Large volume spacer devices and the influence of high dose beclomethasone dipropionate on hypothalamo-pituitary-adrenal axis function.

BACKGROUND: The systemic effects of the inhaled corticosteroid beclomethasone dipropionate are reduced if the drug is inhaled through a large volume spacer. Use of spacers may therefore permit higher doses to be given without causing hypothalamo-pituitary-adrenal suppression. METHODS: Randomised, double blind, double dummy, parallel group study was carried out in adults with chronic asthma to determine the dose of beclomethasone dipropionate causing hypothalamo-pituitary-adrenal suppression when the drug was administered by metered dose aerosol with and without a large volume spacer. After a four week run in taking 1.5 mg beclomethasone daily 50 patients underwent tests of hypothalamo-pituitary-adrenal function (measurement of 0900 h serum cortisol concentration and 24 hour urinary free cortisol excretion and the short tetracosactrin test). Six patients had hypothalamo-pituitary-adrenal suppression (results of at least two tests subnormal) and asthma was well controlled in six others. Thirty eight patients received increasing doses of beclomethasone with (group S) or without (group MDI) a 750 ml spacer. The daily dose was increased by 0.5 mg at monthly intervals until hypothalamo-pituitary-adrenal suppression developed or a dose of 5 mg/day was achieved. Asthma symptoms and peak expiratory flow were recorded daily. RESULTS: Twenty three patients completed the study, one (group S) reaching a dose of 5 mg beclomethasone dipropionate daily without hypothalamo-pituitary-adrenal suppression. Reasons for withdrawal were poor compliance (n = 10), the patient's decision (n = 3), and asthma that was too unstable (n = 2). "Intention to treat" analysis showed that the median dose of beclomethasone causing hypothalamo-pituitary-adrenal suppression was similar in the two groups (3.25 mg in S v 3.0 mg in MDI; 95% confidence interval (CI) for difference -1.0 to 1.0 mg). At 2 mg/day of beclomethasone most patients in both groups had well controlled asthma and there were no differences in symptoms or peak flow between the groups. Good control at this dose did not permit conclusions to be drawn about the efficacy of higher doses. CONCLUSIONS: There is wide interindividual variation in the dose of beclomethasone dipropionate causing hypothalamo-pituitary-adrenal suppression. Whether or not a spacer is used, doses higher than the currently accepted maximum of 2 mg/day can be taken by many adults with asthma without causing subnormal function of the hypothalamo-pituitary-adrenal axis. Whether these higher doses are more effective in controlling asthma remains to be established.     

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.     

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.     

Effects of high doses of inhaled corticosteroids on adrenal function in children with severe persistent asthma.

BACKGROUND--Childhood asthma generally responds well to inhaled corticosteroids within the dosage range recommended by the manufacturers, but it is sometimes necessary to use higher doses--that is, above 400 micrograms/day--a practice which has become more widespread recently. Whereas the lack of adrenal suppression in children given inhaled corticosteroids in normal doses is well documented, little is known about the effects of higher doses. METHODS--The effects on adrenal function of high dose (above 400 micrograms/day) inhaled corticosteroids were evaluated by measuring cortisol concentration in the morning and performing a short tetracosactrin test in 49 children taking budesonide (mean age 9.2 years (range 4 to 16 years) and 28 children taking beclomethasone dipropionate (10.2 years (5 to 13 years)). Twenty three non-asthmatic children (8.9 years (4.9 to 13 years)) who were under investigation for short stature served as controls for the study. RESULTS--Compared with controls mean basal cortisol concentration was lower in children taking budesonide and beclomethasone dipropionate (control 401 (26.8) nmol/l, budesonide 284 (22) nmol/l, beclomethasone dipropionate 279 (23.2) nmol/l). Sixteen of the 49 children taking budesonide had subnormal basal cortisol concentrations compared with seven of the 28 taking beclomethasone dipropionate. Mean stimulated cortisol concentrations were lower in children taking inhaled corticosteroids than in controls, with no difference between those taking budesonide or beclomethasone dipropionate. CONCLUSIONS--Adrenal suppression occurs in some children who are given inhaled corticosteroids in doses greater than 400 micrograms/day. It may therefore be advisable to try alternative treatments before such doses are used.     

Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler.

