Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes

Frontiers in Pharmacology

George N. Cox¹  Christie M. Orschell³  Tessa Miller⁶  Brian L. Fish⁶  Jayashree Narayanan⁶  Feng Gao⁶  Tracy Gasperetti⁶  Meetha Medhora⁷  Elizabeth R. Jacobs⁷  Aniko Szabo⁸ 

[1] Bolder BioTechnology Inc., Boulder, CO, United States;Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States;Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States;Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States;Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States;Department of Veterans Affairs, Research Service, Zablocki VAMC, Milwaukee, WI, United States;Institute for Health and Equity, Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, United States;

关键词: polypharmacy;    acute radiation syndrome;    delayed effects of acute radiation exposure;    mitigation;    hematopoietic growth factor;    lisinopril;   

DOI  :  10.3389/fphar.2021.634477

来源: DOAJ

【 摘 要 】

There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS occurs by 30-days following total body irradiation (TBI), and manifests as potentially lethal gastrointestinal (GI) and hematopoietic (H-ARS) toxicities after >12.5 and >7 Gy, respectively. DEARE, which includes potentially lethal lung and kidney injuries, is observed after partial body irradiation >12.5 Gy, with one hind limb shielded (leg-out PBI). The goal of this study is to enhance survival from ARS and DEARE by polypharmacy, since no monotherapy has demonstrated efficacy to mitigate both sets of injuries. For mitigation of ARS following 7.5 Gy TBI, a combination of three hematopoietic growth factors (polyethylene glycol (PEG) human granulocyte colony-stimulating factor (hG-CSF), PEG murine granulocyte-macrophage-CSF (mGM-CSF), and PEG human Interleukin (hIL)-11), which have shown survival efficacy in murine models of H-ARS were tested. This triple combination (TC) enhanced survival by 30-days from ∼25% to >60%. The TC was then combined with proven medical countermeasures for GI-ARS and DEARE, namely enrofloxacin, saline and the angiotensin converting enzyme inhibitor, lisinopril. This combination of ARS and DEARE mitigators improved survival from GI-ARS, H-ARS, and DEARE after 7.5 Gy TBI or 13 Gy PBI. Circulating blood cell recovery as well as lung and kidney function were also improved by TC + lisinopril. Taken together these results demonstrate an efficacious polypharmacy to mitigate radiation-induced ARS and DEARE in rats.

【 授权许可】

Unknown