: Neuroprotection refers to the concept of administering a drug that ameliorates at the cellular level those biochemical perturbations leading to brain damage after an acute stroke. Many neuroprotective drugs have been shown to reduce damage in animal models of stroke. For instance, drugs that block glutamate receptors or downstream effects of glutamatergic activity reduce infarct volume by about 50% in rats. However, Clinical trials of these same drugs have failed to demonstrate efficacy. There are probably many reasons for these failures, but in summary, we have failed to design our clinical studies to match the circumstances under which these drugs are effective in the laboratory. For instance: 1. We have started drugs 6-24 hours after stroke onset in humans when they have only been effective in the lab if started within 2-3 hours. 2. We have standardized stroke severity and location in the lab, but have not done so when selecting patients for Clinical trials. 3. We have not routinely coupled neuroprotective therapy to attempts at reperfusion (i.e. giving them along with thrombolytic drugs), even though they are most effective in laboratory models of temporary arterial occlusion. 4. Because of side effects that limit doses we are able to give medically unstable stroke patients, we have not been able to achieve blood levels that are effective in animal models. Another important reason for our clinical failures may be that the drugs we have tested have not been sufficiently potent at protecting cells and reversing the biological abnormalities that occur after stroke. Stronger drugs or combinations of drugs affecting multiple pathways may be needed. This is a proposal for a pilot study that will address all these deficiencies. In work carried out in our laboratory over the past 2 years, we have found that the combination of various doses of ethanol and caffeine can reduce infarct volume by up to 80% after reversible middle cerebral artery occlusion, while the same doses given alone of ethanol are harmful and of caffeine are only slightly protective. This combination is effective if started up to 3 hours after the onset of stroke, and produces blood levels which are within the range that are very well tolerated in humans (i.e. below the legal intoxicating blood alcohol level and roughly 3 cups of coffee). Finally, this treatment is even more effective if coupled with mild hypothermia (body temperature reduced to 35 C). See Preliminary Results and Appendix #7 for details. A number of questions remain. The mechanism(s) of action of this combination are unclear. Caffeine blocks adenosine receptors that may lead to changes in glutamate release. Ethanol may affect glutamate and GABA, and also enhances the cellular uptake of a number of substances. These mechanisms need to be explored in future laboratory studies, which have been recently funded in a NIH RO-1, grant to Dr. Aronowski. The combination is less effective in animals that had been previously exposed to ethanol, suggesting a tolerance effect. This may limit its use or require higher doses in a population where alcohol is widely consumed. Finally, the optimal dose of this combination remains to be established in human stroke patients. There are no known reports of the use of the combination of ethanol and caffeine in human stroke patients. One lesson from previous neuroprotective trials is that we should try to achieve doses in humans resulting in blood levels at the high range of efficacy in animals. This may be particularly true in the case of ethanol/caffeine because of previous exposure of our patients to ethanol. In laboratory studies, 5-10% ethanol and 10-mg./kg. caffeine given intravenously in combination over 1 hour are most effective; higher doses provide no additional benefit in naive animals. It is unclear if these doses will be tolerated or effective in human stroke patients. However, the doses to be used in this study are well within the usually consumed amounts of these compounds.
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