Protocol Number: 05-N-0075

Title:

Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Long-Term Intravenous Nitrite Infusion in Healthy Volunteers

Number:

05-N-0075

Summary:

This study will determine the dose of sodium nitrite that can safely be used to prevent constriction, or tightening, of the arteries. Narrowed arteries in the brain can cause stroke. Animal studies show that nitrite injections improve blood flow and that injections over long periods of time prevent damage to the arteries in the brain; however, there is no information on the effects of prolonged nitrite infusion in humans. This study will establish the safe dose and side effects of nitrite infusion in humans.

Healthy normal volunteers between 21 and 60 years of age may be eligible for this study. Candidates are screened for high or low blood pressure, aspirin use, pregnancy, and blood levels of nitrite and methemoglobin (a substance that temporarily and slightly lowers the oxygen carried in the red blood cells). Pregnant women are excluded from the study.

Participants are admitted to the Clinical Center for 16 1/4 days, the first 2 days in the hospital's intensive care unit (ICU). Upon admission they provide a medical history, have physical and cardiovascular examinations, and blood tests. For the infusion procedure, a catheter (thin plastic tube) is inserted into an artery in the wrist or the crease of the elbow to measure blood pressure, and catheters are placed in a vein in each arm for administering the nitrite and withdrawing blood samples.

In the morning of day 1, after initial blood pressure and heart rate measurements are taken and a blood sample is drawn, a saline (salt water) infusion is started. Blood pressure and heart rate are monitored every 30 minutes for 6 hours, then every hour for 6 hours, then every 2 hours for 12 hours. Blood samples are collected every 4 hours for 24 hours. On day 2, the sodium nitrite infusion begins. Blood pressure and methemoglobin are monitored every 10 minutes for the first 2 hours. If blood pressure remains stable, the frequency of measurements is decreased to every 30 minutes for 4 hours, then every 1 hour for the next 6 hours, and then every 4 hours for 12 hours. If the pressure continues to remain stable, monitoring continues every 8 hours for the rest of the study. Blood is drawn periodically from the catheter to determine the amount of nitrite and methemoglobin in the body, with decreasing frequency from several times during the first hour of the infusion to every 24 hours. After the first 24 to 48 hours of the nitrite infusion, participants are transferred from the ICU to a general nursing unit for the rest of the study. Then nitrite infusion ends on study day 15 (after 14 days of infusion). Participants are monitored for an additional 24 hours with frequent blood tests and blood pressure measurements and are then discharged. A follow-up visit is scheduled 30 days later for a checkup to look for any effects of long-term use of sodium nitrite.

Sponsoring Institute:

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Subjects must be 21-60 years of age.

Subjects 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 and agree to participate in assessment of menstrual cycle duration before, during, and after infusion.

Subjects must be willing to temporarily stop any medications (except oral contraception), vitamin supplements, herbal medicines.

Subjects will have hemoglobin levels above 11.1 g/dL.

EXCLUSION CRITERIA:

Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 130 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.

Subjects with red blood cell G6PD deficiency (levels below the lower limits of normal).

Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis.

Subjects with a baseline methemoglobin level greater than 1%.

Pregnant women, since nitrite may cross the placenta; nitrite effect on fetus is unknown and mother's methemoglobinemia may be dangerous to the fetus.

Breast-feeding females, since nitrite crosses into breast milk and could cause methemoglobinemia in the infant.

Subjects with a blood pressure of less than 100/70 mmHg on the study day.

Subjects treated with nitrates (e.g. nitroglycerin).

Special Instructions:

Currently Not Provided

Keywords:

Vasodilation

Hypotension

Hypertension

EDRF

Methemoglobinemia

Recruitment Keyword(s):

Healthy Volunteer

HV

Condition(s):

Healthy

Investigational Drug(s):

Sodium Nitrite Injection

Investigational Device(s):

None

Intervention(s):

Drug: Sodium Nitrite

Drug: Sodium Nitrite Injection

Supporting Site:

National Institute of Neurological Disorders and Stroke

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Afshar JK, Pluta RM, Boock RJ, Thompson BG, Oldfield EH. Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg. 1995 Jul;83(1):118-22.

Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003 Dec;9(12):1498-505. Epub 2003 Nov 02.

Furchgott 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.

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