Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults

Study Overview
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Brief Summary
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This proposal hypothesizes that oral supplementation with sodium nitrite or nitrate will result in in vivo conversion of nitrate to nitrite and nitrite to nitric oxide with limited toxicity in the doses proposed in healthy adult normal volunteers. We utilize a powerful in vivo technique (pharmacokinetic testing) and are the first to design inorganic nitrate and nitrite capsules for cardiovascular disease.

Detailed Description
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Preclinical and clinical research over the last decade has revealed the important vasoprotective effects of nitrates and nitrites with regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction. New findings suggest an effect of nitrate and nitrite therapy in the regulation of glucose-insulin homeostasis. Development of an oral formulation of nitrate and nitrite salts is attractive, whereby nitrite would ensure rapid acting effects upon absorption, while the nitrate would continuously provide a slow formation of nitrite over a prolonged period of time via the enterosalivary circulation pathway. For this reason, development of an oral formulation of nitrate and nitrite salts is attractive, whereby nitrite would ensure rapid acting effects upon absorption, while the nitrate would continuously provide a slow formation of nitrite over a prolonged period of time via the enterosalivary circulation pathway. This study aims to establish the pharmacokinetics, metabolism and interconversion of nitrate to nitrite and nitrite to nitric oxide in vivo in healthy adult normal volunteers.

Official Title
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An Open-Label Study of Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults

Conditions
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Focus of Study of Healthy Adults

Intervention / Treatment
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* Drug: 15Nitrogen(15N)-labeled sodium nitrite
* Drug: 15Nitrogen(15N)-labeled sodium nitrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60 years Systolic blood pressure ≤130 and diastolic blood pressure ≤85 mm Hg Exclusion Criteria: Positive urine pregnancy test or breastfeeding Concurrent use of medications affecting glucose or lipid metabolism Recent addition or change in dosing of hormonal contraceptive medications (oral contraceptive pill, intrauterine device, DepoProvera) Current use of ≥2 anti-hypertensive agents regardless of blood pressure control or normotensive on a single agent Current use of phosphodiesterase 5 inhibitors or organic nitrates Not stable on treatments for the prior three months or not planning to remain on current dose of medications for blood pressure, contraception, etc Known chronic psychiatric or medical conditions including diabetes, liver or kidney disease or obesity syndromes Smoker

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral 15N-labeled sodium nitrate<br>Oral sodium nitrate 1,000 mg once first, then washout followed by oral sodium nitrite 20 mg once | Drug: 15Nitrogen(15N)-labeled sodium nitrite<br>* 15Nitrogen(15N)-labeled sodium nitrite 20 mg once<br>Drug: 15Nitrogen(15N)-labeled sodium nitrate<br>* 15Nitrogen(15N)-labeled sodium nitrate 1,000 mg once<br>|
| Experimental: Oral 15N-labeled sodium nitrite<br>Oral sodium nitrite 20 mg once first, then washout followed by oral sodium nitrate 1,000 mg once | Drug: 15Nitrogen(15N)-labeled sodium nitrite<br>* 15Nitrogen(15N)-labeled sodium nitrite 20 mg once<br>Drug: 15Nitrogen(15N)-labeled sodium nitrate<br>* 15Nitrogen(15N)-labeled sodium nitrate 1,000 mg once<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Nitrate Concentration Over 24 Hour Study Period | Post-doses refers to that subjects will receive a single dose of each study drug, oral 15Nitrogen(15N)-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses | 
| Peak Plasma Nitrite Concentration Over 24 Hour Study Period | Post-doses refers to that subjects will receive a single dose of each study drug, oral 15Nitrogen(15N)-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses | 
| Peak Red Blood Cell (RBC) Iron-nitrosyl Hemoglobin (NO-Hb) Concentrations Over 24 Hour Study Period | Post-doses refers to that subjects will receive a single dose of each study drug, oral 15Nitrogen(15N)-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Percentage Level of Methemoglobin Over 24 Hour Study Period | Post-doses refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses | 
| Peak Change in Mean Arterial Pressure Over 24 Hour Study Period | Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline) then every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose, change at 0.75 hours reported | 
| Peak Change in Systolic Blood Pressure Over 24 Hour Study Period | Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline) then every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose, change at 1.5 hours reported | 
| Peak Change in Diastolic Blood Pressure Over 24 Hour Study Period | Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline) then every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose, change at 0.75 hours reported | 
| Peak 15Nitrogen Nitro-conjugated Linoleic Acid (cLA) Concentrations Over 24 Hour Study Period | Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at time 0 (trough), every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose | 
| Percent Platelet Activation at 6 Hours | at timepoint with greatest change from 0 (trough); Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period; percentage of platelets that express 2 specific markers identifying activated platelets (CD41 and CD62-P) were quantified using flow cytometry | measured at 0 (baseline), 6 and 24 hours post-dose | 
| Peak Change in Heart Rate Over 24 Hour Study Period | Post-dose refers to that subjects will receive a single dose of each study drug, oral 15N-labeled sodium nitrate and nitrite, in random order, separated by a 3-7 day washout period | measured at 0 (baseline), every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose, change at 1.5 hours for nitrate and 24 hours for nitrite |