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Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Moderate-to-high doses of ionizing irradiation can lead to potentially life-threatening morbidities and increase mortality risk. In preclinical testing, 5-androstenediol has been shown to be effective in protecting against hematopoietic acute radiation syndrome. This agent is important for innate immunity, serves to modulate cell cycle progression, reduces radiation-induced apoptosis, and regulates DNA repair. The drug has been evaluated clinically for its pharmacokinetics and safety. The United States Food and Drug Administration granted investigational new drug status to its injectable depot formulation (NEUMUNE). Its safety and efficacy profiles make it an attractive candidate for further development as a radiation countermeasure., (Published by Elsevier Ltd.)

Threats of radiological or nuclear disasters are of serious concern and a top priority for government agencies involved in domestic security and public health preparedness. There is a need for sensitive bioassays for biodosimetric assessments of radiation exposures originating from unanticipated nuclear/radiological events. The Food and Drug Administration Animal Rule approval pathway requires an in-depth understanding of the mechanisms of radiation injury, drug efficacy and biomarkers for radiation medical countermeasure approval. Biomarkers can be helpful for extrapolating the efficacious countermeasure dose in animals to humans. We summarised here our studies to identify candidate biomarkers for the acute radiation injury using various omic platforms (metabolomics/lipidomics, proteomics, microbiome and transcriptomics/microRNA) using murine and non-human primate models conducted in our laboratory. Multi-omic platforms appear to be highly useful in assessing radiation exposure levels and for identifying biomarkers of radiation injury and countermeasure efficacy, which can expedite the regulatory approval of countermeasures., (Published by Oxford University Press 2023.)

Background: Animal models are vital for the development of radiation medical countermeasures for the prophylaxis or treatment of acute radiation syndrome and for the delayed effects of acute radiation exposure. Nonhuman primates (NHPs) play an important role in the regulatory approval of such agents by the United States Food and Drug Administration following the Animal Rule. Reliance on such animal models requires that such models are well characterized., Methods: Data gathered from both male and female animals under the same conditions and gathered concurrently are limited; therefore, the authors compared and contrasted here the radiosensitivity of both male and female NHPs provided different levels of clinical support over a range of acute, total-body gamma irradiation, as well as the influence of age and body weight., Results: Under matched experimental conditions, the authors observed only marginal, but clearly evident differences between acutely irradiated male and female NHPs relative to the measured response endpoints (rates of survival, blood cell changes, and cytokine fluctuations). These differences appeared to be accentuated by the level of exposure as well as by the nature of clinical support., Conclusion: Additional studies with both sexes under various experimental conditions and different radiation qualities run concurrently are needed.

Introduction: Radiological/nuclear accidents, hostile military activity, or terrorist strikes have the potential to expose a large number of civilians and military personnel to high doses of radiation resulting in the development of acute radiation syndrome and delayed effects of exposure. Thus, there is an urgent need for sensitive and specific assays to assess the levels of radiation exposure to individuals. Such radiation exposures are expected to alter primary cellular proteomic processes, resulting in multifaceted biological responses., Areas Covered: This article covers the application of proteomics, a promising and fast developing technology based on quantitative and qualitative measurements of protein molecules for possible rapid measurement of radiation exposure levels. Recent advancements in high-resolution chromatography, mass spectrometry, high-throughput, and bioinformatics have resulted in comprehensive (relative quantitation) and precise (absolute quantitation) approaches for the discovery and accuracy of key protein biomarkers of radiation exposure. Such proteome biomarkers might prove useful for assessing radiation exposure levels as well as for extrapolating the pharmaceutical dose of countermeasures for humans based on efficacy data generated using animal models., Expert Opinion: The field of proteomics promises to be a valuable asset in evaluating levels of radiation exposure and characterizing radiation injury biomarkers.

