Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Bennion, Brian J.; Malfatti, Michael; Be, Nicholas A.; Enright, Heather A.; Hok, Saphon; Cadieux, C. Linn; Carpenter, Timothy S.; Lao, Victoria; Kuhn, Edward A.; McNerney, M. Windy; Lightstone, Felice C.; Nguyen, Tin; Valdez, Carlos A.

doi:10.1038/s41598-021-94963-2

Cited by 10 publications

(13 citation statements)

References 60 publications

(60 reference statements)

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“…3,4,[16][17][18] As a result, it became one of the most significant terrorist attacks in world history, with 5,500 people injured. 3,4,16,17 Nerve agents have also 19,20 These findings are in line with previous research that the use of chemical weapons in terrorist attacks, although rare, remains a significant challenge and concern because of their ability to inflict massive numbers of casualties. 21 Previous literature has determined that among global chemical terror attacks from 1970 through 2017, the most common routes of exposure were dermal-mucosal (43.8%), inhalational (37.2%), enteral (16.9%), parenteral (1.7%), and multiple (0.4%).…”

Section: Discussionsupporting

confidence: 86%

Terrorism-Related Attacks in East Asia from 1970 through 2020

Shin

Hertelendy

Hart

et al. 2023

Prehosp. Disaster med.

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Aim: This study aims to analyze and describe terrorism-related attacks in East Asia from 1970 through 2020. Background: East Asia consists of South Korea, North Korea, Singapore, Hong Kong, China, Japan, Taiwan, and Macao. According to the Global Terrorism Index (GTI) 2022, the impact of terrorism in East Asia is very low. However, the assassination of former Japanese Prime Minister Shinzo Abe on July 8, 2022 demonstrates that East Asia is not safe from terrorist attacks. This descriptive analysis of terrorist attacks in East Asia will help first responders, Emergency Medical Services (EMS), hospital-based medical providers, and policymakers establish a more refined hazard vulnerability assessment (HVA) framework and develop a Counter-Terrorism Medicine (CTM) mitigation, preparedness, response, and recovery plan. Methods: This is a descriptive observational study drawing data from the Global Terrorism Database (GTD) from January 1, 1970 through December 31, 2020. Epidemiology outcomes included primary weapon type, primary target type, the country where the incident occurred, and the number of total deaths and injured collected. Data from 2021 were not yet available at the time of this study. Results were exported into an Excel spreadsheet (Microsoft Corp.; Redmond, Washington USA) for analysis. Results: There were 779 terrorism-related events in East Asia from 1970 through 2020. In total, the attacks resulted in 1,123 deaths and 9,061 persons injured. The greatest number of attacks (371; 47.63%) occurred in Japan and the second most occurred in China (268; 34.4%). Explosives were the most used primary weapon type (308; 39.54%) in the region, followed by incendiary devices (260; 33.38%). Terrorist attacks drastically diminished from their peak of 92 in 1990, but there were additional peaks of 88 in 1996, 18 in 2000, 20 in 2008, and 36 attacks in 2014. Conclusions: A total of 779 terrorist attacks occurred from 1970 through 2020 in East Asia, resulting in 1,123 deaths and 9,061 injuries. Of those, 82.03% attacks occurred in Japan and China. Terrorist attacks drastically diminished since their peak in 1996, but there is an overall uptrend in attacks since 1999.

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Section: Discussionsupporting

confidence: 86%

Terrorism-Related Attacks in East Asia from 1970 through 2020

Shin

Hertelendy

Hart

et al. 2023

Prehosp. Disaster med.

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“…Recently, the reactivation of OP-inhibited AChE was shown to depend on a fine fit of the oxime not only being close to the phosphorylated catalytic serine, but also acquiring an angle of 180 degrees, which is essential to ensure a thermodynamically favorable nucleophilic attack from the side of the oxime group (Bennion et al, 2021).…”

Section: Re Ver Sal Of Op Toxicit Y By Oxime Smentioning

confidence: 99%

Recent advances in cholinergic mechanisms as reactions to toxicity, stress, and neuroimmune insults

Kovarik

Moshitzky

Hrvat

et al. 2023

Journal of Neurochemistry

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This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter‐change under acute states, age, sex, and COVID‐19 infection; all of which modulate ACh‐mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime‐assisted reactivation of inhibited AChE. The over‐arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti‐cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long‐term deleterious effects of OPs.image

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“…Nerve agents are a class of chemical warfare agents that have been used by various terrorist groups in recent years and have the potential for large-scale military use. − These chemical agents are organophosphate compounds, which act by inhibiting acetylcholinesterase, leading to acetylcholine accumulation, respiratory paralysis, and death. ,, Nerve agents are classified as G- or V-series, and V-series agents are phosphonothioate compounds, which have been developed more recently than G-series agents. ,, Additionally, V-series nerve agents are more toxic than G-series agents . Due to the potential of nerve agents to be used for targeted attacks on individuals, populations, and strategic resources, , reliable detection of these compounds over a wide range of environmental parameters is crucial for defense against these lethal agents.…”

Section: Introductionmentioning

confidence: 99%

MOF-Enabled Electrochemical Sensor for Rapid and Robust Sensing of V-Series Nerve Agents at Low Concentrations

Marlar,

Harb

2024

ACS Appl. Mater. Interfaces

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Among nerve agents, V-series nerve agents are some of the most toxic, making low-concentration detection critical for the protection of individuals, populations, and strategic resources. Electrochemical sensors are ideally suited for the real-time and infield sensing of these agents. While V-series nerve agents are inherently nonelectroactive, they can be hydrolyzed to electroactive products compatible with electrochemical sensing. Zr(IV) MOFs are next-generation nanoporous materials that have been shown to rapidly catalyze the hydrolysis of nerve agents. This work makes use of these nanomaterials to develop, for the first time, an MOFenabled electrochemical sensor for V-series nerve agents. Our work demonstrates that the VX thiol hydrolysis product can be electrochemically detected at low concentrations using commercially available gold electrodes. We demonstrate that low-concentration thiol oxidation is an irreversible reaction that is dependent on both mass transport and adsorption. Demeton-S-methylsulfon, a VX simulant, is used to demonstrate the full range of sensor operation that includes hydrolysis and electrochemical detection. We demonstrate that MOF-808 rapidly, selectively, and completely hydrolyzes demeton-S-methylsulfon to less-hazardous dimethyl phosphate and 2-ethylsulfonylethanethiol. Low-concentration measurements of 2-ethylsulfonylethanethiol are performed by using electrochemical techniques. This sensor has a limit of detection of 30 nM or 7.87 μg/L for 2-ethylsulfonylethanethiol, which is near the nerve agent exposure limit for water samples established by the United States military. Our work demonstrates the feasibility of rapid, robust electrochemical sensing of V-series nerve agents at low concentrations for in-field applications.

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Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Cited by 10 publications

References 60 publications

Terrorism-Related Attacks in East Asia from 1970 through 2020

Terrorism-Related Attacks in East Asia from 1970 through 2020

Recent advances in cholinergic mechanisms as reactions to toxicity, stress, and neuroimmune insults

MOF-Enabled Electrochemical Sensor for Rapid and Robust Sensing of V-Series Nerve Agents at Low Concentrations

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