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Effects of Low and High Doses of Inhaled Flunisolide and Triamcinolone Acetonide on Basal and Dynamic Measures of Adrenocortical Activity in Healthy Volunteers

Department of Clinical Pharmacology and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY

Address all correspondence and requests for reprints to: Dr. B. J. Lipworth, Department of Clinical Pharmacology and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY.

	Abstract

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The objective of this study was to evaluate the effects of inhaled flunisolide (FN) and triamcinolone acetonide (TAA) on basal and dynamic adrenocortical activity. A randomized cross-over design was used, comparing placebo (PL), low (L) and high (H) doses of FN (Aerobid; 250 µg/actuation; without spacer; L, 1000 µg; H, 2000 µg/day), and TAA (Azmacort; 100 µg/actuation; with integrated actuator/spacer; L, 800 µg; H, 1600 µg/day). Each dose was given at 0800 and 2200 h for 3 days, and treatments were separated by a 10-day washout. Twelve normal volunteers (mean ± SE age, 24.2 ± 2.4 yr) were studied. After 3 days of treatment, blood samples were taken before ACTH stimulation at 0800 h (10 h after the sixth dose) and after ACTH (0.5 µg) stimulation for determination of serum cortisol. Overnight (starting at 2200 h on the third day of treatment) and early morning urine collections were taken for measurements of urinary cortisol corrected for creatinine excretion.

For serum cortisol (pre- and post-ACTH stimulation), there was no significant difference compared with placebo for either drug. Post-ACTH cortisol (nanomoles per L) values were: PL, 666.3; H FN, 617.0; H TAA, 591.4; L FN, 699.2; and L TAA, 686.0. For overnight corrected urinary cortisol/creatinine excretion (nanomoles per mmol) compared with PL (6.4), there was a significant suppression (P < 0.05) at the high dose of both drugs (H FN, 2.6; H TAA, 2.3) but not at the low dose (L FN, 4.2; L TAA, 4.5). Likewise, values for early morning corrected urinary cortisol/creatinine (nanomoles per mmol) showed significant suppression (P < 0.05) only with high doses of both drugs (PL, 39.0; H FN, 26.5; H TAA, 26.6; L FN, 37.2; L TAA, 36.5).

The following conclusions were reached. 1) Overnight and early morning corrected urinary cortisol/creatinine excretion was more sensitive at detecting adrenocortical suppression than basal 0800 h serum cortisol or response to 0.5 µg ACTH stimulation. 2) There were no significant differences between inhaled FN (without spacer) and TAA (with integrated actuator/spacer), which only produced detectable adrenocortical suppression at the highest recommended doses and was not associated with impaired adrenal reserve. 3) Even at the high dose, the suppression observed with both drugs is unlikely to be of clinical relevance.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
INHALED corticosteroids have gained widespread acceptance as first line antiinflammatory therapy for the treatment of asthma in both Europe and the USA. International guidelines suggest that corticosteroids should be introduced at an early stage in the management of asthma (1). It is well recognized, however, that all inhaled corticosteroids are associated with dose-related systemic adverse effects (2).

Adrenal suppression is recognized as a sensitive and reproducible marker of systemic bioactivity (3). Nevertheless, measuring adrenal suppression in terms of early morning serum cortisol concentration or urinary cortisol excretion only gives information about the basal adrenocortical activity. It is also pertinent to look at the effect of stress on adrenocortical activity, as this will indicate the degree of adrenal reserve. In this respect it is known that stimulation with low dose ACTH (0.5 µg) is more sensitive at detecting impaired adrenocortical reserve than the conventional high dose (250 µg) test in patients receiving long term inhaled corticosteroids (4). The 250-µg dose of ACTH (tetracosactrin) is considered to be supraphysiological, with the 0.5-µg dose being a much better reflection of a physiological stress response and correlating well with the insulin stress response (5). Unfortunately, the ACTH stimulation test is now contraindicated in the UK data sheet (Synacthen, Ciba Laboratories, Horsham, UK) in asthmatics because of occasional reports of hypersensitivity and fatal anaphylactic reaction. Hence, for ethical reasons, at least in the United Kingdom, studies using ACTH stimulation are limited to healthy volunteers.

