Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients

BACKGROUND: In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms. The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate (FP) and budesonide (B) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients. METHODS: Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second (FEV1) 89.0% predicted and mid forced expiratory flow (FEF25-75) 58.9% predicted, on 400 micrograms/day or less of inhaled corticosteroid, were studied in a double blind, placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms, 500 micrograms, and 1000 micrograms twice daily. Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing. Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours, 10 hours after the eighth dose. RESULTS: The plasma cortisol levels (nmol/ l) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels: F500 333.8, B500 415.2 (95% CI 28.9 to 134.0); F1000 308.3, B1000 380.3 (95% CI 10.5 to 133.5); F2000 207.3, B2000 318.5 (95% CI 5.8 to 216.7); placebo 399.9. Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio (nmol/mmol) at all three dose levels: F500 3.12, B500 5.55 (95% CI 0.16 to 3.79); F1000 2.54, B1000 6.12 (95% CI 1.25 to 5.91); F2000 2.07, B2000 6.09 (95% CI 0.88 to 7.18); placebo 5.23. CONCLUSIONS: With repeated dosing across a dose range of 250-1000 micrograms twice daily, fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol. It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients. Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency, prolonged receptor residency time, greater tissue retention, and a longer elimination half life.


     

Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic children.

BACKGROUND: The aim of this study was to compare the systemic bioactivity of inhaled budesonide (B) and fluticasone propionate (F), each given by large volume spacer, on a microgram equivalent basis in asthmatic children. METHODS: Ten stable asthmatic children of mean age 11 years and forced expiratory volume in one second (FEV1) 81.6% predicted, who were receiving treatment with < or = 400 micrograms/day of inhaled corticosteroid, were studied in a placebo controlled single blind (investigator blind) randomised crossover design comparing single doses of inhaled budesonide and fluticasone propionate 400 micrograms, 800 micrograms, and 1250 micrograms. Doses were given at 20.00 hours with mouth rinsing and an overnight 12 hour urine sample was collected for estimation of free cortisol and creatinine excretion. RESULTS: The results of overnight 12 hour urinary cortisol output (nmol/12 hours) showed suppression with all doses of fluticasone propionate (as geometric means): F400 micrograms (11.99), F800 micrograms (6.49), F1250 micrograms (7.00) compared with placebo (24.43), whereas budesonide caused no suppression at any dose. A comparison of the drugs showed that there were differences at 800 micrograms and 1250 micrograms levels for urinary cortisol: B800 micrograms versus F800 micrograms (2.65-fold, 95% CI 1.26 to 5.58), B1250 micrograms versus F1250 micrograms (2.94-fold, 95% CI 1.67 to 5.15). The results for the cortisol/creatinine ratio were similar to that of urinary cortisol, with fluticasone causing suppression at all doses and with differences between the drugs at 800 micrograms and 1250 micrograms. CONCLUSIONS: Single doses of inhaled fluticasone produce greater systemic bioactivity than budesonide when given by large volume spacer on a microgram equivalent basis in asthmatic children. The systemic bioactivity of fluticasone, like budesonide, is due mainly to lung bioavailability.     

Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients.

BACKGROUND: A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis, each given by metered dose inhaler to asthmatic patients. METHODS: Twelve asthmatic patients of mean age 29.9 years, with a forced expiratory volume in one second (FEV1) 92.9% predicted and forced expiratory flow 25-75% (FEF25-75) 69.5% predicted, on less than or equal to 400 micrograms/day inhaled corticosteroid, were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400, 1000, 1600, 2000 micrograms and fluticasone propionate 500, 1000, 1500, 2000 micrograms. Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later. RESULTS: Serum cortisol levels compared with placebo (mean 325.2 nmol/l) were suppressed by fluticasone at doses of 1500 micrograms (211.6 nmol/l) and 2000 micrograms (112.3 nmol/l) and by budesonide at 2000 micrograms (243.4 nmol/l). Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms (95% CI for difference 42.9 to 219.2). The dose ratio (geometric mean) for the relative potency was 2.89 fold (95% CI 1.19 to 7.07). In terms of percentage suppression versus placebo, fluticasone propionate also produced greater effects (means and 95% CI for difference): budesonide 1600 micrograms (16.0) versus fluticasone propionate 1500 micrograms (40.9) (95% CI -0.6 to 50.6), budesonide 2000 micrograms (26.0) versus fluticasone 2000 micrograms (65.2) (95% CI 10.5 to 67.8). Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range (150 nmol/l) for fluticasone and five of 24 for budesonide. Fluticasone propionate also caused greater ACTH suppression than budesonide (as % versus placebo): budesonide 1600 micrograms (12.0) versus fluticasone propionate 1500 micrograms (31.9) (95% CI 7.6 to 32.1), budesonide 2000 micrograms (13.5) versus fluticasone propionate 2000 micrograms (44.4) (95% CI 13.2 to 48.7). For overnight 10 hour urinary cortisol (nmol/10 hours) there was a difference between the lowest doses of the two drugs: budesonide 400 micrograms (37.2) versus fluticasone propionate 500 micrograms (19.9) (95% CI 6.9 to 27.8). CONCLUSIONS: Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption. Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients.     

