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Sample records for nerve agent vx

  1. Fingerprinting malathion vapor: a simulant for VX nerve agent

    NASA Astrophysics Data System (ADS)

    Song, Renbo; Ding, Yujie J.; Zotova, Ioulia B.

    2008-04-01

    Being motivated by the possibility of fingerprinting and detecting VX nerve agent, we have investigated its stimulant, i.e. malathion vapor, which is less toxic and commercially available, in the far-infrared/THz transition region and THz frequency range. Such a spectroscopic study was carried out by using Fourier transform infrared spectroscopy (FTIR). Our intention is to obtain a specific spectroscopic signature of VX nerve agent as a chemical warfare agent. Following our experimental result, we have successfully observed eleven new absorption peaks from malathion vapor in the spectral ranges from 15 cm -1 to 68 cm -1 and from 75 cm -1 to 640 cm -1. Specifically, in the far-infrared/THz transition region, we have observed eight peaks and whereas in the THz region we have identified three relatively weak transition peaks. In addition, we have investigated the dependence of the absorption spectra on temperature in the range from room temperature to 60°C. In both of the frequency ranges, we have found that absorption coefficients significantly increase with increasing temperature. By comparing the transition peaks in the two frequency ranges, we have concluded that the frequency range of 400-640cm -1 is an optimal range for fingerprinting this chemical specie. We have designated two peaks for effectively and accurately identifying the VX nerve agents and one peak for differentiating between malathion and VX nerve agent.

  2. Theoretical proton affinity and fluoride affinity of nerve agent VX.

    PubMed

    Bera, Narayan C; Maeda, Satoshi; Morokuma, Keiji; Viggiano, Al A

    2010-12-23

    Proton affinity and fluoride affinity of nerve agent VX at all of its possible sites were calculated at the RI-MP2/cc-pVTZ//B3LYP/6-31G* and RI-MP2/aug-cc-pVTZ//B3LYP/6-31+G* levels, respectively. The protonation leads to various unique structures, with H(+) attached to oxygen, nitrogen, and sulfur atoms; among which the nitrogen site possesses the highest proton affinity of -ΔE ∼ 251 kcal/mol, suggesting that this is likely to be the major product. In addition some H(2), CH(4) dissociation as well as destruction channels have been found, among which the CH(4) + [Et-O-P(═O)(Me)-S-(CH(2))(2)-N(+)(iPr)═CHMe] product and the destruction product forming Et-O-P(═O)(Me)-SMe + CH(2)═N(+)(iPr)(2) are only 9 kcal/mol less stable than the most stable N-protonated product. For fluoridization, the S-P destruction channel to give Et-O-P(═O)(Me)(F) + [S-(CH(2))(2)-N-(iPr)(2)](-) is energetically the most favorable, with a fluoride affinity of -ΔE ∼ 44 kcal. Various F(-) ion-molecule complexes are also found, with the one having F(-) interacting with two hydrogen atoms in different alkyl groups to be only 9 kcal/mol higher than the above destruction product. These results suggest VX behaves quite differently from surrogate systems. PMID:21117653

  3. [The VR, the Russian version of the nerve agent VX].

    PubMed

    Cuquel, A-C; Dorandeu, F; Ceppa, F; Renard, C; Burnat, P

    2015-05-01

    A product of the arms race during the Cold War, the Russian VX, or VR, is an organophosphorus compound that is a structural isomer of the western VX compound (or A4), with which it shares a very high toxicity. It is much less studied and known than VX because the knowledge of its existence is relatively recent. A very low volatility and high resistance in the environment make it a persistent agent. Poisoning occurs mainly following penetration through skin and mucosa but vapour inhalation is a credible risk in some circumstances. The clinical presentation may be differed by several hours and despite the absence of signs and symptoms, the casualty should not be considered as contamination or intoxication-free. This agent has a long residence time in blood, a characteristics that clearly differentiates it from other compounds such as sarin. The protocols for antidote administration may thus have to be changed accordingly. The fact that VR poisoned individuals will less respond to the current oxime therapy used in France, the 2-PAM and that VR represents a higher threat than VX, being probably possessed by some proliferating states, justify the interest for this toxic product. PMID:25592653

  4. Evidence of VX nerve agent use from contaminated white mustard plants

    PubMed Central

    Gravett, Matthew R.; Hopkins, Farrha B.; Self, Adam J.; Webb, Andrew J.; Timperley, Christopher M.; Baker, Matthew J.

