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

• Sponsor: University of Miami (Other)
• Overall Status: Completed
• CT.gov ID: NCT01216748
• Collaborator: National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 7
• Patients Per Site Per Month: 1.4

Study Details

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	N/A

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
• 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: Jan 1, 2010
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Aug 1, 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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.

• Responsible Party: Matthias Salathe, Professor of Medicine, University of Miami
• ClinicalTrials.gov Identifier: NCT01216748
• Other Study ID Numbers: 20070583; R01HL060644
• First Posted: Oct 7, 2010
• Last Update Posted: May 27, 2016
• Last Verified: Nov 1, 2014

• Keywords provided by Matthias Salathe, Professor of Medicine, University of Miami: airway blood flow; albuterol; acidosis; alkalosis

Study Results

Participant Flow

Arm/Group Title	All Study Participants
Arm/Group Description	healthy lifetime non smokers were challenged with 4 respiratory manouvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation in random order.
Period Title: Overall Study
STARTED	10
Quiet Breathing	10
Hypocapnic Hyperventilation	10
Hypercapnic Hyperventilation	10
Eucapnic Hyperventilation	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Controls
Arm/Group Description	health-lifetime non-smokers were enrolled
Overall Participants	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	45
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Health Controls
Arm/Group Description	Health lifetime non smokers were recruited.
Measure Participants	10
quiet breathing	16.8 (1.9)
eucapnic hyperventilation	14.5 (2.4)
hypocapnic hyperventilation	-0.2 (1.8)
hypercapnic hyperventilation	2.0 (1.5)

2. Secondary Outcome

Title	Exhaled Breath Condensate (EBC) pH Variation
Description	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.
Time Frame	10 minutes after each respiratory manouver.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Health Controls
Arm/Group Description	Health lifetime non smokers were recruited.
Measure Participants	10
quiet breathing	6.39 (0.14)
hypocapnic hyperventilation	6.31 (0.08)
hypercapnic hyperventilation	6.59 (0.15)
eucapnic hyperventilation	5.88 (0.14)

Adverse Events

Arm/Group Title	Health Controls
Arm/Group Description	Health lifetime non smokers were recruited.
All Cause Mortality
	Health Controls
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Health Controls
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Health Controls
	Affected / at Risk (%)	# Events
Total	0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.