Time course of response to oral and inhaled corticosteroids in non-asthmatic chronic airflow obstruction.

One hundred and twenty one patients considered on clinical grounds to have non-asthmatic chronic airflow obstruction completed a double blind, crossover trial comparing oral prednisolone 40 mg per day with inhaled beclomethasone dipropionate 500 micrograms thrice daily, each given for 14 days, with a 14 day washout period between treatments. The time course of response was analysed for the 57 occasions where there was a significant increase in mean daily peak expiratory flow (PEF) over the treatment period. Mean daily PEF was still rising at day 14 on 12 occasions. After withdrawal of treatment mean daily PEF remained above pretreatments levels for more than two weeks in half the responses analysed. The peak response occurred earlier with inhaled beclomethasone (median 9.5 (range 3-14) days) than with oral prednisolone (median 12 (range 1-14) days), though both treatments produced a response that was sustained for a similar period. The results suggest that a trial of treatment with corticosteroids in this group of patients should last more than 14 days, and that in a study with a crossover design the washout period should be longer than two weeks.     

Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction.

BACKGROUND--The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS--A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS--Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS--High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment.     

Does nedocromil sodium have a steroid sparing effect in adult asthmatic patients requiring maintenance oral corticosteroids?

A randomised, double blind, placebo controlled trial of nedocromil sodium was undertaken to assess its corticosteroid sparing effect in 50 adults with asthma who had required an oral corticosteroid dose of (or equivalent to) at least 5 mg prednisolone a day continuously during the preceding year, in addition to inhaled beclomethasone dipropionate and bronchodilators. Patients having corticosteroids other than prednisolone were changed to prednisolone. A four week baseline period was followed by 20 weeks of inhaled nedocromil sodium (16 mg daily) or placebo. After four weeks of the treatment phase an attempt was made to reduce the oral prednisolone maintenance dose by 2.5 mg a fortnight until a dose of 5 mg daily was reached and thereafter by 1 mg a fortnight, provided that there was no significant clinical deterioration as judged by clinic assessments and daily diary cards. Of 50 patients recruited, 47 entered the treatment phase (age range 16-64 years), 24 receiving nedocromil sodium and 23 placebo. The total steroid reduction achieved was 2.5 mg in the nedocromil group and 3 mg in the placebo group, which did not differ significantly. There was no significant change in symptoms, lung function or inhaler use in either group during the study. The number of patient requiring short term upward adjustment of booster doses of oral prednisolone for exacerbations of asthma was similar in the two groups (26 with placebo, 28 with nedocromil). Thus nedocromil sodium does not appear to provide an oral corticosteroid sparing effect in chronic steroid dependent asthma.     

Value of serial peak expiratory flow measurements in assessing treatment response in chronic airflow limitation.

A double blind, randomised, placebo controlled, crossover trial of prednisolone (40 mg/day for 14 days) was carried out in 33 patients with chronic airflow limitation (mean age 62 years, mean FEV1 1.01 litres, mean FEV1/FVC ratio 44%), to assess the value of serial peak expiratory flow (PEF) measurements, taken five times daily in evaluating treatment response by comparison with other objective measurements and with measurements of symptoms. The mean serial PEF after a one week run in period was 189 1 min-1, during the second week of placebo 193 1 min-1, and during the second week on prednisolone 231 1 min-1. The difference in mean PEF values between placebo and prednisolone was significant (p less than 0.01). With regard to the response to steroids of the individual patients, 13 of the 33 had a detectable trend of improvement on visual inspection of serial PEF measurements during prednisolone treatment but only one during placebo administration. Of all the objective measurements made after the run in and after each treatment phase (12 minute walking distance, FEV1, forced vital capacity (FVC), serial PEF), the serial PEF chart provided the best discrimination between placebo and prednisolone treatment. There was no statistically significant association between steroid induced improvement in serial PEF measurements and in breathlessness, partly because of placebo improvements in symptoms in those who had no improvement in serial PEF values. This study indicates the importance of making objective measurements to identify a genuine steroid response rather than relying on symptomatic improvement alone. The best simple measurement to make is serial PEF during steroid trials. This is more sensitive in detecting a steroid response than are the 12 minute walking distance, FEV1, or FVC, and is also less likely than these measurements to show spurious placebo responses.     

Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group.

BACKGROUND--High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma. Although effective, they may cause systemic side effects. Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses. METHODS--Fluticasone propionate, 1.5 mg per day, was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate. The study was multicentre, double blind and of a parallel design. For the first three months patients attended the clinic every four weeks and completed daily diary cards. For the next nine months they were only seen at three monthly intervals in the clinic. RESULTS--During the first three months diary card peak expiratory flow (PEF) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate (difference in morning PEF 15 l/min (95% CI 6 to 25)), and these differences were apparent at the end of the first week. The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8% compared with those receiving beclomethasone dipropionate. No significant differences between the two groups were observed in morning plasma cortisol levels, urinary free cortisol levels, or response to synthetic ACTH stimulation. In addition, both the rates of withdrawal and of adverse events were low, and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate. CONCLUSIONS--This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate, with no increase in systemic or other side effects.     

Twice daily beclomethasone dipropionate administered with a concentrated aerosol inhaler: efficacy and patient compliance.

The efficacy of twice daily inhaled beclomethasone dipropionate administered by a concentrated aerosol inhaler (one puff twice daily-500 micrograms/day) has been compared with that of treatment four times daily with a standard dose inhaler (two puffs four times daily-400 micrograms/day) in 21 patients with stable asthma. Double placebo inhalers were used in a randomised crossover fashion during two four week treatment periods. Mean peak expiratory flow (PEF), mean symptom scores, and number of extra salbutamol inhalations required were not significantly different between the two treatment periods. Local side effects were more common during treatment with the four times daily active preparation; overt oropharyngeal candidiasis, however, was not found in either group during the study. On completion of the crossover study patients were transferred to the twice daily regimen. At the three month follow up all patients had remained stable and the outpatient PEF was significantly higher (mean 382 (SD 26)l min-1) than at entry into the trial (mean 345 (24)l min-1) (p less than 0.05). Twice daily beclomethasone administered by a concentrated aerosol inhaler appears to be as effective as the standard four times daily regimen in controlling stable asthma.     

Response of patients receiving high dose beclomethasone dipropionate

Costello, J. F. and Clark, T. J. H. (1974).Thorax, 29, 571-573. Response of patients receiving high dose beclomethasone dipropionate. Beclomethasone dipropionate was inhaled by 16 patients with asthma in a dose of 1 mg daily for periods up to 24 weeks. No evidence of adrenal suppression was found in these patients as judged by basal cortisol levels. A further group of five patients with asthma inhaled 2 mg daily of beclomethasone dipropionate for periods up to 10 weeks and no evidence of adrenal suppression was found. A separate group of five patients was found to respond to increasing doses of beclomethasone dipropionate by increasing their forced expiratory volume in the first second. The results suggest that increased doses of beclomethasone dipropionate may provide additional benefit while continuing to avoid unwanted systemic side effects.     

Comparison of inhaled beclomethasone dipropionate 1000 micrograms twice daily and oral prednisone 10 mg once daily in asthmatic patients.

