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Figure.
Blood cortisol levels before and after budesonide respule therapy. Error bars indicate 95% confidence intervals. To convert cortisol to nanomoles per liter, multiply by 27.588.

Blood cortisol levels before and after budesonide respule therapy. Error bars indicate 95% confidence intervals. To convert cortisol to nanomoles per liter, multiply by 27.588.

Table 1. 
Description of Patient Population
Description of Patient Population
Table 2. 
Poststimulation Cortisol Levelsa
Poststimulation Cortisol Levelsa
Table 3. 
Distribution of Secondary Outcome Measures
Distribution of Secondary Outcome Measures
1.
Lethbridge-Cejku  MSchiller  JSBernadel  L Summary health statistics for US adults: National Health Interview Survey, 2002. Vital Health Stat 10 2004; (222) 1- 151
PubMed
2.
Murphy  MPFishman  PShort  SOSullivan  SDYueh  BWeymuller  EA  Jr Health care utilization and cost among adults with chronic rhinosinusitis enrolled in a health maintenance organization. Otolaryngol Head Neck Surg 2002;127 (5) 367- 376
PubMedArticle
3.
Lund  VJBlack  JHSzabo  LZSchrewelius  CAkerlund  A Efficacy and tolerability of budesonide aqueous nasal spray in chronic rhinosinusitis patients. Rhinology 2004;42 (2) 57- 62
PubMed
4.
Fokkens  WJCserhati  Edos Santos  JM  et al.  Budesonide aqueous nasal spray is an effective treatment in children with perennial allergic rhinitis, with an onset of action within 12 hours. Ann Allergy Asthma Immunol 2002;89 (3) 279- 284
PubMedArticle
5.
Meltzer  EO Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol 1998;81 (2) 128- 134
PubMedArticle
6.
Creticos  PFireman  PSettipane  GBernstein  DCasale  TSchwartz  HRhinocort Aqua Study Group, Intranasal budesonide aqueous pump spray (Rhinocort Aqua) for the treatment of seasonal allergic rhinitis. Allergy Asthma Proc 1998;19 (5) 285- 294
PubMedArticle
7.
Day  JAlexander  MDrouin  M  et al.  Budesonide aqueous nasal spray and pressurized metered dose inhaler in the treatment of adult patients with seasonal allergic rhinitis. Am J Rhinol 1997;11 (1) 77- 83
PubMedArticle
8.
Stanaland  BE Once-daily budesonide aqueous nasal spray for allergic rhinitis: a review. Clin Ther 2004;26 (4) 473- 492
PubMedArticle
9.
Yu  CChen  FDYWang  J  et al.  Effect of Pulmicort respule on rehabilitation after functional endoscopic sinus surgery. Acta Chimi Sin 2007;21 (2) 100- 102
10.
Baker  JWMellon  MWald  JWelch  MCruz-Rivera  MWalton-Bowen  K A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103 (2) 414- 421
PubMedArticle
11.
Kemp  JPSkoner  DPSzefler  SJWalton-Bowen  KCruz-Rivera  MSmith  JA Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999;83 (3) 231- 239
PubMedArticle
12.
Shapiro  GGMendelson  LMPearlman  DS Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) maintains pulmonary function and symptoms of asthmatic children previously receiving inhaled corticosteroids. Ann Allergy Asthma Immunol 2001;86 (6) 633- 640
PubMedArticle
13.
Williams  GHDluhy  RG Disorders of the adrenal cortex. Dluhy  RGBraunwald  EFauci  ASKasper  DLPrinciples of Internal Medicine. 15th ed. New York, NY McGraw-Hill2001;2084- 2105
14.
Piccirillo  JFMerritt  MGJ  JrRichards  ML Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg 2002;126 (1) 41- 47
PubMedArticle
15.
Grinspoon  SKBiller  BM Clinical review 62: laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79 (4) 923- 931
PubMed
16.
González-González  JGDe la Garza-Hernandez  NEMancillas-Adame  LGMontes-Villarreal  JVillarreal-Pérez  JZ A high-sensitivity test in the assessment of adrenocortical insufficiency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufficiency. J Endocrinol 1998;159 (2) 275- 280
PubMedArticle
17.
Dorin  RIQualls  CRCrapo  LM Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139 (3) 194- 204
PubMedArticle
18.
Scott  MBSkoner  DP Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999;104 (4, pt 2) 200- 209
PubMedArticle
19.
Shapiro  GMendelson  LKraemer  MJCruz-Rivera  MWalton-Bowen  KSmith  JA Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998;102 (5) 789- 796
PubMedArticle
20.
Reid  AMurphy  CSteen  HJMcGovern  VShields  MD Linear growth of very young asthmatic children treated with high-dose nebulized budesonide. Acta Paediatr 1996;85 (4) 421- 424
PubMedArticle
21.
Murphy  KUryniak  TSimpson  BO’Dowd  L Growth velocity in children with perennial allergic rhinitis treated with budesonide aqueous nasal spray. Ann Allergy Asthma Immunol 2006;96 (5) 723- 730
PubMedArticle
22.
Agertoft  LPedersen  S Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343 (15) 1064- 1069
PubMedArticle
23.
Pauwels  RAPedersen  SBusse  WW  et al. START Investigators Group, Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361 (9363) 1071- 1076
PubMedArticle
24.
Richy  FBousquet  JEhrlich  GE  et al.  Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review. Osteoporos Int 2003;14 (3) 179- 190
PubMed
Original Article
March 2009

