BACKGROUND: Focal cerebral ischaemia causes release of excitatory amino acid 
(EAA) neurotransmitters, principally glutamate, with resultant over-stimulation 
of EAA receptors and downstream pathways. Excess glutamate release is a pivotal 
event in the evolution of irreversible ischaemic damage in animal models of 
ischaemia, and drugs that modulate glutamate action either by inhibiting its 
release, or blocking post-synaptic receptors, are potent neuroprotective agents. 
Many clinical trials with EAA modulating drugs have been conducted, none 
individually demonstrating efficacy.
OBJECTIVES: To synthesise all the available data on all different classes of EAA 
modulators and to evaluate evidence of effects on outcome systematically.
SEARCH STRATEGY: Relevant trials were identified in the Specialised Register of 
Controlled Trials (last searched May 2001). In addition, MEDLINE and EMBASE 
online searches for the terms "neuroprotection" (and its variants), 
"neuroprotective agent", for all individual drugs and drug classes included in 
the review, hand searches of conference proceedings from European, 
International, American Heart Association and Princeton conferences on Stroke, 
American Neurological Association and American Academy of Neurology meetings 
from 1992-2001, and direct contact with individual investigators and 
pharmaceutical companies.
SELECTION CRITERIA: Trials were included if they were randomised, controlled 
studies giving agents with pharmacological properties that included modification 
of release of EAAs, or blockade of EAA receptors, in stroke within 24h of onset. 
Efficacy analysis was restricted to trials with a parallel group design: dose 
escalation studies were excluded. Intention-to-treat analyses were performed on 
all data. Outcome had to be reported in terms of death or dependence 1-12 months 
after the acute event.
DATA COLLECTION AND ANALYSIS: Data were available for 36 of 41 relevant trials 
identified, involving 11,209 subjects. Data were unavailable for 632 
participants (517 in trials fulfilling criteria for efficacy analysis). Seven 
trials did not report disability data, which were available for 29 trials 
involving 10,802 subjects. Twenty one of these trials, involving 10,342 
subjects, were parallel group studies included in the primary efficacy analysis. 
Efficacy analysis included data derived from 9 trials not primarily designed to 
assess efficacy (1022 subjects). The primary (efficacy) end-point was the 
proportion of patients dead or disabled at final follow-up (defined by Barthel 
Index<60 at 3 months by preference). Mortality was a secondary end-point. Drugs 
were considered as individual agents, and also grouped principally into 
categories of ion channel modulators (glutamate release inhibition) and NMDA 
antagonists.
MAIN RESULTS: There was no significant heterogeneity of outcome amongst 
individual drugs, or of drug classes either for the primary efficacy analysis 
(death or dependence) or for mortality at final follow-up. For the primary 
efficacy analysis, odds of death or dependence were 1.03 [95% confidence 
interval 0.96-1.12], and for mortality 1.02 [0.92-1.12]. Neither ion channel 
modulators (death or dependence 1.02 [0.90-1.16]) nor NMDA antagonists (death or 
dependence 1.05 [0.95-1.16]) differed from the principal analysis including all 
compounds. Trends for increased mortality with three NMDA antagonists were seen 
- selfotel (OR 1.19 [0.81-1.74]), aptiganel (OR 1.32 [0.91-1.93]) and gavestinel 
(OR 1.12 [0.95-1.32]) - but this did not achieve significance for the NMDA 
antagonists considered as a class (1.09 [0.96-1.23]). Aptiganel was also 
associated with a trend towards worse functional outcome (OR 1.20 [0.88-1.65]) 
although this was not the case for either of the other two compounds. No 
statistically significant detriment of psychotomimetic NMDA antagonists was 
found, although a trend towards higher mortality in this sub-group was seen (OR 
1.25 [0.96-1.64]).
REVIEWER'S CONCLUSIONS: There was no evidence of significant benefit or harm 
from drugs modulating excitatory amino acid action. Reductio]).
REVIEWER'S CONCLUSIONS: There was no evidence of significant benefit or harm 
from drugs modulating excitatory amino acid action. Reduction of death or 
dependence by 8% or more has been excluded for gavestinel and lubeluzole, which 
contribute most of the data for this review. However, mechanistic understanding 
of neuroprotection is too poor to extrapolate from these two failed development 
plans to all glutamate modulators. Further clinical trials of neuroprotective 
agents remain justified, since confidence limits around estimates of effect 
remain wide for most agents, and cannot reliably exclude benefit. Although 
numbers of patients are too small to confirm or refute a trend towards increased 
mortality with some NMDA antagonists, further commercial development of these 
agents is exceedingly unlikely.