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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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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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Cornelissen, A.S. (author), van Groningen, T. (author), Bohnert, S. (author), Klaassen, S.D (author), Joosen, M.J.A. (author)Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of...article 2020
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Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigsJoosen, 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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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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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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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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Degenhardt, C.E.A.M. (author), Pleijsier, K. (author), van der Schans, M.J. (author), Langenberg, J.P. (author), Preston, K.E. (author), Solano, M.I. (author), Maggio, V.L. (author), Barr, J.R. (author), Prins Maurits Laboratorium TNO (author)One of the most appropriate biomarkers for the verification of organophosphorus nerve agent exposure is the conjugate of the nerve agent to butyrylcholinesterase (BuChE). The phosphyl moiety of the nerve agent can be released from the BuChE enzyme by incubation with fluoride ions, after which the resulting organophosphonofluoridate can be...article 2004
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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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van Helden, H.P.M. (author), Trap, H.C. (author), Kuijpers, W.C. (author), Oostdijk, J.P. (author), Benschop, H.P. (author), Langenberg, J.P. (author), Prins Maurits Laboratorium TNO (author)The purpose of this pilot study was to indicate, for low-level exposure of conscious guinea pigs and marmoset monkeys to sarin vapour in air, the lowest-observable-adverse-effect level (LOAEL) of sarin for miosis. This is the concentration × time (C·t) value (t = 5 h) of exposure at which miosis becomes significant. The ratio of pupil and iris...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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van Helden, H.P.M. (author), Trap, H.C. (author), Oostdijk, J.P. (author), Kuijpers, W.C. (author), Langenberg, J.P. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed...article 2003
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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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Prins Maurits Laboratorium TNO (author), Bueters, T.J.H. (author), IJzerman, A.P. (author), van Helden, H.P.M. (author), Danhof, M. (author)Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A1 receptor partial agonist 2′-deoxy-N6-cyclopentyladenosine in sarin-poisoned rats. Bueters, T.J.H., IJzerman, A.P., Van Helden, H.P.M., and Danhof, M. (2003). The objective of the present study was to determine (1) the influence of sarin...article 2003
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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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- Spruit, W.E.T. (author), Trap, H.C. (author), Langenberg, J.P. (author), Benschop, H.P. (author) article 2001
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Spruit, W.E.T. (author), Langenberg, J.P. (author), Trap, H.C. (author), van der Wiel, H.J. (author), Helmich, R.B. (author), van Helden, H.P.M. (author), Benschop, H.P. (author)We report the first toxicokinetic studies of (±)-sarin. The toxicokinetics of the stereoisomers of this nerve agent were studied in anesthetized, atropinized, and restrained guinea pigs after intravenous bolus administration of a dose corresponding to 0.8 LD50 and after nose-only exposure to vapor concentrations yielding 0.4 and 0.8 LCt50 in an...article 2000
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Trap, H.C. (author), Langenberg, J.P. (author), Department of Chemical Toxicology, TNO Prins Maurits Laboratory, P.O. Box 45, 2280 AA, Rijswijk, Netherlands (author)A method is presented for the continuous analysis of generated vapors of the nerve agents soman and satin and the blistering agent sulfur mustard. By using a gas sampling valve and a very short (15 cm) column connected to an on-column injector with a 'standard length' column, the system can either be calibrated or used for performing high speed...article 1999
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