The Effect of Nasally Administered Budesonide Respules on Adrenal Cortex Function in Patients With Chronic Rhinosinusitis

Author Affiliations

Author Affiliations: Division of Clinical Outcomes Research, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri.

Arch Otolaryngol Head Neck Surg. 2009;135(3):303-307. doi:10.1001/archoto.2008.555
Abstract

Objectives  To evaluate whether nasal administration of budesonide in adults with chronic rhinosinusitis for 30 days suppresses adrenal function and to assess its clinical efficacy.

Design  An open-label prospective study.

Setting  Academic medical center.

Patients  We assessed adrenal function in 9 patients using the cosyntropin test before and after budesonide therapy.

Intervention  Budesonide respule therapy.

Main Outcome Measure  Scores from the Sino-Nasal Outcome Test–20 (SNOT-20), a tool for assessing rhinosinusitis health and quality of life, were used to assess efficacy of budesonide treatment.

Results  All of our patients showed adequate adrenal response to cosyntropin stimulation before and after the budesonide trial. The mean difference in SNOT-20 scores was −1 (95% confidence interval, −1.77 to −0.23; P = .02), indicating clinically significant improvement after therapy.

Conclusion  Our findings suggest that using budesonide nasal wash may be clinically effective in decreasing the symptoms of chronic rhinosinusitis and does so without suppression of the hypothalamic-pituitary-adrenal axis in patients with chronic rhinosinusitis.

Chronic rhinosinusitis is one of the most prevalent conditions among adults in the United States, affecting up to 14% of the population.1 This condition has a considerable economic impact on patients' lives, which is mainly attributable to additional visits to primary care physicians and increased pharmacy fill use.2

Budesonide, as an aqueous nasal spray with anti-inflammatory properties, has been shown to have a positive impact for those with chronic rhinosinusitis3 and perennial allergic rhinitis.4,5 Multiple studies68 demonstrate its safety as a topical nasal steroid spray. Budesonide is also available as a respule, a small, plastic, liquid-containing device that can be easily opened and used to deliver unit-dose medications in a sterile fashion (Pulmicort Respules, 0.25 mg and 0.5 mg; AstraZeneca LP, AstraZeneca LP, Wilmington, Delaware), for the maintenance treatment of asthma and as prophylactic therapy in children aged 12 months to 8 years. Yu et al9 studied the use of budesonide respules as rehabilitation after functional endoscopic sinus surgery. They found that using budesonide respules locally was beneficial for relieving mucosal inflammation, shortening the stage of epithelization, and accelerating the recovery of mucosa after functional endoscopic sinus surgery. Anecdotally, we are aware of many physicians who also prescribe budesonide respules for patients with chronic sinusitis, many of whom have not had sinus surgery.

The safety of inhaled budesonide respules has been assessed in 3 separate 12-week randomized clinical trials,1012 and all have demonstrated no significant systemic effects in pediatric patients with asthma. Safety was assessed in these studies through measurement of the hypothalamic-pituitary-adrenal (HPA) axis function using a corticotropin-stimulation test and observation of rates of adverse events. To our knowledge, a similar demonstration of the safety of a nasally administered budesonide wash has not been performed.

