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The recent article by Harrison and colleagues has limitations which were not adequately addressed.1 It was perhaps hardly surprising to find no differences in plasma budesonide concentrations between normal and asthmatic subjects due to the higher levels and a relatively insensitive assay compared with fluticasone.
The respective dry powder inhaler devices for each drug differ markedly in their fine particle dose delivery which will determine peripheral lung deposition and, in turn, systemic absorption. The fine particle dose expressed as a percentage of the nominal dose for fluticasone Accuhaler (Diskus) is 12% compared with 40% for budesonide Turbuhaler.2 Moreover, there is a much higher proportion of coarse particles from the Accuhaler than from the Turbuhaler.3 The study was therefore biased towards showing greater attenuation of peripheral lung absorption with fluticasone Accuhaler in asthmatic subjects.
The authors state that they are unaware of any previous direct comparisons of the effects of fluticasone and budesonide on osteocalcin concentrations. In adult asthmatic subjects steady state dosing for 12 days showed greater percentage suppression with fluticasone than with budesonide of 08.00 hour plasma cortisol levels compared with placebo (48% v 20%) which was mirrored by suppression of 08.00 hour serum osteocalcin levels (37%v 12%).4 This would not be consistent with the hypothesis of Harrison et althat fluticasone and budesonide may have differential effects on the HPA axis and bone metabolism.
Finally, it is worth noting that a meta-analysis of 21 studies evaluating dose related suppression of urinary cortisol levels showed a 4.3-fold (p<0.001) difference in slope when comparing fluticasone and budesonide.5
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authors' reply We thank Professor Lipworth for his interest in our paper. The main hypothesis being tested was a comparison of the total cortisol metabolite levels after 7 days of treatment with fluticasone propionate and budesonide between healthy and asthmatic subjects. Although we were interested in the plasma levels of the two drugs, limitations in the assays available prevented us from studying this in more detail. Brutsche et al 1-1 have, however, also shown markedly lower fluticasone plasma levels in subjects with asthma compared with healthy controls, and we now have data confirming that budesonide plasma levels are identical in healthy and asthmatic subjects.
We accept that part of the explanation for the difference between fluticasone and budesonide may have resulted from differences in the inhalers used. We used dry powder inhalers because we wanted to reduce the effects of inhaler technique and because dry powder inhalers had been used in a number of studies comparing fluticasone and budesonide in healthy subjects.1-2-1-4 It is also worth noting that Brutsche et al 1-1 studied metered dose inhalers with a large volume spacer and produced similar results to ours.
We are grateful to Professor Lipworth for bringing our attention to his letter reporting a study in subjects with mild asthma.1-5This appears to be the same as a later publication that we had referenced in which the osteocalcin data were omitted.1-6The reduction in osteocalcin concentrations with budesonide but not fluticasone at microgram equivalent doses was an unexpected finding and we did state that confirmation of this finding was required.
Finally, we have major reservations about the meta-analysis published by Lipworth, not only because it combined studies performed in healthy and asthmatic subjects but because it included a number of studies which did not compare fluticasone and budesonide, so it does not satisfy the methodology for a meta-analysis.1-7
The study by Harrison and colleagues2-1 suggests that inhaled fluticasone in a dose of 1500 μg/day can cause pituitary suppression as measured by urinary total cortisol metabolites (TCM) in healthy subjects compared with asthmatics, but that budesonide in a dose of 1600 μg/day does not. For fluticasone, the mean difference between healthy and asthmatic TCM after 7 days treatment with fluticasone was significant but the same comparison for budesonide was not. The confidence interval for the mean difference in TCM between the healthy and asthmatic subjects given budesonide was positive but with a p value of 0.2. Is this explained by the omission of a sign?
However, when change from baseline is examined in healthy subjects, both drugs suppress TCM and the difference between them was not significant. If equipotent dosages of 750 μg fluticasone/day and 1600 μg budesonide/day had been given, would the urinary TCM be significantly different for healthy subjects? This is of practical importance if inhaled corticosteroids are considered for treating patients who do not have asthma. Children with isolated persistent cough, which is not asthma,2-2 are often prescribed inhaled corticosteroids.2-3 Adrenal crises in patients believed to have asthma who have been prescribed inhaled steroids must be examined carefully.
This paper and others which have reported systemic effects of inhaled steroids in healthy subjects2-4-2-6 should caution against the indiscriminate use of these drugs in patients who do not have asthma.
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authors' reply We thank Dr McKenzie for her interest in our paper. The confidence interval for the mean difference in TCM between budesonide in healthy and asthmatic subjects should be –484 to 2904 as in the abstract.
We agree that the systemic effects of some inhaled corticosteroids may be greater in subjects without asthma than in those with asthma and airflow obstruction, and that caution is needed if inhaled corticosteroids are prescribed for such patients. Our study does not allow a comparison of 750 μg fluticasone propionate and 1600 μg budesonide in healthy subjects. Whether these doses given by their respective dry powder inhalers are truly equally effective in patients who do not have asthma is also unknown, however.