Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
J Radiat Res. 2012 Jul;53(4):633-40. doi: 10.1093/jrr/rrs004. Epub 2012 Jun 6.
Our goal is to develop countermeasures for pulmonary injury following unpredictable events such as radiological terrorism or nuclear accidents. We have previously demonstrated that captopril, an angiotensin converting enzyme (ACE) inhibitor, is more effective than losartan, an angiotensin type-1 receptor blocker, in mitigating radiation-pneumopathy in a relevant rodent model. In the current study we determined the dose modifying factors (DMFs) of captopril for mitigation of parameters of radiation pneumonitis. We used a whole animal model, irradiating 9-10-week-old female rats derived from a Wistar strain (WAG/RijCmcr) with a single dose of irradiation to the thorax of 11, 12, 13, 14 or 15 Gy. Our study develops methodology to measure DMFs for morbidity (survival) as well as physiological endpoints such as lung function, taking into account attrition due to lethal radiation-induced pneumonitis. Captopril delivered in drinking water (140-180 mg/m(2)/day, comparable with that given clinically) and started one week after irradiation has a DMF of 1.07-1.17 for morbidity up to 80 days (survival) and 1.21-1.35 for tachypnea at 42 days (at the peak of pneumonitis) after a single dose of ionizing radiation (X-rays). These encouraging results advance our goals, since DMF measurements are essential for drug labeling and comparison with other mitigators.
我们的目标是针对放射性恐怖主义或核事故等不可预测事件引起的肺损伤制定对策。我们之前的研究表明，血管紧张素转换酶（ACE）抑制剂卡托普利比血管紧张素 1 型受体阻滞剂氯沙坦在相关啮齿动物模型中更能减轻放射性肺损伤。在本研究中，我们确定了卡托普利减轻放射性肺炎参数的剂量修正因子（DMF）。我们使用整体动物模型，对来自 Wistar 品系（WAG/RijCmcr）的 9-10 周龄雌性大鼠胸部单次照射 11、12、13、14 或 15Gy 的剂量。我们的研究开发了一种方法来测量发病率（存活率）和生理终点（如肺功能）的 DMF，同时考虑到因致命性放射性肺炎引起的损耗。卡托普利通过饮用水给药（140-180mg/m2/天，与临床给予的剂量相当），在照射后一周开始给药，对于 80 天（存活率）的发病率和 42 天（肺炎高峰期）的呼吸急促的 DMF 为 1.07-1.17 和 1.21-1.35，单次给予电离辐射（X 射线）。这些令人鼓舞的结果推进了我们的目标，因为 DMF 测量对于药物标签和与其他缓解剂的比较至关重要。