Our primary aim in this study was to evaluate whether nasal administration of budesonide in adult patients with chronic rhinosinusitis with or without nasal polyps for 30 days suppresses adrenal function as a result of systemic absorption. We assessed adrenal function in patients with sinusitis using the cosyntropin test.13 We also assessed the clinical efficacy of budesonide in treatment of chronic rhinosinusitis using the Sino-Nasal Outcome Test–20 (SNOT-20) questionnaire as a secondary outcome measure.14

METHODS
DESIGN

This was an open-label study of subjects with chronic rhinosinusitis. The enrolled subjects had their adrenal function assessed before initiating budesonide therapy. They also completed the SNOT-20 questionnaire. The patients received sufficient budesonide for 30 days of therapy and were instructed to use it on a daily basis. After 30 days of use, adrenal function was assessed again, and subjects completed the SNOT-20 questionnaire and a drug satisfaction survey.

STUDY SUBJECTS

Subjects were recruited from the offices of two of us (J.F.P. and S.E.T.) at the Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri. Enrollment began January 2005 and continued until February 2006. Patients between the ages of 18 and 70 years were included and had to have a history of chronic rhinosinusitis with or without nasal polyps. Patients were excluded from the study if they met any one of the following criteria: concurrent or recent use (within the past 30 days) of systemic corticosteroids; history of pituitary disease; morbid obesity (body mass index [calculated as weight in kilograms divided by height in meters squared] >38); concurrent or recent use of medications that accelerate the clearance of cortisol, such as dilantin, rifampin, amphetamines, or lithium carbonate; concurrent use of medications that interfere with the production of cortisol, such as ketoconazole, amphotericin B, bupropion, Echinacea, fluoroquinolones, itraconazole, licorice, and ma huang (Ephedra); use of oral contraception; use of female or male hormone therapy; a radioactive scan performed within 7 days before the test; known hypersensitivity to cortisol, corticotropin, or cosyntropin; allergic disease associated with anaphylactic reactions or breathing difficulties; or pregnancy.

We successfully enrolled 10 subjects. Subsequently, one of the subjects dropped out of the study and was excluded from all analyses. The Washington University Human Studies Committee approved this study.

DRUG ADMINISTRATION

Patients were instructed to use budesonide, 0.25 mg, 1 respule per nostril once daily, with the following protocol. First, patients poured a small amount of isotonic sodium chloride (saline) solution into a clean container or a small disposable cup. They then emptied 1 respule into a separate container or cup and mixed the contents of the respule with 5 mL of saline solution using a 5-mL syringe. They irrigated each nostril with the single respule diluted in 5 mL of saline solution in each of the following 3 positions:

  • Head down and back or head down and forward. The patient lies in a supine position with his or her head over the side of the bed. The hair should be pointing toward the floor while the patient looks directly at a wall. The nostrils will be facing the ceiling.

  • Head in downward position. The patient turns his or her head to the same side as the nostril to be irrigated. The patient remains in position 1, yet rolls to the same side as the nostril to be irrigated.

  • The patients lies in a supine position with his or her head held flat to allow the head to tilt back at about a 45° angle.

The patients instilled the 5-mL solution in approximately 3 applications.

The patients were to hold their head in each position for 2 to 3 minutes and to sit up and rest between each position. Patients completed this process on one side and then repeated the process for the opposite nostril. They were instructed to discard syringes every other day.

MEASUREMENTS

Baseline levels of cortisol in the bloodstream were measured at the patients' first visit. Participants then received 0.25 mg of cosyntropin and 10 mg of mannitol reconstituted with 1 mL of 0.9% sodium chloride as an intramuscular injection to stimulate the adrenal cortex. The patients' stimulated levels of blood cortisol were then measured approximately 30 minutes later. This procedure was repeated on the completion of the 30 days of nasally administered budesonide therapy.

Measuring blood levels of cortisol after cosyntropin stimulation is the standard way to assess for suppressive effects on the HPA axis. If nasally administered budesonide is systemically absorbed, this will result in a reduced output of the adrenal cortex relative to that before stimulation. This, in turn, will result in inadequate cortisol levels in response to cosyntropin in the posttreatment period. However, if nasally administered budesonide is not absorbed and has no systemic effect on the HPA axis, there will be no difference in the blood cortisol stimulation between the 2 periods.

Blood cortisol levels were measured by the General Clinical Research Center Immunoassay Core Laboratory, Washington University School of Medicine. Blood insulin levels were also measured as a calibration for the blood cortisol levels. Cortisol levels were measured in micrograms per deciliter (to convert to nanomoles per liter, multiply by 27.588).

Scores from the SNOT-2014 questionnaire, a valid patient-based tool for assessing rhinosinusitis health status and quality of life, were used to assess the efficacy of budesonide treatment. Each of the 20 individual items are scored from 0 to 5, with 0 indicating no problem and 5 indicating that the particular item had the greatest burden. Each subject completed the survey at the initial and final visits. The total SNOT-20 score was calculated by adding up the response values of each individual item and dividing by the total number of items answered. The difference in total score between initial and final visit is a measure of the change in rhinosinusitis health status and quality of life. A negative change score implies improvement in rhinosinusitis health status and, based on previous research,14 a change of −0.8 or greater indicates a clinically significant improvement.

At the final visit, subjects also completed a drug satisfaction survey addressing the level of global improvement with 7 choices ranging from “very much better” to “very much worse”; adverse effects with choices ranging from “none” to “extremely severe”; and whether they would recommend nasally administered budesonide lavage therapy to a friend.

ANALYSES

The primary analysis was the observation of poststimulation blood cortisol levels before and after the administration of nasally administered budesonide lavage. A poststimulation level below 20 μg/dL indicated an insufficient adrenal response to cosyntropin stimulation. The SNOT-20 scores were obtained before and after administration of budesonide, and a change score was calculated as the difference between initial and final score. We used paired sample t tests to determine the statistical significance of cortisol and SNOT-20 changes. All analyses were performed using SAS statistical software (SAS Corporation, Cary, North Carolina), and P < .05 was considered as statistically significant.

RESULTS

The majority of patients were white, nonsmoking women who had previously undergone sinus surgery (Table 1). The prestimulation and poststimulation cortisol levels at baseline and after 30 days of therapy are shown in the Figure. There was no significant difference in mean prestimulation cortisol levels between baseline and after 30 days of budesonide therapy. Cosyntropin-induced cortisol levels spike were robust at each assessment time. The poststimulation cortisol level at 30 days was slightly, although not statistically significantly, higher than the poststimulation cortisol value at baseline. At baseline, the mean poststimulation cortisol level was 33.9 μg/dL (95% confidence interval [CI], 30.50-37.28 μg/dL). After 30 days of budesonide therapy, the mean poststimulation cortisol level was 35.2 μg/dL (95% CI, 30.66-39.70 μg/dL). Overall, none of the subjects' poststimulation cortisol level was below the critical level of 18 to 20 μg/dL, thus suggesting that daily use of budesonide nasal respules for 30 days does not suppress adrenal function to a significant degree. The peak cortisol level in response to cosyntropin stimulation is an important measure in terms of assessing adrenal insufficiency15; a peak cortisol level between 18 and 20 μg/dL is considered an adequate response indicating no adrenal insufficiency and is well supported in the literature.1517 In our cohort, poststimulation levels of serum cortisol were higher than 18 μg/dL before and after the budesonide trial for all patients (Table 2). This further validates our findings; there were no signs of adrenal suppression in our patient population.

The total SNOT-20 score was 2.4 (95% CI, 1.7 to 3.1) at baseline and 1.4 (95% CI, 0.8 to 2.1) at the 30-day visit. This difference of −1 was both statistically and clinically significant (95% CI, −1.77 to −0.23; P = .02). Budesonide nasal lavage treatment resulted in 6 of the 9 patients (67%) experiencing a reduction of 0.8 point or greater.

The subjects all reported some form of overall improvement with the use of budesonide, and 6 of the 9 patients (67%) would recommend this drug to a friend (Table 3). Of the 10 patients enrolled in the study, 1 patient discontinued the study because of the lack of an effect. Of the remaining 9 patients, 2 patients reported nosebleeds and 1 patient reported a headache. One of the patients in this group experienced diarrhea, dyspepsia, and irritability. The 6 remaining patients reported no adverse effects. There were no unexpected safety concerns during the course of this trial.

COMMENT

In this study, we found that the use of budesonide respules as a nasal lavage in patients with chronic rhinosinusitis does not suppress the HPA axis. On the contrary, we found a slight increase in the mean level of cosyntropin-induced cortisol secretion after 30 days of budesonide lavage. In addition, we assessed the efficacy of budesonide through the use of a patient-based assessment of rhinosinusitis health status. The decrease in SNOT-20 questionnaire scores was sufficient to suggest a clinically meaningful improvement when compared with historical data from a cohort of patients with rhinosinusitis.14 Without the use of a control group we cannot definitively conclude that this improvement was due to the budesonide nasal lavage. The decrease of SNOT-20 scores was consistent for all 9 patients, supporting the evidence for the clinical efficacy of this intervention. The drug satisfaction survey showed that patients were overall satisfied with this treatment for their rhinosinusitis.

