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Bohnert, S. (author), van den Berg, R.M. (author), Mikler, J. (author), Klaassen, S.D (author), Joosen, M.J.A. (author)Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating a toxic syndrome that can be lethal if left untreated (Cannard, 2006). It is standard practice to treat Sarin (GB) intoxication with an oxime, an antimuscarinic such as atropine...article 2020
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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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Valle da Silva, J.A. (author), Modesto-Costa, L. (author), de Koning, M.C. (author), Borges, I. (author), Costa França, T.C. (author)In this work, quaternary and non-quaternary oximes designed to bind at the peripheral site of acetylcholinesterase previously inhibited by organophosphates were investigated theoretically. Some of those oximes have a large number of degrees of freedom, thus requiring an accurate method to obtain molecular geometries. For this reason, the density...article 2018
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Horn, G. (author), de Koning, M.C. (author), van Grol, M. (author), Thiermann, H. (author), Worek, F. (author)Poisoning by organophosphorus compounds (OP) is characterized by inhibition of the key enzyme acetylcholinesterase (AChE) and potentially fatal outcomes in humans. Insufficient efficacy of the standard therapy with atropine and AChE reactivators (oximes) against certain OP initiated synthesis of novel non-oxime reactivators basing on the common...article 2018
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da Silva, J.A.V. (author), Modesto-Costa, L. (author), de Koning, M.C. (author), Borges, I.Jr. (author), França, T.C.C. (author)In this work, quaternary and non-quaternary oximes designed to bind at the peripheral site of acetylcholinesterase previously inhibited by organophosphates were investigated theoretically. Some of those oximes have a large number of degrees of freedom, thus requiring an accurate method to obtain molecular geometries. For this reason, the density...article 2018
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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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de Koning, M.C. (author), Joosen, M.J.A. (author), Worek, F. (author), Nachon, F. (author), van Grol, M. (author), Klaassen, S.D. (author), Alkema, D.P.W. (author), Wille, T. (author), de Bruijn, H.M. (author)Recently, a new class of reactivators of chemical warfare agent inhibited acetylcholinesterase (AChE) with promising in vitro potential was developed by the covalent linkage of an oxime nucleophile and a peripheral site ligand. However, the complexity of these molecular structures thwarts their accessibility. We report the compatibility of...article 2017
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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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Joosen, M.J.A. (author), Vester, S.M. (author), Hamelink, J. (author), Klaassen, S.D. (author), van den Berg, R.M. (author)One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of...article 2016
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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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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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Koek, M.M. (author), Muilwijk, B. (author), van der Werf, M.J. (author), Hankemeier, T. (author), TNO Kwaliteit van Leven (author)An analytical method was set up suitable for the analysis of microbial metabolomes, consisting of an oximation and silylation derivatization reaction and subsequent analysis by gas chromatography coupled to mass spectrometry. Microbial matrixes contain many compounds that potentially interfere with either the derivatization procedure or analysis...article 2006
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van der Schans, M.J. (author), Lander, B.J. (author), van der Wiel, H. (author), Langenberg, J.P. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(±)P(±)-soman and (±)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (±)-VX. A validated method was developed to determine blood levels of (±)-VX by means of achiral gas chromatography at blood levels ≥10 pg/ml. The ratio of the...article 2003
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TNO Pharma (author), Melchers, B.P.C. (author), Philippens, I.H.C.H.M. (author), Wolthuis, O.L. (author)The therapeutic efficacy of the oximes HI-6 and HLo-7 (132.5 μmol/kg), in combination with atropine, in soman- or tabun-intoxicated guinea pigs was compared, particularly with respect to recovery of shuttlebox performance and electroencephalograms (EEGs). After 1.5 x LD50 soman SC, therapy with HI-6 or HLo-7 resulted in survival of 87.5% of the...article 1994
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van Helden, H.P.M. (author), van der Wiel, H.J. (author), Zijlstra, J.J. (author), Melchers, B.P.C. (author), Busker, R.W. (author)The oximes HI-6, HLo-7, HGG-12, HGG-42 and obidoxime were used in a previously developed rat model to evaluate the therapeutic effects of oximes other than acetylcholinesterase (AChE) reactivation (so-called 'nonreactivating effects'). To test this anaesthetized, atropinized and artificially ventilated rats (n = 8 or 16) were poisoned with a...article 1994
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van Helden, H.P.M. (author), de Lange, J. (author), Busker, R.W. (author), Melchers, B.P.C. (author), Medisch Biologisch Laboratorium TNO (author)Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 (see Compounds) showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT...article 1991
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de Jong, L.P.A. (author), Verhagen, M.A.A. (author), Langenberg, J.P. (author), Hagedorn, I. (author), Löffler, M. (author), Prins Maurits Laboratorium TNO (author)Purification of (+)-tabun was accomplished by treatment with electric eel acetylcholinesterase (AChE) in order to bind contaminating (-)-tabun, the more potent enantiomer with respect of AChE inhibition. Electric eel AChE inhibited with (-)-tabun and with purified (+)-tabun show similar properties in reactivation reactions with oximes (pH 7.5,...article 1989
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Prins Maurits Laboratorium TNO (author), Johnson, M.K. (author), Willems, J.L. (author), de Bisschop, H.C. (author), Read, D.J. (author), Benschop, H.P. (author)Organophosphorus-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE; formerly known as neurotoxic esterase), followed by an “aging” of the phosphorylated NTE. Protection against OPIDP should thus be achieved by production of an inhibited but “nonaging” NTE. Inhibited NTE...article 1988
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Prins Maurits Laboratorium TNO Medisch Biologisch Laboratorium TNO (author), Benschop, H.P. (author), Konings, C.A.G. (author), van Genderen, J. (author), de Jong, L.P.A. (author)The four stereoisomers of the nerve agent pinacolyl methylphosphonofluoridate (soman), designated as C(+)P(+), C(+)P(-), C(-)P(+), and C(-)P(-), have different toxicologic properties due to stereospecific interactions in living organisms. We report the isolation of these stereoisomers with more than 99% optical purity. This result was realized...article 1984
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- Prins Maurits Laboratorium TNO (author), van Havere, W. (author), Lenstra, A.T.H. (author), Geise, H.J. (author), van den Berg, G.R. (author), Benschop, H.P. (author) article 1982
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