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Development of a metal-organic framework/textile composite for the rapid degradation and sensitive detection of the nerve agent VX

de Koning, M.C. (author), Ma, K. (author), van Grol, M. (author), Iordanov, I. (author), Kruijne, M.J.L. (author), Idrees, K.B. (author), Xie, H. (author), Islamoglu, T. (author), Bross, R.P.T. (author), Farha, O.K. (author)

In the case of an incident with nerve agents, the timely and ready detection and identification of such a substance on suspected surfaces is essential. However, the detection of low levels of nerve agents on a surface is a considerable challenge for conventional detection equipment, especially with VX, a highly toxic nerve agent with low...

article 2022

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Effective degradation of Novichok nerve agents by the zirconium metal−organic framework MOF-808

de Koning, M.C. (author), Vieiro Soares, C. (author), van Grol, M. (author), Bross, R.P.T. (author), Maurin, G. (author)

Novichoks are a novel class of nerve agents (also referred to as the A-series) that were employed in several poisonings over the last few years. This calls for the development of novel countermeasures that can be applied in protective concepts (e.g., protective clothing) or in decontamination methods. The Zr metal−organic framework MOF-808 has...

article 2022

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A delayed treatment model for the evaluation of scopolamine for VX nerve agent intoxication

Cornelissen, A.S. (author), Garcia, F.E. (author), Raulli, R.E. (author), Laney, J. (author), Joosen, M.J.A. (author)

Most research on medical countermeasures for nerve agent exposure assumes a military scenario, in which (autoinjector) treatment is envisaged to be available immediately. In a civilian setting however, treatment is delayed until arrival of first-aid responders. This may significantly affect treatment efficacy and the requirements for secondary...

article 2021

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Early detection of exposure to toxic chemicals using continuously recorded multi-sensor physiology

van Baardewijk, J.U. (author), Agarwal, S. (author), Cornelissen, A.S. (author), Joosen, M.J.A. (author), Kentrop, J. (author), Varon, C. (author), Brouwer, A.M. (author)

Early detection of exposure to a toxic chemical, e.g., in a military context, can be life-saving. We propose to use machine learning techniques and multiple continuously measured physiological signals to detect exposure, and to identify the chemical agent. Such detection and identification could be used to alert individuals to take appropriate...

article 2021

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Enzymatic decontamination of G-type, V-type and Novichok nerve agents

Jacquet, P. (author), Rémy, B. (author), Bross, R.P.T. (author), van Grol, M. (author), Gaucher, F. (author), Chabrière, E. (author), de Koning, M.C. (author), Daudé, D. (author)

Organophosphorus nerve agents (OPNAs) are highly toxic compounds inhibiting cholin-ergic enzymes in the central and autonomic nervous systems and neuromuscular junctions, causing severe intoxications in humans. Medical countermeasures and efficient decontamination solutions are needed to counteract the toxicity of a wide spectrum of harmful...

article 2021

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Pharmacokinetics and efficacy of atropine sulfate/obidoxime chloride co-formulation against VX in a guinea pig model

Kentrop, J. (author), Savransky, V. (author), Klaassen, S.D. (author), van Groningen, T. (author), Bohnert, S. (author), Cornelissen, A.S. (author), Cochrane, L. (author), Barry, J. (author), Joosen, M.J.A. (author)

Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for...

article 2021

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Laboratory analysis of chemical warfare agents, adducts, and metabolites in biomedical samples

van der Schans, M.J. (author)

Chemical warfare agents (CWAs) are the most toxic compounds that have ever been produced. In order to develop medical countermeasures against the effects of these agents, analytical procedures to analyze these agents in their intact form in biological matrices are essential for a better understanding of the toxicological process. Although the...

bookPart 2020

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Synthesis and in vitro evaluation of novel non-oximes for the reactivation of nerve agent inhibited human acetylcholinesterase

de Koning, M.C. (author), Horn, G. (author), Worek, F. (author), van Grol, M. (author)

Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich...

article 2020

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Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase

de Koning, M.C. (author), Horn, G. (author), van Grol, M. (author)

Organophosphorous (OP) compounds (such as nerve agents) inhibit the enzyme acetylcholinesterase (AChE) by covalent phosphylation of a key serine residue in the active site of the enzyme resulting in severe symptoms and ultimately death. OP intoxications are currently treated by administration of certain oxime compounds. The presently fielded...

