title: Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.
abstract: OBJECTIVE
  NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days.
  
  
  RESULTS
  One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group.
  
  
  CONCLUSIONS
  NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.
authors.affiliation: University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK. k.r.lees@clinmed.gla.ac.uk
authors.forename: K R
authors.initials: KR
authors.lastname: Lees
authors.forename: D
authors.initials: D
authors.lastname: Barer
authors.forename: G A
authors.initials: GA
authors.lastname: Ford
authors.forename: W
authors.initials: W
authors.lastname: Hacke
authors.forename: V
authors.initials: V
authors.lastname: Kostulas
authors.forename: A K
authors.initials: AK
authors.lastname: Sharma
authors.forename: T
authors.initials: T
authors.lastname: Odergren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001557:Benzenesulfonates; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D016166:Free Radical Scavengers / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012720:Severity of Illness Index; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy*; D015996:Survival Rate; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium