CERESTAT AND OTHER NMDA ANTAGONISTS IN ISCHEMIC STROKE

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes t o ischemic injury. Glutamate antagonism by any of several mechanisms c an ameliorate the extent of infarction. These antagonists comprise non competitive blockers of the ion channel associated with the N-methyl-D -aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive a ntagonists of the glutamate recognition site of the NMDA receptor (e.g ., selfotel) or of the glycine recognition site (e.g., ACEA. 1021, GV1 50526), 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 e xperience suggests that although some NMDA antagonists are poorly tole rated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with o thers (e.g., aptiganel), though tolerable adverse effects are frequent ly observed. These clinical effects include hypertension (which is pro bably preferable to the hypotension seen with nimodipine and lifarizin e), sedation, confusion or hallucinations and, at high doses, catatoni a. Glycine antagonists may be associated with fewer adverse effects, b ut preclinical studies suggest that brain penetration may be low. Alth ough recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence fur a satisfactory risk/benefit rati o, encouraging experience with aptiganel, magnesium, and glycine antag onists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outco me, 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 ischem ic stroke. Outcome is assessed by the modified Rankin Scale at 3 month s.