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 ions contribute to vasodilation.
STUDY POPULATION
The study population will include sixteen 48-hour infusion healthy volunteers (out of 40 screened volunteers) of both genders, age 21-60, who will have a continuous intravenous infusion of sodium nitrite (the source of the drug will be determined by a CRADA).
DESIGN
This is a Phase I toxicity study of intermediate (48-hour) intravenous infusion of sodium nitrite in healthy volunteers.
OUTCOME MEASURES
Sixteen healthy volunteers of both genders, age 21-60, will have a 48-hour continuous intravenous infusion of sodium nitrite during which the subjects' clinical condition, blood levels of nitrite/methemoglobin, hematology, blood chemistry, and pressure will be meticulously monitored.
The first subject will receive the sodium nitrite infusion at 12 mg/48 hours. This dose, according to our knowledge from the former studies and detailed analysis of pharmacokinetics of sodium nitrite, will result in blood levels of sodium nitrite below 80 nmol/L, levels that are significantly below levels reported as normal (0.5 micromol/L to 1 micromol/L). Thus, we will use the modified accelerated titration design for Phase I Clinical studies. In the accelerated design the initial patient will start with the dose 1 nmol/min/kg/48hr, i.e. 12 mg total over 48 hours for a person weighting 60 kg. Cohorts of one new subject per dose level and double dose steps will be used during the initial accelerated stage. When the first instance of dose-limiting toxicity (DLT) is observed at any dose level, the next lower dose level cohort will be expanded to three patients and revert to the use of conventional modified Fibonacci escalation/de-escalation. If no DLT is observed at level 10, the cohort will be expanded to a total of three and de-escalated as appropriate. If no more than one subject among three patients experience DLT at this dose, level 10 will be considered to be the maximum tolerated dose (MTD).
The results of this 48-hour infusion phase 1 trial will be submitted to FDA before initiation of a 14-day clinical study.
