Bert W. Maidment

Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents

Abstract Cassatt, D. R., Kaminski, J. M., Hatchett, R. J., DiCarlo, A. L., Benjamin, J. M. and Maidment, B. W. Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents. Radiat. Res. 170, 540–548 (2008). Exposure to radionuclides disseminated by a radiological dispersion device or deposited as fallout after a nuclear power plant accident or detonation of an improvised nuclear device could result in internal contamination of a significant number of individuals. Internalized radionuclides may cause both acute and chronic radiation injury and increase an individuals risk of developing cancer. This damage and risk can be mitigated by the use of decorporation agents that reduce internal contamination. Unfortunately, most effective agents decorporate only a limited range of radionuclides, and some are formulated in ways that would make administration in mass casualty situations challenging. There is a need for new radionuclide decorporation agents, reformulations of existing agents, and/or expansion of the labeled indications for existing treatments. Researchers developing novel or improved decorporation agents should also understand the regulatory pathway for these products. This workshop, the first in nearly half a century to focus exclusively on radionuclide decorporation, brought together researchers and scientific administrators from academia, government and industry as well as senior regulatory affairs officers and U.S. Food and Drug Administration personnel. Meeting participants reviewed recent progress in the development of decorporation agents and contemplated the future of the field.

Rapid radiation dose assessment for radiological public health emergencies: roles of NIAID and BARDA.

A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received by thousands of individuals to allow for prompt triage and appropriate medical treatment. Measuring absorbed doses of ionizing radiation will require a system architecture or a system of platforms that contains diverse, integrated diagnostic and dosimetric tools that are accurate and precise. For large-scale incidents, rapidity and ease of screening are essential. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health is the focal point within the Department of Health and Human Services (HHS) for basic research and development of medical countermeasures for radiation injuries. The Biomedical Advanced Research and Development Authority within the HHS Office of the Assistant Secretary for Preparedness and Response coordinates and administers programs for the advanced development and acquisition of emergency medical countermeasures for the Strategic National Stockpile. Using a combination of funding mechanisms, including funds authorized by the Project BioShield Act of 2004 and those authorized by the Pandemic and All-Hazards Preparedness Act of 2006, HHS is enhancing the nations preparedness by supporting the radiation dose assessment capabilities that will ensure effective and appropriate use of medical countermeasures in the aftermath of a radiological or nuclear incident.

Animal models and medical countermeasures development for radiation-induced lung damage: report from an NIAID Workshop.

Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.

Medical Planning and Response for a Nuclear Detonation: A Practical Guide

This article summarizes major points from a newly released guide published online by the Office of the Assistant Secretary for Preparedness and Response (ASPR). The article reviews basic principles about radiation and its measurement, short-term and long-term effects of radiation, and medical countermeasures as well as essential information about how to prepare for and respond to a nuclear detonation. A link is provided to the manual itself, which in turn is heavily referenced for readers who wish to have more detail.

Development and Licensure of Medical Countermeasures to Treat Lung Damage Resulting from a Radiological or Nuclear Incident

Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.

Medical Countermeasures for Platelet Regeneration after Radiation Exposure

Abstract The events of September 11, 2001 and their aftermath increased awareness of the need to develop medical countermeasures (MCMs) to treat potential health consequences of a radiation accident or deliberate attack. The medical effects of lethal exposures to ionizing radiation have been well described and affect multiple organ systems. To date, much of the research to develop treatments for mitigation of radiation-induced hematopoietic damage has focused on amelioration of radiation-induced neutropenia, which has long been considered to be the primary factor in determining survival after an unintentional radiation exposure. Consistent with historical data, recent studies have highlighted the role that radiation-induced thrombocytopenia plays in radiation mortality, yet development of MCMs to mitigate radiation damage to the megakaryocyte lineage has lagged behind anti-neutropenia approaches. To address this gap and to foster research in the area of platelet regeneration after radiation exposure, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on March 22–23, 2010 to encourage collaborations between NIAID program awardees and companies developing pro-platelet approaches. NIAID also organized an informal, open discussion between academic investigators, product development contractors, and representatives from the U.S. Food and Drug Administration (FDA) and other relevant government agencies about drug development toward FDA licensure of products for an acute radiation syndrome indication. Specific emphasis was placed on the challenges of product licensure for radiation/nuclear MCMs using current FDA regulations (21 CFR Parts 314 and 601) and on the importance of animal efficacy model development, design of pivotal protocols, and standardization of irradiation and animal supportive care.