BACKGROUND--Glucocorticosteroids are widely used as drugs of first choice in the treatment of moderate to severe asthma. The effects of inhaled steroids in high doses have been compared with oral prednisone in asthmatic patients in a double blind crossover study. METHODS--The trial consisted of a two week run in period followed by two four week treatment periods separated by a four week washout. During the treatment period patients took either 1000 micrograms beclomethasone dipropionate twice daily and placebo tablets once daily, or 10 mg prednisone daily in one morning dose and placebo inhaler twice daily. The effects of treatment on the provocative dose of histamine producing a 20% fall in FEV1 (PC20 histamine), peak flow measurements at home, and spirometric measurements in the clinic, as well as on the basal and stimulated plasma cortisol levels were measured. RESULTS--Seventeen patients with asthma completed the study. After four weeks of treatment beclomethasone dipropionate showed a significantly better effect on morning peak expiratory flow rate than prednisone. There was a trend to a greater improvement in the PC20 histamine in patients receiving beclomethasone dipropionate than in those receiving prednisone. There were no significant differences in spirometric values, symptom scores, or basal and stimulated cortisol levels between the treatments. The within treatment analysis showed a significant effect of prednisone on stimulated cortisol levels but not of beclomethasone dipropionate. CONCLUSIONS--Beclomethasone dipropionate 1000 micrograms twice daily has a slightly greater therapeutic effect in this population of asthmatic patients than 10 mg of prednisone once a day with less effect on adrenocortical function.     

Morning serum cortisol concentrations after 2 mg inhaled beclomethasone dipropionate in normal subjects: effect of a 750 ml spacing device.

Large spacing devices have been shown to provide more selective delivery of an inhaled steroid to the lung but the effect on the hypothalamo-pituitary-adrenal suppression associated with high dose inhaled corticosteroids has been little studied. The effect of a large spacing device (Volumatic; 750 ml) on suppression of 0900 h cortisol after 2 mg inhaled beclomethasone dipropionate was therefore investigated in normal, healthy volunteers. Twenty four subjects (12 male, 12 female) took part in a randomised, double blind, placebo controlled cross over study in which a single dose of 2 mg beclomethasone dipropionate was taken at 2300 h on two occasions seven days apart, once from a metered dose inhaler alone and once from a metered dose inhaler attached to a 750 ml spacing device. The 0900 h serum cortisol concentration was the same on the morning before each administration (468 nmol/l, 95% confidence interval (CI) 390-561 nmol/l, day 1 v 479 nmol/l, 95% CI 463-494 nmol/l, day 8). The 0900 h serum cortisol concentration the following morning, however, was lower when 2 mg beclomethasone dipropionate was given by metered dose inhaler alone (182 (95% CI 128-264) nmol/l) than when it was given by a spacing device (363 (95% CI 281-475) nmol/l). These results suggest that a large spacing device attached to a metered dose inhaler may decrease the risk of hypothalamo-pituitary-adrenal suppression by high dose inhaled steroid treatment.     

Effect of high dose inhaled beclomethasone dipropionate on carbohydrate and lipid metabolism in normal subjects.

The metabolic effects of four weeks' high dose inhaled beclomethasone dipropionate (500 micrograms twice daily) were studied in nine normal subjects with an open study design. No effect was found on fasting blood glucose concentration or glycosylated haemoglobin concentration. Peak blood glucose concentration 30 minutes after a 75 g oral glucose load was, however, significantly higher (7.1 (SEM 0.2) versus 6.7 (0.1) mmol/l, or 128 (3.6) v 121 (1.8) mg/100 ml). After treatment there was a 36% increase in fasting serum insulin concentration (7.6 (0.7) versus 5.6 (0.5) mU/l) and a 32% increase in the area under the serum insulin concentration curve after glucose challenge. High dose inhaled beclomethasone dipropionate treatment raised the fasting plasma cholesterol concentration (4.62 (0.25) v 4.16 (0.26) mmol/l, or 178 (9.7) v 161 (10.0) mg/100 ml) and high density lipoprotein cholesterol (1.19 (0.065) versus 0.97 (0.065) mmol/l, or 45 (2.5) v 37 (2.5) mg/100 ml). Fasting blood lactate and pyruvate concentrations were also significantly higher and blood glycerol lower. The findings indicate that high dose inhaled beclomethasone dipropionate may disturb both carbohydrate and lipid metabolism.