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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.

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.

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