title: Dose-modifying factor for captopril for mitigation of radiation injury to normal lung.
abstract: 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.
authors: Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. medhoram@mcw.edu
authors: Meetha
authors: M
authors: Medhora
authors: Feng
authors: F
authors: Gao
authors: Brian L
authors: BL
authors: Fish
authors: Elizabeth R
authors: ER
authors: Jacobs
authors: John E
authors: JE
authors: Moulder
authors: Aniko
authors: A
authors: Szabo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D002216:Captopril / Q000627:therapeutic use*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008168:Lung / Q000528:radiation effects*; D055370:Lung Injury / Q000517:prevention & control*; D016016:Proportional Hazards Models; D011832:Radiation Injuries / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000528:radiation effects; D059246:Tachypnea / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril