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

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 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.

• Authors: K R Lees, A K Sharma, D Barer, G A Ford, V Kostulas, Y F Cheng, T Odergren
• Journal: Stroke (Stroke) Vol. 32 Issue 3 Pg. 675-80 (Mar 2001) ISSN: 1524-4628 [Electronic] United States
• PMID: 11239186 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Benzenesulfonates
• Membrane Glycoproteins
• Neuroprotective Agents
• Nitrogen Oxides
• SPINT2 protein, human
• disufenton sodium
• Trypsin Inhibitor, Kunitz Soybean

Topics

• Adult
• Aged
• Aged, 80 and over
• Benzenesulfonates
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Drug Evaluation
• Female
• Humans
• Infusions, Intravenous
• Magnetic Resonance Imaging
• Male
• Membrane Glycoproteins (urine)
• Metabolic Clearance Rate
• Middle Aged
• Neuroprotective Agents (administration & dosage, adverse effects, pharmacokinetics)
• Nitrogen Oxides (administration & dosage, adverse effects, pharmacokinetics)
• Severity of Illness Index
• Stroke (diagnosis, drug therapy)
• Survival Rate
• Tomography, X-Ray Computed
• Treatment Outcome
• Trypsin Inhibitor, Kunitz Soybean