Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway

Healthy Volunteers Clinical Trial

Official title:

Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01216748
• Other study ID #: 20070583
• Secondary ID: R01HL060644
• Status: Completed
• Phase: N/A
• First received: October 6, 2010
• Last updated: December 15, 2014
• Start date: January 2010
• Est. completion date: August 2010

Study information

• Verified date: November 2014
• Source: University of Miami
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. Methods: Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation

Description:

The lungs provide a unique absorptive surface for drug delivery. Many inhaled drugs are rapidly absorbed into the airway because of their lipophilic chemical characteristics. However, the majority of the currently used β2-adrenergic bronchodilators cannot freely diffuse across the epithelial cell membrane because of their transient or permanent positive charge at physiological pH. Inhaled albuterol, a β2-adrenergic agonist used widely for the treatment of obstructive airway disease, is charged positively in neutral or acidic conditions and thus requires active transport across the airway epithelium. Previous studies in the lab have shown that albuterol uptake into airway epithelia occurs via a pH sensitive cation transporter (OCTN2). The vasodilator response to an inhaled β2-adrenergic agonist could be an expression of epithelial cation transport. The investigators propose that the magnitude and duration of vasodilation in the airway caused by an inhaled hydrophilic β2-adrenergic agonist such as albuterol may be altered by changes in airway pH. The purpose of this protocol is to determine the effect of ASL pH on the response of Qaw to inhaled albuterol by manipulating airway pH through ventilatory maneuvers in health subjects: hyperventilation to raise pH and ventilation with CO2 bleed-in to lower pH.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Lifetime non-smokers

• FEV1 > 80% predicted value and FEV1/FVC > 0.75

Exclusion Criteria:

• Cardiovascular disease or use of cardiovascular or vasoactive drugs;

• Lung disease or use of airway drugs (i.e. inhaled corticosteroids, ß adrenergic agonists);

• Respiratory infection during the 4 weeks preceding the study

• Use of systemic glucocorticoids within 4 weeks of the study

• Pregnant or nursing females

Study Design

Endpoint Classification: Bio-availability Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Other:
• quiet breathing
Subjects were instructed to breath normally at room air.
• Hypocapnic Hyperventilation
hypocapnic hyperventilation, the subjects were instructed to breathe fast and deep until their end-tidal pCO2 fell to 30 mmHg, corresponding to a systemic pH increase of about 0.1 pH units.
• Hypercapnic Hyperventilation
For hypercapnic hyperventilation, a modification of a previously described procedure (15). While monitoring SaO2 using pulse oximetry and end-tidal CO2 by mass-spectrometry on a breath by breath basis, CO2 was bled into the inspired air to achieve an end-tidal pCO2 of at least 55 mmHg
• eucapnic hyperventilation
For eucapnic hyperventilation, the subjects were instructed to increase their ventilation to the highest level of ventilation recorded in the previous two hyperventilation maneuvers, while CO2 was bled into the inspired air to maintain end-tidal pCO2 at 40 mmHg.

Locations

Country	Name	City	State
United States	Pulmonary Human Research Laboratory, University of Miami School of Medicine	Miami	Florida

Sponsors (3)

Lead Sponsor	Collaborator
University of Miami	National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Horvath G, Schmid N, Fragoso MA, Schmid A, Conner GE, Salathe M, Wanner A. Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway. Am J Respir Cell Mol Biol. 2007 Jan;36(1):53-60. Epub 2006 Aug 17. — View Citation

Paget-Brown AO, Ngamtrakulpanit L, Smith A, Bunyan D, Hom S, Nguyen A, Hunt JF. Normative data for pH of exhaled breath condensate. Chest. 2006 Feb;129(2):426-30. — View Citation

Vaughan J, Ngamtrakulpanit L, Pajewski TN, Turner R, Nguyen TA, Smith A, Urban P, Hom S, Gaston B, Hunt J. Exhaled breath condensate pH is a robust and reproducible assay of airway acidity. Eur Respir J. 2003 Dec;22(6):889-94. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Airway Blood Flow After 180µg Albuterol by Inhalation (?Qaw) vs Baseline	Effect of airway pH on albuterol responsiveness as reflected by the change in airway blood flow after 180µg albuterol by inhalation (?Qaw) vs baseline.	15 minutes after albuterol inhalation	No
Secondary	Exhaled Breath Condensate (EBC) pH Variation	EBC samples were collected at each respiratory maneuver by directing the subject's exhaled breath into a pre-cooled (-10C) tube for 10 min.; pH was measured immediately after collection.	10 minutes after each respiratory manouver.	No