conference paper 2018

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Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigs

Joosen, M.J.A. (author), Klaassen, S.D. (author), Verheij, E. (author), van Groningen, T. (author), Cornelissen, A.S. (author), Skiadopoulos, M.H. (author), Cochrane, L. (author), Shearer, J.D. (author)

The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG)...

article 2018

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Fatal sarin poisoning in Syria 2013: forensic verification within an international laboratory network

John, H. (author), van der Schans, M.J. (author), Koller, M. (author), Spruit, W.E.T. (author), Worek, F. (author), Thiermann, H. (author), Noort, D. (author)

During the United Nations fact-finding mission to investigate the alleged use of chemical warfare agents in the Syrian Arab Republic in 2013, numerous tissues from a deceased female victim, who had displayed symptoms of cholinergic crisis, were collected. The Organisation for the Prohibition of Chemical Weapons (OPCW) authorized two specialized...

article 2018

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The impact of skin decontamination on the time window for effective treatment of percutaneous VX exposure

Joosen, M.J.A. (author), van den Berg, R.M. (author), de Jong, A.L. (author), van der Schans, M.J. (author), Noort, D. (author), Langenberg, J.P. (author)

The main goal of the present study was to obtain insight into depot formation and penetration following percutaneous VX poisoning, in order to identify an appropriate decontamination window that can enhance or support medical countermeasures. The study was executed in two phases, using the hairless guinea pig as an animal model. In the first...

article 2017

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Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

de Almeida, J.S.F.D. (author), Cuya Guizado, T.R. (author), Guimarães, A.P. (author), Ramalho, T.C. (author), Gonçalves, A.S. (author), de Koning, M.C. (author), França, T.C.C. (author)

In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human...

article 2016

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A step toward the reactivation of aged cholinesterases-crystal structure of ligands binding to aged human butyrylcholinesterase

Wandhammer, M. (author), de Koning, M. (author), van Grol, M. (author), Loiodice, M. (author), Saurel, L. (author), Noort, D. (author), Goeldner, M. (author), Nachon, F. (author)

Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to...

article 2013

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Timing of decontamination and treatment in case of percutaneous VX poisoning: A mini review

Joosen, M.J.A. (author), van der Schans, M.J. (author), Kuijpers, W.C. (author), van Helden, H.P.M. (author), Noort, D. (author)

Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single...

article 2013

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Increasing oxime efficacy by blood-brain barrier modulation

Joosen, M.J.A. (author), van der Schans, M.J. (author), van Dijk, C.G.M. (author), Kuijpers, W.C. (author), Wortelboer, H.M. (author), van Helden, H.P.M. (author)

One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might...

article 2011

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Peripheral site ligand-oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase

de Koning, M.C. (author), Joosen, M.J.A. (author), Noort, D. (author), van Zuylen, A. (author), Tromp, M.C. (author)

A conceptually novel approach to the design of reactivators of nerve agent-inhibited acetylcholinesterase (AChE) is presented. The concept comprises the linkage of a peripheral site ligand via a spacer to a reactivating moiety with the eventual goal to develop non-ionic reactivators with sufficient affinity for AChE to induce reactivation and...

article 2011

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Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase

de Koning, M.C. (author), van Grol, M. (author), Noort, D. (author)

Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was...

article 2011

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Comprehensive gas chromatography with Time of Flight MS and large volume introduction for the detection of fluoride-induced regenerated nerve agent in biological samples

van der Meer, J.A. (author), Trap, H.C. (author), Noort, D. (author), van der Schans, M.J. (author), TNO Defensie en Veiligheid (author)

Recently, several methods have been developed to verify exposure to nerve agents. Most of these methods, such as the fluoride reactivation technique and the analysis of inhibited phosphonylated butyrylcholinesterase (BuChE), are based on mass spectrometry. The high specificity of the mass spectrometer might also imply a disadvantage, because the...

article 2010

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Activity-based protein profiling reveals broad reactivity of the nerve agent sarin

TNO Defensie en Veiligheid (author), Tuin, A.W. (author), Mol, M.A.E. (author), van den Berg, R.M. (author), Fidder, A. (author), van der Marel, G.A. (author), Overkleeft, H.S. (author), Noort, D. (author)

Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which...

article 2009