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

该项目的目标是证明，主要的CounterAct化合物阿替洛尔（AT）和左乙拉西坦 (LV)在有机磷农药和神经毒剂诱发癫痫持续状态（SE）后给予， 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， 损伤、获得性癫痫（AE）和苔藓纤维发芽。SE是一种主要的医疗紧急情况， 由于恐怖主义袭击的化学威胁或由于意外事故或自然灾害而接触有机磷。 SE引起的癫痫发作和OP引起的胆碱能危象的治疗已取得进展 暴露，但目前没有可用的治疗方法来预防死亡率和长期发病率 与OP SE相关。我们的研究在了解OP SE如何引起方面取得了重大进展 mortality.我们的PR表明，OP SE后前7天的心脏易激惹是死亡的主要原因 这可以通过AT和LV治疗来减少。我们在初步结果（PR）上取得了突破性进展 表明AT加LV可使死亡率降低70%以上， 超过50%，包括行为异常、认知障碍和AE的发展。这 PR还表明，AT和LV可以减少OP SE后的心脏应激性以及心脏和神经元损伤。 本研究将使用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 进行这些研究，并已发展必要的技能，以实现以下具体目标：目标1： 确定AT和LV是否可以降低POX诱导SE后的死亡率，并进行药代动力学研究 当静脉内给药时，CounterACT先导化合物AT和LV的药效学分析 肌肉和口腔。目的2：确定AT和LV是否可以降低DFP和沙林后的死亡率 诱发SE，并评估肌肉注射对注射部位的急性和慢性影响 肌肉组织目的3：评价AT和LV是否可以降低心脏应激性和心脏病理 POX、DFP和沙林SE之后的变化。目的4：确定AT加LV是否可以减少 抑郁样症状的发展，并提供神经保护后POX，DFP和沙林SE。目的 5.评估AT加LV是否可以减少认知障碍的发展，AE的发展 POX、DFP和沙林SE后苔藓纤维发芽。PR证明了这些方法的可行性。 研究，并强调进行这项研究的潜在意义。AT和LV已用于 多年来在临床上分别用于治疗高血压和癫痫发作，因此它们在人类中的应用已经被广泛接受。 很好地建立了。如果这些初步结果记录在本研究中，我们将召开IND前会议 与FDA最终获得IND，用于肌内给药AT和LV， 降低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.