BACKGROUND: High doses of inhaled corticosteroids are absorbed systemically and may cause long term side effects. As rinsing the mouth out after use and inhaling through a spacing device may reduce systemic absorption this has been further investigated. METHODS: Three crossover studies were carried out to assess the effect of budesonide given by dry powder inhaler (Turbuhaler) with and without mouth rinsing and beclomethasone dipropionate given by metered dose inhaler with or without a spacing device (Volumatic) on serum cortisol concentrations and urinary cortisol excretion in patients with asthma taking an inhaled corticosteroid. Each treatment period was two weeks with in a two week washout period. Serum cortisol concentrations at 0800 hours on day 14 and the 24 hour urinary excretion of cortisol were measured. In study 1 24 patients taking beclomethasone dipropionate 500 micrograms twice a day inhaled with (n = 10) or without (n = 14) a Volumatic spacing device were switched to a budesonide dry powder inhaler, 600 micrograms to be taken twice a day without mouth rinsing. In study 2 10 patients took budesonide 800 micrograms twice a day with and without mouth rinsing and without swallowing the rinsing water. In study 3 17 patients took budesonide 800 micrograms twice daily with mouth rinsing and beclomethasone dipropionate 500 micrograms twice daily with the spacing device and mouth rinsing. RESULTS: In study 1 no difference was seen between budesonide without mouth rinsing and beclomethasone dipropionate without a spacer: beclomethasone with spacer caused less suppression of cortisol (mean (SD) serum cortisol concentration: beclomethasone and spacer 487(148), budesonide 368(145) nmol/l). In study 2 mouth rinsing caused less suppression of morning serum cortisol concentrations (rinsing 440(63), no rinsing 375(56) nmol/1). In study 3 there was no difference in serum or urinary cortisol concentrations between twice daily beclomethasone dipropionate 500 micrograms inhaled by Volumatic spacer or budesonide by Turbuhaler 800 micrograms twice daily, both with mouth rinsing. Individual serum cortisol values were within the normal range in all patients except one in study 1. CONCLUSION: Systemic absorption of a corticosteroid inhaled from a metered dose inhaler is reduced by using a spacing device and that from a dry powder inhaler by mouth rinsing.     

Comparison of two high dose corticosteroid aerosol treatments, beclomethasone dipropionate (1500 micrograms/day) and budesonide (1600 micrograms/day), for chronic asthma.

Twenty eight patients with chronic asthma took part in a double blind single crossover controlled trial of inhaled budesonide and inhaled beclomethasone dipropionate, using high doses of 1600 micrograms and 1500 micrograms daily respectively. Both drugs were administered by pressurised aerosol inhaler; the inhaler containing budesonide and its matching placebo were fitted with a collapsible spacer device. There was no significant difference in the control of asthma during the two six week treatment periods. There was no significant difference in FEV1 and forced vital capacity after four and six weeks of treatment or in mean morning and evening peak expiratory flow rates for the last 21 days of treatment. There was a small but statistically significant reduction in the daytime wheeze score while they were taking high dose budesonide but there was no difference for daytime activity, cough, and night symptoms. The mean basal cortisol concentrations were significantly lower after six weeks of high dose treatment than before treatment (budesonide p less than 0.01, beclomethasone p less than 0.05). There was no difference between mean basal cortisol values after six weeks of high dose treatment, and there was no effect on the rise of cortisol obtained after a short tetracosactrin test. High dose inhaled corticosteroids produced few side effects and were well tolerated.     

Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids?

When used in high doses, inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal axis. The influence of the mode of drug inhalation on the degree of this suppression is not clear. Hypothalamo-pituitary-adrenal function was assessed by measurement of 0900 h serum cortisol concentrations, a short tetracosactrin test, and 24 hour urine free cortisol excretion in 48 adults with asthma taking 1500-2500 micrograms beclomethasone dipropionate daily via a metered dose aerosol. Twelve patients had hypothalamo-pituitary-adrenal suppression, as judged by subnormal results from at least two of the three tests or (in one patient) by an abnormal insulin stress test response. These patients then changed to inhaling the same dose of beclomethasone dipropionate through a 750 ml spacer device (Volumatic). The endocrine tests were repeated from nine days to eight weeks later in 10 patients. Comparison with initial values showed that adding the spacing device caused an increase in the median 0900 h cortisol concentration from 126 nmol/l to 398 nmol/l, in the post-tetracosactrin cortisol concentration from 402 nmol/l to 613 nmol/l and in 24 hour urine free cortisol excretion from 54 nmol to 84 nmol. The rise in serum cortisol concentration in response to tetracosactrin did not change. Evidence of persisting hypothalamo-pituitary-adrenal axis suppression was present in only four of the 10 patients; the most pronounced improvements in function tended to occur in those who had never required long term oral corticosteroids. The results from this uncontrolled study suggest that asthmatic patients taking high dose beclomethasone dipropionate may minimise adverse effects by using a large volume spacer device.     

