Gentamicin for Improving Survival and Outcome after Subarachnoid Hemorrhage.

庆大霉素可改善蛛网膜下腔出血后的生存和结果。

基本信息

批准号：
8554383
负责人：
FATIMA A SEHBA
金额：
$ 20.45万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554383
关键词：
Acute Agonist Aneurysmal Subarachnoid Hemorrhages Animals Antibiotics Apoptosis Behavior Behavioral Blood Brain Injuries Calcium Cerebrum Cessation of life Chemotaxis Clinical Cognitive Control Animal Creatinine Creatinine clearance measurement Data Development Diagnosis Dose Effectiveness Emergency Situation Funding Gentamicins Goals Health Healthcare Hemorrhage Hour Injury Kidney Knowledge Life Longevity Measures Medical Mission Modeling Monitor Morbidity - disease rate Nerve Degeneration Neurologic Neurological outcome Neurological status Neuronal Injury Neurons Operative Surgical Procedures Outcome Outcomes Research Patients Pb clearance Phagocytosis Phase Play Proteins Public Health Publishing Renal function Research Respiratory Burst Role Safety Saline Serum Staging Subarachnoid Hemorrhage Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Toxic effect Translating Translations Urea Urine Vasodilator Agents Work base burden of illness constriction disability improved inhibitor/antagonist innovation medical attention mortality neutrophil patient population receptor research study sensor time interval

项目摘要

DESCRIPTION (provided by applicant): Aneurysmal subarachnoid hemorrhage is a medical emergency associated with high early mortality and morbidity. The mechanisms underlying early deaths are poorly understood and no specific therapy to reduce early mortality currently exists. Survival and outcome are influenced by SAH intensity; the greater the intensity the greater the chances of death and disability. Our long term goal is to identify treatments that increase survival and improve outcome after SAH. We are studying contribution of brain injury in early mortality after high intensity experimental SAH. We have found that injury in cerebral vasculature and in neurons is present within 24 hours after SAH. Vessel injury is observed as structural damage and neuronal injury as degeneration and apoptosis. In addition, we have found substantial behavioral and neurological deficits and limited survival (at most 72 hours) in SAH animals. In preliminary experiments we have found that gentamicin administered post-SAH increases survival and improves neurological outcome in SAH animals. The objective of this application is to obtain proof of principle on efficacy of gentamicin in extending survival and improving neurological outcome after SAH. The data obtained will be used as a guide to apply for funds to develop gentamicin as first-line therapy against mortality and morbidity in SAH patients. The rationale that underlies proposed research is that it will identify a therapeutic option that would reduce early mortality and morbidity after SAH. Guided by strong preliminary data this hypothesis will be tested by pursuing three specific aims: 1) establish an optimal dose range of gentamicin for reducing mortality and improving outcome after SAH; (2) examine the effectiveness of delayed gentamicin treatment on post-SAH mortality and outcome; and (3) establish safety of gentamicin after SAH. As the purpose of this application is to obtain data towards clinical translation, all studies will include both low and high intensity SAH groups. Under the first aim, three doses of gentamicin will be compared for improvement in survival and neurological outcome after SAH. Under the second aim, the duration after SAH for which gentamicin remains effective in improving survival and outcome will be determined; the first 24 hours will be studied. Under the third aim, time required for serum gentamicin clearance, serum creatinine and urea and urine protein concentration in dose and time matched SAH and sham operated animals will be compared. The approach is innovative because it focuses on gentamicin, currently not used against SAH to reduce mortality and improve neurological outcome. The proposed study is significant because it is expected to establish a therapeutic agent that could dramatically reduce early mortality and morbidity in a patient population for which currently no such therapy option exist.

描述（由申请人提供）：动脉瘤性蛛网膜下腔出血是一种与高早期死亡率和发病率相关的医疗紧急情况。人们对早期死亡的机制知之甚少，目前尚无降低早期死亡率的具体疗法。生存率和结果受 SAH 强度的影响；强度越大，死亡和残疾的机会就越大。我们的长期目标是找到能够提高 SAH 后生存率并改善预后的治疗方法。我们正在研究脑损伤对高强度实验性蛛网膜下腔出血后早期死亡的影响。我们发现 SAH 后 24 小时内就会出现脑血管和神经元损伤。血管损伤表现为结构损伤，神经元损伤表现为变性和凋亡。此外，我们还发现 SAH 动物存在严重的行为和神经缺陷以及有限的生存（最多 72 小时）。在初步实验中，我们发现 SAH 后给予庆大霉素可提高 SAH 动物的存活率并改善神经系统结果。本申请的目的是获得庆大霉素在 SAH 后延长生存期和改善神经学结果方面功效的原理证明。获得的数据将用作申请资金开发庆大霉素作为降低 SAH 患者死亡率和发病率一线疗法的指南。拟议研究的基本原理是，它将确定一种可以降低 SAH 后早期死亡率和发病率的治疗方案。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验：1）建立庆大霉素的最佳剂量范围，以降低SAH后的死亡率并改善预后； (2) 检查延迟庆大霉素治疗对 SAH 后死亡率和结局的有效性； (3) 确定 SAH 后庆大霉素的安全性。由于本申请的目的是获取临床转化数据，因此所有研究都将包括低强度和高强度 SAH 组。第一个目标是比较三种剂量的庆大霉素对 SAH 后生存率和神经系统结果的改善情况。根据第二个目标，将确定 SAH 后庆大霉素在改善生存和预后方面仍有效的持续时间；将研究前 24 小时。在第三个目标下，将比较剂量和时间匹配的 SAH 和假手术动物的血清庆大霉素清除所需的时间、血清肌酐和尿素以及尿蛋白浓度。该方法具有创新性，因为它的重点是庆大霉素，目前尚未用于治疗SAH以降低死亡率和改善神经系统结果。这项拟议的研究意义重大，因为它有望建立一种治疗剂，可以显着降低目前尚无此类治疗选择的患者群体的早期死亡率和发病率。