Advice on assistance and protection by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents

Timperley, Christopher M.; Abdollahi, Mohammad; Alamri, Abdullah; Baulig, Augustin; Benachour, Djafer; Borrett, Veronica; Cariño, Flerida A.; Geist, Michael; González, David; Kane, William M.; Kovarik, Zrinka; Martínez‐Álvarez, Roberto; Mourão, Nicia Maria Fusaro; Neffe, S.; Raza, S. K.; Rubaylo, Valentin; Suárez, Alejandra G.; Takeuchi, Koji; Tang, Cheng; Trifirò, Ferruccio; Straten, Francois Mauritz van; Vanninen, Paula; Vučinić, Slavica; Zaitsev, Vladimir; Zafar-uz-Zaman, M.; Zina, Mongia Saïd; Holen, Stian; Forman, Jonathan E.; Alwan, Wesam S.; Suri, Vivek

doi:10.1016/j.tox.2018.11.009

Cited by 28 publications

(21 citation statements)

References 94 publications

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“…Medical management of victims percutaneously exposed to nerve agents might be greatly affected by the remaining intact agent within the skin after decontamination 36,37 . Low volatile nerve agents, such as VX, are suggested to form depots in the deeper layers of the skin, which may cause continuous agent release and sustained symptoms [7][8][9] .…”

Section: Discussionmentioning

confidence: 99%

Efficient agent degradation within skin is important for decontamination of percutaneously exposed VX

Thors

Wigenstam

Qvarnström

et al. 2021

Cutaneous and Ocular Toxicology

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Aim of the study: Following percutaneous exposure to the nerve agent VX, the remaining intact agent within the skin after decontamination is of great concern. Consequently, this leads to prolonged agent release to the blood circulation resulting in sustained intoxication, which may complicate the medical management. The decontamination procedure used should therefore possess the ability for agent removal both on and within the skin. The efficacy of three decontamination procedures was evaluated by measuring VX and the primary degradation product ethyl methyl phosphonic acid (EMPA) penetrated through human skin and the amount remaining within the skin. Materials and methods: Decontamination was initiated 5 min post-exposure to VX on human dermatomed skin. Experiments were conducted using an in vitro skin penetration model and the amount remaining within the skin was determined by combining the tape-stripping technique and acetylcholinesterase activity measurements. Results: In control experiments without decontamination, higher amounts of VX were recovered in the deeper layers of skin compared to EMPA, which was primarily located in the stratum corneum. Both Reactive Skin Decontamination Lotion (RSDL) and the RSDL training kit (TRSDL) significantly reduced the amount of VX within the skin and decreased the penetration through the skin. However, the degradation ability of RSDL was demonstrated to be beneficial by the reduction of intact agents remaining in the skin compared to TRSDL without agent degradation capability. Soapy water decontamination caused a "wash-in" effect of VX with decreased agent amounts within stratum corneum but increased the amount VX penetrated through the skin. Conclusion: Efficient skin decontamination of VX requires skin decontaminants reaching deeper layers of the skin, and that both absorption and degradation properties are important. In addition, the "washin" effect by using soapy water may enhance VX release to the blood circulation.

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Section: Discussionmentioning

confidence: 99%

Efficient agent degradation within skin is important for decontamination of percutaneously exposed VX

Thors

Wigenstam

Qvarnström

et al. 2021

Cutaneous and Ocular Toxicology

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“…Methamidophos and fenamiphos are phosphoramidates that already have oxo-phosphate form, which could make them effective cholinergic inhibitors similar to their analogue, a well-known nerve agent tabun 14 . To successfully prevent cholinergic crisis and avoid severe health effects after exposure to OPs, prompt dephosphylation of AChE active centre needs to be done by compounds with strong nucleophile such as an oxime group 18 , 19 . The current medically approved oxime-antidotes (Fig.…”

Section: Introductionmentioning

confidence: 99%

Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

Čadež

Kolić

Šinko

et al. 2021

Sci Rep

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Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides—ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators—bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks.

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“…Therefore, OP-induced seizures require effective treatment to minimise brain damage such as treatment with benzodiazepine anticonvulsants diazepam, lorazepam, and midazolam ( 133 , 134 ). Other drugs are also being studied to that effect, including agonists of the inhibitory neurotransmitter system or antagonists of the excitatory neurotransmitter system ( 127 ) and compounds with neuroprotective properties like anti-glutamatergic drugs, including NMDA antagonists ketamine and gacyclidine or AMPA/GluK1 receptor antagonist tezampanel ( 135 , 136 ).…”

Section: Treatment Of Nerve Agent Poisoningmentioning

confidence: 99%

“…Contaminated items of clothing are to be removed and skin scrubbed and rinsed profusely with water (unless there is none) and soap (if available). Alternatively, there are skin decontamination kits available for military personnel, such as M291, which is a mixture of reactive adsorbents (Ambersorb 348F carbonaceous adsorbent) and charcoal or RSDL, which contains Dekon 139 and a small amount of 2,3 butadiene monoxime (DAM) dissolved in a solvent composed of polyethylene glycol monomethyl ether (MPEG) and water ( 135 ).…”

Section: Casualty Treatmentmentioning

confidence: 99%

Counteracting poisoning with chemical warfare nerve agents

Hrvat

Kovarik

2020

Archives of Industrial Hygiene and Toxicology

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Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

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Cited by 28 publications

References 94 publications

Efficient agent degradation within skin is important for decontamination of percutaneously exposed VX

Efficient agent degradation within skin is important for decontamination of percutaneously exposed VX

Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

Counteracting poisoning with chemical warfare nerve agents

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