 800 microg/d of BDP, there was no accelerated decline in FEV(1) compared with the general population. Increasing the dose of BDP in a small group of patients with an accelerated fall in FEV(1) (initially treated with a moderate dose of BDP) resulted in no significant improvement in FEV(1), PC(20), PEF indexes, and symptom scores.     

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.