An Effective Therapeutic Regimen for the Hemopoietic Phase of the Acute Radiation Syndrome in Dogs

Sorensen, D. K.; Bond, V.P.; Cronkite, Eugene P.; Perman, V.

doi:10.2307/3571030

Cited by 34 publications

(17 citation statements)

References 9 publications

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“…It has been recognized for several decades that supportive care alone can significantly improve the likelihood of surviving exposure to high doses of ionizing radiation (Brook et al 2004;Sorensen et al 1960;Miller et al 1952;Furth et al 1953;Byron et al 1964;MacVittie et al 1991MacVittie et al , 2005Waselenko et al 2004). Recommendations on medical management of HARS include supportive care based on specific trigger-to-treat and -stop indications.…”

Section: Discussionmentioning

confidence: 97%

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

Thrall

Love

OʼDonnell³

et al. 2015

Health Physics

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The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures.

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Section: Discussionmentioning

confidence: 97%

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

Thrall

Love

OʼDonnell³

et al. 2015

Health Physics

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“…Studies performed over 50 y ago using canines showed the efficacy of supportive care centered on fresh platelet transfusions, systemic antibiotics, and fluids (Furth et al 1953;Jackson et al 1959;Perman et al 1962;Sorensen et al 1960;Bagdasarov et al 1959). Sorenson et al (1960) reported on the effectiveness of several antibiotics in combination with fresh whole blood transfusions and fluids to control hemorrhage, sepsis, and dehydration in reducing lethality from an LD99/30 to an LD20/30 in a canine model of the H-ARS (Sorensen et al 1960).…”

Section: The Acute H-ars In Response To Tbi Morbiditymentioning

confidence: 97%

The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques

MacVittie

Farese²,

Jackson³

2015

Health Physics

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Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total body irradiation (TBI) with 250 kVp or 2 MeV x radiation, Co gamma radiation and reactor- and nuclear weapon-derived mixed gamma: neutron-radiation, delivered at various dose rates from a total body, bilateral, rotational, or unilateral exposure aspect. The DRRs established by a probit analysis vs. linear dose relationship were characterized by two main parameters or dependent variables: a slope and LD50/30. Respective LD50/30 values for studies that used 250 kVp x radiation (five primary studies combined, n = 338), 2 MeV x radiation, Co gamma radiation, and steady-state reactor-derived mixed gamma:neutron radiation for total body uniform exposures were 521 rad [498, 542], 671 rad [632, 715], 644 rad [613, 678], and 385 rad [357, 413]. The respective slopes were steep and ranged from 0.738 to 1.316. The DRR, LD50/30 values and slopes were also determined for total body, non-uniform, unilateral, pulse-rate exposures of mixed gamma:neutron radiation derived at reactor and nuclear weapon detonations. The LD50/30 values were, respectively, 395 rad [337, 432...

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“…The trigger-based administration of medical management can be "population-based," as for mouse studies, or "patient-based" for studies using NHP. There is a significant preclinical database supporting the use and timing of effective medical management in mice, canines, and NHP (MacVittie et al 1991(MacVittie et al , 2001Sorensen et al 1960;Booth et al 2012b;Farese et al 2012a;Plett et al 2012;Garofalo et al 2014;MacVittie 2012MacVittie , 2014. All supportive care measures are adapted from consensus-based clinical standards of treatment (Waselenko et al 2004;Schimpff 1990;Hughes 2002;Gafter-Gvili et al 2005;Freifeld et al 2011;Fliedner et al 2001).…”

Section: Time Of Administration Of Medical Managementmentioning

confidence: 98%

The MCART Consortium Animal Model Series

MacVittie¹

2015

Health Physics

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An Effective Therapeutic Regimen for the Hemopoietic Phase of the Acute Radiation Syndrome in Dogs

Cited by 34 publications

References 9 publications

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques

The MCART Consortium Animal Model Series

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