Rapid translation of novel cyanide treatment drugs to clinical practice using DOS

总体目标： 这是一个综合的合作项目，其总体目标是： 为新型氰化物解毒剂药物快速转化为临床提供并实施新方法 阶段使用独特的兔氰化物毒性模型和非侵入性宽带漫射光学 光谱学评估氰化物中毒的病理生理事件和治疗反应。 RFA目标和与计划优先事项的相关性： 本提案直接涉及以下所有RFA-NS-08-003和RFA-NS-08-004目标， “代谢/细胞毒物，如氰化物”： 1)加强紧急情况下的诊断和治疗反应能力 2)新诊断技术的快速发展 3)开发和使用动物模型来识别先导化合物以及推进临床前研究。 研究 4)开发更好的诊断工具和技术 5)使用新的和经验证的动物模型筛选治疗/诊断的有效性 本研究提案涉及以下RFA-NS-06-005建议的组件： 1)基于毒性和化学威胁剂的疗法，2）基于氰化物硫供体的疗法3） 新的和改进的疗法的替代给药途径，这些途径将是安全、有效和易于 在大规模伤亡情况下进行管理，以及4）改进快速诊断技术/技术， 鉴别诊断、分诊、亚临床暴露检测、预后和组织预测的目的 损害 提案核心基础： 我们已经1）开发了一个可靠的，可重复的氰化物毒性兔模型，2）证明了能力 扩散光学光谱（DOS）技术最近在贝克曼激光研究所开发， 非侵入性评估氰化物毒性和标准逆转期间发生的病理生理事件 药物（羟钴胺素和亚硝酸盐诱导的Met血红蛋白诱导）。我们打算利用这种动物 模型和新的光学技术评估方法在合作研究，以迅速转化 潜在的新型氰化物治疗药物进入临床试验阶段。 目的： 为了评估和优化1）可宾酰胺，2）巯基丙酮酸二噻烷钠盐（3-MPDT）， 和3）在兔模型中用可宾酰胺和3-MPDT联合治疗来逆转氰化物毒性 与目前可用的治疗和对照相比。 具体目标： 对于每种药物（和药物组合），将研究以下特定目的： 1.这些药物在氰化物中毒治疗中的剂量反应关系是什么？ 2.氰化物毒性逆转的速率和程度如何？ 氰化物水平和生理指标的变化吗 3.什么样的给药模式可以用于这些药物的有效输送，什么是最佳的 以下每种给药模式的参数： a.静脉注射B。肌内注射c.气雾剂（雾化、直接气管滴注、干粉） 提出了动物模型和宽带无创DOS光学检测与监测 能力，解决这些基本的药物翻译问题将大大加快，潜力 风险将降到最低，药物开发成本也可能降低。在未来，DOS技术可以 易于小型化，可用于氰化物毒性检测和监测， 大规模伤亡筛查和护理。在更广泛的层面上，DOS正在使技术能够用于广泛的 毒理学和其他临床需要。

Overall goal: This is an integrated collaborative project with the overall goal: To provide and implement new methods for rapid translation of novel cyanide antidote drugs to clinical stages using a unique rabbit cyanide toxicity model and noninvasive broadband diffuse optical spectroscopy assessment of pathophysiologic events of cyanide poisoning and therapeutic response. RFA Objectives and relevance to program priorities: This proposal directly addresses all of the following RFA-NS-08-003 and RFA-NS-08-004 objectives for "metabolic/cellular poisons such as cyanide": 1) Enhancing diagnostic and treatment response capabilities during an emergency 2) The rapid advancement of new diagnostic techniques 3) The development and use of animal models to identify lead compounds as well as advance preclinical studies 4) Development of better diagnostic tools and techniques 5) Efficacy of screening of therapeutic/diagnostics using new and validated animal models This research proposal involves the following RFA-NS-06-005 suggested components: 1) Therapies based on toxicity and chemical threat agents, 2) therapies based on cyanide sulfur donors 3) alternative routes of administration for new and improved therapies that would be safe, effective and easy to administer during a mass casualty scenario, and 4) improved rapid diagnostic techniques/technologies for the purpose of differential diagnosis, triage, detection of subclinical exposures, prognosis, and prediction of tissue damage. Proposal Core Foundation: We have 1) developed a reliable, reproducible rabbit model of cyanide toxicity, and 2) demonstrated the ability of diffuse optical spectroscopy (DOS) technologies recently developed at Beckman Laser Institute to noninvasively assess the pathophysiologic events occurring during cyanide toxicity and reversal with standard agents (hydroxocobalamin, and nitrite induced met hemoglobin induction). We propose to utilize this animal model and new optical technology assessment methodology in collaborative studies to rapidly translate potential novel cyanide treatment drugs to clinical testing stages. Purpose: To assess and optimize the capabilities of 1) cobinamide, 2) Mercaptopyruvate Dithiane sodium salt (3-MPDT), and 3) combination therapies of cobinamide and 3-MPDT to reverse cyanide toxicity in a rabbit model compared to currently available treatments and controls. Specific aims: For each drug (and drug combination), the following specific aims will be investigated: 1. What is the dose response relationship of these drugs in cyanide toxicity treatment? 2. What are the rates and extent of cyanide toxicity reversal and how well does noninvasive DOS correlate with cyanide levels and physiologic measurements during these drug treatments? 3. What drug administration modes can be utilized for effective delivery of these drugs and what are the optimal parameters for each of the following administration modes: a. Intravenous b. Intramuscular c. Aerosol (Nebulized, Direct tracheal instillation, Dry power) With the proposed animal models and broadband noninvasive DOS optical detection and monitoring capabilities, addressing these fundamental drug translation questions will be considerably accelerated, potential risks will be minimized, and drug development costs may be reduced. In the future, DOS technologies can be readily miniaturized and made available for cyanide toxicity detection and monitoring on a level needed for mass casualty screening and care. On a broader level, DOS is enabling technology for a wide range of toxicologic and other clinical needs.