on November 14, 2002
Published online before print November 14, 2002, doi: 10.1161/01.STR.0000043823.37955.FB
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 23, 2002
From the Department of Neurology, University Hospital Groningen, Groningen, Netherlands (J-W.E., G.A.S., A.W.T., J. De K.); Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland (M.K.); Medicine and Therapeutics Department, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Abteilung Neurologie, Universität Essen, Essen, Germany (H.C.D.); Service Neurologie, CHU Hopital Michalon, Grenoble, France (M.H.); and Schering AG, SBU Therapeutics CV/CNS, Berlin, Germany (M.V.). * To whom correspondence should be addressed. E-mail: j.w.j.elting{at}neuro.azg.nl.
Background and Purpose—S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the Methods—In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS). Results—In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons. Conclusions—The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.
Accepted on July 26, 2002
AMPA Antagonist ZK200775 in Patients With Acute Ischemic Stroke. Possible Glial Cell Toxicity Detected by Monitoring of S-100B Serum Levels
Jan-Willem Elting MD*;
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients.
Key words: excitatory amino acid antagonists • nerve tissue protein S-100 • neuron-specific enolase • neurotoxins • receptors, AMPA • stroke, acute • stroke, ischemic