Network Pharmacology for Epilepsy Prevention

摘要 癫痫的预防是神经病学中一个主要的未满足的需求。大约20%的癫痫是 由于急性脑损伤，例如创伤性脑损伤（TBI，5%）、中风（10%）和中枢神经系统感染 在这些损伤之后，在癫痫发展之前存在数天至数年的潜伏期。这 提供了干预治疗以预防或改变癫痫的机会。没有这种待遇 存在. 癫痫是一种复杂的网络现象。急性中枢神经系统损伤后的癫痫发生涉及 不同的病理生理过程。我们以前曾提出，理性组合 针对癫痫网络的不同靶点的药物可能是一种更有效的方法， 预防性治疗策略优于单一特定药物治疗。我们最近测试了 网络方法在啮齿动物癫痫持续状态（SE）后癫痫模型中的应用 结合多种临床批准的药物，通过各种途径靶向癫痫发生， 机制，包括抗炎，抗氧化，神经保护和神经递质- 调节效应这些研究的积极成果为目前的研究奠定了基础。 建议开发基于网络药理学的癫痫预防治疗， FDA批准药物的再利用 我们将 (1)比较两种药物联合治疗的药代动力学、耐受性和疗效 FDA批准的药物（PrevEp 001和PrevEp 002）具有良好的安全性， 在预防和/或改善PTE中的抗癫痫作用（三联组合）， 经验证的PTE的TBI模型，大鼠液压冲击模型， (2)开发三联制剂的新型静脉注射制剂，并建立GMP生产 确保临床试验供应的流程。 (3)通过以下方法评价大鼠静脉注射三联制剂给药的耐受性和毒性： 进行符合GLP的多次给药毒性研究。 (4)使用从本项目获得的数据与FDA召开IND前会议， 从我们以前的SE癫痫发生研究，使人类I-IIa期发展计划。 总的来说，该项目将为进行第一次人类胚胎学研究提供基础， 三重组合。

ABSTRACT Prevention of epilepsy is a major unmet need in neurology. Approximately 20% of all epilepsy is due to acute brain insult such as traumatic brain injury (TBI, 5%), stroke (10%), and CNS infection (~5%).Following these injuries, there is a latency of days to years before epilepsy develops. This offers opportunity to intervene with treatment to prevent or modify epilepsy. No such treatment exists. Epilepsy is a complex network phenomenon. Epileptogenesis after acute CNS injury involves different pathophysiological processes. We have previously proposed that rational combinations of drugs that engage different targets of the epileptogenic network may be a more effective preventive treatment strategy than treatment with single specific drugs. We recently tested the network approach in rodent models of epilepsy after status epilepticus (SE) by rationally combining a variety of clinically approved drugs that target epileptogenesis by various mechanisms, including anti-inflammatory, anti-oxidant, neuroprotective, and neurotransmitter- modulating effects. Positive outcome from those studies provides the basis for the present proposal to develop epilepsy prevention therapy based on network pharmacology and the repurposing of FDA approved drugs. We shall (1) Compare pharmacokinetics, tolerability and efficacy of treatment with two drug combinations of FDA approved drugs (PrevEp001 and PrevEp002) with good safety profile and different antiepileptogenic effects (triple combinations) in prevention and/or amelioration of PTE in in a validated TBI model of PTE, the rat fluid percussion model (2) Develop novel i.v. formulation(s) of the triple combination and establish a GMP manufacturing process to enable clinical trial supply. (3) Evaluate tolerance and toxicity of the i.v. triple combination formulation treatment in rats by conducting a GLP compliant multiple dose toxicity study. (4) Conduct a pre-IND meeting with the FDA using data obtained from the present project and from our previous SE epileptogenesis studies to allow human phase I-IIa development programs. Overall, the project will provide the basis for conducting the first in human PoC study with the triple combination.