Stroke Treatment by Chemically-induced Hypothermia

 描述(申请人提供)：在美国，中风是人类死亡和残疾的主要原因，而急性中风的临床治疗是有限的和不令人满意的。临床试验中的许多失败有力地支持了这样一种观点，即为了对抗这种多方面的麸质障碍，需要针对多种细胞类型和不同机制的新策略，以实现对人类的治疗效果。在这种方法的几种可能的治疗方法中，低温在动物和人类研究中显示出显著的神经保护作用(高达90%)，对脑缺血具有保护作用。不幸的是，可用的物理冷却技术是无效的，而且往往不切实际。因此，长期以来，人们一直在寻找可用于低温治疗的药物化合物来治疗中风。预计使用药物诱导的低温(PIH)可以更早地开始治疗，而即使在中风后早期几小时内体温下降1-20摄氏度，也应该可以防止有害的中风后体温过高。轻度至中度低温(降低2-5oC)将延缓缺血性损伤的演变，并可能延长其他干预措施的治疗窗口，例如FDA批准的唯一使用重组组织型纤溶酶原激活剂(TPA)的溶栓治疗。在我们的第一阶段研究中，我们在小鼠和大鼠模型上展示了几种新的神经降压素受体1(NTR1)化合物的降温作用以及它们对缺血性卒中、出血性卒中和创伤性脑损伤(TBI)所致脑损伤的显著神经保护作用。我们已经确定了两种主要化合物，可以转移到拟议的第二阶段调查。我们的初步研究也证明了先导化合物对非人类灵长类动物的降温作用。在第二阶段研究中，特殊目标1将检验我们的假设，即妊高征治疗作为一种可能的现场治疗 急性治疗，不仅具有神经保护作用，而且可以延长tPA治疗的治疗窗口期。我们将在模拟临床情况的小鼠栓塞性中风模型中研究这种可能性。具体目标2将确定我们的化合物可能的副作用和毒性，以确认它们是否适合于进一步的临床前和临床开发和完成 IND准备所需的实验。具体目标3将检查选定的NTR1衍生物在猴子身上的降温效果，以了解剂量-反应关系，并确定其降温效果的持续时间和复温动力学。在猴体内的MRI成像将为药物对妊高征后脑温、脑血流量、血脑屏障、灰质和白质变化以及出血转化的影响提供有价值的数据。预计未来将有1种或多种先导化合物在中风猴子模型和人类临床试验中得到验证。这项转化研究是由一群在基础和临床前中风领域拥有互补专业知识的科学家进行的，将为临床中风治疗的潜在突破提供令人信服的证据。

 DESCRIPTION (provided by applicant): Stroke is a leading cause of human death and disability in the United States while clinical therapy for acute stroke is limited and unsatisfactoy. The many failures in clinical trials strongly endorse the idea that to battle this multifaceted bran disorder, novel strategies that target multiple cell types and different mechanisms are needed to achieve therapeutic effects in humans. Among a few potential treatments of this approach, hypothermia has shown remarkable neuroprotective (up to 90%) effects against brain ischemia in animal and human studies. Unfortunately, available physical cooling techniques are ineffectual and often impractical. Thus, pharmacological compounds that can be utilized for hypothermia therapy have long been sought for the treatment of stroke. It is expected that using pharmacologically induced hypothermia (PIH) the treatment can be initiated much earlier while even a small (1-2oC) decrease in body temperature during early hours after stroke should prevent detrimental post-stroke hyperthermia. A mild to moderate hypothermia (2-5oC reduction) will delay the evolution of ischemic injury and may extend the therapeutic window for other interventions such as the only FDA approved thrombolytic treatment using recombinant tissue plasminogen activator (tPA). In our Phase I investigation, we demonstrated hypothermic effects of several novel neurotensin receptor 1 (NTR1) compounds and their marked neuroprotective effects against brain damage induced by ischemic stroke, hemorrhage stroke and traumatic brain injury (TBI) in mouse and rat models. We have identified two leading compounds for moving to the proposed Phase II investigation. Our pilot study has also demonstrated the hypothermic effect of the leading compounds in non-human primates. In the Phase II study, Specific Aim 1 will test our hypothesis that the PIH therapy, as a possible on-site acute treatment, is not only neuroprotective but also can prolong the therapeutic window of tPA treatment. We will investigate this possibility in an embolic stroke model of mice that mimics clinical situations. Specific Aim 2 will identify possible side-effects and toxicity of our compouns in order to confirm their suitability for further preclinical and clinical development and complete experiments necessary for IND preparation. Specific Aim 3 will examine the hypothermic effect of the selected NTR1 derivatives in monkeys to understand the dose-response relationship and determine the duration and rewarming kinetics of their hypothermic effects. MRI imaging in monkeys will provide valuable data for the drug effect on brain temperature, cerebral blood flow, the blood brain barrier, gray and white matter changes, and hemorrhage transformation after PIH. It is expected that 1 or more leading compounds will be validated for a future study in stroke monkey models and clinical trials in humans. The translational research is pursued by a group of scientists with complementary expertise in basic and pre-clinical stroke fields and will provide compelling evidence for a potential breakthrough in clinical stroke therapy.