Network Pharmacology for Epilepsy Prevention

摘要 癫痫的预防是神经病学中尚未得到满足的主要需求。大约20%的癫痫患者 由于急性脑损伤，如创伤性脑损伤(5%)、中风(10%)和中枢神经系统感染 (~5%)。在这些损伤之后，癫痫的发展需要几天到几年的潜伏期。这 提供干预治疗以预防或改善癫痫的机会。没有这样的待遇 是存在的。 癫痫是一种复杂的网络现象。急性中枢神经系统损伤后癫痫的发生涉及 不同的病理生理过程。我们之前曾提出，合理的组合 结合致痫网络的不同靶点的药物可能更有效 预防性治疗策略优于单一特效药治疗。我们最近测试了 合理运用网络技术建立癫痫持续状态(SE)大鼠模型 结合各种临床批准的药物，通过不同的方法来针对癫痫的发生 机制，包括抗炎，抗氧化，神经保护和神经递质- 调制效应。这些研究的积极结果为目前的研究提供了基础 开展基于网络药理学的癫痫预防治疗的建议 重新调整FDA批准的药物的用途。 我们会 (1)比较两种药物组合的药代动力学、耐受性和疗效 FDA批准的药物(PrevEp001和PrevEp002)具有良好的安全性和不同 抗癫痫作用(三联)在预防和/或改善癫痫发作中的作用 大鼠液压撞击模型PTE模型的验证 (2)开发新颖的静脉输液。制定(S)三者结合，建立GMP制造 启用临床试验供应的流程。 (3)评价静脉注射的耐受性和毒性。三联制剂对大鼠的治疗作用 进行符合GLP的多剂量毒性研究。 (4)使用从本项目获得的数据与FDA举行IND前会议，并 从我们之前的SE癫痫发生研究中，我们可以进行人类I-IIa阶段的发育计划。 总体而言，该项目将为开展第一次人类PoC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.