Effect of prednisone and beclomethasone dipropionate on airway responsiveness in asthma: a comparative study.

To examine the effect of corticosteroids on bronchial hyperresponsiveness, a randomised, double dummy, single blind crossover study was performed in 18 subjects with chronic asthma, comparing the effect of three weeks' treatment with inhaled beclomethasone dipropionate, 1200 micrograms daily, and oral prednisone 12.5 mg daily. The 12 week study began with a three week run in period of baseline treatment, which was continued unchanged throughout the study, and the two treatment periods were separated by a three week washout period. Patients kept daily Airflometer readings and attended the laboratory every three weeks for spirometry and a histamine inhalation test for determining the provocative dose of histamine causing a 20% fall in FEV1 (PD20). The mean FEV1 at the start was 1.9 litres (56% predicted). There was no significant change in PD20 with prednisone treatment, the mean PD20 being 0.56 and 0.59 mumol before and after treatment. There was, however, a significant improvement in PD20 with beclomethasone dipropionate treatment, the geometric mean PD20 being 0.38 and 1.01 mumol before and after treatment (p less than 0.001). There was a small but significant improvement in mean FEV1 after beclomethasone dipropionate treatment--from 1.9 to 2.2 litres--but no change after prednisone. Both medications produced significant and similar improvements in morning and evening Airflometer readings, post-bronchodilator improvement, and diurnal variation. Thus at doses that had similar beneficial effects on lung function beclomethasone dipropionate caused a significant improvement in bronchial hyperresponsiveness whereas prednisone caused no change. The superior topical anti-inflammatory effect of beclomethasone dipropionate may account for the different effects on bronchial hyperresponsiveness.     

Effect of eight months of inhaled beclomethasone dipropionate and budesonide on carbohydrate metabolism in adults with asthma.

BACKGROUND--The safety of high dose inhaled steroids has been a subject of debate. The efficacy and safety of beclomethasone dipropionate and budesonide inhalations were evaluated by measuring their effects on pulmonary function, on the hypothalamic-pituitary-adrenocortical axis, and on carbohydrate metabolism in adults with unstable asthma. METHODS--Fifteen adults with unstable asthma and 15 healthy controls were studied. Eight patients were treated with beclomethasone dipropionate in initially high (2 mg/day for five months) and subsequently lower (1 mg/day for three months) doses. Seven patients were treated with budesonide at doses of 1.6 mg/day for five months followed by 0.8 mg/day for three months. Blood glucose and serum insulin were measured in an oral glucose tolerance test and plasma cortisol in an adrenocorticotrophic hormone test. The antiasthmatic effect of treatment was evaluated by measuring peak morning expiratory flow rates and forced expiratory volume in one second (FEV1). RESULTS--The FEV1 increased significantly after one month of treatment (medians 88% v 96%, p < 0.01), and nocturnal symptoms disappeared within two weeks of treatment in both groups. At one month, the high dose significantly decreased serum insulin concentrations as calculated from the areas under the incremental two hours curves in the glucose tolerance test. The decrease was 59% for beclomethasone dipropionate (medians 76 v 31 mU/l/h, p < 0.005) and 42% for budesonide (medians 79 v 46 mU/l/h, p < 0.01). The median areas at five and eight months were intermediate for both drugs. No significant differences were found when the five and eight month values were compared either with the baseline or with one month values. The difference between the baseline values of both groups and the respective values in healthy controls was significant (medians 79 v 49 mU/l/h, p < 0.01). The one month values for the patients and control subjects were similar. Paralleling the changes for insulin, the area under the incremental two hour blood glucose curve decreased significantly (medians 1.4 v 0.4 mmol/l/h, p < 0.05) during the first month of treatment. The five and eight month values were intermediate (medians 0.8 and 0.7 mmol/l/h, respectively). These changes were not significant compared with the baseline or the one month areas. Similar changes were seen in both treatment groups. Neither treatment had any significant effect on plasma cortisol in the one hour adrenocorticotrophic hormone test. CONCLUSIONS--In patients stressed by uncontrolled asthma, the antiasthmatic effect of high dose beclomethasone dipropionate and budesonide was accompanied by a significant initial decrease in insulin resistance with a parallel improvement in glucose tolerance. During prolonged treatment a small increase in insulin sensitivity was found. The overall effect of beclomethasone dipropionate and budesonide inhalations on carbohydrate metabolism may be beneficial in patients with uncontrolled asthma.     

