AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels.
OBJECTIVE
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 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients.


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.
Elting
Jan-Willem
JW
Department of Neurology, University Hospital Groningen, Groningen, Netherlands. j.w.j.elting@neuro.azg.nl
Sulter
Geert A
GA
Kaste
Markku
M
Lees
Kennedy R
KR
Diener
Hans C
HC
Hommel
Marc
M
Versavel
Mark
M
Teelken
Albert W
AW
De Keyser
Jacques
J
D000208:Acute Disease; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000097:blood; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D063065:Organophosphonates / Q000009:adverse effects* / Q000627:therapeutic use; D010751:Phosphopyruvate Hydratase / Q000097:blood; D011810:Quinoxalines / Q000009:adverse effects* / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D012720:Severity of Illness Index; D020521:Stroke / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome
D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D009414:Nerve Growth Factors; D063065:Organophosphonates; D011810:Quinoxalines; D018091:Receptors, AMPA; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C114423:ZK 200775; D010751:Phosphopyruvate Hydratase