    2014-01-01

    The Chemical Weapons Convention prohibits the development, production, acquisition, stockpiling, retention, transfer or use of chemical weapons by Member States. Verification of compliance and investigations into allegations of use require accurate detection of chemical warfare agents (CWAs) and their degradation products. Detection of CWAs such as organophosphorus nerve agents in the environment relies mainly upon the analysis of soil. We now present a method for the detection of the nerve agent VX and its hydrolysis products by gas chromatography and liquid chromatography mass spectrometry of ethanol extracts of contaminated white mustard plants (Sinapis alba) which retained the compounds of interest for up to 45 days. VX is hydrolysed by the plants to ethyl methylphosphonic acid and then to methylphosphonic acid. The utility of white mustard as a nerve agent detector and remediator of nerve agent-polluted sites is discussed. The work described will help deter the employment of VX in conflict. PMID:25104906

  5. Evidence of VX nerve agent use from contaminated white mustard plants.

    PubMed

    Gravett, Matthew R; Hopkins, Farrha B; Self, Adam J; Webb, Andrew J; Timperley, Christopher M; Baker, Matthew J

    2014-08-01

    The Chemical Weapons Convention prohibits the development, production, acquisition, stockpiling, retention, transfer or use of chemical weapons by Member States. Verification of compliance and investigations into allegations of use require accurate detection of chemical warfare agents (CWAs) and their degradation products. Detection of CWAs such as organophosphorus nerve agents in the environment relies mainly upon the analysis of soil. We now present a method for the detection of the nerve agent VX and its hydrolysis products by gas chromatography and liquid chromatography mass spectrometry of ethanol extracts of contaminated white mustard plants (Sinapis alba) which retained the compounds of interest for up to 45 days. VX is hydrolysed by the plants to ethyl methylphosphonic acid and then to methylphosphonic acid. The utility of white mustard as a nerve agent detector and remediator of nerve agent-polluted sites is discussed. The work described will help deter the employment of VX in conflict. PMID:25104906

  6. Quantification of nerve agent VX-butyrylcholinesterase adduct biomarker from an accidental exposure.

    PubMed

    Solano, Maria I; Thomas, Jerry D; Taylor, James T; McGuire, Jeffrey M; Jakubowski, Edward M; Thomson, Sandra A; Maggio, Vincent L; Holland, Kerry E; Smith, J Richard; Capacio, Benedict; Woolfitt, Adrian R; Ashley, David L; Barr, John R

    2008-01-01

    The lack of data in the open literature on human exposure to the nerve agent O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) gives a special relevance to the data presented in this study in which we report the quantification of VX-butyrylcholinesterase adduct from a relatively low-level accidental human exposure. The samples were analyzed by gas chromatography-high resolution mass spectrometry using the fluoride ion regeneration method for the quantification of multiple nerve agents including VX. Six human plasma samples from the same individual were collected after the patient had been treated once with oxime immediately after exhibiting signs of exposure. Detection limits of approximately 5.5 pg/mL plasma were achieved for the G-analogue of VX (G-VX). Levels of the G-VX ranged from 81.4 pg/mL on the first day after the exposure to 6.9 pg/mL in the sample taken 27 days after the exposure. Based on the reported concentration of human butyrylcholinesterase in plasma of approximately 80 nM, it can be calculated that inhibition levels of >or= 0.05% of BuChE can be accurately quantified. These data further indicate that the fluoride ion regeneration method is a potentially powerful tool that can be used to assess low-level exposure to VX. PMID:18269796

  7. Chromogenic and fluorogenic detection and discrimination of nerve agents Tabun and Vx.

    PubMed

    Kumar, Vinod; Rana, Hemlata

    2015-11-28

    Our approach uses squaraine (SQ) as the molecular-receptor as well as an indicator for the chromogenic and fluorogenic detection and discrimination of nerve agents Tabun and Vx. To mimic a real-life scenario, the protocols were implemented in spiked water and soil samples, on surfaces, and in the gas phase. The lower detection limit will be useful to protect human health and national security. PMID:26394304

