Conclusion

The recent history of neuroprotective clinical trials in stroke reveals multiple agents that demonstrated efficacy in preclinical studies failed to achieve expected results in clinical trials. Although the exact reasons for this are unknown, possibilities include: longer time window in clinical trials than in animal studies, lower tolerated drug levels, a more heterogeneous variety of strokes compared to "pure" middle cerebral artery (MCA) stroke animal studies, the majority of clinical strokes involving "permanent" ischemia compared to transient reperfusion MCA

filament animal studies, insensitive clinical endpoints, and inadequately powered studies. In an effort to improve the ability of preclinical trials to predict clinical success, a more rigorous preclinical evaluation program is advocated (STAIR criteria). Development of neuroprotective agents unhampered by side effects might involve modifications in structure to improve benefit-to-risk ratios and allow for improved central nervous system levels. Currently, the most promising area involves anti-free radical agents, and it is hoped that the results of the SAINT II trial will confirm the efficacy seen in SAINT I. Finally, novel agents that have not yet completed clinical trials hold the promise of potential efficacy in such areas as targeting gene and protein expression following stroke.

In the future, optimal therapy might be achieved by combining neuroprotective agents with reperfusion mechanisms to produce additive benefits. Alternatively, they might be used prior to recombinant tissue plasminogen activator therapy in an effort to "slow the brain down," so the time window for thrombolysis can be extended. Because these drugs will most likely not display adverse effects in those patients with hemorrhagic stroke, ambulance crews could begin administering this "stroke cocktail."

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