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Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke

Lookup NU author(s): Professor David Barer, Professor Gary Ford

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Abstract

Background and Purpose-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 mu mol/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.

Publication metadata

Author(s): Barer D; Ford GA; Lees KR; Sharma AK; Kostulas V; Cheng YF; Odergren T; SA-NXY-003 Investigators

Publication type: Article

Publication status: Published

Journal: Stroke

Year: 2001

Volume: 32

Issue: 3

Pages: 675-680

ISSN (print): 0039-2499

ISSN (electronic): 1524-4628

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1161/01.STR.32.3.675

DOI: 10.1161/01.STR.32.3.675

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