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Gasperetti T, Miller T, Gao F, et al. Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes. Front Pharmacol. 2021;12:634477doi: 10.3389/fphar.2021.634477.
Gasperetti, T., Miller, T., Gao, F., Narayanan, J., Jacobs, E. R., Szabo, A., Cox, G. N., Orschell, C. M., Fish, B. L., & Medhora, M. (2021). Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes. Frontiers in pharmacology, 12634477. https://doi.org/10.3389/fphar.2021.634477
Gasperetti, Tracy, et al. "Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes." Frontiers in pharmacology vol. 12 (2021): 634477. doi: https://doi.org/10.3389/fphar.2021.634477
Gasperetti T, Miller T, Gao F, Narayanan J, Jacobs ER, Szabo A, Cox GN, Orschell CM, Fish BL, Medhora M. Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes. Front Pharmacol. 2021 May 17;12:634477. doi: 10.3389/fphar.2021.634477. eCollection 2021. PMID: 34079456; PMCID: PMC8165380.
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Front Pharmacol. 2021 May 17;12:634477. doi: 10.3389/fphar.2021.634477. eCollection 2021.

Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes.

Frontiers in pharmacology

Tracy Gasperetti, Tessa Miller, Feng Gao, Jayashree Narayanan, Elizabeth R Jacobs, Aniko Szabo, George N Cox, Christie M Orschell, Brian L Fish, Meetha Medhora

Affiliations

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

PMID: 34079456 PMCID: PMC8165380 DOI: 10.3389/fphar.2021.634477

Abstract

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.

Copyright © 2021 Gasperetti, Miller, Gao, Narayanan, Jacobs, Szabo, Cox, Orschell, Fish and Medhora.

Keywords: acute radiation syndrome; delayed effects of acute radiation exposure; hematopoietic growth factor; lisinopril; mitigation; polypharmacy; radiation pneumonitis; supportive care

Conflict of interest statement

GC is an employee of Bolder BioTechnology, Inc. and has a financial interest in the company. GC and CO are inventors on patents related to use of PEG-HGFs to treat ARS. GC, CO, BF, and MM are inventor

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