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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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Joosen, M.J.A. (author), Smit, A.B. (author), van Helden, H.P.M. (author)Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical...article 2011
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Joosen, M.J.A. (author), Jousma, E. (author), van den Boom, T.M. (author), Kuijpers, W.C. (author), Smit, A.B. (author), Lucassen, P.J. (author), van Helden, H.P.M. (author), TNO Defensie en Veiligheid (author)To date, treatment of organophosphate (OP) poisoning shows several shortcomings, and OP-victims might suffer from lasting cognitive deficits and sleep–wake disturbances. In the present study, long-term effects of soman poisoning on learning ability, memory and neurogenesis were investigated in rats, treated with the anticholinergic atropine and...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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TNO Defensie en Veiligheid (author), Philippens, I.H.C.H.M. (author), Joosen, M.J.A. (author), Vanwersch, R.A.P. (author)During military operations, soldiers may be exposed to mixtures of chemicals and to physical, emotional and psychological stress factors, which all may influence efficacy of any treatment, including the nerve agent pretreatment regimen. The purpose of this study was therefore to investigate the influence of chronic intermittent, variable,...article 2005
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Philippens, I.H.C.H.M. (author), Jongsma, M.J. (author), Vanwersch, R.A.P. (author), Prins Maurits Laboratorium TNO (author)The efficacy against lethality and post-intoxication incapacitation after 2x LD50 soman of different subacute pretreatment scenarios of 12 days was tested with or without post-intoxication therapy in guinea pigs. These pretreatment regimes were 1) the currently used pretreatment with pyridostigmine (PYR, 0.04 mg/kg/hr), 2) the combination of...conference paper 2004
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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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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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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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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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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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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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Benschop, H.P. (author), Trap, H.C. (author), Spruit, H.E.T. (author), van der Wiel, H.J. (author), Langenberg, J.P. (author), de Jong, L.P.A. (author), Prins Maurits Laboratorium TNO (author)In order to initiate a quantitative basis for the toxicology of low level exposure to nerve agents, the toxicokinetics of soman stereoisomers during nose-only exposure for 5 h to 20 ppb (160 μg/m3) of C(±)P(±)- soman in air were studied in restrained, anesthetized, and atropinized guinea pigs. The concentrations of the toxic C(±)P(-)-soman...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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Degenhardt, C.E.A.M. (author), Kientz, C.E. (author), TNO Prins Maurits Laboratorium (author)The use of large volume injections has been studied for the verification of intact organophosphorus chemical warfare agents in water samples. As the use of ethyl acetate caused severe detection problems new potential solvents were evaluated. With the developed procedure, the nerve agents sarin, tabun, soman, DFP and VX can be determined in...article 1996
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TNO Prins Maurits Laboratorium (author), Langenberg, J.P. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)Several p-nitrophenyl phosphoramidates with the general formula RO(NH2)P(O)OC6H4-p-NO2, in which R = CH2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2CH2CH2CH3, and CH2CH2Cl, as well as (NH2)2P(O)OC6H4-p-NO2 were administered intravenously to guinea pigs as pretreatment compounds for protection against the lethal effects of 1,2,2-trimethylpropyl...article 1996
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