Acute Airway Vascular Smooth Muscle Effects of Inhaled Budesonide

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 Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Budesonide 360ug; Drug: Budesonide 720ug; Drug: Budesonide 1440ug; Drug: Budesonide720ug 4 times; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Pulmonary Human Research Laboratory, University of Miami, Miller School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: budesonide 360ug; asthmatic subject received different doses of inhaled budesonide in random other	Drug: Budesonide 360ug; A single inhaled dose of 360ug budesonide from a DPI.; Other Names: Pulmicort Flexhaler
Experimental: budesonide 720ug; asthmatic subject received different doses of inhaled budesonide in random other	Drug: Budesonide 720ug; A single inhaled dose of 720ug budesonide from a DPI.; Other Names: Pulmicort Flexhaler
Experimental: budesonide 1440ug; asthmatic subject received different doses of inhaled budesonide in random other	Drug: Budesonide 1440ug; A single dose of 1440ug of the budesonide from DPI.; Other Names: Pulmicort Flexhaler
Placebo Comparator: placebo; asthmatic subject received inhaled placebo	Drug: Budesonide720ug 4 times; 720ug of budesonide will be inhaled by the subjects 4 times, separated by 30 minutes.; Other Names: Pulmicort Flexhaler
Experimental: Budesonide720ug 4 times; asthmatic subject received 720ug of inhaled budesonide 4 times separated by 30 minutes.	Drug: Placebo; A single inhaled dose of placebo from a DPI.; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Airway Blood Flow (Qaw)	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.	participants will be followed for 6 hours after budesonide dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1)	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.	participant will be followed up to 6 hours after budesonide dose

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Eliana Mendes, MD, University of Miami

Publications and helpful links

General Publications

• 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. doi: 10.1152/ajplung.00054.2003. 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. doi: 10.1165/ajrcmb.25.4.4559.
• 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. doi: 10.1183/09031936.03.00072402.
• 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. doi: 10.1164/ajrccm.161.1.9905068.
• Mendes ES, Rebolledo P, Campos M, Wanner A. Immediate antiinflammatory effects of inhaled budesonide in patients with asthma. Ann Am Thorac Soc. 2014 Jun;11(5):706-11. doi: 10.1513/AnnalsATS.201307-220OC.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: October 12, 2010
• First Submitted That Met QC Criteria: October 12, 2010
• First Posted (Estimate): October 13, 2010

Study Record Updates

• Last Update Posted (Estimate): January 16, 2015
• Last Update Submitted That Met QC Criteria: January 7, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Asthma, airway blood flow, budesonide, glucocorticosteroid.
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Budesonide
• Other Study ID Numbers: 20071068; IRUSBUPF0002 (Other Identifier: Sponsor)