Preclinical efficacy and toxicity evaluation of carnosine in stroke

描述（由申请人提供）：中风是美国第三大死亡原因，也是成人残疾的最大单一原因。静脉注射组织纤溶酶原激活剂（t-PA）是唯一一种经美国食品药品监督管理局（FDA）批准的缺血性卒中急性药物治疗，必须在症状发作后3小时内和排除脑出血后给药。主要是由于治疗时间窗短，溶栓治疗用于所有住院卒中患者的不到2%。中风期间脑灌注的中断引发了一系列有害事件，最终可能导致细胞死亡。该过程通过多种途径发生，但尚未确定明确的最终途径。以前的神经保护策略集中在靶向单一通路。然而，“理想的”神经保护剂应该有利地影响多个途径，应该是安全的和良好耐受的，并且应该具有长的治疗时间窗。肌肽是一种二肽，是一种内源性抗氧化剂，也是一种流行的膳食补充剂，没有已知的副作用或与其他药物的不良相互作用。相当多的数据表明，它也可能有利地影响中风中激活的多种有害途径，并且它似乎在中风动物模型中具有强大的保护作用。基于这些数据，肌肽似乎是一个很好的候选人作为治疗中风。然而，在进行临床试验之前，需要严格和广泛的临床前药代动力学，安全性和有效性数据。这些数据目前不可用。本项目的目的是生成肌肽作为脑卒中神经保护治疗的临床前药代动力学、疗效和安全性数据。短暂性和永久性缺血大鼠模型将用于毒性和疗效研究。这些数据将用于计划更详细的临床前研究，最终将允许在人体中进行测试。长期目标是开发一种新的安全有效的中风治疗方法，使更多的人受益。 中风是美国死亡和残疾的主要原因之一。FDA唯一批准的治疗必须在症状发作后三小时内进行，但大多数中风患者没有资格接受这种治疗，因为他们到达医院太晚了。该项目的目标是在临床前评估一种名为肌肽的安全，创新和有前途的天然药物，因为它在早期临床前中风研究中取得了优异的结果，并有可能使更多的中风患者受益。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of mortality in the United States and the largest single cause of adult disability. Intravenous tissue plasminogen activator (t-PA) is the only Food and Drug Administration (FDA) approved acute drug therapy for ischemic stroke and must be administered within three hours of symptom onset and after intracerebral hemorrhage has been excluded. Primarily due to this short time window for treatment, thrombolytic therapy is used in less than 2% of all hospitalized stroke patients. The interruption of cerebral perfusion during stroke initiates a cascade of detrimental events that may ultimately lead to cell death. This process occurs via multiple pathways but no clear final pathway has been identified. Previous neuroprotection strategies have focused on targeting single pathways. However, an "ideal" neuroprotectant should favorably influence multiple pathways, should be safe and well tolerated, and should have a long therapeutic time window. Carnosine, a dipeptide, is an endogenous antioxidant and a popular dietary supplement with no known side effects or adverse interactions with other drugs. Considerable data suggest that it may also favorably influence multiple deleterious pathways that are activated in stroke and it appears to robustly protect in an animal model of stroke. Based on these data, carnosine appears to be an excellent candidate as a therapy for stroke. However, before clinical testing can take place, rigorous and extensive preclinical pharmacokinetic, safety and efficacy data are required. These data are not available at this time. The aims of this project are to generate pre-clinical pharmacokinetic, efficacy and safety data for the use of carnosine as a neuroprotective therapy in stroke. The rat model of transient and permanent ischemia will be used for both toxicity and efficacy studies. These data will be used to plan more detailed preclinical studies that will allow eventual testing in humans. The long term goal is to develop a new safe and effective stroke therapy that will benefit far more people than the currently available therapy. Stroke is one of the leading causes of death and disability in the United States. The only approved FDA therapy must be administered within three hours of symptom onset but most stroke victims are not eligible for this treatment because they arrive in hospital too late. The goal of this project is to evaluate pre-clinically, a safe, innovative and promising natural drug called carnosine, because it has produced excellent results in early preclinical stroke studies and has the potential to benefit many more stroke patients.