Public health and medical preparedness for a nuclear detonation: the nuclear incident medical enterprise

AbstractResilience and the ability to mitigate the consequences of a nuclear incident are enhanced by (1) effective planning, preparation and training; (2) ongoing interaction, formal exercises, and evaluation among the sectors involved; (3) effective and timely response and communication; and (4) continuous improvements based on new science, technology, experience, and ideas. Public health and medical planning require a complex, multi-faceted systematic approach involving federal, state, local, tribal, and territorial governments; private sector organizations; academia; industry; international partners; and individual experts and volunteers. The approach developed by the U.S. Department of Health and Human Services Nuclear Incident Medical Enterprise (NIME) is the result of efforts from government and nongovernment experts. It is a “bottom-up” systematic approach built on the available and emerging science that considers physical infrastructure damage, the spectrum of injuries, a scarce resources setting, the need for decision making in the face of a rapidly evolving situation with limited information early on, timely communication, and the need for tools and just-in-time information for responders who will likely be unfamiliar with radiation medicine and uncertain and overwhelmed in the face of the large number of casualties and the presence of radioactivity. The components of NIME can be used to support planning for, response to, and recovery from the effects of a nuclear incident. Recognizing that it is a continuous work-in-progress, the current status of the public health and medical preparedness and response for a nuclear incident is provided.

NIAID/NIH radiation/nuclear medical countermeasures product research and development program.

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. The U.S. Government has addressed these threats with a two-pronged strategy of preventing organizations from obtaining weapons of mass destruction and preparing in case an event occurs. The National Institute of Allergy and Infectious Diseases (NIAID) contributes to these preparedness efforts by supporting basic research and development for chemical, biological, radiological, and nuclear countermeasures for civilian use. The Radiation Countermeasures Program at NIAID has established a broad research agenda focused on the development of new medical products to mitigate and treat acute and long-term radiation injury, promote the clearance of internalized radionuclides, and facilitate accurate individual dose and exposure assessment. This paper reviews the recent work and collaborations supported by the Radiation Countermeasures Program.

Building the Strategic National Stockpile Through the NIAID Radiation Nuclear Countermeasures Program

The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and long‐term radiation injuries that would result in the event of large‐scale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proof‐of‐concept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individuals radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP.

Development and Licensure of Medical Countermeasures for Platelet Regeneration after Radiation Exposure

The Department of Health and Human Services (HHS) is charged with protecting civilian populations by providing leadership in research, development, acquisition, deployment and use of effective medical countermeasures (MCMs) for treatment of injuries resulting from a radiological/nuclear incident. HHS has assigned the National Institute of Allergy and Infectious Diseases (NIAID) to develop and implement a research and development agenda (1). After unintentional radiation exposure in the hematopoietic dose range (,2 Gy to 8 Gy), potentially life-threatening neutropenia and thrombocytopenia can result, increasing the risk of death due to opportunistic infections and/ or hemorrhage (2). Although both conditions are likely to be major contributors to mortality in untreated individuals, little recent work had been done to develop drugs to enhance platelet counts after irradiation, and there are currently no licensed therapeutics (other than blood products) in the Strategic National Stockpile for treatment of this radiation-induced complication. To address this aspect of radiation damage, NIAID funded a portfolio of grants in late 2008 to develop MCMs to mitigate/treat radiation-induced thrombocytopenia and enhance survival. Supported research includes studies designed to generate data that would be required by the U.S. Food and Drug Administration (FDA) for licensure of an MCM as a mitigator of radiation-induced thrombocytopenia (RIT). The NIAID Radiation Countermeasures Program held a workshop on March 22–23, 2010 to bring together representatives from U.S. Government (USG) agencies with researchers who are developing MCMs and animal models to evaluate approaches to enhance regeneration of platelets after radiation exposure [(3); available online at http://dx.doi.org/10.1667/ RROL01.1]. The main goal of the discussion session that followed the science presentations was to clarify issues regarding potential paths forward for FDA licensure of products for a hematopoietic, acute radiation syndrome (ARS) indication and encourage discussion about the challenges involved in development of NIAID-funded (and other) MCMs to minimize thrombocytopenia and enhance survival after unintentional radiation exposure. After irradiation, megakaryocytes, which give rise to platelets, migrate to the osteoblastic niche (4). Megakaryocytes in the circulation are known to be more radioresistant to radiation than other bone marrowderived cells; however, their progenitor populations appear to be more radiosensitive (5). Depending on the degree of radiation damage, a drop in platelet count can be observed in less than a week (6), with the risk of life-threatening bleeding increased as the level of circulating platelets drops below 20,000/mm. In small accidents, supportive transfusion will be part of medical management; however, logistical requirements to provide care to large numbers of victims after a mass casualty incident are great, and emergency preparedness experts believe that an effective pharmacological therapy that mitigates or treats radiation-induced thrombocytopenia would offer dramatic advantages. Thus preferred drugs are those that can be easily administered (e.g. oral, subcutaneous, intramuscular routes of delivery) with low toxicity. Although some drugs are currently in development to treat RIT after cancer radiotherapy, they are often administered as radioprotectors – in advance of the radiation exposure. Due to the challenges involved in providing MCMs in the wake of a mass casualty incident, treatments are not expected to be available until least 24 h after an event, so drugs that are effective at this time postexposure (and beyond) are the most desirable.