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

描述（由申请人提供）：已知暴露于中枢作用军用神经毒剂和有机磷（OP）农药会导致死亡和神经损伤（Coupland 2005，Karalliedee 1989，Buckley 2004）。需要改进这些化合物中毒的对策。在马里兰州大学医学院（UMB）进行的由NIH资助NS 059344支持的许多研究（阿尔伯克基，2006年）中，加兰他敏已被证明可提供针对这些毒素的致弱作用的保护。该项目的目的是完成IND，使临床前研究能够使这种具有高商业化潜力的药物更接近可用性。反补贴公司拥有知识产权的商业化权利，并作为商业伙伴与马里兰州大学合作，推动药物技术的可用性。这项SBIR拨款提案是根据NIH快速通道机制提交的。第一阶段：保护率研究迄今为止，UMB的研究已经评价了加兰他敏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（阿尔伯克基2006）中，暴露前剂量的加兰他敏和暴露后剂量的阿托品已被证明能够使100%的豚鼠动物受试者在高达2.0 x LD 50的OP毒素暴露水平下存活。在溴化吡啶斯的明FDA实质性批准依据（SBA）中引用的研究中，采用了一种称为“保护率”的方法来评价对神经毒剂的保护能力。保护率方法的目的是通过测定在给药（保护）组动物中产生1.0 x LD 50的OP暴露水平，对药物的保护能力进行强制降解试验。I期研究的目的是使用保护比方法评价加兰他敏与吡啶斯的明对暴露于梭曼和沙林的保护特性。第二阶段：PK和疗效GLP研究计划在II期开展6项IND临床前研究，包括非灵长类动物和非人灵长类动物种属。 7豚鼠药效初步研究1和2目的：确定加兰他敏的最佳水平，以防止梭曼暴露水平分别为1.5 x LD 50和2.0 x LD 50。 7存活性豚鼠功效研究目的：使用前两项研究中确定的梭曼暴露水平和加兰他敏剂量水平进行存活性和神经组织保护的GLP功效测试。 7豚鼠药代动力学研究目的：收集加兰他敏给药和暴露于梭曼后选定时间点的PK数据。 7非人灵长类动物初步研究目的：确定加兰他敏的最佳水平，以防止第二个物种在1.5 x LD 50或2.0 x LD 50的暴露水平下受到梭曼的伤害。 7存活性非人灵长类动物有效性研究目的：在非人灵长类动物模型中对梭曼的存活性和神经组织保护的GLP有效性测试。 公共卫生相关性： 为神经毒剂袭击提供更好的对策的公共卫生价值是不言而喻的。这些拟议的临床前试验研究将解决最近FDA IND前会议上提出的意见，并直接支持NINDS CounterACT计划的目标，以促进新化学对策的开发和可用性。我们希望这项研究将有助于为扩大神经毒剂和有机磷农药的应用奠定基础。

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.