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(Stroke. 2002;33:309.)
© 2002 American Heart Association, Inc.

Controversies in Stroke

Neuroprotection: Establishing Proof of Concept in Human Stroke

Stephen M. Davis, MD, FRACP Geoffrey A. Donnan, MD, FRACP

From the Department of Neurology, Royal Melbourne Hospital (S.M.D.), and the National Stroke Research Institute, Austin & Repatriation Medical Centre (G.A.D.), University of Melbourne, Parkville, Victoria, Australia.

Correspondence to Prof Stephen M. Davis, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail stephen.davis@mh.org.au

Key Words: clinical trials • neuroprotection • stroke assessment

The failure to translate the positive effects of a variety of neuroprotective strategies from animal models to human trials has perplexed investigators. This contrasts with the success of tissue plasminogen activator, where efficacy in animal models was translated into positive trial results. Postulated reasons for these expensive trial failures include defective trial design (particularly time window and trial size) and the heterogeneity and complexity of human stroke compared with animal infarct models. Further explanations might be the lack of entry of neuroprotective compounds into the ischemic brain (suggesting that these agents might require thrombolysis to facilitate access), their lack of benefit in white matter, and the fairly modest effect of neuroprotection in penumbral salvage, even if reperfusion has occurred.

We agree with Grotta that the animal experiments should be replicated as closely as possible in trials, including standardization of stroke severity and appropriately short times to treatment. Importantly, he also mentions that compounds with multiple sites of action on the neurotoxic cascade may be more effective. Lees has pointed out that improved trial design, tightened entry criteria, and more sophisticated endpoint selection have already occurred and should increase the chances of success.

Despite the plethora of negative neuroprotective trials, an array of compounds has been shown to dramatically reduce infarct volume in animal models. It seems quite implausible to us that these experiments should not be translated to human stroke, given a potent agent, adequate drug levels in ischemic tissue, a short time window, lack of toxicity, and well-designed stroke . . . [Full Text of this Article]

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