Neuroprotective agents in traumatic brain injury.
The role of neuroprotection in traumatic brain injury (TBI) is reviewed. Basic research and experimental investigations have identified many different compounds with potential neuroprotective effect. However, none of the Phase III trials performed in TBI have been successful in convincingly demonstrating efficacy in the overall population. A common misconception is that consequently these agents are ineffective. The negative results as reported in the overall population may in part be caused by specific aspects of the head injury population as well as by aspects of clinical trial design and analysis. The heterogeneity of the TBI population causes specific problems, such as a risk of imbalances between placebo and treated groups but also causes problems when a possible treatment effect is evaluated in relation to the prognostic effect present. Trials of neuroprotective agents should be targeted first of all to a population in which the mechanism at which the agent is directed is likely to be present and secondly to a population in which the chances of demonstrating efficacy are realistic, e.g., to patients with an intermediate prognosis. The possibilities for concomitant or sequential administration of different neuroprotective agents at different times deserve consideration. The potential for neuroprotection in TBI remains high and we should not be discouraged by recent failures obtained up until now. Rather, prior to initiating new trials, careful consideration of experimental evidence is required in order to optimise chances for mechanistic targeting and lessons learned from previous experience need to be taken to heart in the design of future studies.
Erasmus University Medical Center Rotterdam, Department of Neurosurgery, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. maas@neur.azr.nl
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy*; D002118:Calcium / Q000502:physiology; D002986:Clinical Trials as Topic; D005609:Free Radicals; D015316:Genetic Therapy; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D015227:Lipid Peroxidation; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D005609:Free Radicals; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D018698:Glutamic Acid; D002118:Calcium