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

描述（由申请人提供）：本项目的目标是制定有效缓解和治疗啮齿动物放射性肺炎和肺纤维化的对策。具体而言，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，以安全有效地缓解和治疗。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联合使用。我们将使用两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；bbb12gy胸部局部照射治疗肺纤维化。我们提出的剂量和模型模拟了暴露于放射性或核攻击后在支持性护理下可能存活的条件。我们的产品开发里程碑是：1)确定一种安全有效的ACEi，具有缓解和治疗肺炎的最佳给药时间-从开始时间起6-8个月；2)确定EUK-207或sEHi1471联合ACE抑制剂缓解和治疗肺炎的疗效-时间线从开始6-12个月；3)测定ACEi对减轻放射性肺纤维化的作用-起始后12个月；4)在幼年动物和雌雄大鼠中确认最有效的缓解方案-时间为开始后13-15个月；5)确定最有效缓解方案的剂量调整因子(DMF) -时间线从开始13-15个月；6)在第二种啮齿类动物——小鼠（合作）身上测试最有效的缓解方案。我们的目标是为了满足该RFA的目标，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.