HealthyPhase 1NCT00102271
Nitrite Infusion Studies
A Phase 1 study testing Oxypurinol and Sodium Nitrite in people with Healthy, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
This study will examine 1) how nitrite (a natural blood substance that relaxes blood vessels) increases blood flow and lowers blood pressure, and 2) how to increase the effects of nitrite on blood pressure. Healthy volunteers between 21 and 40 years of age may be eligible for this study. Read more about this study
- Who is it for?
- Ages 21 to 40 years
- Conditions the study is for
- Healthy
- What is being tested?
- Oxypurinol and Sodium Nitrite
- How many people
- 36 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Jan 2005to 12 Apr 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Subjects must be 21-40 years of age.
- Subject must be in good health.
- Subjects must provide informed, written consent for participation in this study.
- Female subjects of childbearing age must have a negative pregnancy test.
Who cannot join
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 160 mg/dL), or diabetes mellitus (fasting blood glucose greater than 126 mg/dL)
- Subjects who have a history of smoking within two years
- Subjects who have a history of cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Individuals with a future cardiovascular risk greater than 1 % in the next 10 years will be excluded from the study. Risk will be calculated using the Framingham risk calculator published on the web site: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof.
- Subjects with red blood cell G6PD deficiency (levels below the lower limits of normal).
- Subjects with known cytochrome B5 deficiency will not participate in this study.
Show all 12Show fewer
- Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis will not participate in this study.
- Subjects with a baseline methemoglobin level greater than 1.9% will not receive nitrite infusions.
- Lactating females will not participate since nitrite crosses into breast milk and could cause methemoglobinemia in the infant.
- No volunteer subject will be allowed to take any medication (oral contraceptive agents are allowed), vitamin supplements that contain arginine, herbal preparations, nutriceuticals or other "alternative therapies" for at least one month prior to study and will not be allowed to take aspirin for one week prior to study
- Subjects with a blood pressure of less than 90/60 mmHg or a MAP (mean arterial blood pressure) of less than 70 on the study day will be excluded from the protocol.
- Due to exposure of high doses of ascorbic acid in this protocol calcium oxalate stone formers, patients on dialysis or with serious kidney disease, and patients with hemochromatosis and other iron overload diseases will be excluded.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Systemic Nitrite Infusion
This study will examine 1) how nitrite (a natural blood substance that relaxes blood vessels) increases blood flow and lowers blood pressure, and 2) how to increase the effects of nitrite on blood pressure.
Healthy volunteers between 21 and 40 years of age may be eligible for this study. They must be non-smokers and have no history of high blood pressure, high cholesterol, or diabetes. Candidates are screened with a medical history, physical examination, electrocardiogram, and blood tests. This study is either done in the NIH Clinical Center intensive care unit or on the general clinical ward. Participants are enrolled in Part A of the study. After completion of Part A participants will be enrolled in Part B of the study.
Read more
Part A:
Participants lie in a reclining chair during the study. Small catheters (plastic tubes) are inserted into an artery and vein in the forearm. Another tube is placed in the vein of the opposite arm. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. This device helps us to measure blood flow through the arm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in both forearms. Then blood is drawn from the tube in the right vein to measure blood counts, proteins, and other chemicals. Participants then are given small doses of either saline, ascorbic acid, or a medicine called oxypurinol, a form of a drug that is often taken to prevent gout. After 30 minutes, sodium nitrite is injected in increasing doses into the artery for 30 minutes. Blood flow is measured and blood is drawn every 5 minutes during the infusion. At the end of the 30 minutes, blood is drawn from the vein every 30 minutes for 3 hours. After 3 hours, sodium nitrite infusions are restarted for 2 hours and blood flow is measured and samples collected every 30 minutes during this period.
Part B: Participants lie in a reclining chair during the study. A small catheter (plastic tube) is placed in the artery of the left forearm to draw blood samples. A larger catheter called a central line is placed in a deeper vein in the neck. Another tube is advanced through the central line into the chambers of the heart, through the heart valve, and into the lung artery to measure pressures in the heart and lungs. Blood is drawn after 30 minutes to obtain baseline measurements. Then saline (sterile salt water) is put into the tube in the lung artery. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm, which helps us to measure flow through the arm. When the cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in the forearm and blood samples are drawn from the tube in the left artery to measure blood counts, proteins, and other chemicals.
