Clinical trial NCT01216748: Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway
Official title: Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy Volunteers
Keywords: airway blood flow
albuterol
acidosis
alkalosis
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-10-07
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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

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.

Eligibility 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

Primary outcomes:
measure: Changes in Airway Blood Flow After 180μg Albuterol by Inhalation (ΔQaw) vs Baseline
timeFrame: 15 minutes after albuterol inhalation
Secondary outcomes:
measure: Exhaled Breath Condensate (EBC) pH Variation
timeFrame: 10 minutes after each respiratory manouver.
Other outcomes:
Locations:
city: Miami
country: United States
facility: Pulmonary Human Research Laboratory, University of Miami School of Medicine
state: Florida
Study officials:
affiliation: University of Miami
name: Matthias Salathe
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1183/09031936.03.00038803.
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):426-430. doi: 10.1378/chest.129.2.426.
citation: 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. doi: 10.1165/rcmb.2006-0230OC. Epub 2006 Aug 17.
citation: 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.