Conventionally, 24-h urinary cortisol excretion has been used as a method of assessing integrated basal endogenous adrenocortical activity (6) and has been shown to be more sensitive than early morning serum cortisol in detecting suppression with inhaled corticosteroids (7). It has since been shown that fractionated overnight and early morning urinary cortisol measurements are equally sensitive as a 24-h urine collection (8) and are more sensitive than 0800 h plasma cortisol in detecting impaired basal adrenocortical activity in asthmatics receiving inhaled corticosteroids (9, 10, 11, 12).

Triamcinolone acetonide (TAA) and flunisolide (FN) are two frequently used inhaled corticosteroids in the treatment of asthma in the USA; both have similar profiles in terms of systemic potency and elimination half-life. It is, therefore, important to know how these steroids compare in their propensity to cause adrenal suppression in terms of both basal and dynamic activities. In particular, this is the first study to evaluate the effects of these inhaled corticosteroids on fractionated urinary cortisol and low dose ACTH stimulation.

	Subjects and Methods

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Subjects

Twelve healthy volunteers (three women and nine men; mean ± SD age, 24.2 ± 8.3 yr) completed the study. All subjects had normal full blood count and biochemical profile (including creatinine, urea, electrolytes, and liver function), normal urinalysis, and normal spirometry. In light of the case reports of anaphylaxis in atopic subjects after injection of Synacthen, all volunteers were screened for atopy. Any volunteer with grade 1 or greater (>3 mm) response to a skin test with house dust mite, grass, or tree pollen was excluded. No subject had previously been treated with inhaled or nasal corticosteroids, nor was any subject receiving regular medication. All gave written informed consent. Approval for the study was obtained from the Tayside medical ethics committee.

Study design

A single (investigator) blind placebo (PL)-controlled randomized cross-over design was used. Subjects were randomized to receive either TAA (100 µg/actuation; as Azmacort with integrated actuator/spacer; Rhone Poulenc Rorer Pharmaceuticals, Collegeville, PA) or FN (250 µg/actuation without spacer; as Aerobid metered dose inhaler; Forest Pharmaceuticals, St. Louis, MO). These drugs were used according to the manufacturer’s labeling.

Six patients received TAA first, and the other six received FN first in sequence. Each drug was given for 6 days (each dose for 3 days) in twice daily doses at 0800 and 2200 h. Subjects were requested to rinse their mouth with water after each dose. The dosing sequence was as follows, each given sequentially for 3 days: TAA, four puffs twice daily and eight puffs twice daily (i.e. total daily doses of 800 and 1600 µg, respectively); FN, two puffs twice daily and four puffs twice daily (i.e. total daily doses of 1000 and 2000 µg, respectively). Each puff was given at approximately 20-s intervals. The total daily dose of each drug was chosen to reflect the lowest (L) and the highest (H) recommended dose according to the manufacturers’ labeling. Prior to the first treatment sequence, each patient received a PL treatment sequence (two puffs twice daily for 3 days). The PL device used corresponded to the first treatment device (FN pMDI without spacer or Azmacort with integrated actuator/spacer). There was a 10-day washout between treatments. Laboratory evaluations were made after PL, after low and high doses of each drug, and after washout. Each inhaler was discharged twice before inhalation, and each inhalation was followed by mouth rinsing.

The inhalers were masked and sealed in envelopes by a pharmacist along with instruction sheets at the beginning of the trial to make it investigator blind. Before the study and at each visit, subjects were given detailed tuition by a third party observer on how to use their inhaler according to the manufacturer’s package insert instructions along with the use of a Vitalograph aerosol inhalation monitor device to check on coordination (Vitalograph, Maids Moreton, UK). Each subject received a written instruction sheet to follow while using their inhaler at home, and a simple tick chart was used as an aide to compliance.

