A wealth of experimental evidence demonstrates that
cerebral ischemia causes excessive release of
glutamate and that
glutamate contributes to ischemic injury.
Glutamate antagonism by any of several mechanisms can ameliorate the extent of
infarction. These antagonists comprise noncompetitive blockers of the
ion channel associated with the
N-methyl-D-aspartate (
NMDA) receptor [e.g.,
aptiganel (
Cerestat)], competitive antagonists of the
glutamate recognition site of the
NMDA receptor (e.g.,
selfotel) or of the
glycine recognition site (e.g.,
ACEA 1021,
GV150526), antagonists at the
polyamine site (e.g.,
eliprodil), and drugs that may interfere with
glutamate release by
sodium channel blockade as well as having other actions (e.g.,
lubeluzole,
619C89). Clinical experience suggests that although some
NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g.,
selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g.,
aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include
hypertension (which is probably preferable to the
hypotension seen with
nimodipine and
lifarizine), sedation,
confusion or
hallucinations and, at high doses,
catatonia.
Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with
selfotel and
eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with
aptiganel,
magnesium, and
glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with
aptiganel (
Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of
ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.