  8. Investigating the Affinities and Persistence of VX Nerve Agent in Environmental Matrices

    SciTech Connect

    Love, A H; Vance, A L; Reynolds, J G; Davisson, M L

    2004-03-09

    Laboratory experiments were conducted to determine environmental variables that affect the affinities and persistence of the nerve agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) at dilute concentrations in environmental matrices. Quantitative analyses of VX and its degradation products were performed using LC-MS. Batch hydrolysis experiments demonstrated an increasing hydrolysis rate as pH increased, as shown in previous studies, but also indicated that dissolved aqueous constituents can cause significant differences in the absolute hydrolysis rate. Adsorption isotherms from batch aqueous experiments revealed that VX has a high affinity for hydrophobic organics, a moderate affinity for montmorillonite clay, and a very low affinity for an iron-oxyhydroxide soil mineral, goethite. The adsorption on goethite was increased with the presence of dissolved organic matter in solution. VX degraded rapidly when dried onto goethite, when an inner-sphere complex was forced. No enhanced degradation occurred with goethite in small amounts water. These results suggest that aqueous conditions have important controls on VX adsorption and degradation in the environment and a more mechanistic understanding of these controls is needed in order to enable accurate predictions of its long-term fate and persistence.

  9. In vivo decontamination of the nerve agent VX using the domestic swine model.

    PubMed

    Misik, Jan; Pavlik, Michal; Novotny, Ladislav; Pavlikova, Ruzena; Chilcott, Robert P; Cabal, Jiri; Kuca, Kamil

    2012-11-01

    The purpose of this in vivo study was to assess a new, putatively optimised method for mass casualty decontamination ("ORCHIDS protocol") for effectiveness in removing the chemical warfare agent VX from the skin of anaesthetised, domestic white pigs. ORCHIDS protocol consists of a 1.5-minute shower with a mild detergent (Argos™) supplemented by physical removal. A standard method of wet decontamination was used for comparison. Experimental animals were divided into four groups (A-D). Two groups were exposed to a supra-lethal percutaneous dose (5 × LD(50); 300 μg kg(-1)) of VX for 1 h prior to decontamination with either the ORCHIDS (C) or standard protocol (D). A third (B, positive control) group was exposed but not subject to decontamination. Blank controls (A) received anaesthesia and the corresponding dose of normal saline instead of VX. Observations of the clinical signs of intoxication were supplemented by measurements of whole blood cholinesterase (ChE) performed on samples of arterial blood acquired at 30-minute intervals for the duration of the study (up to 6 h). Untreated (B) animals displayed typical cholinergic signs consistent with VX intoxication (local fasciculation, mastication, salivation, pilo-erection and motor convulsions) and died 165-240 min post exposure. All animals in both decontamination treatment groups (C, D) survived the duration of the study and exhibited less severe signs of cholinergic poisoning. Thus, both the standard and ORCHIDS protocol were demonstrably effective against exposure to the potent nerve agent VX, even after a delay of 1 h. A critical advantage of the ORCHIDS protocol is the relatively short shower duration (1½ min compared to 3 min). In practice, this could substantially improve the rate at which individuals could be decontaminated by emergency responders following exposure to toxic materials such as chemical warfare agents. PMID:22963275

  10. Percutaneous exposure to the nerve agent VX: Efficacy of combined atropine, obidoxime and diazepam treatment.

    PubMed

    Joosen, Marloes J A; van der Schans, Marcel J; van Helden, Herman P M

    2010-10-01

    The nerve agent VX is most likely to enter the body via liquid contamination of the skin. After percutaneous exposure, the slow uptake into the blood, and its slow elimination result in toxic levels in plasma for a period of several hours. Consequently, this has implications for the development of toxic signs and for treatment onset. In the present study, clinical signs, toxicokinetics and effects on respiration, electroencephalogram and heart rate were investigated in hairless guinea pigs after percutaneous exposure to 500 microg/kg VX. We found that full inhibition of AChE and partial inhibition of BuChE in blood were accompanied by the onset of clinical signs, reflected by a decline in respiratory minute volume, bronchoconstriction and a decrease in heart rate. Furthermore, we investigated the therapeutic efficacy of a single dose of atropine, obidoxime and diazepam, administered at appearance of first clinical signs, versus that of repetitive dosing of these drugs on the reappearance of signs. A single shot treatment extended the period to detrimental physiological decline and death for several hours, whereas repetitive administration remained effective as long as treatment was continued. In conclusion, percutaneous VX poisoning showed to be effectively treatable when diagnosed on time and when continued over the entire period of time during which VX, in case of ineffective decontamination, penetrates the skin. PMID:20599844

  11. Showering effectiveness for human hair decontamination of the nerve agent VX.

    PubMed

    Josse, Denis; Wartelle, Julien; Cruz, Catherine

    2015-05-01

    In this work, our goals were to establish whether hair decontamination by showering one hour post-exposure to the highly toxic organophosphate nerve agent VX was effective, whether it required the addition of a detergent to water and, if it could be improved by using the adsorbent Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering. Hair exposure to VX and decontamination was performed by using an in vitro model. Hair showering led to 72% reduction of contamination. Addition of detergent to water slightly increased the decontamination effectiveness. Hair treatment with FE or RSDL improved the decontamination rate. Combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. Hair wiping after showering was shown to contribute to hair decontamination. Altogether, our results highlighted the importance of considering hair decontamination as an important part of body surface decontamination protocols. PMID:25791764

  12. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

    SciTech Connect

    Nambiar, Madhusoodana P.; Doctor, Bhupendra P.

    2007-03-15

    To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m{sup 3} of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.

  13. Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX

    PubMed Central

    Rice, Helen; Dalton, Christopher H.; Price, Matthew E.; Graham, Stuart J.; Green, A. Christopher; Jenner, John; Groombridge, Helen J.; Timperley, Christopher M.

    2015-01-01

    To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM–VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

  14. Synthesis and biodegradation of the VX nerve agent derivative 2-DIISO-propylaminoethylsulfonic acid

    SciTech Connect

    Warner, C.H.; Labare, M.P.; Wessel, T.E.

    1996-10-01

    The United States is currently examining biodegradation methods to demilitarize chemical weapons. The nerve agent, O-ethyl-S-(2-diisopropylamino-ethyl)methylphosphonothiolate (VX) is first chemically inactivated with water at 90% yielding two fragments. One fragment is 2-diisopropylaminoethanethiol which quickly reacts with another thiol fragment forming the disulfide, bis(2-diisopropylaminoethyl)disulfide. The presence of the disulfide bond in this compound renders it resistant to biodegradation. Methods for converting the disulfide to the sulfonic acid are currently being pursued by treatment with performic acid. However, the sulfonic: acid has been synthesized by an independent method. Preliminary experiments indicate that the sulfonic acid at 1.0 and 0.5 mM is degraded by Rhodococcus dp. strain IGTS8 as evidenced by an increase in the optical density at 600 nm.

  15. High-throughput immunomagnetic scavenging technique for quantitative analysis of live VX nerve agent in water, hamburger, and soil matrixes.

    PubMed

    Knaack, Jennifer S; Zhou, Yingtao; Abney, Carter W; Prezioso, Samantha M; Magnuson, Matthew; Evans, Ronald; Jakubowski, Edward M; Hardy, Katelyn; Johnson, Rudolph C

    2012-11-20

    We have developed a novel immunomagnetic scavenging technique for extracting cholinesterase inhibitors from aqueous matrixes using biological targeting and antibody-based extraction. The technique was characterized using the organophosphorus nerve agent VX. The limit of detection for VX in high-performance liquid chromatography (HPLC)-grade water, defined as the lowest calibrator concentration, was 25 pg/mL in a small, 500 μL sample. The method was characterized over the course of 22 sample sets containing calibrators, blanks, and quality control samples. Method precision, expressed as the mean relative standard deviation, was less than 9.2% for all calibrators. Quality control sample accuracy was 102% and 100% of the mean for VX spiked into HPLC-grade water at concentrations of 2.0 and 0.25 ng/mL, respectively. This method successfully was applied to aqueous extracts from soil, hamburger, and finished tap water spiked with VX. Recovery was 65%, 81%, and 100% from these matrixes, respectively. Biologically based extractions of organophosphorus compounds represent a new technique for sample extraction that provides an increase in extraction specificity and sensitivity. PMID:23126363

