Center of Catalytic Bioscanvenger Medical Defense Research II: Discovery, Formula

催化生物扫描仪医疗防御研究中心 II：发现、配方

• 批准号: 8551627
• 负责人: Douglas Mark Cerasoli
• 金额: $ 236.49万
• 依托单位: U.S. ARMY MEDICAL RESEARCH INST CHEM DEF
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551627
• 关键词: Advanced Development; Atropine; Bioavailable; Biological Availability; Blood; Blood Circulation; Cessation of life; Chlorpyrifos; Convulsants; Development; Diagnosis; Dose; Drug Formulations; Drug Metabolic Detoxication; Ensure; Enzymes; Generations; Goals; Health; Hour; In Vitro; Individual; Intramuscular Injections; Libraries; Life; Medical; Metabolism; Organophosphorus Compounds; Oximes; Paraoxonase 1; Parathion; Pesticides; Pharmaceutical Preparations; Pharmacotherapy; Phorate; Poisoning; Population; Publishing; Recombinants; Reporting; Research; Therapeutic; Treatment Efficacy; United States National Institutes of Health; VX nerve gas; Variant; Vision; Work; base; bioscavenger; conventional therapy; design; directed evolution; drug candidate; enzyme activity; in vivo; meetings; nerve agent; preclinical evaluation; public health relevance; research study; residence; screening; sound; tool

DESCRIPTION (provided by applicant): Organophosphorus (OP) compounds, including both nerve agents and pesticides, represent a serious potential threat to the health of the civilian population. Because they are relatively easy to synthesize, are extremely toxic, and may be difficult to rapidly diagnose or treat in a mass casualty situation, they are considered to be a likely tool for use by terrorists in civilian settings. The CounterACT solicitation identifies a need for a rapid, post-exposure protection that can be easily administered to civilians in a mass casualty scenario. We intent to fulfill this requirement by developing a drug formulation that is amenable to use in an autoinjector, can be delivered via intramuscular injection, will become rapidly bioavailable, will have a sufficient long in vivo residence to protect against slowly metabolized OP compounds, and will have sufficient catalytic efficiency and broad spectrum reactivity to protect against a variety of OP threats. The overarching goal of this U54 Center renewal effort, the "Center for Catalytic Bioscavenger Medical Defense Research II: Discovery, Formulation and Preclinical Evaluation", is to define, characterize, and transition to the NIH for advanced development a drug formulation that will afford post-exposure protection to victims of OP poisoning. The path we will utilize to accomplish this goal has three major initiatives that will be performed in parallel; the vision for this approach is that at the end of year three all of the concurrent efforts will combine to identify a single best candidate drug which will then become the Center's focus for the remaining two years. The first initiative that the Center will pursue is the generation through rationale design, directed evolution, and high throughput library screening of enzyme variants based on OPH (from fi. diminuta) and/or on a recombinant, bacterially expressible paraoxonase 1 (P0N1). Variants will be screened for broad spectrum activity against multiple OP pesticides and nerve agents. They will also be designed to possess high catalytic efficiency, which will allow for the rapid detoxification of OPs in the blood of exposed individuals. These efforts will identify a single "best variant" or cocktail of variants that meet the disparate requirements for high catalytic activity and broad spectrum reactivity. The second major initiative of the Center will be the characterization of different encapsulation and formulation approaches that will stabilize enzyme activity in vitro (to promote economical long term storage), will allow rapid (>5 minutes) bioavailability in circulation after an intramuscular injection (to be consistent with the intended use in a mass casualty situation), and to result in long (>48 hour) circulatory stability, ensuring that protection is afforded against both rapid onset OPs like the G agents, slow onset OPs like VX and VR, and pesticides that require in vivo metabolism to be converted into their more toxic forms; to afford protection against different OP compounds with very disparate distribution profiles, we will require both rapid bioavailability and long-lived circulatory stability. The third major initiative will be a determination of the utility of co- administration of conventional therapeutic drugs (atropine, an oxime, and/or an anti-convulsant) as an adjunct that will enhance the therapeutic efficacy of a catalytic scavenger. One of the only published reports detailing the use of a catalytic bioscavenger to provide protection against an OP also included an experiment where atropine and the oxime 2-PAM were co-administered with an enzyme; the amount of protection afforded was substantially greater than was predicted based on the efficacy of either drug therapy alone, suggesting that the use of conventional therapeutic drugs with a catalytic scavenger may result in a synergistic rather than additive level of protection.

描述（由申请人提供）：包括神经剂和农药在内的有机磷（OP）化合物对平民健康构成了严重的潜在威胁。由于它们相对容易合成，具有极高的毒性，并且在大规模的伤亡情况下可能很难快速诊断或治疗，因此它们被认为是在平民环境中被恐怖分子使用的工具。反对征求的招标确定了在大规模的伤亡情况下可以轻松地给平民管理的快速暴露后保护。我们意图通过开发可在自动注射器中使用的药物配方来满足这一要求，可以通过肌肉注射来提供，将变得迅速生物利用，将有足够长的体内居住地，以防止缓慢代谢的OP化合物，并具有足够的催化效率和广泛的反应性。这个U54中心更新工作的总体目标是“催化生物载体医疗防御研究中心II：发现，制定和临床前评估”，是为了定义，表征和过渡到NIH，以进行先进的开发，以便在对OP中毒的受害者中提供暴露后的药物制剂。我们将利用实现这一目标的道路有三个主要的举措，这些计划将并行执行；这种方法的愿景是，在第三年末，所有并发的努力都将结合起来，以确定一种最佳候选药物，然后将成为剩余两年中心的重点。该中心将追求的第一项举措是通过基于OPH（fi。Diminuta）和/或重组，可重组的，细菌表达的寄生虫酶1（P0N1）的酶变体的酶变体的高吞吐量库筛选（P0N1）。将筛选出针对多种OP农药和神经剂的广泛活性的变体。它们还将被设计为具有较高的催化效率，这将允许在暴露个人的血液中快速排毒。这些努力将确定一个单一的“最佳变体”或鸡尾酒，这些变体符合高催化活性和广泛反应性的不同要求。该中心的第二个主要举措将是表征不同的封装和制剂方法，这些方法将稳定体外酶活性（以促进经济的长期存储），将允许快速（5分钟）在肌内注射后循环中的生物利用度（> 5分钟）的生物利用度（在大规模偶然的情况下都可以在循环中及时及时使用），并且在大规模偶然的情况下均可使用（> 48小时）（> 48小时）诸如G剂，VX和VR等缓慢发作的OPS OPS以及需要体内代谢的农药将其转化为更具毒性的形式；为了防止具有非常不同的分布曲线的不同OP化合物的保护，我们将需要快速的生物利用度和长寿循环稳定性。第三个主要倡议将确定常规治疗药物（阿托品，摄影和/或抗惊厥药）的共同施用，作为辅助功能，将增强催化清道夫的治疗功效。详细介绍使用催化生物载体的唯一已发表的报告之一，还包括一项实验，其中阿托品和Oxime 2-PAM与酶共同管理；基于任何一种药物治疗的功效，提供的保护量大大要大，这表明使用具有催化清除剂的常规治疗药物可能会导致协同的保护，而不是加性保护水平。