AZ, MZ, and the Pulmonary System Response to Hypoxia

Overview

The purpose of this proposal is to compare the physiological effects of acetazolamide (AZ) and methazolamide (MZ) on the control of breathing and hypoxic pulmonary vasoconstriction. The first objective is to assess the effects of AZ and MZ on the control of breathing in normoxia and hypoxia. To achieve this the ventilatory interaction between oxygen and carbon dioxide will be measured and effects compared between placebo, AZ, and MZ conditions. In addition, the isocapnic and poikilocapnic hypoxic ventilatory response and hypercapnic ventilatory response will be measured with each drug. The second objective is to assess the effects of AZ and MZ on the control of the pulmonary vasculature during hypoxia. Pulmonary pressure and cardiac output will be measured during 60 minutes of poikilocapnic hypoxia.

Full Title of Study: “The Effect of Carbonic Anhydrase Inhibitors on the Pulmonary System Response to Hypoxia”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Crossover Assignment
  • Primary Purpose: Basic Science
  • Masking: Double (Participant, Investigator)
• Study Primary Completion Date: August 2016

Interventions

• Drug: Acetazolamide
• Drug: Methazolamide
• Drug: Placebo

Arms, Groups and Cohorts

• Experimental: Acetazolamide
  • Participants will be dosed 250mg Acetazolamide (p.o.) three times per day for two days prior to and a single dose on the day of study.
• Experimental: Methazolamide
  • Participants will be dosed 100mg Methazolamide (p.o.) twice daily separated by a placebo for two days prior to and a single dose on the day of study. The placebo dose is provided to match the dosing schedule between conditions.
• Placebo Comparator: Placebo
  • Participants will take (p.o.) placebo pills three times per day for two days prior to and a single dose on the day of study.

Clinical Trial Outcome Measures

Primary Measures

• Change in ventilation
  • Time Frame: Baseline and 60 minutes of poikilocapnic hypoxia
  • To quantify the isocapnic hypoxic ventilatory response, the hypercapnic ventilatory response, and the hypercapnic hypoxic ventilatory response, ventilation will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal partial pressure for carbon dioxide will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal partial pressure of oxygen as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
• Change in pulmonary artery pressure
  • Time Frame: Baseline and 60 minutes of poikilocapnic hypoxia
  • Pulmonary artery systolic pressure (PASP) will be derived using the modified Bernoulli equation and the regurgitant velocity across the tricuspid valve. Estimates of right atrial pressure will be evaluated based upon the collapsibility index of the inferior vena cave during a sniff test. The pulmonary artery pressure response will be measured during 60 minutes of exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)

Secondary Measures

• Change in cerebral blood velocity
  • Time Frame: Baseline and 60 minutes
  • To quantify the isocapnic hypoxic cerebral blood velocity response, the hypercapnic cerebral blood velocity response, and the hypercapnic hypoxic cerebral blood velocity response, cerebral blood velocity in the middle and posterior cerebral arteries will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal carbon dioxide partial pressure will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal oxygen partial pressure as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)

Participating in This Clinical Trial

Inclusion Criteria

• 18-40 years of age – regularly physically active – male Exclusion Criteria:

• ex-smokers – pulmonary function <80% of predicted – contraindications to carbonic anhydrase inhibitors (eg. severe or absolute glaucoma, adrenocortical insufficiency, hepatic insufficiency, renal insufficiency, sulfa allergy or an electrolyte imbalance such as hyperchloremic acidosis) – Obese (BMI>30Kg/m2) – diuretic medication use – blood thinner use – anti-platelet drug use.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 40 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

• Lead Sponsor
  • University of British Columbia
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Glen E Foster, Ph.D., Principal Investigator, University of British Columbia