Measurements

The subjects reported to laboratory at 0730 h (i.e. 9.5 h after taking the sixth dose of each study drug at 2200 h). A cannula was inserted into the antecubital fossa vein, and subjects then rested supine for 30 min. After the rest period, blood samples were taken for measurement of serum cortisol at exactly 0800 h. ACTH (Synacthen, Ciba Laboratories) was diluted to 0.5 µg/mL by injecting the 250-µg vial into a 500-mL bag of 0.9% saline solution. After mixing, 1-mL aliquots were withdrawn from the bag and used for injection. Subjects received the injection immediately after the 0800 h serum sample, and additional serum samples were taken after 20 and 30 min to evaluate the peak cortisol response.

Subjects emptied their bladder soon after taking the evening dose of study drug and collected all voided urine from 2200 h (the time of the sixth dose) until 0700 h the following morning. Patients also voided another early morning sample of urine at 0830 h. The volumes of the overnight urine specimen and the early morning urine specimen were measured. Aliquots were kept for assay of cortisol and creatinine levels. Both the overnight and early morning urinary cortisol levels were corrected for creatinine excretion and expressed as a corrected ratio.

Assays

Serum and urinary cortisol were measured using a commercial RIA kit with no cross-reactivity for either steroid (Immunodiagnostic Systems, Boldon, Tyne and Wear, UK). The within-assay coefficient of variation for analytical imprecision for serum was 8.1%, and the between-assay coefficient of variation was 6.6%; for urinary free cortisol excretion, the within-assay coefficient of variation was 10%, and the between-assay coefficient of variation was 5.7%. Urinary creatinine was measured on a Cobas-Bio autoanalyzer (Roche Products, Welwyn Garden City, UK). The intraassay coefficient of variation was 1.76%, and the interassay coefficient of variation was 2.93%. The lower limits for a normal 0800 h and ACTH-stimulated serum cortisol in our laboratory are 150 nmol/(5.4 µg/dL) and 500 nmol/L (18 µg/dL), respectively.

Statistical analysis

The study was designed with a sample size of 12, with 80% power (ß error = 0.2) to detect a 20% difference in overnight urinary cortisol (the primary end point), with the error set at 0.05 (two-tailed test). The peak response to ACTH stimulation was taken as the highest of the samples taken after 20 and 30 min. All data were analyzed using a Statgraphics software package (STSC Software Group, Rockville, MD). An overall analysis of variance, with subject, treatment, dose, and period effects was performed. In addition, a comparison was made to assess any carryover effect between the two treatment periods by comparing values for PL and washout in order of sequence. Bonferroni’s multiple range testing was then applied to assess whether there were significant differences between each dose of each treatment and PL to obviate multiple parameter comparisons. Bonferroni’s range test was set with 95% confidence limits; hence, any significant differences are only reported at the P < 0.05 level. The number of individual values for overnight urinary cortisol levels below 10 nmol (3.6 µg) and early morning urinary cortisol levels below 20 nmol (7.2 µg), 0800 h serum cortisol levels below 150 nmol/L (5.4 µg/dL), and serum cortisol response to ACTH below 500 nmol/L (18 µg/dL) were also analyzed using the ² test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
There were no significant carryover effects between PL and washout values in sequence for any of the parameters measured: pre-ACTH serum cortisol, 481.8 vs. 513.7 nmol/L; post-ACTH serum cortisol, 666.3 vs. 668.9 nmol/L; overnight corrected urinary cortisol/creatinine ratio, 6.4 vs. 5.7 nmol/mmol; and early morning corrected urinary cortisol/creatinine ratio, 39.0 vs. 39.5 nmol/mmol. Mean values (after PL or washout) before starting treatment with either FN or TAA, respectively, were also not significantly different (FN vs. TAA): pre-ACTH serum cortisol, 502.0 vs. 493.6 nmol/L; post-ACTH serum cortisol, 676.2 vs. 659.0 nmol/L; overnight corrected urinary cortisol/creatinine ratio, 6.3 vs. 5.8 nmol/mmol; or early morning corrected urinary cortisol/creatinine ratio, 40.9 vs. 36.0 nmol/mmol.

