Clinical Trial: Nitrite Infusion in Healthy Volunteers

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief 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 ar

Detailed Summary:

Nitric oxide (NO) is beneficial in treatment of many animal models of diseases like heart and brain ischemia, reperfusion injury, and delayed cerebral vasospasm after subarachnoid hemorrhage. It also has been shown to open blood-brain barrier facilitating transfer of chemotherapeutic agents, dilate constricted pulmonary arteries, and inhibit apoptosis, as well as modulate angiogenesis. Until recently, all these biological effects were attributed to the regional synthesis of nitric oxide by the endothelium and its local influence of vascular tone. However, "NO bioactivity" may be transported in blood and have biological effects at a distance from the site of entry into the circulation. These 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 have shown that (1) regional, intra-arterial infusion of nitrite elicits a downstream vasodilator response in humans and (2) intravenous long-lasting administration prevents development of delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). These studies suggest a potential new therapeutic approach to many diseases. Despite extensive data documenting the pharmacokinetics and safety of the bolus and short intravascular infusions of nitrite, there are no human data evaluating safety and toxicity of prolonged delivery of nitrite, which would be required for treatment of vascular diseases.

OBJECTIVES

This study has the following objectives: (1) to determine the safety and (2) toxicity of a 48-hour and 14-day intravenous infusion of nitrite. The study should also help to elucidate the mechanism(s) through which nitrite
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Current Primary Outcome:

Original Primary Outcome:

Current Secondary Outcome:

Original Secondary Outcome:

Information By: National Institutes of Health Clinical Center (CC)

Dates:
Date Received: February 5, 2005
Date Started: February 4, 2005
Date Completion:
Last Updated: January 24, 2017
Last Verified: May 10, 2011