Introduction: The possibility of exposure to high doses of total- or partial-body ionizing radiation at a high dose rate due to radiological/nuclear accidents or terrorist attacks is increasing. Despite research and development during the last six decades, there is a shortage of nontoxic, safe, and effective radiation medical countermeasures (MCMs) for radiological and nuclear emergencies. To date, the US Food and Drug Administration (US FDA) has approved only four agents for the mitigation of hematopoietic acute radiation syndrome (H-ARS)., Area Covered: We present the current status of a promising radiation countermeasure, gamma-tocotrienol (GT3; a component of vitamin E) as a radiation MCM that has been investigated in murine and nonhuman primate models of H-ARS. There is significant work with this agent using various omic platforms during the last few years to identify its efficacy biomarkers., Expert Opinion: GT3 is a newer type of radioprotector having significant injury-countering potential and is currently under advanced development for H-ARS. As a pre-exposure drug, it requires only single doses, lacks significant toxicity, and has minimal, ambient temperature storage requirements; thus, GT3 appears to be an ideal MCM for military and first responders as well as for storage in the Strategic National Stockpile.

There is a need to develop and deploy medical countermeasures (MCMs) in order to support astronauts during space missions against excessive exposures to ionizing radiation exposure. The radiation environment of extraterrestrial space is complex and is characterized by nearly constant fluences of elemental atomic particles (protons being a dominant particle type) with widely different energies and ionization potentials. Chronic exposure to such ionizing radiation carries both near- and long-term health risks, which are generally related to the relative intensity and duration of exposure. These radiation-associated health risks can be managed only to a limited extent by physical means, but perhaps they might be more effectively managed biomedically. The Armed Forces Radiobiology Research Institute/Uniformed Services University of the Health Sciences has a long history of researching and developing MCMs specifically designed to support terrestrial-based military missions involving a radiation-threat component. The development of MCMs for both low and high doses of radiation are major aims of current research, and as such can provide lessons learned for the development of countermeasures applicable to future space missions and its extraterrestrial radiation environment., Competing Interests: Declaration of Competing Interest Authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: The high attrition rate during drug development remains a challenge that costs a significant amount of time and money. Improving the probabilities of success during the early stages of radiation medical countermeasure (MCM) development for approval by the United States Food and Drug Administration (US FDA) following the Animal Rule will reduce this burden., Area Covered: This article focuses on new technologies involving various organ-on-chip platforms. Of late, there has been rapid development of these technologies, especially in terms of mimicking both normal and abnormal physiological conditions. Here, we suggest possible applications of these novel systems for the discovery and development of radiation MCMs for the acute radiation syndrome (ARS)., Expert Opinion: Each organ-on-a-chip system has its own strengths and shortcomings. As such, the system selected for MCM discovery, development, and regulatory approval should be carefully considered and optimized to the fullest extent in order to augment successful drug testing and the minimization of attrition rates of candidate agents. The recent encouraging progress with organ-on-a-chip technology will likely lead to additional radiation MCMs for ARS. The acceptance of organ-on-a-chip technology may be a promising step toward improving the success rate of pharmaceuticals in MCM development.

Detonation of an improvised nuclear weapon, or a radiological dispersal device by terrorists, or an unintended radiological/nuclear accident in populated areas would result in a mass casualty scenario with radiation exposures of different severities. Such incidences are perceived as national security threats of major consequences. Acute radiation syndrome (ARS) is triggered by an exposure to a high dose of penetrating ionizing radiation during a short time window. In humans, moderate exposure to 2 to 4 Gy of ionizing radiation results in clinically manageable hematopoietic ARS (H-ARS), characterized by severe depletion of vital blood cells and bone marrow progenitors. Since 2015, the United States Food and Drug Administration (U.S. FDA) has approved four radiation medical countermeasures for H-ARS following the Animal Rule; namely, Neupogen, Neulasta, Leukine and Nplate (romiplostim). Here, we briefly present the treatment modalities for H-ARS. We have discussed the latest FDA-approved agent, romiplostim, as a treatment modality for H-ARS. The nature of this agent and the preclinical and clinical work that preceded its FDA approval as a radiation medical countermeasure are discussed, as are the development and use of related thrombopoietic agents for the treatment of radiation-exposed victims., (Copyright 2022 Clarivate Analytics.)