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Safety and pharmacokinetics of sodium nitrite in patients with subarachnoid hemorrhage: a phase IIa study.

Journal of neurosurgery (2013-05-28)
Edward H Oldfield, Johanna J Loomba, Stephen J Monteith, R Webster Crowley, Ricky Medel, Daryl R Gress, Neal F Kassell, Aaron S Dumont, Craig Sherman
ABSTRACT

Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion. Methods In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter. In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14. Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium nitrite, 99.999% trace metals basis
Supelco
Nitrite ion standard solution, 0.1 M NO2-, for ion-selective electrodes
Supelco
Nitrite ion standard solution, 0.01 M NO2-, for ion-selective electrodes
Sigma-Aldrich
Sodium nitrite, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥97%
Sigma-Aldrich
Sodium nitrite, ReagentPlus®, ≥99.0%
Sigma-Aldrich
Sodium nitrite, ACS reagent, ≥97.0%
Sigma-Aldrich
Sodium nitrite, anhydrous, Redi-Dri, ReagentPlus®, ≥99.0%