Novel Counteract Agents To Reduce Mortality And Morbidity Following Organophosphate Status Epilepticus

这个项目的目标是证明铅中和化合物阿替洛尔(AT)和左乙拉西坦 有机磷(OP)农药和神经毒剂诱发癫痫持续状态(SE)后给予(LV)是安全的 和有效的治疗，以减少OP SE的死亡率和发病率，包括行为异常、认知障碍 损害、获得性癫痫(AE)和苔藓纤维发芽。SE是一种重大医疗紧急情况，与 接触有机磷农药、化学威胁、恐怖袭击、意外或自然灾害。 与SE相关的癫痫和OP引起的胆碱能危象的治疗取得进展 暴露，但目前没有可用的治疗方法来预防死亡和长期发病率 与OP SE相关联。我们的研究在理解OP SE的原因方面取得了重大进展 死亡率。我们的PR表明，OP SE后前7天的心脏应激性是死亡的主要原因 而用AT和LV治疗可以减少这种情况。我们在初步结果(PR)方面取得了突破 表明AT加LV可将死亡率降低70%以上，并显著降低发病率 超过50%，包括行为异常、认知障碍和AE的发展。这 PR还提示，AT和LV可以减轻OP SE后心脏应激反应和心脏和神经元的损伤。 这项研究将使用OP杀虫剂对氧磷(POX)，OP神经毒剂替代品二异丙基- 氟磷酸盐(DFP)和神经毒剂沙林诱导大鼠SE。我们的实验室非常适合于 开展这些研究，并培养了必要的技能，以实现以下具体目标：目标1： 确定AT和LV能否降低POX所致SE后的死亡率并进行药代动力学研究 中和先导化合物AT和LV腔内给药的药效学分析 肌肉发达，口感也不错。目的2：确定AT和LV能否降低DFP和沙林的死亡率 诱发SE及评价注射部位肌肉注射的急慢性效应 肌肉学。目的3：评价AT和LV能否减轻心脏应激性和心脏病理改变 POX、DFP和沙林SE后的变化。目标4：确定AT加LV是否可以减少 在POX、DFP和沙林SE后，可出现抑郁样症状，并提供神经保护。目标 5.评估AT加LV是否可以减少认知障碍的发展，以及AE的发展 POX、DFP和沙林SE后可见苔藓纤维萌发。公关证明了这些措施的可行性 研究并强调开展这项研究的潜在意义。AT和LV已用于 多年来临床上分别用于治疗高血压和癫痫，因此它们在人类中的使用 久负盛名。如果这些初步发现被记录在这项研究中，我们将举行一次IND前会议 与FDA合作，最终获得通过肌肉注射使用AT和LV作为 减少OP SE死亡率和发病率的有效治疗。

The goal of this project is to demonstrate that lead CounterAct compounds atenolol (AT) and levetiracetam (LV) given after organophosphate (OP) pesticide and nerve agent induced status epilepticus (SE) are a safe and effective treatment to reduce OP SE mortality and morbidity, including behavioral abnormalities, cognitive impairment, acquired epilepsy (AE) and mossy fiber sprouting. SE is a major medical emergency seen with exposure to OPs from chemical threats from terrorist attacks or from exposure by accident or natural disasters. Advances have been made to treat the seizures associated with SE and the cholinergic crisis from OP exposure, but at present there are no therapies available to prevent mortality and the long term morbidities associated with OP SE. Our research has made a major advance in understanding how OP SE causes mortality. Our PR indicate that cardiac irritability in the first 7 days after OP SE is the major cause of mortality and this can be reduced by treatment with AT and LV. We made a breakthrough in our preliminary results (PR) indicating that AT plus LV may reduce mortality by greater than 70% and also significantly reduce morbidity by greater than 50%, including behavioral abnormalities, cognitive impairments and the development of AE. This PR also suggests that AT and LV can reduce cardiac irritability and cardiac and neuronal damage after OP SE. This study will use the OP pesticide paraoxon (POX), the OP nerve agent surrogate diisopropyl- fluorophosphate (DFP) and the nerve agent sarin to induce SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims: Aim 1: Determine whether AT and LV can reduce mortality following POX induced SE and conduct pharmacokinetic and pharmacodynamic analyses for CounterACT lead compounds AT and LV when administered intra- muscularly and orally. Aim 2: Determine whether AT and LV can reduce mortality following DFP and sarin induced SE and evaluate the acute and chronic effects of intramuscular injections on injection site musculature. Aim 3: Evaluate whether AT and LV can reduce cardiac irritability and cardiac pathological changes following POX, DFP and sarin SE. Aim 4: Determine whether AT plus LV can reduce the development of depression-like symptoms and provide neuroprotection following POX, DFP and sarin SE. Aim 5. Evaluate whether AT plus LV can reduce the development of cognitive impairment, the development of AE and mossy fiber sprouting following POX, DFP and sarin SE. The PR demonstrate the feasibility of these studies and underscore the potential significance of conducting this research. AT and LV have been used for many years clinically to treat hypertension and seizures, respectively, and thus their use in humans has been well established. If these preliminary findings are documented in this study, we will conduct a pre-IND meeting with the FDA for ultimately getting an IND for the use of AT and LV by intramuscular administration as an effective treatment for reducing mortality and morbidity from OP SE.