Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults
- Conditions
- Focus of Study of Healthy Adults
- Interventions
- Registration Number
- NCT01681836
- Lead Sponsor
- Gladwin, Mark, MD
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 11
- Age 18-60 years
- Systolic blood pressure ≤130 and diastolic blood pressure ≤85 mm Hg
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Oral 15N-labeled sodium nitrate 15Nitrogen(15N)-labeled sodium nitrite Oral sodium nitrate 1,000 mg once first, then washout followed by oral sodium nitrite 20 mg once Oral 15N-labeled sodium nitrate 15Nitrogen(15N)-labeled sodium nitrate Oral sodium nitrate 1,000 mg once first, then washout followed by oral sodium nitrite 20 mg once Oral 15N-labeled sodium nitrite 15Nitrogen(15N)-labeled sodium nitrate Oral sodium nitrite 20 mg once first, then washout followed by oral sodium nitrate 1,000 mg once Oral 15N-labeled sodium nitrite 15Nitrogen(15N)-labeled sodium nitrite Oral sodium nitrite 20 mg once first, then washout followed by oral sodium nitrate 1,000 mg once
- Primary Outcome Measures
Name Time Method Peak Red Blood Cell (RBC) Iron-nitrosyl Hemoglobin (NO-Hb) Concentrations Over 24 Hour Study Period measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses "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
Peak Plasma Nitrate Concentration Over 24 Hour Study Period measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses "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
Peak Plasma Nitrite Concentration Over 24 Hour Study Period measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses "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
- Secondary Outcome Measures
Name Time Method Peak Percentage Level of Methemoglobin Over 24 Hour Study Period measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses "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
Peak Change in Mean Arterial Pressure Over 24 Hour Study 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 "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
Peak Change in Systolic Blood Pressure Over 24 Hour Study 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 "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
Peak Change in Diastolic Blood Pressure Over 24 Hour Study 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 "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
Peak 15Nitrogen Nitro-conjugated Linoleic Acid (cLA) Concentrations Over 24 Hour Study 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 "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
Percent Platelet Activation at 6 Hours measured at 0 (baseline), 6 and 24 hours post-dose 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
Peak Change in Heart Rate Over 24 Hour Study 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 "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
Trial Locations
- Locations (1)
Montefiore Hospital of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States