Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal–axis activity

doi:10.1016/S0091-6749(98)70354-9

Journal of Allergy and Clinical Immunology

Volume 101, Issue 4, April 1998, Pages 470-474

https://doi.org/10.1016/S0091-6749(98)70354-9 Get rights and content

Abstract

Background: Intranasal corticosteroids are regarded as the first-line treatment for allergic rhinitis, but few studies have directly compared their systemic effects. Objective: We sought to compare the hypothalamic-pituitary-adrenal (HPA)–axis suppression with three intranasal corticosteroids in terms of basal and dynamic adrenocortical activity. Methods: Sixteen healthy volunteers (mean age, 30.7 years) were studied in a single-blind, randomized, four-way crossover study comparing placebo with 200 μg/day fluticasone propionate (FP), 220 μg/day triamcinolone acetonide (TAA), and 336 μg/day beclomethasone dipropionate (BDP). After 4 days of treatment, an overnight urine collection was taken for cortisol and creatinine excretion starting at 10 pm (14 hours after the fourth dose), and blood was taken for serum cortisol at 8 am (24 hours after the fourth dose) and after stimulation with adrenocorticotrophic hormone (ACTH) (0.5 μg). Results: For overnight urinary cortisol excretion compared with placebo (20.8 nmol), there was a significant (p < 0.05) degree of suppression with FP (11.8 nmol) but not with TAA (16.0 nmol) or BDP (16.5 nmol). In terms of fold difference (95% CI for difference) from placebo, this amounted to 1.75-fold (1.01 to 3.03) for FP (43% suppression), 1.30-fold (0.75 to 2.25) for TAA (23% suppression), and 1.26-fold (0.73 to 2.18) for BDP (21% suppression). There was also a trend towards suppression of overnight urinary cortisol/creatinine excretion, but this was not statistically significant (placebo, 5.2 nmol/mmol; TAA, 5.0 nmol/mmol; BDP, 4.3 nmol/mmol; and FP, 4.3 nmol/mmol). Values for serum cortisol before and after ACTH stimulation showed no significant suppression. Conclusion: Suppression of overnight urinary cortisol occurred with intranasal FP (43%), TAA (23%), and BDP (21%), although this was only statistically significant with FP. None of the drugs were associated with blunting of the response to ACTH stimulation. Further studies are indicated to establish whether the systemic effects of inhaled and intranasal corticosteroids are additive.

Section snippets

Patients

Sixteen healthy, nonallergic volunteers (nine women and seven men; mean age [SEM], 30.7 [2.7] years) completed the study. All subjects had normal full blood counts and biochemical profiles (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 an atopic history or a positive skin prick test response. Any volunteer with a

RESULTS

There was no significant carryover effect between the nonrandomized placebo and the randomized placebo, respectively, with any of the parameters measured (as geometric means ± SEM) (overnight urinary cortisol, 17.1 ± 2.3 vs 20.8 ± 2.8 nmol; pre-ACTH serum cortisol, 547.5 ± 23.2 vs 574.0 ± 24.3 nmol/L; or post-ACTH, 781.2 ± 32.6 vs 761.0 ± 31.7 nmol/L). The randomized placebo was used for all comparisons with the three active treatments.

DISCUSSION

Suppression of overnight urinary cortisol occurred with FP (43%), TAA (23%), and BDP (21%), although this was only statistically significant for FP. The presence of detectable adrenal suppression does not necessarily imply that the observed effects are clinically relevant, although it is evident from the scatter plot that individuals differ in their susceptibility to the systemic adverse effects of intranasal corticosteroids. It is important to point out that this degree of suppression would

Acknowledgements

We thank Rhone-Poulenc Rorer Inc. (USA) for supplying the nasal sprays.