Subjects then breathe a mixture of oxygen and nitrogen through a facemask for 30 minutes, then room air for 30 minutes, and then the oxygen and nitrogen mixture for another 30 minutes. While breathing the mixture the second time, sodium nitrite is injected through the tube in the artery in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is drawn from the tubes in the neck. Forearm blood flow is also measured every 5 minutes. After 30 minutes, the subject breathes room air for 3 hours and 15 minutes and then the sodium nitrite is injected again in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is taken from the tube in the neck and forearm blood flow is measured
Read the detailed description
Although regional synthesis of nitric oxide (NO) by the endothelium contributes importantly to local vasodilator tone, we have previously shown that NO bioactivity may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. These endocrine effects of NO are mediated by intravascular NO-stores - candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies by our group show that regional, intra-arterial infusion of nitrite elicits downstream vasodilator response. The mechanism of nitrite reduction in vivo may involve a number of pathways. We have observed that nitrite is reduced to NO by its reaction with deoxyheme proteins. This chemistry suggests a role for hemoglobin and other heme proteins as an oxygen dependent nitrite reductase and further that nitrite ions might contribute to systemic hypoxic vasodilation. Other research groups have proposed pH-dependent mechanisms, the involvement of electron donors such as ascorbic acid, or xanthinoxidase as a reducing agent.
The present study will be conducted in two stages (Parts A and B) with the following objectives: Part A will determine 1) whether systemic (intravenous) infusion of nitrite modulates vascular tone in the systemic circulation, 2) whether oxypurinol (a potent inhibitor of xanthine oxidase activity) lowers or ascorbic acid potentiates nitrite-induced vasodilation, 3) elucidate the pharmacokinetic profile of nitrite application in humans and 4) determine phase I data for dosing nitrite in human disease. Part B will determine whether the systemic and pulmonary vascular responses to nitrite infusion are potentiated under hypoxic conditions and are mediated by NO gas per se as measured by NO content in exhaled breath.
- Conditions
- Healthy
- Being tested
- Oxypurinol, Sodium Nitrite
- Keywords
- Sodium Nitrite, Oxypurinol, Ascorbic Acid, Hypoxic Gas, Forearm Blood Flow, Healthy Volunteer, HV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OxypurinolDrug
Sodium NitriteDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2005 (estimated)
- Study start19 Jan 2005
- Study completion12 Apr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00102271
- Sponsor's protocol ID
- 050088
- Other IDs
- 05-H-0088
- Status last verified
- 12 Apr 2011
- First submitted
- 25 Jan 2005
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28. doi: 10.1007/s000180050352.
PubMed 10484661Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
PubMed 6253831Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535-60. doi: 10.1146/annurev.pa.30.040190.002535. No abstract available.
PubMed 2188578
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Systemic Nitrite Infusion
- ClinicalTrials.gov ID
- NCT00102271
- Acronym / sponsor ID
- 050088
- Conditions
- Healthy
- Keywords
- Sodium Nitrite, Oxypurinol, Ascorbic Acid, Hypoxic Gas, Forearm Blood Flow, Healthy Volunteer, HV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 19 Jan 2005
- Study completion
- 12 Apr 2011 (actual)
- First posted
- 26 Jan 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine 1) how nitrite (a natural blood substance that relaxes blood vessels) increases blood flow and lowers blood pressure, and 2) how to increase the effects of nitrite on blood pressure.
Healthy volunteers between 21 and 40 years of age may be eligible for this study. They must be non-smokers and have no history of high blood pressure, high cholesterol, or diabetes. Candidates are screened with a medical history, physical examination, electrocardiogram, and blood tests. This study is either done in the NIH Clinical Center intensive care unit or on the general clinical ward. Participants are enrolled in Part A of the study. After completion of Part A participants will be enrolled in Part B of the study.
