AZ, MZ, and the Pulmonary System Response to Hypoxia

Study Overview
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Brief Summary
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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.

Official Title
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The Effect of Carbonic Anhydrase Inhibitors on the Pulmonary System Response to Hypoxia

Conditions
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Altitude Sickness, Hypertension, Pulmonary

Intervention / Treatment
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* Drug: Acetazolamide
* Drug: Methazolamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetazolamide<br>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<br> <br> |
| Experimental: Methazolamide<br>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<br> <br> |
| Placebo Comparator: Placebo<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ventilation | 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) | Baseline and 60 minutes of poikilocapnic hypoxia | 
| Change in pulmonary artery pressure | 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) | Baseline and 60 minutes of poikilocapnic hypoxia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebral blood velocity | 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) | Baseline and 60 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acetazolamide, Methazolamide, Control of breathing, Hypoxic pulmonary vasoconstriction