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Optimization of AEOL10150 treatment of sulfur mustard-induced lung toxidrome in a pig model

AEOL10150 治疗猪芥子气肺中毒模型的优化

基本信息

批准号：
10434637
负责人：
Brian J Day
金额：
$ 78.43万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434637
关键词：
Acute Acute Lung Injury Advanced Development Alkylating Agents Alkylation Animals Antioxidants Attenuated Biological Markers Cessation of life Chemical Agents Chemical Warfare Agents Chemistry Chlorine Chronic Clinical Dose Drug Kinetics Exposure to Family suidae Formulation Functional disorder Funding Goals Grant Hour Human Hydrogen Peroxide Inhalation Injections Injury Lead Lethal Dose 50 Lipid Peroxides Lower respiratory tract structure Lung Manganese Mechlorethamine Medical Membrane Military Personnel Mitochondria Modeling Monkeys Morbidity - disease rate Mus Mustard Gas NOEL Nitrogen Oxidative Stress Oxygen Pathologic Peroxonitrite Pharmacodynamics Pharmacologic Substance Phase Phosgene Play Pneumonia Population Porphyrins Process Pulmonary Edema Rattus Reactive Oxygen Species Regimen Rodent Model Role Route Safety Soman Sulfides Superoxides Thrombosis Tissues Treatment Efficacy Ulcer Work animal rule cell injury clinically relevant crosslink design drug development effective therapy efficacy study gas induced lung injury indexing injured airway macromolecule mass casualty medical countermeasure meetings mortality porcine model pulmonary function radiation mitigator radiation-induced lung injury safety study toxic industrial chemical treatment duration vapor

项目摘要

Our long term goal is to develop the catalytic antioxidant AEOL10150 as medical countermeasure for sulfur mustard gas-induced acute lung injury. Sulfur mustard gas is a commonly stockpiled chemical warfare agent that has been deployed on military personnel and in civilian populations producing mass casualties. Currently there are no effective treatments for sulfur mustard gas exposure. AEOL10150 uniquely targets reactive oxygen and nitrogen species that have been implicated in cellular and tissue damage produced by alkylating agents such and sulfur and nitrogen mustards. We have previously shown that AEOL10150 can protect the lung against several chemical agent exposures including chlorine, phosgene, soman, and sulfur mustard gases in rodent models. AEOL10150 is in advanced development as a mitigator of radiation-induced lung injury by Aeolus Pharmaceuticals. AEOL10150 is in advanced drug development with completed GLP chronic safety studies in mice and monkeys, completed Chemistry, Manufacturing, and Control (CMC), and a phase 1A clinical safety trials in humans. The purpose of this UO1 grant is to optimize AEOL10150 dose and delivery in a swine model of SM-induced acute lung injury as part of the requirements of the FDA Animal Rule. We will achieve this goal through 3 specific aims. The first aim will establish a swine sulfur mustard inhalation model that produces acute respiratory injury and mortality within 24 to 48 hours. The second aim will optimize AEOL10150 pharmacodynamics in the swine sulfur mustard inhalation model. And the third aim will determine the efficacy of AEOL10150 in a swine model of SM-induced acute lung injury while mitigating mortality. These studies will allow AEOL10150 to move forward and help design the pivotal safety and efficacy studies needed for regulatory FDA approval of AEOL10150 under the animal rule. AEOL10150 has the potential to be a broad spectrum medical counteragent against traditional chemical warfare agents and toxic industrial chemicals that inflict a lung toxidrome.

我们的长期目标是开发催化抗氧剂AEOL 10150作为硫的医疗对策芥子气引起的急性肺损伤芥子气是一种常见的化学战剂已经在军事人员和平民中使用，造成大规模伤亡。目前对于硫芥子气暴露没有有效的治疗方法。AEOL 10150独特地靶向反应性氧和氮物质与烷基化产生的细胞和组织损伤有关试剂，如硫和氮的化合物。我们之前已经证明，AEOL10150可以保护肺对几种化学试剂的暴露，包括氯气，光气，梭曼和硫芥子气在啮齿动物模型中。AEOL 10150作为放射性肺损伤的缓解剂处于高级开发阶段，风神药业。AEOL 10150处于高级药物开发阶段，已完成GLP长期安全性在小鼠和猴中进行的研究，完成了化学、生产和控制（CMC），以及1A期人体临床安全性试验UO1资助的目的是优化AEOL 10150剂量和输送， SM诱导的急性肺损伤猪模型，作为FDA动物规则要求的一部分。我们将通过三个具体目标实现这一目标。第一个目标是建立一个猪硫芥吸入模型在24到48小时内造成急性呼吸道损伤和死亡。第二个目标将优化 AEOL 10150在猪硫芥吸入模型中的药效学。第三个目标将决定 AEOL 10150在SM诱导的急性肺损伤猪模型中的功效，同时降低死亡率。这些研究将使AEOL 10150向前推进，并帮助设计所需的关键安全性和有效性研究 FDA批准AEOL 10150的动物法规。AEOL 10150有可能成为一种广泛的光谱医学对抗剂对传统的化学战剂和有毒的工业化学品，造成肺部中毒