Part A:
Participants lie in a reclining chair during the study. Small catheters (plastic tubes) are inserted into an artery and vein in the forearm. Another tube is placed in the vein of the opposite arm. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. This device helps us to measure blood flow through the arm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in both forearms. Then blood is drawn from the tube in the right vein to measure blood counts, proteins, and other chemicals. Participants then are given small doses of either saline, ascorbic acid, or a medicine called oxypurinol, a form of a drug that is often taken to prevent gout. After 30 minutes, sodium nitrite is injected in increasing doses into the artery for 30 minutes. Blood flow is measured and blood is drawn every 5 minutes during the infusion. At the end of the 30 minutes, blood is drawn from the vein every 30 minutes for 3 hours. After 3 hours, sodium nitrite infusions are restarted for 2 hours and blood flow is measured and samples collected every 30 minutes during this period.
Part B: Participants lie in a reclining chair during the study. A small catheter (plastic tube) is placed in the artery of the left forearm to draw blood samples. A larger catheter called a central line is placed in a deeper vein in the neck. Another tube is advanced through the central line into the chambers of the heart, through the heart valve, and into the lung artery to measure pressures in the heart and lungs. Blood is drawn after 30 minutes to obtain baseline measurements. Then saline (sterile salt water) is put into the tube in the lung artery. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm, which helps us to measure flow through the arm. When the cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in the forearm and blood samples are drawn from the tube in the left artery to measure blood counts, proteins, and other chemicals.
Subjects then breathe a mixture of oxygen and nitrogen through a facemask for 30 minutes, then room air for 30 minutes, and then the oxygen and nitrogen mixture for another 30 minutes. While breathing the mixture the second time, sodium nitrite is injected through the tube in the artery in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is drawn from the tubes in the neck. Forearm blood flow is also measured every 5 minutes. After 30 minutes, the subject breathes room air for 3 hours and 15 minutes and then the sodium nitrite is injected again in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is taken from the tube in the neck and forearm blood flow is measured
Detailed description
Although regional synthesis of nitric oxide (NO) by the endothelium contributes importantly to local vasodilator tone, we have previously shown that NO bioactivity may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. These endocrine effects of NO are mediated by intravascular NO-stores - candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies by our group show that regional, intra-arterial infusion of nitrite elicits downstream vasodilator response. The mechanism of nitrite reduction in vivo may involve a number of pathways. We have observed that nitrite is reduced to NO by its reaction with deoxyheme proteins. This chemistry suggests a role for hemoglobin and other heme proteins as an oxygen dependent nitrite reductase and further that nitrite ions might contribute to systemic hypoxic vasodilation. Other research groups have proposed pH-dependent mechanisms, the involvement of electron donors such as ascorbic acid, or xanthinoxidase as a reducing agent.
The present study will be conducted in two stages (Parts A and B) with the following objectives: Part A will determine 1) whether systemic (intravenous) infusion of nitrite modulates vascular tone in the systemic circulation, 2) whether oxypurinol (a potent inhibitor of xanthine oxidase activity) lowers or ascorbic acid potentiates nitrite-induced vasodilation, 3) elucidate the pharmacokinetic profile of nitrite application in humans and 4) determine phase I data for dosing nitrite in human disease. Part B will determine whether the systemic and pulmonary vascular responses to nitrite infusion are potentiated under hypoxic conditions and are mediated by NO gas per se as measured by NO content in exhaled breath.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 21 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Subjects must be 21-40 years of age.
- Subject must be in good health.
- Subjects must provide informed, written consent for participation in this study.
- Female subjects of childbearing age must have a negative pregnancy test.
Key exclusion criteria (12 listed)
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 160 mg/dL), or diabetes mellitus (fasting blood glucose greater than 126 mg/dL)
- Subjects who have a history of smoking within two years
- Subjects who have a history of cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Individuals with a future cardiovascular risk greater than 1 % in the next 10 years will be excluded from the study. Risk will be calculated using the Framingham risk calculator published on the web site: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof.
- Subjects with red blood cell G6PD deficiency (levels below the lower limits of normal).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oxypurinol | Drug | – |
| Sodium Nitrite | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 10484661Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28. doi: 10.1007/s000180050352.
- Background: PubMed 6253831Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
- Background: PubMed 2188578Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535-60. doi: 10.1146/annurev.pa.30.040190.002535. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Oxypurinol and Sodium Nitrite in people with Healthy, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00102271, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.