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

描述(由申请人提供)：我们这个项目的目标将是开发有效减轻和治疗放射性肺炎和啮齿类动物肺纤维化的对策。具体地说，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的组合。我们将使用两个相关的损伤模型来测试对策：肺炎的单次10Gy全身照射(TBI)；以及肺纤维化的&gt；12Gy局部胸部照射。我们提出的剂量和模型模拟了暴露在放射性或核攻击后，在支持性护理下可能可以存活的条件。我们的产品开发里程碑是：1)确定一种安全有效的ACEI，给药时间最长，以缓解和治疗肺炎-时间表为6-8个月；2)确定制剂EUK-207或sEHi1471与ACE抑制剂联合用于缓解和治疗肺炎的疗效-时间表为6-12个月；3)确定ACEI对缓解放射性肺纤维化的效果-12个月；4)确定对幼年动物和大鼠最有效的缓解方案-时间表为13-15个月；5)确定最有效的缓解方案的剂量修正系数(DMF)--开始后13-15个月的时间表；以及6)在第二种啮齿动物物种--小鼠身上测试最有效的缓解方案(合作)。我们的目标旨在满足本RFA的目标，即加快有前景的医疗产品的研究和开发，用于缓解和治疗放射性肺损伤。

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.