Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke.
OBJECTIVE
Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat.


METHODS
This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days.


RESULTS
One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h.


CONCLUSIONS
NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.
Lees
K R
KR
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK.
Sharma
A K
AK
Barer
D
D
Ford
G A
GA
Kostulas
V
V
Cheng
Y F
YF
Odergren
T
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001557:Benzenesulfonates; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000652:urine; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy*; D015996:Survival Rate; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014360:Trypsin Inhibitor, Kunitz Soybean
D001557:Benzenesulfonates; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C109148:SPINT2 protein, human; C120851:disufenton sodium; D014360:Trypsin Inhibitor, Kunitz Soybean