A concern regarding the use of glucocorticoids is that they are unsafe because of systemic absorption. A pooled analysis18 of the 3 clinical trials10,11,19 of budesonide inhalation suspension has shown that, after a 52-week extension study period, baseline and corticotropin-stimulated cortisol levels were not significantly different in children compared with those receiving conventional treatments for asthma. Our study showed that adrenal function was not suppressed through nasal administration. Whether budesonide affects growth is a topic with differing opinions. In the 52-week extension studies of the clinical trials,10,11,19 1 of the 3 studies showed that asthmatic children randomized to budesonide inhalation suspension experienced a significant reduction in growth velocity.18 Some studies20,21 reported no effect on growth with budesonide treatments, while others22,23 suggest that budesonide therapy may have a transient effect on growth rate. These effects should be investigated in children with sinusitis if there is widespread use of budesonide respules as a nasal wash. A recent meta-analysis24 showed that corticosteroids may have an effect on bone mineral density and other bone markers in an adult patient population with asthma and chronic obstructive pulmonary disease. Whether these phenomena would occur in a chronic rhinosinusitis population when treated with budesonide respules as a nasal wash on a limited (ie, 3-month basis) remains an open question.

Our study was limited in that we did not have a control group to compare against for the SNOT-20 outcome score. Because the patients were not blinded to their treatment, this may have had an impact on the patients assessment of their treatment.

The clinical significance of this study is that budesonide nasal respules appear safe for short-term use for the relief of symptoms associated with chronic sinusitis. Budesonide respules seem to provide an effective treatment option for the patient with chronic rhinosinusitis with minimal fear of systemic adverse effects. It should be noted that the use of budesonide as a nasal lavage constitutes “off-label” use. The Food and Drug Administration has not approved the use of budesonide for nasal lavage. The off-label use of medications is legal and an accepted part of medical practice. As with any prescription or use of a medical device, the physician has an obligation to disclose reasonable risks associated with the use of the product. This research helps to inform the discussion of medical risk.

A future study to assess the safety of budesonide nasal respules would be to measure bone mineral density in an adult chronic rhinosinusitis population. An additional future study would be to conduct a randomized placebo-controlled trial of nasal budesonide. Assuming that 30% of patients using a saline nasal wash and 66% of patients using budesonide nasal respules would receive a clinically meaningful benefit in a double-blinded, placebo-controlled, randomized clinical trial, the total sample size needed to detect a clinically significant difference would be 66 patients. Given the amount of patients with chronic sinusitis, it should not be difficult to conduct this study.

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Article Information

Correspondence: Jay F. Piccirillo, MD, Division of Clinical Outcomes Research, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, Campus Box 8115, 660 S Euclid Ave, St Louis, MO 63110 (piccirilloj@ent.wustl.edu).

Submitted for Publication: April 7, 2008; final revision received June 15, 2008; accepted July 8, 2008.

Author Contributions: Dr Piccirillo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Piccirillo, Kramper, and Thawley. Acquisition of data: Piccirillo. Analysis and interpretation of data: Sachanandani, Piccirillo, Kramper, and Vlahiotis. Drafting of the manuscript: Sachanandani and Piccirillo. Critical revision of the manuscript for important intellectual content: Piccirillo, Thawley, and Vlahiotis. Statistical analysis: Sachanandani, Piccirillo, and Vlahiotis. Obtained funding: Piccirillo. Study supervision: Piccirillo, Kramper, and Thawley.

Financial Disclosure: None reported.

Funding/Support: This research was supported, in part, by grant T32 RR023255 from the National Institutes of Health Roadmap T32 Predoctoral Clinical Research Training Program (Drs Piccirillo and Sachanandani) and the Washington University General Clinical Research Center.

Previous Presentation: This study was presented at the Annual American Academy of Otolaryngology–Head and Neck Surgery Meeting; September 17, 2007; Washington, DC.

