Neuroprotectants in the treatment of stroke--an overview.

The concept of neuroprotection against the excitotoxic cascade that accompanies ischemic stroke has been proved in animal models. However, no clinical trial has so far shown a statistically significant benefit for a neuroprotectant in patients with acute ischemic stroke on primary end point measures. Some of these failures can be ascribed to poor study design, small sample sizes, or poor choice of primary outcome measures. Trials of NMDA (N-methyl-D-aspartate) antagonists, however, have been troubled by psychotomimetic side effects that may well have meant that the maximal dose that could be tolerated was suboptimal in terms of neuroprotection. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) lacks psychotomimetic side effects and has undergone a large randomized placebo-controlled trial--CLASS (Clomethiazole Acute Stroke Study). This study failed to detect a statistically significant overall effect of clomethiazole. However, a post hoc analysis based on a prospective clinical classification showed that clomethiazole was effective in a subgroup of patients who had deficits of a major stroke. A further clinical trial of clomethiazole in patients with deficits consistent with a major ischemic stroke is currently underway (CLASS-I). In absolute terms, the size of benefit that can be expected from a neuroprotectant may be relatively small, but even small benefits could make the difference between independence and dependence on others for activities of daily living. Even small effects could therefore produce meaningful improvements in quality of life for both patients and their families and could produce significant reductions in long-term costs. The introduction of an effective neuroprotectant will increase the need for stroke to be treated as urgent by both the public and emergency services.