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.     

Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function.

Studies of adrenal function were performed on 54 asthmatic patients who were taking long term high doses of inhaled beclomethasone dipropionate ranging from 500 to 2000 micrograms/day for between six and 60 months. Of the 43 patients taking up to 1500 micrograms/day, 39 (91%) had normal basal plasma cortisol concentrations and normal short tetracosactrin responses and 24 hour urinary free cortisol excretion was within the normal range in eight of nine patients tested. Some evidence of adrenal suppression was found in patients taking 2000 micrograms/day, with basal plasma cortisol below the normal range in four out of 11 patients and 24 hour urinary free cortisol excretion below the normal range in five out of six patients tested. Only one of the 11 patients taking 2000 micrograms/day had a short tetracosactrin response below the normal range: the mean rise in plasma cortisol was, however, significantly lower in this group than in those taking 1000 micrograms/day (328 (SE 30) and 506 (34) nmol/l respectively) (p less than 0.01). Patients taking more than 1500 micrograms/day of inhaled beclomethasone may require systemic corticosteroids during prolonged stress.     

Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma

BACKGROUND: Cigarette smokers with asthma are insensitive to short term inhaled corticosteroid therapy, but efficacy when given for a longer duration at different doses is unknown. METHODS: Ninety five individuals with mild asthma were recruited to a multicentre, randomised, double blind, parallel group study comparing inhaled beclomethasone in doses of 400 microg or 2000 microg daily for 12 weeks in smokers and non-smokers. The primary end point was the change in morning peak expiratory flow (PEF). Secondary end points included evening PEF, use of reliever inhaler, number of asthma exacerbations, spirometric parameters, and asthma control score. RESULTS: After 12 weeks of inhaled beclomethasone there was a considerable difference between the morning PEF measurements of smokers and non-smokers with asthma (-18 (95% CI -35 to -1), adjusted p = 0.035). Among those receiving 400 microg daily there was a difference between the mean (95% CI) morning PEF (l/min) in smokers and non-smokers (-25 (95% CI -45 to -4), adjusted p = 0.019) and in the number of asthma exacerbations (6 v 1 in smokers and non-smokers, respectively, p = 0.007). These differences were reduced between smokers and non-smokers receiving 2000 microg inhaled beclomethasone daily. CONCLUSIONS: Compared with non-smokers, smokers with mild persistent asthma are insensitive to the therapeutic effect of low dose inhaled corticosteroid treatment administered for a 12 week period. The disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid. These findings have important implications for the management of individuals with mild asthma who smoke.     

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.     

Fluticasone propionate 750 µg/day versus beclomethasone dipropionate 1500 µg/day: comparison of efficacy and adrenal function in paediatric asthma

