Strategies for Neuroprotection with Glutamate Antagonists

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Abstract
Over fifty patients with severe head injury, and one hundred with stroke, have now been treated with the competitive NMDA antagonist CGS 19755 (selfotel). Preliminary analysis has shown possible evidence of benefit for both these clinical indications, and several other glutamate antagonists are now being evaluated for these indications in Phase II trials. The optimal dose of CGS 19755 (selfotel) for efficacy for severe head trauma has not yet been identified, but may be > 3 mg/kg, as at this dose there was evidence of an ICP lowering effect and improved CPP. For stroke, however, the maximal tolerated dose was 1.5 mg/kg, because these conscious patients developed hallucinations and agitation. There were no other significant drug-associated adverse events in either of these studies. It is difficult to determine the "neuroprotective" dose for this compound in humans. By extrapolating from animal studies the "best estimate" would be around 5 mg/kg in patients with severe head trauma. For stroke, behavioral side effects were the major limiting factor for dosing. Although several NMDA antagonists, including CGS 19755 (selfotel), are currently entering efficacy trials for stroke, based upon their tremendous potency in animal models, the problem of psychomimetic effects may necessitate the use of additional management strategies, e.g., more intensive monitoring and concomitant medications.
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