title: Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation.
abstract: It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) "Animal Efficacy Rule", we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar®) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m(2)/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jmoulder@mcw.edu
authors.forename: John E
authors.initials: JE
authors.lastname: Moulder
authors.forename: Eric P
authors.initials: EP
authors.lastname: Cohen
authors.forename: Brian L
authors.initials: BL
authors.lastname: Fish
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D053099:Azotemia / Q000209:etiology; D002216:Captopril / Q000627:therapeutic use*; D006973:Hypertension / Q000209:etiology; D007668:Kidney / Q000187:drug effects / Q000528:radiation effects*; D016014:Linear Models; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D011507:Proteinuria / Q000209:etiology; D011832:Radiation Injuries / Q000188:drug therapy*; D051381:Rats; D051437:Renal Insufficiency / Q000209:etiology; D014481:United States; D014486:United States Food and Drug Administration; D014916:Whole-Body Irradiation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D019808:Losartan