Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults

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

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.

Study Overview

• Status: Completed
• Conditions: Focus of Study of Healthy Adults
• Intervention / Treatment: Drug: 15Nitrogen(15N)-labeled sodium nitrite; Drug: 15Nitrogen(15N)-labeled sodium nitrate

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Montefiore Hospital of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gladwin, Mark, MD
• Investigators: Principal Investigator: Kara S Hughan, MD, University of Pittsburgh; Study Director: Mark T Gladwin, MD, University of Pittsburgh; Study Director: Bret Goodpaster, PhD, University of Pittsburgh

Publications and helpful links

General Publications

• Hughan KS, Wendell SG, Delmastro-Greenwood M, Helbling N, Corey C, Bellavia L, Potti G, Grimes G, Goodpaster B, Kim-Shapiro DB, Shiva S, Freeman BA, Gladwin MT. Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate. Hypertension. 2017 Sep;70(3):634-644. doi: 10.1161/HYPERTENSIONAHA.117.09016.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: July 3, 2012
• First Submitted That Met QC Criteria: September 5, 2012
• First Posted (Estimate): September 10, 2012

Study Record Updates

• Last Update Posted (Actual): September 4, 2018
• Last Update Submitted That Met QC Criteria: August 31, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: PRO11120134