Supporting Fundamental Chemical Toxicology Research To Inform Medical Countermeasure Developments: The National Institutes of Health Chemical Countermeasures Research Program

Yeung, David T.; Harper, Jill R.; Platoff, Gennady E.

doi:10.1021/acs.chemrestox.0c00086

Cited by 8 publications

(5 citation statements)

References 4 publications

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“…Traditionally, chemical, biological, radiological, and nuclear agents were viewed as threats to only the military until the events of September 11, 2001, and the anthrax mailing incidents in October 2001. These incidents, as well as the sarin attacks in Tokyo and Syria, VX attacks in Malaysia, and Novichok attacks in England revealed the vulnerability of civilians to unconventional terrorism threats such as nerve agents (Morita et al, 1995;Suzuki et al, 1995;Okumura et al, 1996;Miyaki et al, 2005;Yanagisawa et al, 2006;Zarocostas, 2017;Jett et al, 2020;Yeung et al, 2020). Until recently, preventing acute deaths due to OPNA exposure had taken a top priority.…”

Section: Discussionmentioning

confidence: 99%

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

Gage

Rao

Samidurai

et al. 2022

Front. Cell. Neurosci.

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Modeling a real-world scenario of organophosphate nerve agent (OPNA) exposure is challenging. Military personnel are premedicated with pyridostigmine, which led to the development of OPNA models with pyridostigmine/oxime pretreatment to investigate novel therapeutics for acute and chronic effects. However, civilians are not premedicated with pyridostigmine/oxime. Therefore, experimental models without pyridostigmine were developed by other laboratories though often only in males. Following OPNA exposure, prolonged convulsive seizures (CS) or status epilepticus (SE) are concerning. The duration and severity of CS/SE determine the extent of brain injury in survivors even after treating with medical countermeasures (MCM)/antidotes such as atropine, an oxime, and an anticonvulsant such as diazepam/midazolam. In this study, using a large mixed sex cohort of adult male and female rats, without pretreatment, we demonstrate severe SE lasting for >20 min in 82% of the animals in response to soman (GD,132 μg/kg, s.c.). Atropine sulfate (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.) were administered immediately following soman, and midazolam (3 mg/kg, i.m.) 1 h post-exposure. Immediate MCM treatment is impractical in civilian exposure to civilians, but this approach reduces mortality in experimental models. Interestingly, female rats, irrespective of estrous stages, had an average of 44 min CS (stage ≥ 3), while males had an average of 32 min CS during SE, starting from soman exposure to midazolam treatment. However, in telemetry device implanted groups, there were no significant sex differences in SE severity; males had 40 min and females 43 min of continuous CS until midazolam was administered. No animals died prior to midazolam administration and less than 5% died in the first week after soman intoxication. In telemetered animals, there was a direct correlation between EEG changes and behavioral seizures in real-time. In the long-term, convulsive spontaneously recurring seizures (SRS) were observed in 85% of randomly chosen animals. At 4-months post-soman, the brain histology confirmed reactive gliosis and neurodegeneration. The novel findings of this study are that, in non-telemetered animals, the SE severity following soman intoxication was significantly greater in females compared to males and that the estrous cycle did not influence the response.

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Section: Discussionmentioning

confidence: 99%

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

Gage

Rao

Samidurai

et al. 2022

Front. Cell. Neurosci.

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“…The AR approval relies on adequate and well-controlled studies in relevant animal models to determine efficacy of the MCM as well as extensive safety studies in human volunteers. The foundational pillars of the AR necessitate (1) a well-understood pathophysiology sequelae of the insult/injury (chemical, biological, radiological) and its resolution by the MCM, (2) efficacy in more than one animal model predictive of response in humans, (3) study endpoints related to desired benefits in humans (reduction in major morbidity or mortality), and (4) pharmacokinetic (PK)/ pharmacodynamic (PD) assessments in animal models and humans that allow for appropriate MCM dose scaling.…”

