Clinical trial NCT01681836: Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults
Official title: An Open-Label Study of Oral Nitrite and Nitrate in Healthy Normal Volunteer Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Focus of Study of Healthy Adults
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2012-09-10
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Peak Plasma Nitrate Concentration Over 24 Hour Study Period
timeFrame: measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses
measure: Peak Plasma Nitrite Concentration Over 24 Hour Study Period
timeFrame: measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses
measure: Peak Red Blood Cell (RBC) Iron-nitrosyl Hemoglobin (NO-Hb) Concentrations Over 24 Hour Study Period
timeFrame: measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses
Secondary outcomes:
measure: Peak Percentage Level of Methemoglobin Over 24 Hour Study Period
timeFrame: measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses
measure: Peak Change in Mean Arterial Pressure Over 24 Hour Study Period
timeFrame: 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
measure: Peak Change in Systolic Blood Pressure Over 24 Hour Study Period
timeFrame: 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
measure: Peak Change in Diastolic Blood Pressure Over 24 Hour Study Period
timeFrame: 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
measure: Peak 15Nitrogen Nitro-conjugated Linoleic Acid (cLA) Concentrations Over 24 Hour Study Period
timeFrame: measured at time 0 (trough), every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose
measure: Percent Platelet Activation at 6 Hours
timeFrame: measured at 0 (baseline), 6 and 24 hours post-dose
measure: Peak Change in Heart Rate Over 24 Hour Study Period
timeFrame: 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
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Montefiore Hospital of UPMC
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Kara S Hughan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Mark T Gladwin, MD
role: STUDY_DIRECTOR
affiliation: University of Pittsburgh
name: Bret Goodpaster, PhD
role: STUDY_DIRECTOR
References:
citation: 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.