BACKGROUND—Previousstudies have suggested a 2:1 efficacy advantage of fluticasonepropionate (FP) over beclomethasone dipropionate (BDP) in adults onhigh dose inhaled steroids and children on low dose inhaled steroids.The lower doses of FP required to provide equivalent efficacy to BDPalso appear to have fewer systemic effects as measured by adrenal function.
METHODS—The efficacyand safety of FP 750 µg/day and BDP 1500 µg/day were compared in 30 children with persistent asthma (requiring 1000-2000 µg/day ofinhaled corticosteroids) in a 12 week randomised double blind crossoverstudy. Medication was delivered by a spacer device in two divideddoses. Primary efficacy variables were peak expiratory flows (PEF).Adrenal function was assessed by 24 hour urinary free cortisol levelsat eight and 12 weeks and ACTH and low dose synacthen tests (LDST) at12 weeks. The results were adjusted for sequence and period differences.
RESULTS—There was nodifference in the primary efficacy variables over the two 12 weektreatment periods (difference in adjusted means for morning PEF 1.3 l/min (95% CI -6.1 to 8.8), p = 0.112) and symptom scores (cough,tachypnoea, wheeze, shortness of breath; difference in adjusted meansof night time scores: -0.06 (95% CI -0.14 to 0.03); p = 0.136).Similar degrees of mild adrenal dysfunction were found during BDP andFP treatment phases. Identical height gain velocities were shown duringthe corresponding periods.
CONCLUSIONS—FP 750 µg/day is as effective as BDP 1500 µg/day in children withpersistent asthma. At these very high doses we were unable todemonstrate a safety advantage of FP over BDP as assessed by adrenalfunction. However, measures of adrenal function may have beeninfluenced by concurrent and previous systemic steroid usage, andpossibly by effects of disease activity.

     

Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years

BACKGROUND: Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity, but the risks and benefits of using them in patients with milder asthma are less clear. We have compared the change in bone mineral density over 2 years in adults with mild asthma randomised to receive an inhaled corticosteroid or non-corticosteroid treatment. METHODS: Subjects with mild asthma (mean forced expiratory volume in one second (FEV(1)) 86% predicted, mean age 35 years, taking beta agonists only) were randomised to receive inhaled budesonide, inhaled beclomethasone dipropionate, or non-corticosteroid treatment for 2 years in a prospective randomised open study in 19 centres in France, New Zealand, Spain, and the UK. The corticosteroid dose was adjusted according to a written self-management plan. The main outcome measure-change in bone mineral density after 6, 12, and 24 months-was measured "blind". Secondary outcomes included lung function, the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism. RESULTS: Of 374 subjects randomised, 239 (64%) completed the study and were included in the analysis. The median daily doses of inhaled budesonide (n=87) and beclomethasone (n=74) were 389 microg and 499 microg, respectively. Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group (n=78). Change in bone mineral density did not differ between the three groups over the 2 years, nor did it correlate with changes in markers of bone metabolism. The mean change in bone mineral density over 2 years in the budesonide, beclomethasone dipropionate, and reference groups was 0.1%, -0.4%, and 0.4% for the lumbar spine and -0.9%, -0.9%, and -0.4% for neck of the femur. Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck. CONCLUSION: In subjects with mild asthma an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years. The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone. Since inhaled steroid dose is also related inversely to lung function, an effect of asthma severity on bone density was also possible.     

Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma.

BACKGROUND--Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. METHODS--Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. RESULTS--Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. CONCLUSIONS--These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.     

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.     

Bone turnover during high dose inhaled corticosteroid treatment.

This study was performed to determine the effects of high doses of two inhaled corticosteroids, beclomethasone dipropionate and budesonide, on biochemical indices of bone turnover (urinary hydroxyproline:creatine and calcium:creatinine ratios, plasma alkaline phosphatase, and parathyroid hormone). Twelve healthy male doctors, aged 25-36 (mean 30) years, were studied. After a week's run in period eight subjects inhaled beclomethasone dipropionate 2000 micrograms/day and eight inhaled budesonide 1800 micrograms/day for 28 days; this was followed by a week without any treatment. During treatment with beclomethasone dipropionate there was a significant increase in the hydroxyproline:creatinine ratio (a 46% increase at 28 days), and a fall in serum alkaline phosphatase activity (a 7.4% fall at 28 days). There were no significant changes during budesonide treatment. Thus high dose inhaled beclomethasone dipropionate increased biochemical markers of bone resorption and reduced serum alkaline phosphatase, a marker of bone mineralisation. A prospective study in asthmatic patients is indicated to assess the long term effects of high dose inhaled corticosteroids on bone mass.     

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.     

Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice

BACKGROUND: Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma. METHODS: In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 microgram beclomethasone dipropionate (BDP) daily and inhaled beta(2) agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 microgram BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 microgram BDP) over a six month period was examined. RESULTS: One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects. CONCLUSION: There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.