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.

Fig. 1.

Kaplan–Meier plots of survival by radiation dose and treatment; survival truncated at 80 days.

Fig. 2.

Observed and fitted probability of 60-day survival with exact binomial 95% confidence intervals versus radiation dose on log-scale. The X-coordinates of the observed values have been shifted slightly to avoid overlaps. The observed values are shown for captopril-treated (▲) and age-matched animals (•).

Fig. 3.

Observed and fitted mean breathing interval at 42 days with 95% bootstrap confidence limits versus radiation dose on log scale. The X-coordinates of the observed values have been shifted slightly to avoid overlaps. The observed values are shown for captopril-treated (▲) and age-matched animals (•).