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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oral 15N-labeled sodium nitrate | Experimental | Oral sodium nitrate 1,000 mg once first, then washout followed by oral sodium nitrite 20 mg once |
|
| Oral 15N-labeled sodium nitrite | Experimental | Oral sodium nitrite 20 mg once first, then washout followed by oral sodium nitrate 1,000 mg once |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 15Nitrogen(15N)-labeled sodium nitrite | Drug | 15Nitrogen(15N)-labeled sodium nitrite 20 mg once |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kara S Hughan, MD | University of Pittsburgh | Principal Investigator |
| Mark T Gladwin, MD | University of Pittsburgh | Study Director |
| Bret Goodpaster, PhD | University of Pittsburgh | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montefiore Hospital of UPMC | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28739973 | Derived | 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. |
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11 participants recruited; 11 screened; 0 excluded
Healthy adult participants were recruited between October 2012 and October 2013.
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| ID | Title | Description |
|---|---|---|
| FG000 | Oral 15N-labeled Sodium Nitrate, Then Sodium Nitrite | Oral 15N-labeled sodium nitrate 1,000 mg once in first intervention period and oral 15N-labeled sodium nitrite 20 mg once in second intervention period (after washout period) |
| FG001 | Oral 15N-labeled Sodium Nitrite, Then Sodium Nitrate | Oral 15N-labeled sodium nitrite 20 mg once in first intervention period and oral 15N-labeled sodium nitrate 1,000 mg once in second intervention period (after washout period) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| Washout Period of 3-7 Days |
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| Second Intervention |
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | Includes groups randomized to received oral 15N-labeled sodium nitrate first and sodium nitrite first. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Mean | Standard Error | microMolar (microM) | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses |
|
3-7 days after single dose of each drug
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Oral 15N-labeled Sodium Nitrate | Oral 15N-labeled sodium nitrate 1,000 mg once in either first intervention period or second intervention period |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kara Hughan | University of Pittsburgh | 412-692-5170 | kara.hughan@chp.edu |
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| 15Nitrogen(15N)-labeled sodium nitrate | Drug | 15Nitrogen(15N)-labeled sodium nitrate 1,000 mg once |
|
| 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 |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| Systolic blood pressure | Mean | Standard Deviation | mmHg |
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| Diastolic blood pressure | Mean | Standard Deviation | mmHg |
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| Mean arterial pressure | Mean | Standard Deviation | mmHg |
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| Methemoglobin | Mean | Standard Deviation | percentage level of methemoglobin |
|
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| Primary | 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 | Posted | Mean | Standard Error | microM | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses |
|
|
|
| Primary | 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 | Posted | Mean | Standard Error | microMolar | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Error | percentage level | measured at 0 (baseline), 0.5, 1, 2, 3, 6 and 24 hours post-doses |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Error | mmHg | 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 |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Error | mmHg | 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 |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Error | mmHg | 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 |
|
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| Secondary | 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 | maximal at 24 hours with nitrate treatment, not detectable with nitrite treatment | Posted | Median | Full Range | nanoMolar | measured at time 0 (trough), every 15 minutes during the first 2 hours post-dose, then at 3, 6, and 24 hours post-dose |
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| Secondary | 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 | Posted | Mean | Standard Error | % of platelets that are activated | measured at 0 (baseline), 6 and 24 hours post-dose |
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| Secondary | 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 | Posted | Mean | Standard Error | beats per minute | 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 |
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| 0 |
| 10 |
| 9 |
| 10 |
| EG001 | Oral 15N-labeled Sodium Nitrite | Oral 15N-labeled sodium nitrite 20 mg once in either first intervention period or second intervention period | 0 | 11 | 9 | 11 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Dizziness | General disorders | Systematic Assessment |
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| Stomach ache | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Shortness of breath | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Mean arterial pressure decrease >20% | General disorders | Systematic Assessment |
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