Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment

Ossetrova, Natalia I.; Blakely, William F.; Nagy, Vitaly; McGann, Camille F.; Ney, Patrick H.; Christensen, Christine; Koch, Amory; Gulani, Jatinder; Sigal, George B.; Glezer, Eli N.; Hieber, Kevin

doi:10.1093/rpd/ncw176

Cited by 18 publications

(7 citation statements)

References 39 publications

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“…Several studies have demonstrated that other hematopoietic cytokines and growth factors are dramatically increased in response to TBI, including G-CSF, SAA, IL-6, SCF, MIP1a and 1b, MCP1, FLT-3, IL-10, IL-1β, IL-2, KC/CXCL1 28 . The observed increases in specific cytokines and growth factors are believed to play a role in natural resistance to radiation damage and may be involved in hematopoietic recovery as well as inflammatory responses after radiation 28–30 . We investigated the effect of 48 h delayed administration of low-dose captopril on these cytokines and growth factors following 7.9 Gy TBI.…”

Section: Resultsmentioning

confidence: 99%

Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation

McCart

Lee

Jha³

et al. 2019

Sci Rep

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The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1–4 h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24–48 hours after initial exposure. Using C57BL/6 mice exposed to an LD50-80/30 of 60Co TBI (7.75–7.9 Gy, 0.615 Gy/min), we show that low-dose captopril administration, initiated as late as 48 h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21–30 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48 h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation

McCart

Lee

Jha³

et al. 2019

Sci Rep

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Section: Discussionmentioning

confidence: 99%

“…In a study focused on biodosimetry that used rhesus macaques (n = 8), the LD50/60 value with 50% mortality at 6.5 Gy for 60 Co gamma radiation without supportive care was confirmed (Ossetrova et al 2016). Additional administration of supportive care reduced the 6.5 Gy exposure to nonlethal (Ossetrova et al 2016). Thrall et al recently validated their previous study and supported the overall higher values for LD50/60 of male rhesus, as well as the benefit of supportive care with a dose modification factor of 1.21 between the LD50 values for limited and full supportive care (Thrall et al 2015(Thrall et al , 2020.…”

Section: High Dose Potentially Lethal Bilateral Uniform Tbi Exposure ...mentioning

confidence: 99%

Acute Radiation Effects, the H-ARS in the Non-human Primate: A Review and New Data for the Cynomolgus Macaque with Reference to the Rhesus Macaque

Farese

Drouet²,

Hérodin

et al. 2021

Health Physics

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…The NHP ARS severity scoring sheet we developed here was used successfully in a follow-on study investigating radioresponses using minimum and full supportive care with and without G-CSF treatment. 57 Algorithms based primarily on the hematology and blood chemistry parameters have been developed and used to predict the severity of individual animals' overall hematopoietic ARS, reported as radiation risk and injury categorization, in both minipigs and NHP. 13,14 These algorithms provide useful tools to merge multiple parameters into a single severity scoring scale that can be used to identify animals requiring enhanced monitoring.…”

Section: Discussionmentioning

confidence: 99%

System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta)

et al. 2018

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The currently accepted scheme to assess humans exposed to life-threatening radiation doses is the MEdical TREatment ProtocOLs for Radiation Accident Victims (METREPOL). ME-TREPOL is used to evaluate the time course and severity of radiation injury from acute radiation syndrome (ARS) on the basis of relevant organ-based systems to provide medical management guidance. 26 The METREPOL system is consistent with some of the pioneering work on radiation-induced clinical signs and symptoms. 3,31-33 More recently, METROPOL has been updated for use in a 6-page Armed Forces Radiobiology Research Institute Biodosimetry Worksheet. 65,66 The first verification of the effectiveness of the clinical dosimetry system METREPOL to rapidly and accurately predict later occurring ARS severity and to develop medical management strategies were based on real clinical data from case histories of accidentally exposed patients. 21 Individual assessment of ARS severity response will allow medical responders to better manage irradiation-accident victims consistent with recommended guidelines. 34 Significant gaps exist to enhance radiologic medical countermeasures and biodosimetry capabilities in response to radiologic threats. One major gap is the ability to rapidly identify persons exposed to potentially life-threatening radiation doses and distinguish them from those not exposed or exposed to lower doses. 12 Biodosimetry devices for this purpose should be useful for triage applications involving mass-casualty exposure incidents and must obtain the necessary approvals by governmental regulatory agencies (that is, FDA). 1 Approval by appropriate regulatory agencies for the use of medical radiologic countermeasure drugs involves demonstration of safety and efficacy, ideally in humans. When human data are inaccessible, relevant animal models should be used. No biodosimetry devices are currently approved by the FDA, and approaches to obtain approval for candidate devices will likely be based on initial studies using small rodent models to supplement results from human patients undergoing radiation therapy for cancer and from limited radiation accidents. 42 Because human data are quite sparse, a relevant nonrodent animal model-one that permits characterization of complete doseand time-course responses-is needed for biodosimetry device validation. NHP provide the bridge in scientific research from small laboratory rodents to humans for medical countermeasure and biodosimetry studies.

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Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment

Cited by 18 publications

References 39 publications

Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation

Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation

Acute Radiation Effects, the H-ARS in the Non-human Primate: A Review and New Data for the Cynomolgus Macaque with Reference to the Rhesus Macaque

System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta)

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