Chemical Warfare Agents and the Nervous System

Liu, Jing; Uchea, Chibuzor; Wright, Linnzi; Pope, Carey

doi:10.1016/b978-0-12-800159-2.00034-8

Cited by 4 publications

(5 citation statements)

References 131 publications

(135 reference statements)

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“…Compared to animals treated with atropine alone, both HI-6 and methoxime positively affected only tremors in the 2 h interval. Tremors can be associated with the overstimulation of nicotinic receptors (Liu et al 2015 ), while oximes have been found to modulate nicotinic transmission at several levels (Soukup et al 2011a , 2013 ). Although the selected oximes showed a different impact on the protective indices, the finding correlated well with the administered oxime dose as they were not administered equimolarly but at doses corresponding to 5% of their respective LD 50 (Kuca et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

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Section: Discussionmentioning

confidence: 99%

A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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“…CWAs can be broadly classified into several categories based on their physiological effects: choking agents (chlorine, chloropicrin, phosgene, and diphosgene); blister agents (sulfur mustard, lewisite, and nitrogen mustard); , blood agents (hydrogen cyanide or cyanogen chloride); nerve agents (tabun, sarin, cyclosarin, soman, and VX). − Nerve agents are organophosphate compounds that induce irreversible inhibition of acetylcholinesterase (AChE) activity in the human nervous system. , AChE inhibition is achieved by the covalent binding of the phosphoester adduct in the compound to the active site containing serine residue by losing its leaving group. As a result, irreversible phosphorylation takes place at the serine residue, thereby inactivating its hydrolysis function .…”

Section: Introductionmentioning

confidence: 99%

“…CWAs could also cause significant damage to the central nervous system functionality leading to neurodegenerative disorders such as Alzheimer’s and Huntington’s disease . In addition, alkylating agents such as sulfur and nitrogen mustard permeate the cell and nucleus, to interact with DNA molecules, where they alkylate DNA which results in the death of cells, mainly due to inhibition of the glycolysis pathway . These toxic effects of CWAs at the cellular level, makes them lethal, by either affecting physiological functions at the organism level or by causing its death.…”

Section: Introductionmentioning

confidence: 99%

Metal Organic Framework Functionalized Textiles as Protective Clothing for the Detection and Detoxification of Chemical Warfare Agents—A Review

Balasubramanian

Kulandaisamy

Babu

et al. 2021

Ind. Eng. Chem. Res.

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Chemical warfare agents (CWAs) have been listed as lethal weapons of mass destruction due to their extreme toxicity and devastating effects. Detection and detoxification are essential to protect ourselves from such acutely perilous agents and have therefore generated a great deal of research interest. In this context, studies show that adsorbents such as activated carbon, metal oxides, and metal organic frameworks (MOFs) are active materials for the effective degradation of CWAs. Among them, MOFs are preferred because of their large surface area, tunable porosity, and catalytic, functional, and chemical stability properties. With this background, we comprehensively review the historical purview of the utility of CWAs, the potency of various CWAs, and their toxic profiles. Further, we discuss the research strategies reported to synthesize MOFs of desirable characteristics by tuning the synthesis parameters such as solvents, temperature, guest molecules, and organic ligands. Specifically, we highlight the multifarious studies of the impregnation of MOFs onto fibers/textiles as selfprotecting fabrics using different techniques. Finally, we enumerate the challenges in developing MOFs-incorporated textiles and their functionalization toward the detection and detoxification of CWAs. As a future perspective, further requirements and possibilities of using MOF-modified textiles as wearable electronic devices for the detection and detoxification of CWAs have also been addressed.

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“…The first large scale use of chemical weapons in modern history took place in World War I. Various chemicals have been developed for military purposes since the first use of tear gas, chlorine, phosgene, or mustard gas . Even recent incidents, such as the chemical attack in Syria in 2017, show that chemical warfare agents (CWA) and defense against them are still current issues.…”

Section: Introductionmentioning

confidence: 99%

Simple validated method of LC–MS/MS determination of BZ agent in rat plasma samples

Herman

Dlabková

Cechova

et al. 2020

Drug Testing and Analysis

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Agent BZ (3‐quinuclidinyl benzilate) is a centrally acting synthetic anticholinergic agent, considered as a potential military incapacitating chemical warfare agent. Despite its significance as a model compound in pharmacological research and its potential misuse in chemical attacks, few modern analytical methods for BZ determination in biological samples have been published. The goal of the present work is to develop and validate a sensitive and rapid LC–MS/MS method for the determination of agent BZ in rat plasma. The sample preparation was based on solid‐phase extraction on C‐18 cartridges. The reversed‐phase HPLC coupled with the mass spectrometer with electrospray ionization in the positive ion‐selective reaction monitoring mode was employed in the BZ analysis. Atropine was used as an internal standard. The presented method is selective, accurate, precise, and linear (r2 = 0.9947) in a concentration range from 0.5 ng/mL to 1 000 ng/mL and sensitive enough (limit of detection 0.2 ng/mL; limit of quantification 0.5 ng/mL) to determine the BZ plasma levels in rats exposed to 2 mg/kg and 10 mg/kg of BZ. The highest level of BZ in plasma was observed 5 minutes after intramuscular administration (154.6 ± 22.3 ng/mL in rats exposed to 2 mg/kg of BZ and 1024 ± 269 ng/mL in rats exposed to 10 mg/kg). After 48 h, no BZ was observed at detectable levels. This new method allows the detection and quantification of BZ in biological samples after exposure of an observed organism and it will be further optimized for other tissues to observe the distribution of BZ in organs.

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Chemical Warfare Agents and the Nervous System

Cited by 4 publications

References 131 publications

A-series agent A-234: initial in vitro and in vivo characterization

A-series agent A-234: initial in vitro and in vivo characterization

Metal Organic Framework Functionalized Textiles as Protective Clothing for the Detection and Detoxification of Chemical Warfare Agents—A Review

Simple validated method of LC–MS/MS determination of BZ agent in rat plasma samples

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