Development of ACE Inhibitor as Countermeasure for Radiation-Induced Lung Injury

描述（由申请人提供）：我们该项目的目标是制定有效减轻和治疗啮齿类动物辐射引起的肺炎和肺纤维化的对策。具体来说，我们建议加快 FDA 批准的血管紧张素转换酶抑制剂 (ACEi)、卡托普利、依那普利或福辛普利的开发，以实现安全有效的缓解和治疗。此外，我们将测试一种选定的 ACEi 与自由基清除剂 EUK-207 或抗炎可溶性环氧化物水解酶抑制剂 (sEHi) 1471 的组合。我们将使用 2 种相关的损伤模型来测试对策：单剂量 10 Gy 全身照射 (TBI) 治疗肺炎； >12 Gy 局部胸部照射治疗肺纤维化。我们提出的剂量和模型模拟了在暴露于放射性或核攻击后通过支持性护理可能生存的条件。我们的产品开发里程碑是： 1) 确定一种安全有效的 ACEi，并具有缓解和治疗肺炎的最佳给药持续时间——从开始起 6-8 个月的时间表； 2) 确定 EUK-207 或 sEHi1471 与 ACE 抑制剂联合治疗肺炎的疗效 - 时间线从开始起 6-12 个月； 3) 确定 ACEi 对减轻辐射引起的肺部纤维化的效果 - 从开始起 12 个月； 4) 确认对幼年动物和两性大鼠最有效的缓解方案——时间线从开始起 13-15 个月； 5) 确定最有效缓解方案的剂量修改因子（DMF）——时间线从开始起13-15个月； 6) 在第二种啮齿类动物——小鼠中测试最有效的缓解方案（合作）。我们的目标旨在满足本次 RFA 的目标，即加速有前途的医疗产品的研究和开发，以减轻和治疗辐射引起的肺损伤。

DESCRIPTION (provided by applicant): Our goals for this Project will be to develop countermeasures to effectively mitigate and treat radiation-induced pneumonitis and pulmonary fibrosis in rodents. Specifically we propose to accelerate development of FDA-approved Angiotensin Converting Enzyme inhibitors (ACEi), captopril, enalapril or fosinopril for safe and effective mitigation and treatment. Additionally we will test one selected ACEi in combination with either a free radical scavenger EUK-207 or an anti-inflammatory soluble epoxide hydrolase inhibitor (sEHi), 1471. We will use 2 relevant models of injury to test countermeasures: a single dose of 10 Gy total body irradiation (TBI) for pneumonitis; and >12 Gy localized thoracic irradiation for pulmonary fibrosis. The doses and models we propose simulate conditions that may be survivable with supportive care following exposure to a radiological or nuclear attack. Our product development milestones are to: 1) Identify a safe and effective ACEi with optimal duration of administration for mitigation and treatment of pneumonitis - timeline by 6-8 months from start; 2) Determine efficacy of agents EUK-207 or sEHi1471 in combination with the ACE inhibitor for mitigation and treatment of pneumonitis - timeline 6-12 months from start; 3) Determine the effect of ACEi on mitigation of radiation-induced fibrosis in the lung - 12 months from start; 4) Confirm the most effective mitigating regimen in juvenile animals and rats of both sexes - timeline 13-15 months from start; 5) Determine the dose modification factor (DMF) of the most effective mitigating regimen - timeline 13-15 months from start; and 6) Test the most effective mitigating regimen in a second rodent species, mice (in collaboration). Our aims are designed to satisfy the goal of this RFA to accelerate research and development of promising medical products, for mitigation and treatment of radiation-induced pulmonary injury.