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

• 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
• 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

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作为硫的医疗对策