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。

• 批准号: 8444088
• 负责人: FATIMA A SEHBA
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444088
• 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

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. PUBLIC HEALTH RELEVANCE: Approximately 48% of patients die within 48 hours after subarachnoid hemorrhage. The proposed research is relevant to public health as it will reveal the potential of gentamicin in reducing early mortality and morbidity after experimental SAH and set the stage for the translating this therapy in SAH patients. This research is relevant to the part of NIH's mission as it will produce fundamental knowledge to enhance health, lengthen life and reduce the burdens of illness and disability.

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急诊内科疾病。人们对早期死亡的机制知之甚少，目前还没有专门的治疗方法来降低早期死亡率。生存和预后受蛛网膜下腔出血强度的影响；强度越大，死亡和残疾的机会越大。我们的长期目标是确定能够提高SAH后存活率和改善预后的治疗方法。我们正在研究脑损伤在高强度实验性蛛网膜下腔出血后早期死亡率中的作用。我们发现SAH后24小时内出现脑血管和神经元的损伤。血管损伤主要表现为结构损伤，神经元损伤主要表现为变性和细胞凋亡。此外，我们还发现SAH动物存在严重的行为和神经缺陷，存活时间有限(最多72小时)。在初步实验中，我们发现SAH后给予庆大霉素可增加SAH动物的存活率并改善其神经预后。本应用的目的是获得庆大霉素在延长SAH后生存期和改善神经预后方面疗效的原则证据。获得的数据将作为申请资金的指南，用于开发庆大霉素作为SAH患者死亡率和发病率的一线治疗方法。建议研究的基本原理是，它将确定一种治疗方案，可以降低SAH后的早期死亡率和发病率。在强大的初步数据的指导下，这一假设将通过追求三个具体目标来检验：1)建立降低SAH后死亡率和改善预后的庆大霉素的最佳剂量范围；(2)检查延迟的庆大霉素治疗对SAH后死亡率和预后的有效性；以及(3)建立SAH后庆大霉素的安全性。由于这项应用的目的是获得临床翻译数据，所有研究都将包括低强度和高强度SAH组。在第一个目标下，将比较三种剂量的庆大霉素对SAH后存活率和神经预后的改善。在第二个目标下，将确定在SAH后庆大霉素在改善存活率和预后方面仍然有效的持续时间；前24小时将被研究。在第三个目标下，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时间、血肌酐和尿素以及尿蛋白浓度。这种方法是创新的，因为它专注于庆大霉素，目前不用于治疗SAH，以降低死亡率和改善神经预后。这项拟议的研究意义重大，因为它有望建立一种治疗剂，可以显著降低目前尚不存在此类治疗选择的患者群体的早期死亡率和发病率。 公共卫生相关性：大约48%的患者在蛛网膜下腔出血后48小时内死亡。这项拟议的研究与公共卫生相关，因为它将揭示庆大霉素在降低实验性SAH后早期死亡率和发病率方面的潜力，并为在SAH患者中推广这种疗法奠定基础。这项研究与NIH使命的一部分相关，因为它将产生增进健康、延长寿命和减轻疾病和残疾负担的基础知识。