Preclinical efficacy and toxicity evaluation of carnosine in stroke

描述(申请人提供)：中风是美国第三大致死原因，也是导致成人残疾的最大原因。静脉注射组织型纤溶酶原激活剂(t-PA)是美国食品和药物管理局(FDA)批准的唯一一种治疗缺血性中风的急性药物疗法，必须在症状出现后3小时内和脑出血排除后给予。主要由于治疗时间窗口很短，在所有住院的中风患者中，使用溶栓治疗的患者不到2%。卒中期间脑血流的中断会引发一连串的有害事件，最终可能导致细胞死亡。这一过程通过多条途径发生，但尚未确定明确的最终途径。以往的神经保护策略主要针对单一通路。然而，一种“理想的”神经保护剂应该有利于影响多种途径，应该是安全的，耐受性良好，并且应该有很长的治疗时间窗口。肌肽是一种二肽，是一种内源性抗氧化剂，是一种广受欢迎的膳食补充剂，没有已知的副作用或与其他药物的不良反应。大量数据表明，它也可能有利地影响在中风中被激活的多条有害通路，并且在中风动物模型中似乎具有强大的保护作用。根据这些数据，肌肽似乎是治疗中风的一个很好的候选药物。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。目前还没有这些数据。该项目的目的是生成临床前的药代动力学、有效性和安全性数据，用于将肌肽用作中风的神经保护疗法。短暂性和永久性脑缺血的大鼠模型将用于毒性和疗效研究。这些数据将被用来计划更详细的临床前研究，从而最终在人体上进行测试。长期目标是开发一种新的安全有效的中风疗法，使更多的人受益，而不是目前可用的疗法。 在美国，中风是导致死亡和残疾的主要原因之一。FDA批准的唯一治疗方法必须在症状出现后三个小时内进行，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。该项目的目标是对一种名为肌肽的安全、创新和有前景的天然药物进行临床前评估，因为它在早期临床前中风研究中产生了出色的结果，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.