Treatment of acute stroke ethanol and caffeine

描述(由申请人提供)：神经保护是指在急性中风后，在细胞水平上改善导致脑损伤的生化紊乱的药物的概念。在中风的动物模型中，许多神经保护性药物已经被证明可以减少损害。例如，阻断谷氨酸受体或谷氨酸能活动的下游效应的药物可以将大鼠的脑梗塞体积减少约50%。然而，这些药物的临床试验未能证明疗效。这些失败的原因可能有很多，但总而言之，我们未能设计出与这些药物在实验室中有效的情况相匹配的临床研究。例如： 1.我们在人类中风发作6-24小时后开始服用药物，而这些药物只在 如果在2-3小时内开始使用，在实验室有效。2.我们在实验室中对中风的严重程度和部位进行了标准化，但在选择患者进行临床试验时还没有这样做。 3.我们没有例行公事地将神经保护治疗与再灌注尝试(即给予 它们与溶栓药物一起使用)，即使它们在实验室模型中最有效 暂时性动脉闭塞。4.由于副作用限制了我们能够给医学上不稳定的中风患者提供的剂量，我们无法达到在动物模型中有效的血药浓度。我们临床失败的另一个重要原因可能是我们测试的药物在保护细胞和逆转中风后发生的生物异常方面不够有效。可能需要更强的药物或影响多个途径的药物组合。这是一项试点研究的建议，将解决所有这些缺陷。在我们实验室过去两年的工作中，我们发现，在可逆性大脑中动脉闭塞后，不同剂量的乙醇和咖啡因的组合可以将脑梗塞体积缩小高达80%，而相同剂量的单独给予乙醇是有害的，咖啡因只能起到轻微的保护作用。如果在中风发作后3小时内开始，这种联合是有效的，并且产生的血液水平在人类很好地耐受的范围内(即低于合法的令人陶醉的血液 酒精水平和大约3杯咖啡)。最后，如果结合亚低温(体温降至35摄氏度)，这种治疗甚至更有效。有关详细信息，请参阅初步结果和附录7。许多问题仍然存在。这种结合的作用机制(S)尚不清楚。咖啡因阻断了腺苷受体，腺苷受体可能导致谷氨酸释放的变化。乙醇可能会影响谷氨酸和GABA，也会增强细胞对许多物质的摄取。这些机制需要在未来的实验室研究中探索，这些研究最近由NIH RO-1资助，授予阿罗诺夫斯基博士。这种组合在以前接触过乙醇的动物身上效果较差，这表明了一种耐受效应。这可能会限制它的使用，或者在酒精广泛消费的人群中需要更高的剂量。最后，在人类中风患者中，这种组合的最佳剂量仍有待确定。目前还没有关于在人类中风患者中使用乙醇和咖啡因的联合使用的已知报告。从以前的神经保护试验中得到的一个教训是，我们应该尝试在人类身上实现剂量，从而使血液水平达到动物的高疗效范围。这在乙醇/咖啡因的情况下可能尤其正确，因为我们的患者以前接触过乙醇。在实验室研究中，5-10%乙醇和10毫克/公斤。联合静脉注射咖啡因超过1小时是最有效的；高剂量对幼稚的动物没有额外的好处。目前尚不清楚这些剂量在人类中风患者中是否可以耐受或有效。然而，在这项研究中使用的剂量完全在这些化合物通常的消耗量之内。

DESCRIPTION (provided by the applicant): 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.