References
1.
Lethbridge-Cejku  MSchiller  JSBernadel  L Summary health statistics for US adults: National Health Interview Survey, 2002. Vital Health Stat 10 2004; (222) 1- 151
PubMed
2.
Murphy  MPFishman  PShort  SOSullivan  SDYueh  BWeymuller  EA  Jr Health care utilization and cost among adults with chronic rhinosinusitis enrolled in a health maintenance organization. Otolaryngol Head Neck Surg 2002;127 (5) 367- 376
PubMedArticle
3.
Lund  VJBlack  JHSzabo  LZSchrewelius  CAkerlund  A Efficacy and tolerability of budesonide aqueous nasal spray in chronic rhinosinusitis patients. Rhinology 2004;42 (2) 57- 62
PubMed
4.
Fokkens  WJCserhati  Edos Santos  JM  et al.  Budesonide aqueous nasal spray is an effective treatment in children with perennial allergic rhinitis, with an onset of action within 12 hours. Ann Allergy Asthma Immunol 2002;89 (3) 279- 284
PubMedArticle
5.
Meltzer  EO Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol 1998;81 (2) 128- 134
PubMedArticle
6.
Creticos  PFireman  PSettipane  GBernstein  DCasale  TSchwartz  HRhinocort Aqua Study Group, Intranasal budesonide aqueous pump spray (Rhinocort Aqua) for the treatment of seasonal allergic rhinitis. Allergy Asthma Proc 1998;19 (5) 285- 294
PubMedArticle
7.
Day  JAlexander  MDrouin  M  et al.  Budesonide aqueous nasal spray and pressurized metered dose inhaler in the treatment of adult patients with seasonal allergic rhinitis. Am J Rhinol 1997;11 (1) 77- 83
PubMedArticle
8.
Stanaland  BE Once-daily budesonide aqueous nasal spray for allergic rhinitis: a review. Clin Ther 2004;26 (4) 473- 492
PubMedArticle
9.
Yu  CChen  FDYWang  J  et al.  Effect of Pulmicort respule on rehabilitation after functional endoscopic sinus surgery. Acta Chimi Sin 2007;21 (2) 100- 102
10.
Baker  JWMellon  MWald  JWelch  MCruz-Rivera  MWalton-Bowen  K A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103 (2) 414- 421
PubMedArticle
11.
Kemp  JPSkoner  DPSzefler  SJWalton-Bowen  KCruz-Rivera  MSmith  JA Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999;83 (3) 231- 239
PubMedArticle
12.
Shapiro  GGMendelson  LMPearlman  DS Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) maintains pulmonary function and symptoms of asthmatic children previously receiving inhaled corticosteroids. Ann Allergy Asthma Immunol 2001;86 (6) 633- 640
PubMedArticle
13.
Williams  GHDluhy  RG Disorders of the adrenal cortex. Dluhy  RGBraunwald  EFauci  ASKasper  DLPrinciples of Internal Medicine. 15th ed. New York, NY McGraw-Hill2001;2084- 2105
14.
Piccirillo  JFMerritt  MGJ  JrRichards  ML Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg 2002;126 (1) 41- 47
PubMedArticle
15.
Grinspoon  SKBiller  BM Clinical review 62: laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79 (4) 923- 931
PubMed
16.
González-González  JGDe la Garza-Hernandez  NEMancillas-Adame  LGMontes-Villarreal  JVillarreal-Pérez  JZ A high-sensitivity test in the assessment of adrenocortical insufficiency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufficiency. J Endocrinol 1998;159 (2) 275- 280
PubMedArticle
17.
Dorin  RIQualls  CRCrapo  LM Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139 (3) 194- 204
PubMedArticle
18.
Scott  MBSkoner  DP Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999;104 (4, pt 2) 200- 209
PubMedArticle
19.
Shapiro  GMendelson  LKraemer  MJCruz-Rivera  MWalton-Bowen  KSmith  JA Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998;102 (5) 789- 796
PubMedArticle
20.
Reid  AMurphy  CSteen  HJMcGovern  VShields  MD Linear growth of very young asthmatic children treated with high-dose nebulized budesonide. Acta Paediatr 1996;85 (4) 421- 424
PubMedArticle
21.
Murphy  KUryniak  TSimpson  BO’Dowd  L Growth velocity in children with perennial allergic rhinitis treated with budesonide aqueous nasal spray. Ann Allergy Asthma Immunol 2006;96 (5) 723- 730
PubMedArticle
22.
Agertoft  LPedersen  S Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343 (15) 1064- 1069
PubMedArticle
23.
Pauwels  RAPedersen  SBusse  WW  et al. START Investigators Group, Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361 (9363) 1071- 1076
PubMedArticle
24.
Richy  FBousquet  JEhrlich  GE  et al.  Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review. Osteoporos Int 2003;14 (3) 179- 190
PubMed
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