Section: Fda Requirementsmentioning

confidence: 99%

“… 1 This trans-NIH partnership allows the CCRP to capitalize on relevant subject matter expertise in pulmonary, dermal, ocular, and neurological research that already exists at the respective NIH institutes and their extramural communities. 2 The CCRP at the NIAID is responsible for overall execution of the NIH Strategic Plan and Research Agenda for Medical Countermeasures Against Chemical Threats ( www.niaid.nih.gov/sites/default/files/NIH-Strategic-Plan-and-Research-Agenda200708.pdf ) and provides over-sight and funding to various R21, R01, R34, UG3/UH3, and Small Business research grant and cooperative agreement initiatives administered by partner ICs, including the Countermeasures Against Chemical Threats (CounterACT) translational program.…”

Section: Introductionmentioning

confidence: 99%

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective

Rios,

Garcia,

Hogdahl

et al. 2024

Disaster med. public health prep.

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Although chemical and radiological agents cause toxicity through different mechanisms, the multiorgan injuries caused by these threats share similarities that convene on the level of basic biological responses. This publication will discuss these areas of convergence and explore “multi-utility” approaches that could be leveraged to address common injury mechanisms underlying actions of chemical and radiological agents in a threat-agnostic manner. In addition, we will provide an overview of the current state of radiological and chemical threat research, discuss the US Government’s efforts toward medical preparedness, and identify potential areas for collaboration geared toward enhancing preparedness and response against radiological and chemical threats. We also will discuss previous regulatory experience to provide insight on how to navigate regulatory paths for US Food and Drug Administration (FDA) approval/licensure/clearance for products addressing chemical or radiological/nuclear threats. This publication follows a 2022 trans-agency meeting titled, “Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures,” sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH). Discussions from this meeting explored the overlapping nature of radiation and chemical injury and spurred increased interest in how preparedness for one threat leads to preparedness for the other. Herein, subject matter experts from the NIAID and the Biomedical Advanced Research and Development Authority (BARDA), a part of the Administration for Strategic Preparedness and Response (ASPR), summarize the knowledge gained from recently funded biomedical research, as well as insights from the 2022 meeting. These topics include identification of common areas for collaboration, potential use of biomarkers of injury to identify injuries caused by both hazards, and common and widely available treatments that could treat damage caused by radiological or chemical threats.

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“…The cornea is the most exposed mucosal surface of the eye, and as such, corneal epithelial cells are the main focus in in vitro cell culture models for ocular toxicity (Ronkko et al 2016;Yeung et al 2020). More than 30 yr ago, it was demonstrated that the corneal epithelium is renewed constantly by limbal epithelial stem cells that migrate from the corneo-scleral junction, known as the limbus (Schermer et al 1986).…”

Section: Source Of Corneal Epithelial Cellsmentioning

confidence: 99%

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Kaluzhny

Klausner

2021

In Vitro Cell.Dev.Biol.-Animal

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Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the improvements in primary cell isolation, cell culture techniques, and media, which have led to improved in vitro corneal tissue models and test methods. Most in vitro models for ocular toxicology attempt to reproduce the corneal epithelial tissue which consists of 4-5 layers of non-keratinized corneal epithelial cells that form tight junctions, thereby limiting the penetration of chemicals, xenobiotics, and pharmaceuticals. Also, significant efforts have been directed toward the development of more complex threedimensional (3D) equivalents to study wound healing, drug permeation, and bioavailability. This review focuses on in vitro reconstructed 3D corneal tissue models and their utilization in ocular toxicology as well as their application to pharmacology and ophthalmic research. Current human 3D corneal epithelial cell culture models have replaced in vivo animal eye irritation tests for many applications, and substantial validation efforts are in progress to verify and approve alternative eye irritation tests for widespread use. The validation of drug absorption models and further development of models and test methods for many ophthalmic and ocular disease applications is required.

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Supporting Fundamental Chemical Toxicology Research To Inform Medical Countermeasure Developments: The National Institutes of Health Chemical Countermeasures Research Program

Cited by 8 publications

References 4 publications

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

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