Acute Airway Vascular Smooth Muscle Effects of Inhaled Budesonide

Overview

Glucocorticosteroids recently have been shown to have non-genomic actions that are plasma membrane-mediated and do not require gene transcription and translation. One of these non-genomic effects is the inhibition of adrenergic agonist transport into airway vascular smooth muscle cells with an increase of adrenergic agonist concentrations at adrenergic receptor sites and enhance the physiological effects of endogenous adrenergic agonists (e.g. locally released norepinephrine from noradrenergic neurons) or exogenous adrenergic agonists (e.g. inhaled beta-adrenergic agonists).

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Basic Science
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: August 2012

Detailed Description

Inhaled glucocorticosteroids typically are not recommended for the treatment of acute asthma attacks. This practice is based on the fact that glucocorticosteroids by themselves do not cause rapid bronchodilation. However, the acute inhibition of adrenergic agonist disposal by the non-genomic action of glucocorticosteroids could lead to bronchial vasoconstriction by locally released norepinephrine thereby decongesting the airway wall, and potentiate the bronchodilator effect of a concomitantly administered beta-adrenergic agonist through the same mechanism. The purpose of this study is to assess the vasoconstrictive effects of single and repetitive high-dose budesonide inhalations in moderate to severe asthmatics who use inhaled glucocorticosteroids regularly. As a secondary endpoint, airway inflammation and airway function will also be measured with the expectation that acute improvements in airflow might be detectable as a result of airway decongestion, notably in subjects with moderately severe asthma who have lower baseline lung function.

Interventions

  • Drug: Budesonide 360ug
    • A single inhaled dose of 360ug budesonide from a DPI.
  • Drug: Budesonide 720ug
    • A single inhaled dose of 720ug budesonide from a DPI.
  • Drug: Budesonide 1440ug
    • A single dose of 1440ug of the budesonide from DPI.
  • Drug: Budesonide720ug 4 times
    • 720ug of budesonide will be inhaled by the subjects 4 times, separated by 30 minutes.
  • Drug: Placebo
    • A single inhaled dose of placebo from a DPI.

Arms, Groups and Cohorts

  • Experimental: budesonide 360ug
    • asthmatic subject received different doses of inhaled budesonide in random other
  • Experimental: budesonide 720ug
    • asthmatic subject received different doses of inhaled budesonide in random other
  • Experimental: budesonide 1440ug
    • asthmatic subject received different doses of inhaled budesonide in random other
  • Placebo Comparator: placebo
    • asthmatic subject received inhaled placebo
  • Experimental: Budesonide720ug 4 times
    • asthmatic subject received 720ug of inhaled budesonide 4 times separated by 30 minutes.

Clinical Trial Outcome Measures

Primary Measures

  • Airway Blood Flow (Qaw)
    • Time Frame: participants will be followed for 6 hours after budesonide dose
    • Qaw will be measured before and up to 6 hours after a single inhaled dose of 360ug, 720ug, and 1440ug budesonide or placebo from a DPI, using a double-blinded randomized design on different days.

Secondary Measures

  • Forced Expiratory Volume in 1 Second (FEV1)
    • Time Frame: participant will be followed up to 6 hours after budesonide dose
    • FEV1 will be measured before and up to 6 hours after a single inhaled dose of 360ug, 720ug, and 1440ug budesonide or placebo from a DPI, using a double-blinded randomized design on different days.

Participating in This Clinical Trial

Inclusion Criteria

Twenty lifetime nonsmokers moderate or severe asthmatics; FEV1≥50 of predicted on the screening day Exclusion Criteria:

Women of childbearing potential who do not use accepted birth control measures; pregnant and breast feeding women; Cardiovascular disease and/or use of cardiovascular medication; Subjects with known beta-adrenergic agonist or glucocorticosteroid intolerance; Acute respiratory infection and or acute exacerbation of asthma within four weeks prior to the study; Use of systemic glucocorticosteroids within 4 weeks prior to the study; Daily ICS dose (fluticasone or budesonide) > 500ug; Diabetes mellitus

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Miami
  • Collaborator
    • AstraZeneca
  • Provider of Information About this Clinical Study
    • Principal Investigator: Eliana Mendes, University of Miami – University of Miami
  • Overall Official(s)
    • Eliana Mendes, MD, Principal Investigator, University of Miami

References

Horvath G, Sutto Z, Torbati A, Conner GE, Salathe M, Wanner A. Norepinephrine transport by the extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003 Oct;285(4):L829-37. Epub 2003 Jun 13.

Horvath G, Lieb T, Conner GE, Salathe M, Wanner A. Steroid sensitivity of norepinephrine uptake by human bronchial arterial and rabbit aortic smooth muscle cells. Am J Respir Cell Mol Biol. 2001 Oct;25(4):500-6.

Mendes ES, Pereira A, Danta I, Duncan RC, Wanner A. Comparative bronchial vasoconstrictive efficacy of inhaled glucocorticosteroids. Eur Respir J. 2003 Jun;21(6):989-93.

Brieva JL, Danta I, Wanner A. Effect of an inhaled glucocorticosteroid on airway mucosal blood flow in mild asthma. Am J Respir Crit Care Med. 2000 Jan;161(1):293-6.

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