AZ, MZ, and the Pulmonary System Response to Hypoxia

• ClinicalTrials.gov Identifier: NCT02760121
• Recruitment Status: Completed
• First Posted: May 3, 2016
• Last Update Posted: October 19, 2016
• Sponsor: University of British Columbia
• Information provided by (Responsible Party): University of British Columbia

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Altitude Sickness; Hypertension, Pulmonary	Drug: Acetazolamide; Drug: Methazolamide; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: The Effect of Carbonic Anhydrase Inhibitors on the Pulmonary System Response to Hypoxia
• Study Start Date: May 2016
• Actual Primary Completion Date: August 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Acetazolamide
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.	Drug: Methazolamide
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.	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. 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)
2. 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 Outcome Measures :

1. 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)

Other Outcome Measures:

1. change in arterial oxygen partial pressure [ Time Frame: Baseline and 60 minutes ]
2. Change in arterial carbon dioxide partial pressure [ Time Frame: Baseline and 60 minutes ]
3. Change in arterial pH [ Time Frame: Baseline and 60 minutes ]
4. Change in heart rate [ Time Frame: Baseline and 60 minutes ]
5. change in blood pressure [ Time Frame: Baseline and 60 minutes ]
6. change in end-tidal oxygen and carbon dioxide partial pressure [ Time Frame: Baseline and 60 minutes ]
7. Change in arterial oxygen saturation [ Time Frame: Baseline and 60 minutes ]
8. Change in cardiac output [ Time Frame: Baseline and 60 minutes of poikilocapnic hypoxia ]
   Cardiac output will be determined using the aortic time integral velocity and the diameter of the aortic valve annulus. Data will be collected at baseline and throughout exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
9. Change in pulmonary venous blood velocity [ Time Frame: Baseline and 60 minutes of poikilocapnic hypoxia ]
   Doppler ultrasound will be used to measure the velocity of blood draining from the pulmonary vein at baseline and throughout exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
10. Hemoglobin [ Time Frame: Baseline ]
11. albumin [ Time Frame: Baseline ]
12. iron [ Time Frame: Baseline ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Canada, British Columbia

University of British Columbia

Kelowna, British Columbia, Canada, V1V 1V7

Sponsors and Collaborators

University of British Columbia

Investigators

• Principal Investigator: Glen E Foster, Ph.D.; University of British Columbia

More Information

• Responsible Party: University of British Columbia
• ClinicalTrials.gov Identifier: NCT02760121
• Other Study ID Numbers: H16-00028
• First Posted: May 3, 2016
• Last Update Posted: October 19, 2016
• Last Verified: October 2016

Keywords provided by University of British Columbia:

Acetazolamide; Methazolamide; Control of breathing; Hypoxic pulmonary vasoconstriction

Additional relevant MeSH terms:

Hypertension, Pulmonary; Altitude Sickness; Hypoxia; Signs and Symptoms, Respiratory; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Acetazolamide; Methazolamide; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Diuretics; Natriuretic Agents; Physiological Effects of Drugs