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Quantification of fluticasone propionate in human plasma by LC–MS/MS and its application in the pharmacokinetic study of nasal spray at clinical doses
2024, Drug Metabolism and Pharmacokinetics
We developed a method for quantifying fluticasone propionate (FP) using general-purpose liquid chromatography–tandem mass spectrometry equipment to measure the plasma concentration of FP for the pharmacokinetic study of FP following the administration of a prescribed nasal spray dose (100 μg). Using ammonium acetate (0.01 M)–formic acid (pH 2.9; 499:1, v/v) and methanol as the mobile phase, 3 pg/mL of FP was quantified. The relative error and standard deviation of the lower limit of quantification were <3.1%. The intra- and interday assay reproducibility was <3.5%. After 15 min of administering 200 μg FP nasal spray as the first dose, the FP concentration detected in the plasma of the two participants was 3.99 and 3.69 pg/mL. Subsequent doses of 100 μg FP were administered twice daily. The area under the plasma concentration–time curve values after 8–10 days of repeated administration of 100 μg of FP were approximately 1.6-fold higher than those achieved following a single administration of 200 μg of FP, which confirmed drug accumulation. The bioavailability of nasal FP was estimated to be 2% and 4%. This knowledge might help in reducing anxiety among patients who avoid using FP nasal spray, fearing its adverse effects.
Safety of intranasal corticosteroids
2016, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
However, an effect of fluticasone propionate on the HPA axis has been found in 2 studies. In a 4-way crossover study of fluticasone propionate, beclomethasone propionate, and triamcinolone acetonide in 16 healthy adult volunteers, fluticasone propionate (200 μg/d) but not beclomethasone propionate (336 μg/d) or triamcinolone acetonide (220 μg/d) demonstrated statistically significant suppression of overnight UFC excretion.11 There was no effect of any of the 3 INCSs on serum cortisol before and after adrenocorticotropic hormone stimulation.
Concurrent use of intranasal corticosteroids (INCSs) and inhaled corticosteroids (ICSs) is indicated for patients who are comorbid for asthma and allergic rhinitis. Clinicians need to know the data regarding INCS safety for their patients with asthma.
To discuss INCS safety data for the use of INCSs in patients with asthma and allergic rhinitis.
INCS safety studies were selected for their relevance to the discussion.
To date, most studies regarding INCS safety are performed in patients with allergic rhinitis. These studies reveal no evidence of increased risk of nasal atrophy, and only isolated cases of septal perforation have been reported. Evidence of hypothalamic-pituitary-adrenal axis suppression is inconsistent and not clinically significant. Early growth studies indicated that beclomethasone dipropionate but not other INCSs have systemic effects on growth; however, newer, larger, and better designed studies are detecting small but significant growth effects in other INCSs. INCSs do not increase the risk of cataracts or glaucoma, although there are anecdotal data on transient elevated intraocular pressure. Data on concurrent use of INCSs and ICSs are limited, but these limited data reveal no evidence of systemic effects on the hypothalamic-pituitary-adrenal axis.
More studies of concurrent therapy are needed because concurrent use of ICSs and INCSs is common in practice. Clinicians might want to consider monitoring whether there are risk factors, such as a family history of glaucoma.
Rhinitis in the Elderly
2016, Immunology and Allergy Clinics of North America
Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function
2014, Journal of Pharmaceutical Sciences
In part I of this review, an overview of the designs of hypothalamic–pituitary–adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963–2979, 2014
Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on Hypothalamic-Pituitary-Adrenal Axis Function, Part I: General overview of HPA Axis study design
2013, Journal of Pharmaceutical Sciences
Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (< 6 weeks) for adult trials and blinded, placebo controlled, and long term (≥ 6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained.
Burden of allergic rhinitis: Results from the Pediatric Allergies in America survey
2009, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Of particular note are reports of cortisol suppression and growth slowing during treatment with some INCSs.13-15 Cortisol suppression might be problematic in children because of the absence of weight-based dosing of INCSs to effectively relieve symptoms.13,15,16 Currently available INCSs and other prescription nasal sprays appear to also vary in speed of relief and duration of action and might not provide complete or long-lasting relief of nasal allergy symptoms.63
Allergic rhinitis (AR), a chronic inflammatory disease of the upper airway, is one of the most common chronic diseases in the United States and is estimated to affect up to 60 million people. Pediatric Allergies in America is the largest and most comprehensive survey to date of pediatric patients and parents of patients with allergy, as well as health care providers (HCPs), regarding AR in children and its treatment. The goals of the survey were to determine the prevalence of AR in the US pediatric population and to collect information on what effect the condition has on patients in terms of symptom burden, quality of life, productivity, disease management, and pharmacologic treatment. This national survey screened 35,757 households to identify 500 children with HCP-diagnosed nasal allergies and 504 children without nasal allergies who were between the ages of 4 and 17 years. Parents of young children, as well as children 10 to 17 years of age, were questioned about the condition and its treatment. In parallel, 501 HCPs were interviewed. This survey has captured previously unavailable data on the prevalence of nasal allergies and their most common and most bothersome symptoms, on the effect of nasal allergies on the quality of life of children, and on medication use, including both over-the-counter and prescription medications, and has identified factors affecting satisfaction with treatment. The Pediatric Allergies in America survey also identifies distinct areas for improvement in the management of AR in children. In fact, based on the results of this survey, it appears that HCPs overestimate patients' and parents' satisfaction with disease management and the benefit of medications used for the treatment of nasal allergies in children. Findings from this national survey have identified important challenges to the management of AR, suggesting that its burden on children in the United States has been significantly underestimated.

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^☆: From the Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee.

^☆☆: Supported by Rhone-Poulenc Rorer, Inc.

^★: Reprint requests: Brian J. Lipworth, MD, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.

^★★: 1/1/88664

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Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal–axis activity☆,☆☆,★,★★

Abstract

Section snippets

Patients

RESULTS

DISCUSSION

Acknowledgements

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Ther

J Allergy Clin Immunol

Steroids

Respir Med

Glucocorticosteroids and rhinitis

Allergy

Dose tolerance study of fluticasone propionate aqueous nasal spray in patients with seasonal allergic rhinitis

Ann Allergy

Measures for detecting systemic bioactivity with inhaled and intra-nasal corticosteroids

Thorax

Deposition pattern from a nasal pump spray

Rhinology

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

Thorax