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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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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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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
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TNO Defensie en Veiligheid (author), Langenberg, J.P. (author), van der Schans, M.J. (author), Noort, D. (author)The perceived threat of the use of nerve agents by terrorists against civilian targets implies the need for methods for point-of-care (POC) diagnosis. This review presents an overview of methods that are currently available for the assessment of exposure to nerve agents. Since these methods are mostly MS based, they require complex and expensive...article 2009
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Noort, D. (author), Fidder, A. (author), van der Schans, M.J. (author), Hulst, A.G. (author), TNO Defensie en Veiligheid (author)We present a generic mass spectrometric method to verify exposure to organophosphates, based on the chemical conversion of the phosphylated peptides obtained after pepsin digestion of human butyrylcholinesterase (HuBuChE) to a common precursor peptide. After exposure of plasma to various organophosphates (nerve agents, pesticides), HuBuChE was...article 2006
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Sweeney, R.E. (author), Langenberg, J.P. (author), Maxwell, D.M. (author), TNO Defensie en Veiligheid (author)A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), medium (2-3 × LD50) and high (6 × LD50) levels...article 2006
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van Helden, H.H.P.M. (author), Vanwersch, R.A.P. (author), Kuijpers, W.C. (author), Trap, H.C. (author), Philippens, I.H.C. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)The main purpose of this pilot study was to estimate the lowest observable adverse effect level (LOAEL) for the electroencephalogram (EEG) upon long-term, low-level exposure of vehicle-pretreated and pyridostigmine-pretreated marmoset monkeys to sarin vapour. This is the C·t value (t = 5 h) of exposure at which the EEG becomes significantly...article 2004
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Smulders, C.J.G.M. (author), Bueters, T.J.H. (author), Vailati, S. (author), van Kleef, R.G.D.M. (author), Vijvergberg, H.P.M. (author)Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal α4β2 nicotinic...article 2004
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Prins Maurits Laboratorium TNO (author), van der Schans, M.J. (author), Polhuijs, M. (author), van Dijk, C. (author), Degenhardt, C.E.A.M. (author), Pleijsier, K. (author), Langenberg, J.P. (author), Benschop, H.P. (author)The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies ≥0.01% inhibition of...article 2004
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Bajgar, J. (author), Ševelová, L. (author), Krejčová, G. (author), Fusek, J. (author), Vachek, J. (author), Kassa, J. (author), Herink, J. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be...article 2004
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Prins Maurits Laboratorium TNO (author), Smulders, C.J.G.M. (author), Bueters, T.J.H. (author), van Kleef, R.G.D.M. (author), Vijverberg, H.P.M. (author)Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency...article 2003
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Smit, L.A.M. (author), van Wendel- de Joode, B.N. (author), Heederik, D. (author), Peiris-John, R.J. (author), van der Hoek, W. (author)Background: In many agricultural districts in Sri Lanka, pesticide poisoning is a leading cause of death. This study aims to evaluate the impact of pesticide use on Sri Lankan farmers' health. Methods: A total of 260 subjects were surveyed in both a low and a high exposure period. Acetylcholinesterase activity was measured and data on symptoms...article 2003
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Noort, D. (author), Benschop, H.P. (author), Black, R.M. (author), Prins Maurits Laboratorium TNO (author)In this report an overview of the methods currently available for detection of exposure to a number of chemical warfare agents (CWA), i.e., sulfur mustard, lewisite and nerve agents, is presented. Such methods can be applied for various purposes, e.g., diagnosis and dosimetry of exposure of casualties, confirmation of nonexposure, verification...article 2002
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Fidder, A. (author), Hulst, A.G. (author), Noort, D. (author), de Ruiter, R. (author), van der Schans, M.J. (author), Benschop, H.P. (author), Langenberg, J.P. (author), Prins Maurits Laboratorium TNO (author)In this paper a novel and general procedure is presented for detection of organophosphate-inhibited human butyrylcholinesterase (HuBuChE), which is based on electrospray tandem mass spectrometric analysis of phosphylated nonapeptides obtained after pepsin digestion of the enzyme. The utility of this method is exemplified by the positive analysis...article 2002
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Bueters, T.J.H. (author), Groen, B. (author), Danhof, M. (author), IJzerman, A.P. (author), van Helden, H.P.M. (author), Prins Maurits Laboratorium TNO (author)The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun (O-ethyl-N-dimethylphosphoramidocyanidate), sarin (isopropylmethylphosphonofluoridate), VX (O...article 2002
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de Groot, D.M.G. (author), Bierman, E.P.B. (author), Bruijnzeel, P.L.B. (author), Carpentier, P. (author), Kulig, B.M. (author), Lallement, G. (author), Melchers, B.P.C. (author), Philippens, I.H.C.H.M. (author), van Huygevoort, A.H.B.M. (author)Poisoning with the potent nerve agent soman produces a cascade of central nervous system (CNS) effects characterized by severe convulsions and eventually death. In animals that survive a soman intoxication, lesions in the amygdala, piriform cortex, hippocampus and thalamus can be observed. In order to examine the mechanisms involved in the...article 2001
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Ordentlich, A. (author), Barak, D. (author), Kronman, C. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Ariel, N. (author), Barak, R. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)The stereoselectivity of the phosphonylation reaction and the effects of adduct configuration on the aging process were examined for human acetylcholinesterase (HuAChE) and its selected active center mutants, using the four stereomers of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman). The reactivity of wild type HuAChE toward the P(S)...article 1999
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van Helden, H.P.M. (author), Groen, B. (author), Moor, E. (author), Westerink, B.H.C. (author), Bruijnzeel, P.L.B. (author), Prins Maurits Laboratorium TNO (author)Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is...article 1998
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Prins Maurits Laboratorium TNO (author), Langenberg, J.P. (author), Spruit, W.E.T. (author), van der Wiel, H.J. (author), Trap, H.C. (author), Helmich, R.B. (author), Bergers, W.W.A. (author), van Helden, H.P.M. (author), Benschop, H.P. (author)The toxicokinetics of the four stereoisomers of the nerve agent C(±)P(±)-soman were studied in anesthetized, atropinized guinea pigs for nose-only exposure to soman vapor. During exposure the respiratory minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the...article 1998
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Prins Maurits Laboratorium TNO (author), Philippens, I.H.C.H.M. (author), Busker, R.W. (author), Wolthuis, O.L. (author), Olivier, B. (author), Bruijnzeel, P.L.B. (author), Melchers, B.P.C. (author)The behavioral and neurophysiological effects of the subchronically administered cholinesterase-inhibitor physostigmine (PHY) (0.025 mg/kg/h) either with or without the muscarinergic antagonist scopolamine (SCO) (0.018 mg/kg/h) were determined in guinea pigs. In contrast to a single injection of PHY, subchronic application by osmotic minipumps...article 1998
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