Pre-ACTH 0800 h serum cortisol

There were no significant differences between PL (481.8 nmol/L) and any of the other treatments: L TAA, 519.9 nmol/L; L FN, 545.8 nmol/L; H TAA, 388.7 nmol/L; and H FN, 481.4 nmol/L (Fig. 1). There was one subject who had a value less than 150 nmol/L (5.4 µg/dL, with L FN).

View larger version (30K): [in this window] [in a new window]   Figure 1. Means with SE for PL, L TAA (800 µg/day; TAA-L), H TAA (1600 µg/day; TAA-H), L FN (1000 µg/day; FN-L), and H FN (2000 µg/day; FN-H) for pre- and post-ACTH stimulation serum cortisol. Neither drug had any significant effect either pre- or poststimulation.

There was no significant difference between PL (666.3 nmol/L) and any of the other treatments: L TAA, 686.0 nmol/L; L FN, 699.2 nmol/L; H TAA, 591.4 nmol/L; and H FN, 617.0 nmol/L (Fig. 1). When analyzing the number of individual values less than 500 nmol/L (18 µg/dL) for both dose levels, there was no significant difference between the drugs (3 out of 24 for TAA vs. 2 out of 24 for FN). None of the poststimulated cortisol levels were below 400 nmol/L (14.4 µg/dL).

Overnight corrected urinary cortisol/creatinine excretion

Compared with PL (6.4 nmol/mmol), there was significant suppression (P < 0.05) for H TAA (2.3 nmol/mmol) and H FN (2.6 nmol/mmol), but not for L TAA (4.5 nmol/mmol) or L FN (4.2 nmol/mmol; Fig. 2). There was no significant difference between the two drugs. When analyzing individual values for both dose levels for overnight urinary cortisol levels less than 10 nmol (3.6 µg), there were no differences between the two drugs (13 out of 24 for TAA vs. 11 out of 24 for FN).

View larger version (24K): [in this window] [in a new window]   Figure 2. Means with SE for PL, L TAA (800 µg/day; TAA-L), H TAA (1600 µg/day; TAA-H), L FN (1000 µg/day; FN-L), and H FN (2000 µg/day; FN-H) for overnight (a) and early morning (b) corrected urinary cortisol/creatinine excretion. The asterisk denotes a significant (P < 0.05) difference for either steroid from PL.

Compared with PL (39.0 nmol/mmol), there was significant suppression (P < 0.05) with the high dose of both drugs (H TAA, 26.6 nmol/mmol; H FN, 26.5 nmol/mmol), but no significant suppression with the low doses (L TAA, 36.5 nmol/mmol; L FN, 37.2 nmol/mmol; Fig. 2). When analyzing values less than 20 nmol (7.2 µg) for both dose levels for early morning urinary cortisol, there was no difference between the drugs (6 out of 24 for TAA vs. 6 out of 24 for FN).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our results showed that only the highest recommended doses of both drugs (TAA, 1600 µg/day; FN, 2000 µg/day) produced suppression of basal adrenocortical activity, as measured by corrected urinary cortisol/creatinine excretion, although these effects were not associated with any blunting of the cortisol response to ACTH stimulation. This suggests that the degree of suppression was not clinically relevant in terms of impaired adrenocortical reserve. Thus, it is unlikely that patients would have an acute adrenal crisis if they happened to stop their inhaled steroids abruptly or were exposed to intercurrent stress such as surgery, although we found that certain individuals were particularly susceptible to adrenocortical suppression. We found that fractionated overnight and early morning urinary cortisol excretion corrected for creatinine were more sensitive than either a spot 0800 h serum cortisol sample or the cortisol response to low dose ACTH stimulation. The observed effects on adrenocortical parameters are, however, a marker of potential systemic bioactivity with a given inhaled corticosteroid, although this may not necessarily imply effects on other tissues, such as bone (3).

