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: 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
• 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

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与早期死亡率高和发病率相关的医疗紧急情况。早期死亡的基础机制知之甚少，没有具体的疗法来降低早期死亡率。生存和结果受SAH强度的影响；强度越大，死亡和残疾的机会就越大。我们的长期目标是确定在SAH之后增加生存和改善结果的治疗方法。我们正在研究高强度实验SAH后早期死亡率的脑损伤的贡献。我们发现，在SAH后24小时内，脑血管和神经元的损伤存在。血管损伤被视为结构性损伤和神经元损伤是变性和凋亡。此外，我们发现了SAH动物的大量行为和神经系统缺陷以及有限的生存率（最多72小时）。在初步实验中，我们发现庆大霉素施用后sah增加了生存率，并改善了SAH动物的神经系统效果。该应用的目的是获得庆大霉素在扩展生存和改善SAH后神经系统效果方面有效性原理证明。获得的数据将用于申请资金，以发展庆大霉素为SAH患者死亡率和发病率的一线治疗。拟议研究基础的基本原理是，它将确定一种治疗选择，可以降低SAH后早期死亡率和发病率。在强有力的初步数据的指导下，将通过追求三个特定目的来检验该假设：1）建立最佳剂量范围庆大霉素，以降低SAH之后的死亡率和改善结果； （2）检查延迟庆大霉素治疗对SAH死亡率和结果的有效性； （3）在SAH之后确定庆大霉素的安全。由于本应用的目的是获取用于临床翻译的数据，因此所有研究都将包括低强度和高强度SAH组。在第一个目标下，将比较三剂庆大霉素，以改善SAH后的生存和神经系统效果。在第二个目标下，将确定庆大霉素在改善生存和结果的SAH之后的持续时间；最初的24小时将研究。在第三个目标下，将比较血清庆大霉素清除率，血清肌酐和尿素以及剂量和时间匹配的SAH和假手术动物中的尿液蛋白浓度。这种方法具有创新性，因为它专注于庆大霉素，目前尚未针对SAH来降低死亡率并改善神经系统结果。拟议的研究很重要，因为预计将建立一种治疗剂，该治疗剂可以大大降低目前尚无这种治疗选择的患者人群的早期死亡率和发病率。