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

• ClinicalTrials.gov Identifier: NCT01216748
• Recruitment Status: Completed
• First Posted: October 7, 2010
• Results First Posted: December 17, 2014
• Last Update Posted: May 27, 2016
• Sponsor: University of Miami
• Collaborators: National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Matthias Salathe, University of Miami

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Other: quiet breathing; Other: Hypocapnic Hyperventilation; Other: Hypercapnic Hyperventilation; Other: eucapnic hyperventilation	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway
• Study Start Date: January 2010
• Actual Primary Completion Date: July 2010
• Actual Study Completion Date: August 2010

Arms and Interventions

Arm

Intervention/treatment

Experimental: health life-time non smokers; health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation

Other: quiet breathing; Subjects were instructed to breath normally at room air.; Other: 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.; Other: 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; Other: 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.

Outcome Measures

Primary Outcome Measures :

1. Changes in Airway Blood Flow After 180μg Albuterol by Inhalation (ΔQaw) vs Baseline [ Time Frame: 15 minutes after albuterol inhalation ]
   Effect of airway pH on albuterol responsiveness as reflected by the change in airway blood flow after 180μg albuterol by inhalation (ΔQaw) vs baseline.

Secondary Outcome Measures :

1. Exhaled Breath Condensate (EBC) pH Variation [ Time Frame: 10 minutes after each respiratory manouver. ]

   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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, β 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

Contacts and Locations

Locations

United States, Florida

Pulmonary Human Research Laboratory, University of Miami School of Medicine

Miami, Florida, United States, 33136

Sponsors and Collaborators

University of Miami

National Institutes of Health (NIH)

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Matthias Salathe; University of Miami

More Information

Publications:

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.

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):426-430. doi: 10.1378/chest.129.2.426.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cancado JE, Mendes ES, Arana J, Horvath G, Monzon ME, Salathe M, Wanner A. Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol. BMC Pharmacol Toxicol. 2015 Apr 2;16:9. doi: 10.1186/s40360-015-0008-y.

• Responsible Party: Matthias Salathe, Professor of Medicine, University of Miami
• ClinicalTrials.gov Identifier: NCT01216748
• Other Study ID Numbers: 20070583; R01HL060644 ( U.S. NIH Grant/Contract )
• First Posted: October 7, 2010
• Results First Posted: December 17, 2014
• Last Update Posted: May 27, 2016
• Last Verified: November 2014

Keywords provided by Matthias Salathe, University of Miami:

airway blood flow; albuterol; acidosis; alkalosis