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：
10626938
负责人：
Brian J Day
金额：
$ 76.07万
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/10626938
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 Gases 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 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 Upper respiratory tract Work animal rule cell injury clinically relevant crosslink design drug development effective therapy efficacy evaluation efficacy study gas induced lung injury improved indexing injured airway macromolecule manufacture mass casualty medical countermeasure mortality porcine model pre-Investigational New Drug meeting 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化剂AEOL10150作为硫的医学对策芥末气体诱导的急性肺损伤。硫芥末气是一种常见的化学战剂这已经部署在军事人员和造成大规模伤亡的平民中。现在没有有效的硫芥末气体暴露的治疗方法。 AEOL10150独特地靶向反应性与烷基化产生的细胞和组织损伤有关的氧和氮种药物，硫和氮芥末。我们以前已经表明，AEOL10150可以保护肺对几种化学剂暴露，包括氯，磷，索曼和硫磺气体在啮齿动物模型中。 AEOL10150正在高级发育中，作为缓解辐射诱导的肺损伤的缓解剂 Aeolus Pharmaceuticals。 AEOL10150具有完整的GLP慢性安全性的高级药物开发在小鼠和猴子的研究，完成的化学，制造和对照（CMC）和1A期的研究人类的临床安全试验。该UO1赠款的目的是优化AEOL10150的剂量和交付 SM诱导的急性肺损伤的猪模型是FDA动物规则要求的一部分。我们将通过3个特定目标实现这一目标。第一个目标将建立猪硫芥末吸入模型这会在24至48小时内产生急性呼吸损伤和死亡率。第二个目标将优化猪硫芥末吸入模型中的AEOL10150药效学。第三个目标将决定 AEOL10150在SM诱导的急性肺损伤的同时缓解死亡率的猪模型中的功效。这些研究将允许AEOL10150向前迈进，并帮助设计所需的关键安全性和功效研究为了根据动物规则在AEOL10150的法规FDA批准中。 AEOL10150有可能成为广泛的频谱医学对抗传统的化学战剂和有毒工业化学物质造成肺毒品。