24 hour and fractionated profiles of adrenocortical activity in asthmatic patients receiving inhaled and intranasal corticosteroids

BACKGROUND: As both rhinitis and asthma are allergic conditions, they frequently occur together. The objective of this study was to assess the diurnal adrenocortical activity in asthmatics receiving inhaled (inh) and intranasal (n) formulations of two different corticosteroids, fluticasone propionate (FP) and triamcinolone acetonide (TAA), both given at clinically recommended doses. METHODS: Twelve stable moderately severe asthmatic subjects of mean age 23.9 years and mean forced expiratory volume in one second (FEV1) 84% predicted were recruited into a randomised placebo (PL) controlled two-way crossover study comparing nPL + inhPL, nPL + inhFP (880 micrograms bid), and nFP (200 micrograms once daily) + inhFP (880 micrograms bid) with nPL + inhPL, nPL + inhTAA (800 micrograms bid) and nTAA (220 micrograms once daily) + inhTAA (800 micrograms bid), each given for five days with a 10 day washout period. Twenty four hour integrated and fractionated (overnight, 08.00 hours, daytime) serum cortisol levels and urinary cortisol/creatinine excretion were measured. RESULTS: For 24 hour and fractionated serum cortisol levels and corrected urinary cortisol/creatinine excretion there were significant (p < 0.05) differences between all active treatments and placebo. For 24 hour integrated serum cortisol levels the ratio between inhaled TAA and FP was 2.3 fold (95% CI 1.2 to 4.3), and for 24 hour urinary cortisol/creatinine excretion the ratio was two-fold (95% CI 1.2 to 3.4). For 24 hour urinary cortisol excretion, with all active treatments, individual abnormal low values of < 40 nmol (< 14.4 micrograms) occurred in 17/24 with FP compared with 4/24 with TAA (p < 0.0005). The 24 hour serum cortisol profile was flattened by FP but not with TAA. The addition of nasal corticosteroid did not produce further significant suppression of mean cortisol values, although with intranasal FP there were three more abnormal values for 24 hour urinary cortisol excretion than with inhaled FP alone. CONCLUSIONS: Both inhaled FP and TAA caused significant suppression of adrenocortical activity which was twice as great with FP, the latter being associated with significantly more individual abnormal values and loss of the normal diurnal circadian rhythm. Fractionated serum cortisol levels and urinary cortisol/creatinine excretion were as sensitive as the respective integrated 24 hour measurements. Although the addition of intranasal formulations did not produce further significant suppression of mean values, there were more individual abnormal cortisol values associated with the addition of intranasal FP.     

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.     

Evaluation of the buccal component of systemic absorption with inhaled fluticasone propionate

BACKGROUND: Inhaled corticosteroids have dose related systemic effects determined by oral (swallowed or oropharyngeal absorption) and lung bioavailability. A study was undertaken to evaluate the significance of oropharyngeal absorption for fluticasone propionate. METHODS: Sixteen healthy volunteers of mean age 29.3 years were studied using an open randomised, placebo controlled, four way crossover design. Treatments were: (a) fluticasone metered dose inhaler (pMDI) 250 microg, 8 puffs; (b) fluticasone pMDI 250 microg, 8 puffs + mouth rinsing/gargling (water); (c) fluticasone pMDI 250 microg, 8 puffs + mouth rinsing/gargling (charcoal); and (d) placebo pMDI, 8 puffs + mouth rinsing/gargling (water). Overnight (ONUC) and early morning (EMUC) urinary cortisol/creatinine ratios and 8 am serum cortisol (SC) levels were measured. RESULTS: Significant (p<0. 05) suppression of ONUC, EMUC, and SC occurred with each active treatment compared with placebo. The mean values (95% CI for difference from placebo) were: (a) ONUC (nmol/mmol): fluticasone (2. 8, 95% CI 3.6 to 7.9), fluticasone + water (3.1, 95% CI 3.3 to 7.7), fluticasone + charcoal (2.3, 95% CI 4.1 to 8.5); placebo (8.6); (b) EMUC (nmol/mmol): fluticasone (5.6, 95% CI 8.4 to 24.5), fluticasone + water (7.6, 95% CI 6.6 to 22.4); fluticasone + charcoal (5.6, 95% CI 8.7 to 24.5); placebo (22.1). There were no significant differences between active treatments. The numbers of subjects with an overnight urinary cortisol of <20 nmol/10 hours were 0 (placebo), 11 (fluticasone), 12 (fluticasone + water), and 13 (fluticasone + charcoal). CONCLUSIONS: Oropharyngeal absorption of fluticasone does not significantly contribute to its overall systemic bioactivity as assessed by sensitive measures of adrenal suppression. In view of almost complete hepatic first pass inactivation with fluticasone, there is no rationale to employ mouth rinsing to reduce its systemic effects although it may be of value for reducing oral candidiasis.     

Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects

BACKGROUND: The potential for long term adverse effects from inhaled corticosteroids relates to their systemic absorption, usually assessed from proxy markers in short term studies. When fluticasone propionate and budesonide have been compared in this way the results have been inconsistent. To determine whether this is because of the subjects studied or the sensitivity of the systemic marker used, we have compared the effects of fluticasone propionate and budesonide in healthy and asthmatic subjects and investigated the effect of treatment on three systemic markers. METHODS: Forty six healthy subjects were randomised to receive inhaled fluticasone propionate 1500 microg/day (via an Accuhaler), budesonide 1600 microg/day (via a Turbuhaler), or placebo; 31 subjects with moderately severe asthma were randomised to receive the same doses of fluticasone propionate or budesonide but not placebo. Systemic effects in healthy and asthmatic subjects were compared after 7 days. Treatment was continued for another 21 days in the subjects with asthma when systemic effects and asthma control were assessed. RESULTS: At baseline healthy subjects had higher urinary levels of total cortisol metabolites (TCM) than subjects with asthma. After 7 days of treatment with fluticasone propionate urinary TCM levels in the healthy subjects were significantly lower than in the subjects with asthma (mean difference between groups 1663 microg/day, 95% CI 328 to 2938). This was not the case with budesonide, however, where urinary TCM levels in the healthy subjects remained above those in the asthmatic subjects (mean difference between groups 1210 microg/day, 95% CI -484 to 2904). Urinary TCM levels were considerably more sensitive to the effects of inhaled corticosteroids than morning serum cortisol or osteocalcin concentrations. Only budesonide reduced the serum level of osteocalcin. CONCLUSIONS: When given by dry powder inhaler for 7 days, fluticasone propionate 1500 microg/day has a greater effect on the hypothalamic-pituitary-adrenal axis in healthy subjects than in subjects with asthma, but this is not the case for budesonide 1600 microg/day. These findings, together with the differences in sensitivity between systemic markers, explain many of the discrepancies in the literature.     

Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma

BACKGROUND: The objective of this multicentre, randomised, double blind, parallel group study was to compare the efficacy and safety of the addition of salmeterol with that of doubling the dose of fluticasone propionate in asthmatic patients not controlled by a low or intermediate dose of inhaled corticosteroids. METHODS: After a four week run in period of treatment with fluticasone propionate (100 micrograms twice daily if pre-trial dose was 400-600 micrograms inhaled corticosteroids or 250 micrograms twice daily if pre-trial dose was 800-1200 micrograms inhaled corticosteroids), 274 patients were randomised to treatment for 12 weeks with either salmeterol 50 micrograms twice daily plus the run in dose of fluticasone propionate or twice the run in dose of fluticasone propionate (200 or 500 micrograms twice daily). Outcome measures were daily records of peak expiratory flow (PEF), symptom scores, and clinic lung function. RESULTS: The improvements in both the morning and evening PEF were better in the salmeterol than in the fluticasone propionate group, the mean increase in morning PEF being 19 l/min higher (95% CI 11.0 to 26.1) and in evening PEF being 16 l/min (95% CI 18.4 to 24.0) higher in the salmeterol group. The increase in forced expiratory volume in one second (FEV1) was 0.09 1 greater in the salmeterol group than in the fluticasone propionate group after four weeks of treatment (95% CI 0.01 to 0.18), but not after 12 weeks. Both regimens showed an increase in symptom free days and a reduction in the need for rescue salbutamol both during the day and the night, but these improvements were greater in the salmeterol group. There were no significant differences between the groups in adverse effects or in the number of rescue course of oral corticosteroids. CONCLUSIONS: In this group of patients still symptomatic despite 100 or 250 micrograms fluticasone propionate twice daily, the addition of salmetterol caused a greater improvement in lung function and symptom control than doubling the dose of fluticasone propionate.     

Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour specimens.

BACKGROUND--Inhaled glucocorticoid therapy has systemic effects including hypothalamic-pituitary-adrenal (HPA) suppression. The optimal test for detecting these effects has not been defined. METHODS--Timed urine collections and 09.00 hour plasma cortisol levels were obtained from 12 normal volunteers receiving inhaled placebo, beclomethasone (BDP) 800 or 2000 micrograms/day. The 24 hour urine samples were collected as follows: first hour after waking (hour 1), the next two hours after waking (hours 2 and 3), remainder of day, and overnight, with results expressed as urine cortisol/creatinine (UCC) ratios and as hourly cortisol output in the timed collections. Twenty four hour urinary cortisol excretion was also calculated. Medication was blinded and given in random order with a washout period of at least 11 days between each treatment arm. RESULTS--None of the UCC ratios changed with BDP 800 micrograms/day. UCC ratios at hour 1, hour 2 and 3, and overnight, and 24 hour urinary free cortisol excretion were reduced after BDP 2000 micrograms/day, whilst remainder of day UCC ratio and the plasma cortisol level did not change significantly. Cortisol output showed similar changes. In a follow up study BDP 1400 micrograms/day also reduced UCC ratios for the first two hours after waking. CONCLUSIONS--UCC ratios are as sensitive as the more cumbersome 24 hour urinary free cortisol excretion, and more sensitive than single morning plasma cortisol measurements, in detecting the effects of inhaled beclomethasone on the HPA axis.     

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.     

Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects

BACKGROUND: All currently available inhaled corticosteroids reach the systemic circulation and have the potential to produce adverse effects with long term use. This risk is often assessed by measuring the effect of different inhaled corticosteroids on the hypothalamic-pituitary-adrenal (HPA) axis in healthy subjects. Absorption of fluticasone propionate and its effects on the HPA axis are greater in healthy subjects than in subjects with moderately severe asthma, but we have failed to show any difference in morning budesonide plasma levels or systemic effects between healthy and asthmatic subjects following inhalation of budesonide. To provide more information on the absorption of fluticasone propionate and budesonide, we have compared the plasma levels of both drugs over 8 hours in healthy and asthmatic subjects. METHODS: The area under the plasma concentration-time curves (AUC) and the maximum concentration (Cmax) of fluticasone propionate and budesonide after a single inhaled dose of each drug were compared in 12 healthy control subjects and 12 subjects with moderately severe asthma. RESULTS: Peak plasma levels of budesonide occurred much earlier and were approximately 20-fold higher than those of fluticasone propionate in both healthy and asthmatic subjects. The AUC and Cmax for fluticasone propionate were lower by 307 (95% CI 62 to 522) pg/ml/h or 43% (p=0.02) and 52 (95% CI -11 to 115) pg/ml or 39% (p=0.1) in subjects with asthma compared with healthy control subjects. In contrast, the AUC and Cmax for budesonide were almost identical between the two groups (mean differences 826 (95% CI -1493 to 3143) pg/ml/h (p=0.5) and 157 (95% CI -1026 to 1339) pg/ml (p=0.8). CONCLUSIONS: Following inhalation, healthy subjects have higher plasma levels of fluticasone propionate than subjects with asthma whereas budesonide plasma levels are similar in the two groups of subjects. Comparing the systemic effects of budesonide and fluticasone propionate in healthy subjects is unlikely to be relevant to subjects with asthma.     

