Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

Singh, Vijay K.; Seed, Thomas M.

doi:10.1080/09553002.2021.1969054

Cited by 52 publications

(35 citation statements)

References 115 publications

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“…The extent of injury resulting from exposure to ionizing radiation is dependent on the extent of exposure, with the hematopoietic system being the most susceptible 1 . Development of radiation countermeasures for treatment of Hematopoietic Acute Radiation Syndrome (H-ARS) has focused on drugs that promote hematopoietic recovery and more specifically, agents that stimulate production of white cells and platelets following Total Body Irradiation (TBI) 2 , 3 .…”

Section: Introductionmentioning

confidence: 99%

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)

Kumar

Holmes-Hampton

Biswas

et al. 2022

Sci Rep

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The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source. Single administration of doses ranging from 0.3 to 1 mg/kg, given 4, 8, 12 or 24 h post-TBI (LD70 dose) increased survival by 30–90% as compared to saline control treatment. At the conclusion of the 30-day study, significant increases in bone marrow colony forming units and megakaryocytes were observed in animals administered JNJ-26366821 compared to those administered saline. In addition, enhanced recovery of FLT3-L levels was observed in JNJ-26366821-treated animals. Probit analysis of survival in the JNJ-26366821- and saline-treated cohorts revealed a dose reduction factor of 1.113 and significant increases in survival for up to 6 months following irradiation. These results support the potential use of JNJ-26366821 as a medical countermeasure for treatment of acute TBI exposure in case of a radiological/nuclear event when administered from 4 to 24 h post-TBI.

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Section: Introductionmentioning

confidence: 99%

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)

Kumar

Holmes-Hampton

Biswas

et al. 2022

Sci Rep

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“…Only four medical radiation countermeasures including Neupogen, Neulasta, Leukine, and Nplate have been approved for H-ARS by the U.S. Food and Drug Administration (FDA) for human use, and all four agents are radiomitigators for postexposure use [17][18][19][20][21][22][23][24][25]. The first three agents are available in the Strategic National Stockpile/vendor managed inventory [26,27].…”

Section: Fda-approved H-ars Countermeasuresmentioning

confidence: 99%

Radiation Medical Countermeasures and Use of EPR Biodosimetry to Facilitate Effectiveness of Applied Clinical Procedures

Singh

Swartz

Seed³

2021

Appl Magn Reson

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The utility for electron paramagentic resonance (EPR or ESR)-based radiation biodosimetry has received increasing recognition concerning its potential to assist in guiding the clinical management of medical countermeasures in individuals unwantedly exposed to injurious levels of ionizing radiation. Similar to any of the standard physical dosimetric methods currently employed for screening clinically significant radiation exposures, the EPR-based in vivo dosimetry approach would serve to complement and extend clinical assessments (e.g., blood analyses, cytogenetics, etc.), specifically to more accurately assign the extent of ionizing radiation exposure that individuals might have received. In the case of EPR biodosimetry of biological samples such as nails, teeth, and bones, the method has the capability of providing information on the physical dose at several specific bodily sites and perhaps additonal information on the homogeneity of the exposure as well as its overall magnitude. This information on radiation dose and distribution would be of significant value in providing medical management to given individuals at health risk due to radiation exposure. As these measurements provide information solely on physical measures of the radiation dose and not on the potential biological impact of a particular dose, they are complementary, albeit supplemental, to the array of currently available biologically based biodosimetry and clinical findings. In aggregate, these physical and biological measures of radiation exposure levels (dose) would most certainly provide additional, useful information for the effective medical management of radiation exposed individuals.

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“…Total-or partial-body radiation exposures of ≥ 2 Gray (Gy) are associated with H-ARS and GI-ARS 11 . To date, the United States Food and Drug Administration (US FDA) has approved Neupogen (granulocyte-colony stimulating factor, G-CSF), Neulasta (PEGylated G-CSF), Leukine (granulocyte-macrophage colony-stimulating factor, GM-CSF), and Nplate (romiplostim) for the treatment of H-ARS [12][13][14][15][16][17][18][19][20][21][22][23] . However, these drugs have safety and therapeutic concerns and require parenteral administration shortly after radiation exposure (24 to 48 h), which is not optimal for administration in austere environments.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

Girgis

Jayatilake

et al. 2022

Preprint

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BIO 300, a nanosuspension of genistein, is a radiation countermeasure being developed to treat hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE). Several studies have affirmed its safety and efficacy in alleviating the damaging effects of ionizing radiation. However, dose optimization of any drug has always been an important area of research because unnecessarily high drug doses may result in serious complications. In this study, we assessed the pharmacokinetics (PK) and metabolic profiles of two different doses of BIO 300 Oral Powder (100 mg/kg and 200 mg/kg) when administered orally to nonhuman primates (NHPs). While the Tmax values of both doses remained the same, the area under the curve at 48 h (AUC0−48) was tripled by doubling the dose. Additionally, we monitored serum samples for global metabolomic/lipidomic changes using high resolution mass spectrometry followed by functional pathway analysis prior to and at various time points up to 48 h post drug administration. Interestingly, the metabolomic profiles of sera from NHPs that received the lower dose demonstrated a transient perturbation in numerous metabolites between the 4 and 12 h time points. Eventually, the metabolite abundance reverted to near-normal by 48 h. These study results are consistent with our previous studies focused on the PK and metabolomic analysis for parenteral and oral suspension formulations of BIO 300. This study affirms that administration of a single dose of up to 200 mg/kg of BIO 300 Oral Powder conferred no metabolomic-mediated safety features, suggesting the drug can be safely used to combat radiation injury.

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Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

Cited by 52 publications

References 115 publications

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)

Radiation Medical Countermeasures and Use of EPR Biodosimetry to Facilitate Effectiveness of Applied Clinical Procedures

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

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