title: Safety and pharmacokinetics of sodium nitrite in patients with subarachnoid hemorrhage: a phase IIa study.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Neurological Surgery, University of Virginia, Charlottesville, Virginia 22908-0212, USA. email: eho4u@virginia.edu
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Johanna J
authors.initials: JJ
authors.lastname: Loomba
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Monteith
authors.forename: R Webster
authors.initials: RW
authors.lastname: Crowley
authors.forename: Ricky
authors.initials: R
authors.lastname: Medel
authors.forename: Daryl R
authors.initials: DR
authors.lastname: Gress
authors.forename: Neal F
authors.initials: NF
authors.lastname: Kassell
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Dumont
authors.forename: Craig
authors.initials: C
authors.lastname: Sherman
mesh_terms: D000328:Adult; D000368:Aged; D017542:Aneurysm, Ruptured / Q000150:complications; D016638:Critical Illness / Q000628:therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007262:Infusions, Intravenous; D002532:Intracranial Aneurysm / Q000150:complications; D008297:Male; D008875:Middle Aged; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000209:etiology
chemical_list: D007202:Indicators and Reagents; D012977:Sodium Nitrite