It was perhaps surprising that we were able to detect any adrenocortical suppression even at the highest dose, as both FN and TAA exhibit a low degree of systemic potency and possess a similar glucocorticoid receptor affinity and elimination half-life (13, 14, 15). In this respect, fluticasone propionate exhibits a higher degree of systemic potency due to a longer glucocorticoid receptor residency time and a more prolonged elimination half-life (16, 17). For example, in a recent dose range study, fluticasone propionate (1540 µg/day) exhibited 2-fold greater suppression of urinary cortisol/creatinine excretion than TAA (1600 µg/day) (12). Furthermore, fluticasone propionate caused dose-related sup-pression of 0800 h serum cortisol, whereas TAA did not. Similar differences in systemic potency have been found between fluticasone propionate and budesonide (10).

It is also worth considering the dosage and delivery for both drugs. We decided to use the lowest and highest recommended labeled doses for both TAA (with integrated actuator/spacer) and FN (without spacer). It is conceivable that the respirable fraction for TAA will be higher than that for FN, as the metered dose inhaler device for the former also has an integrated spacer, which would improve lung delivery of respirable particles. In this respect, it is known that the lung bioavailability from the respirable dose is the main determinant of overall systemic absorption (18).

After 3 days of treatment with twice daily administration, there was no blunting of the cortisol response to ACTH stimulation. However, with more prolonged treatment it is possible that blunting of the cortisol response to ACTH stimulation may occur as a consequence of adrenocortical atrophy. We have recently shown that after 3 days of inhaled budesonide (1000 µg twice daily), there is evidence of attenuated cortisol and ACTH responses to stimulation with a 100-µg bolus of CRH (19).

We chose to use the low dose (0.5 µg) of ACTH in the present study, as this is known to be a better reflection of the physiological stress response than the high (250 µg) dose of ACTH. Indeed, in a cross-sectional study of asthmatic adults and children receiving long term inhaled beclomethasone dipropionate (median daily dose, 482 µg) or budesonide (median daily dose, 507 µg), over 24% of the cases exhibited an insufficient cortisol response to 0.5 µg ACTH, but showed a normal cortisol response to 250 µg ACTH (4).

In our study we used fractionated overnight and early morning collections for urinary cortisol corrected for creatinine excretion, as these have been shown to be as sensitive as a full 24-h uncorrected urinary cortisol collection (8). Indeed, we have previously shown that the use of overnight urinary cortisol corrected for creatinine was a highly sensitive parameter for detecting adrenal suppression (9, 10, 11, 12). When looking at overnight and early morning corrected urinary cortisol/creatinine excretion, our results are also in keeping with those of McIntyre et al. (8), who showed that this collection is more sensitive than early morning serum cortisol. They also showed that high dose (2000 µg/day), but not low dose (800 µg/day), inhaled beclomethasone dipropionate produced significant suppression of both overnight and early morning corrected urinary cortisol/creatinine, as was the case in our study with low and high dose TAA and FN. Thus, for everyday routine clinical out-patient assessment, compliance is likely to be worse with a 24-h urine collection than with an overnight or early morning urine collection. Further population-based studies appear to be indicated to investigate this issue.

Received September 2, 1997.

Revised November 13, 1997.

Accepted November 21, 1997.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wilson, A. M. Articles by Lipworth, B. J. Search for Related Content PubMed PubMed Citation Articles by Wilson, A. M. Articles by Lipworth, B. J.