Airway and systemic effects of hydrofluoroalkane fluticasone and beclomethasone in patients with asthma

BACKGROUND: With the transition to hydrofluoroalkane-134a propellants in metered dose inhalers, it is important to consider the efficacy and safety profiles of formulations containing inhaled corticosteroids. We examined the airway and systemic effects of hydrofluoroalkane-134a fluticasone propionate (FLU-HFA) and beclomethasone dipropionate (BEC-HFA) at recommended labelled doses. METHODS: Twenty mild to moderate asthmatics were randomised in crossover fashion to receive 6 weeks of 500 micro g/day followed by 1000 micro g/day FLU-HFA and BEC-HFA. Measurements were made at baseline after placebo run in and washout, and after each randomised treatment. The primary airway outcome for benefit was the dose of methacholine provoking a fall in forced expiratory volume in 1 second (FEV(1)) of 20% or more (methacholine PD(20)) and for systemic adverse effects was overnight urinary cortisol/creatinine (OUCC). RESULTS: For mean responses, both doses of BEC-HFA and FLU-HFA produced significant improvements in PD(20) compared with baseline. The improvement was not significantly greater with 1000 micro g/day FLU-HFA versus BEC-HFA, a 1.69 fold difference (95% CI 0.94 to 3.04). Both doses of BEC-HFA but not FLU-HFA caused significant suppression of OUCC compared with baseline, with significantly (p<0.05) lower values at 1000 micro g/day for BEC-HFA versus FLU-HFA (1.97 fold difference (95% CI 1.28 to 3.02)). CONCLUSION: There was no difference in the airway and systemic effects in patients with mild to moderate asthma between FLU-HFA and BEC-HFA at a dose of 500 micro g/day. At 1000 micro g/day there was increased systemic bioactivity with BEC-HFA compared with FLU-HFA, without any gain in airway efficacy.     

Systemic effects of high dose inhaled steroids: comparison of beclomethasone dipropionate and budesonide in healthy subjects.

ACKGROUND--Systemic absorption of inhaled corticosteroids may adversely influence the function of the hypothalamo-pituitary-adrenal axis, bone metabolism, and circulating leucocytes. These changes can be used to assess the safety of different types and modes of administration of these drugs. METHODS--The study was a randomised, double dummy, crossover design with nine healthy adults. It compared the effects of beclomethasone dipropionate and budesonide (given by metered dose aerosols with and without their respective large volume spacers (Volumatic and Nebuhaler) attached) on serum cortisol, 24 hour urinary free cortisol, and plasma osteocalcin concentrations, and circulating neutrophils and lymphocytes. Subjects inhaled the drug (1 mg) and matching placebo at 0900 and 2200 hours on each of six study days. Blood samples were taken hourly for six hours after the morning dose and at the end of the study period. RESULTS--All results were within the reference ranges. Both drugs caused similar reductions in serum cortisol four to six hours after inhalation. These changes were not affected by the use of a large spacer and did not persist at 24 hours. Use of spacers tended to increase the haematological effects of the steroids. Beclomethasone dipropionate inhaled through a Volumatic provoked a rise in circulating neutrophils compared with placebo although lymphocyte numbers were unaffected. Budesonide did not influence neutrophil numbers but did reduce circulating lymphocytes, numbers of which were further reduced when the Nebuhaler was used. There were no significant changes in plasma osteocalcin concentration or 24 hour urinary free cortisol excretion with budesonide, with or without a spacer. Beclomethasone dipropionate inhaled without a spacer reduced urinary cortisol and plasma osteocalcin at 24 hours; however, use of the Volumatic protected against these effects. CONCLUSIONS--Attaching a Volumatic reduces the systemic effects of 2 mg aerosol beclomethasone dipropionate on the hypothalamo-pituitary-adrenal axis and circulating osteocalcin concentrations. This study did not establish whether the Nebuhaler reduces the systemic effects of budesonide. When large spacers are used, 2 mg per day of beclomethasone dipropionate and budesonide seem to be equivalent in terms of unwanted effects.     

Comparisons of two intranasal corticosteroid preparations in treating allergic rhinitis.

OBJECTIVES: Intranasal corticosteroid preparations can relieve symptoms of allergic rhinitis. Different aqueous corticosteroid forms have been developed for intranasal use. The objectives of this study were to compare efficacy and safety between fluticasone propionate and budesonide in the treatment for patients with allergic rhinitis. METHODS: The study was conducted in a prospective and randomized manner; a total of 24 adult patients were enrolled. All patients received MAST allergen test at entry and again at 2 months after treatments. Fourteen patients received fluticasone propionate 200 microg once daily, and 10 patients received budesonide 200 microg twice daily. To investigate the efficacy of fluticasone propionate and budesonide, a subjective scoring system was designed to evaluate the symptom improvement of patients. Adverse events were recorded on a diary card then were analyzed. Mann-Whitney U test and Kruskal-Wallis 1-way analysis of variance were used for statistical analysis. RESULTS: Analysis on patient-based symptom scores revealed that both fluticasone propionate and budesonide were equally efficacious in improving the symptoms of nasal blockage, sneezing, nasal itching, and watery rhinorrhea. There were no significant side effects reported for both groups during this follow-up period. However, analysis showed that the fluticasone propionate group demonstrated significantly greater improvement in some MAST allergen tests (Candida, mite, house dust; P < 0.05). CONCLUSION: Clinically, fluticasone propionate 200 microg once daily was efficacious as budesonide 200 microg twice daily in the relief of allergic rhinitis symptoms. However, fluticasone propionate can achieve greater immunologic improvement. Both preparations showed no evidence of short-term side effects.     

Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist

BACKGROUND: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. METHODS: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis. RESULTS: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction. CONCLUSIONS: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.


     

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.     

One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density

BACKGROUND: Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma. However, concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation. This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density (BMD) over one year. METHODS: A one year randomised, prospective, open parallel study comparing inhaled fluticasone propionate (FP), 500 micrograms twice daily in 30 patients, and budesonide (BUD), 800 micrograms twice daily in 29 patients, delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma. Biochemical markers of bone turnover (osteocalcin, procollagen type 1 C-terminal propeptide (PICP), immunoreactive free deoxypyridinoline (iFDpd), N-terminal crosslinked telopeptides of type I collagen (NTx)), BMD at the spine and femoral neck, and serum cortisol concentrations were measured at baseline and 12 months later. RESULTS: There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density. Bone mineral density of the spine increased slightly in both groups over the 12 month period. Serum osteocalcin levels increased from baseline in both treatment groups (FP 16.9%, p = 0.02; BUD 14.3%, p = 0.04). PICP did not differ significantly from baseline. Both markers of bone resorption (iFDpd, NTx) varied considerably with no significant changes after one year. There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months (r = 0.4, p = 0.017). Mean serum cortisol levels remained within the normal range in both groups following treatment. CONCLUSION: There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD. The change in spine BMD correlated with the increase in osteocalcin. Studies extending over several years are needed to establish whether these findings persist.     

Time course of action of two inhaled corticosteroids, fluticasone propionate and budesonide

BACKGROUND: It is important to be able to compare the efficacy and systemic effects of inhaled corticosteroids but their slow onset of action makes it difficult to measure the maximum response to a given dose. Submaximal responses could be compared if the time course of action of the inhaled corticosteroids being compared was similar. We have compared the time course of action of fluticasone and budesonide, measuring response as change in the provocative dose of adenosine monophosphate causing a 20% fall in forced expiratory volume in 1 second (PD20AMP). METHODS: Eighteen subjects with mild asthma, aged 18-65, took part in a three way randomised crossover study. Subjects took fluticasone (1500 microg/day), budesonide (1600 microg/day), and placebo each for 4 weeks with a washout period of at least 2 weeks between treatments; PD20AMP and forced expiratory volume in 1 second (FEV1) were measured during and after treatment. The time taken to achieve 50% of the maximum response (T50%) was compared as a measure of onset of action. RESULTS: There was a progressive increase in PD20AMP during the 4 weeks of treatment with both fluticasone and budesonide but not placebo; the increase after 1 and 4 weeks was 2.28 and 4.50 doubling doses (DD) for fluticasone and 2.49 and 3.65 DD for budesonide. T50% was 9.3 days for fluticasone and 7.5 days for budesonide with a median difference between fluticasone and budesonide of 0.1 days (95% CI -1.4 to 2.65). There was a wide range of response to both inhaled corticosteroids but good correlation between the response to fluticasone and budesonide within subjects. FEV1 and morning peak expiratory flow rate (PEFR) increased during the first week of both active treatments and were stable thereafter. There was a small progressive improvement in nocturnal symptoms with both active treatments. CONCLUSION: PD20AMP was a more sensitive marker of response to inhaled corticosteroid therapy than FEV1 and PEFR. The time course of action of fluticasone and budesonide on PD20AMP is similar, suggesting that comparative studies of their efficacy using 1 or 2 week treatment periods are valid. When a new inhaled corticosteroid becomes available, a pilot study comparing its time course of action with that of an established corticosteroid should allow comparative studies to be performed more efficiently.     

Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease

BACKGROUND: Combined treatment with inhaled corticosteroids and long acting beta2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. METHODS: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. RESULTS: PEF was significantly higher after 1 day in patients treated with salmeterol 50 microg twice daily or the salmeterol/fluticasone propionate combination 50/500 microg twice daily than placebo. In patients treated with fluticasone propionate 500 microg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long term response in individual patients. CONCLUSIONS: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.     

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.