Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs.
The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated.
*Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; †Department of Medicine, Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295; ‡Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.
Brian L
BL
Fish
Feng
F
Gao
Jayashree
J
Narayanan
Carmen
C
Bergom
Elizabeth R
ER
Jacobs
Eric P
EP
Cohen
John E
JE
Moulder
Christie M
CM
Orschell
Meetha
M
Medhora
D000208:Acute Disease; D054508:Acute Radiation Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005440:Fluid Therapy / Q000379:methods*; D017706:Lisinopril / Q000008:administration & dosage*; D009102:Multiple Organ Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D051381:Rats; D015996:Survival Rate; D016896:Treatment Outcome; D014867:Water / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D011837:Radiation-Protective Agents; D014867:Water; D017706:Lisinopril
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