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

使用 DOS 将新型氰化物治疗药物快速转化为临床实践

• 批准号: 7573786
• 负责人: MATTHEW BRENNER
• 金额: $ 49.77万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7573786
• 关键词: Address; Aerosols; Animal Model; Antidotes; Caring; Chemicals; Clinical; Combined Modality Therapy; Cyanides; Detection; Development; Diagnostic; Diagnostic Procedure; Differential Diagnosis; Diffuse; Drug Combinations; Drug Delivery Systems; Drug Dose-Response Relationship; Emergency Situation; Event; Foundations; Future; Goals; Hydroxocobalamin; Institutes; Intramuscular; Intravenous; Lasers; Lead; Measurement; Metabolic; Methemoglobin; Methodology; Modeling; Monitor; Nitrites; Optics; Oryctolagus cuniculus; Pharmaceutical Preparations; Physiological; Poison; Poisoning; Purpose; Range; Rate; Research Proposals; Risk; Route; Screening procedure; Sodium; Sodium Chloride; Spectrum Analysis; Staging; Standards of Weights and Measures; Sulfur; Techniques; Technology; Technology Assessment; Therapeutic; Tissues; Toxic effect; Translating; Translations; Triage; base; cobinamide; cost; dithiane; drug development; improved; miniaturize; novel; novel diagnostics; outcome forecast; preclinical study; programs; rapid technique; research clinical testing; response; tool

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.

总体目标： 这是一个综合协作项目，其总体目标： 提供和实施新方法，以快速翻译新型氰化物解毒药物为临床 使用独特的兔氰化物毒性模型和无创宽带弥散光学的阶段 氰化物中毒和治疗反应的病理生理事件的光谱评估。 RFA目标和与计划优先级相关性： 该提案直接解决以下所有RFA-NS-08-003和RFA-NS-08-004目标 “氰化物等代谢/细胞毒物”： 1）在紧急情况下增强诊断和治疗反应能力 2）新诊断技术的快速发展 3）动物模型的开发和使用以识别铅化合物和进步临床前 研究 4）开发更好的诊断工具和技术 5）使用新的和经过验证的动物模型筛查治疗/诊断的功效 该研究建议涉及以下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行政途径，这些疗法安全，有效且易于 在大规模伤亡情况下进行管理，4）改进了快速诊断技术/技术 鉴别诊断，分类，检测亚临床暴露的目的，预后和组织预测 损害。 提案核心基金会： 我们有1）开发了可靠的，可重复的兔毒性模型，2）证明了能力 最近在贝克曼激光研究所开发的弥漫性光谱（DOS）技术 非侵入性评估在氰化物毒性期间发生的病理生理事件和标准逆转 剂（羟羟胺素和亚硝酸盐诱导的MET血红蛋白诱导）。我们建议利用这种动物 合作研究中的模型和新的光学技术评估方法，以快速翻译 潜在的新型氰化物治疗药物用于临床测试阶段。 目的： 为了评估和优化1）核酰胺的能力，2）胃丙酮酸二硫代钠盐（3-MPDT）， 3）核酰胺和3-MPDT的组合疗法在兔模型中逆转氰化物的毒性 与当前可用的治疗和控件相比。 具体目的： 对于每种药物（和药物组合），将研究以下特定目标： 1。这些药物在氰化物毒性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是多少，非侵入性DOS与 这些药物治疗期间的氰化物水平和生理测量？ 3。可以使用哪种药物管理模式有效输送这些药物，哪些是最佳的 以下每个管理模式的参数： 一个。静脉注射b。肌内c。气溶胶（雾化，直接气管滴注，干力） 提出的动物模型和宽带无创DOS光学检测和监测 能力，解决这些基本的药物翻译问题将大大加速，潜在的 风险将最小化，药物开发成本可能会降低。将来，DOS技术可能是 很容易小型化并可以在需要的水平上进行氰化物毒性检测和监测 大规模的伤亡筛查和护理。在更广泛的层面上，DOS正在为广泛的技术启用技术 毒理学和其他临床需求。