Definitive Studies For Use Of Galantamine As A Pre-Treatment Countermeasure Again

描述（由申请人提供）：快速通道SBIR第一期和第二期暴露于集中作用的军用神经毒剂和有机磷（OP）农药已知会导致死亡和神经损伤（Coupland 2005, Karalliedee 1989, Buckley 2004）。需要改进对这些化合物中毒的对策。在美国国立卫生研究院NS059344资助的马里兰大学医学院（UMB）进行的大量研究（Albuquerque 2006）中，加兰他明已被证明可以提供保护，防止这些毒素的衰弱作用。该项目的目的是完成IND的临床前研究，旨在使这种具有高商业化潜力的药物更接近可用性。Countervail公司拥有该知识产权的商业化权利，并与马里兰大学合作，共同推进该药物技术的可用性。这项SBIR拨款提案是在NIH快速通道机制下提交的。第一阶段：保护比率研究迄今为止，UMB的研究已经评估了加兰他明在豚鼠受试者中产生100%存活率的OP暴露水平。在已发表的UMB研究（Albuquerque 2006）中，暴露前剂量的加兰他明和暴露后剂量的阿托品已被证明能够使100%的豚鼠动物受试者抵抗高达2.0倍LD50的OP毒素暴露水平。在吡哆斯的明溴的FDA实质批准基础（SBA）中引用的研究中，采用了一种称为“保护比率”的方法来评估对神经毒剂的保护能力。保护比率法的目的是通过确定在处理（保护）动物组中产生1.0 x LD50的OP暴露水平，对药物的保护能力进行压力测试。第一阶段研究的目的是利用保护比率法评估加兰他敏与吡哆斯的明对暴露于索曼和沙林的保护特性。第二阶段计划进行六项IND临床前研究，包括非灵长类动物和非人类灵长类动物。目的：确定在1.5倍LD50和2.0倍LD50暴露水平下加兰他明对人体的最佳保护水平。目的：GLP在前两项研究中确定的人体暴露水平和加兰他明剂量水平下对生存能力和神经组织保护的功效测试。7豚鼠药代动力学研究目的：收集加兰他明给药和暴露于人体后的特定时间点的PK数据。7非人灵长类动物试点研究目的：确定在第二物种暴露水平为1.5 x LD50或2.0 x LD50时，加兰他明的最佳水平以防止人体感染。目的：在非人灵长类动物模型中测试GLP对人类存活能力和神经组织保护的功效。

DESCRIPTION (provided by applicant): Fast Track SBIR Phase I and Phase II Exposure to centrally acting military nerve agents and organophosphorus (OP) pesticides are known to cause death and neurological damage (Coupland 2005, Karalliedee 1989, Buckley 2004). Improved countermeasures to intoxication from these compounds are needed. In numerous studies (Albuquerque 2006) conducted at the University of Maryland, School of Medicine (UMB) supported by NIH grant NS059344, galantamine, has been shown to provide protection against the debilitating effects of these toxins. The purpose of this project is to complete IND enabling pre-clinical studies intended to move this drug with high potential for commercialization closer to availability. Countervail Corporation owns the commercialization rights to the intellectual property and is working as a business partner with the University of Maryland in advancing the drug technology toward availability. This SBIR grant proposal is being submitted under the NIH Fast Track mechanism. Phase I: Protective Ratio Studies to date, studies at UMB have evaluated OP exposures at levels where galantamine produces 100% survivability in guinea pig subjects. In published UMB studies (Albuquerque 2006), a pre-exposure dose of galantamine followed by a post exposure dose of atropine has been shown to enable survivability of 100% of the guinea pig animal subjects against OP toxin exposure levels of up to 2.0 x LD50. In studies referenced in the pyridostigmine bromide FDA Substantial Basis of Approval (SBA), a method referred to as the "Protective Ratio" was employed to evaluate protective capability against nerve agents. The purpose of the Protective Ratio method is to stress test the protective capability of the drug by determining the OP exposure level that produces a 1.0 x LD50 in the treated (protected) group of animals. The purpose of the phase I studies is to evaluate the protective characteristics of galantamine vs. pyridostigmine using the Protective Ratio method against exposure to soman and sarin. Phase II: PK and Efficacy GLP Studies Six IND enabling pre-clinical studies are planned for Phase II that will include non- primate and non-human primate species. 7 Pilot Guinea Pig Efficacy Studies 1 & 2 Objective: Identify the optimal level of galantamine to protect against soman at exposure levels of 1.5 x LD50 and 2.0 x LD50 respectively. 7 Definitive Guinea Pig Efficacy Study Objective: GLP efficacy testing for survivability and neural tissue protection with soman exposure levels and galantamine dosing levels determined in first two studies. 7 Guinea Pig Pharmacokinetics Study Objective: Collection of PK data at selected time points following galantamine dosing and exposure to soman. 7 Pilot Non-Human Primate Study Objective: Identify the optimal level of galantamine to protect against soman at exposure levels of 1.5 x LD50 or 2.0 x LD50 in a second species. 7 Definitive Non-Human Primate Efficacy Study Objective: GLP efficacy testing for survivability and neural tissue protection against soman in a non-human primate model. PUBLIC HEALTH RELEVANCE: The public health value of providing an improved countermeasure to a nerve agent attack is self evident. These proposed pre-clinical trial studies will address comments raised in a recent FDA pre-IND meeting as well as directly support the goal of the NINDS CounterACT program to facilitate development and availability of new chemical countermeasures. We expect this research will help lay the groundwork for expanded applications both in nerve agents and organophosphorus pesticides.