  16. Solvent Effects on the Reactions of the Nerve Agent VX with KF/Al2O3: Heterogeneous or Homogeneous Decontamination?

    PubMed

    Fridkin, Gil; Yehezkel, Lea; Columbus, Ishay; Zafrani, Yossi

    2016-03-01

    Solvent effects on the reactions of the extremely toxic nerve agent VX with KF/Al2O3 powder were explored. Small quantities of water or methanol (5-10 wt %), which effectively mobilized all components while maintaining the heterogeneous nature of the reaction, promoted much faster rates than those obtained with larger quantities. Any amount of acetonitrile resulted in extremely slow transformations. Surprisingly, 5-50 wt % of heptane led to fast reactions due to the combination of its ability to mediate fast diffusion of VX and a MAS centrifugation effect. PMID:26838963

  17. Subchronic exposure to low-doses of the nerve agent VX: physiological, behavioral, histopathological and neurochemical studies.

    PubMed

    Bloch-Shilderman, Eugenia; Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures. PMID:18485435

  18. Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies

    SciTech Connect

    Bloch-Shilderman, Eugenia Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 {mu}g/kg/day, 0.05 LD{sub 50}) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition ({approx} 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction ({approx} 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.

  19. Effectiveness and reaction networks of H2O2 vapor with NH3 gas for decontamination of the toxic warfare nerve agent, VX on a solid surface.

    PubMed

    Gon Ryu, Sam; Wan Lee, Hae

    2015-01-01

    The nerve agent, O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) must be promptly eliminated following its release into the environment because it is extremely toxic, can cause death within a few minutes after exposure, acts through direct skin contact as well as inhalation, and persists in the environment for several weeks after release. A mixture of hydrogen peroxide vapor and ammonia gas was examined as a decontaminant for the removal of VX on solid surfaces at ambient temperature, and the reaction products were analyzed by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectrometry (NMR). All the VX on glass wool filter disks was found to be eliminated after 2 h of exposure to the decontaminant mixtures, and the primary decomposition product was determined to be non-toxic ethyl methylphosphonic acid (EMPA); no toxic S-[2-(diisopropylamino)ethyl] methylphosphonothioic acid (EA-2192), which is usually produced in traditional basic hydrolysis systems, was found to be formed. However, other by-products, such as toxic O-ethyl S-vinyl methylphosphonothioate and (2-diisopropylaminoethyl) vinyl disulfide, were detected up to 150 min of exposure to the decontaminant mixture; these by-products disappeared after 3 h. The two detected vinyl byproducts were identified first in this study with the decontamination system of liquid VX on solid surfaces using a mixture of hydrogen peroxide vapor and ammonia gas. The detailed decontamination reaction networks of VX on solid surfaces produced by the mixture of hydrogen peroxide vapor and ammonia gas were suggested based on the reaction products. These findings suggest that the mixture of hydrogen peroxide vapor and ammonia gas investigated in this study is an efficient decontaminant mixture for the removal of VX on solid surfaces at ambient temperature despite the formation of a toxic by-product in the reaction process. PMID:26327407

  20. Polysaccharide-thickened aqueous fluoride solutions for rapid destruction of the nerve agent VX. Introducing the opportunity for extensive decontamination scenarios.

    PubMed

    Elias, Shlomi; Saphier, Sigal; Columbus, Ishay; Zafrani, Yossi

    2014-01-01

    Among the chemical warfare agents, the extremely toxic nerve agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is a target of high importance in the development of decontamination methods, due to its indefinite persistence on common environmental surfaces. Liquid decontaminants are mostly characterized by high corrosivity, usually offer poor coverage, and tend to flow and accumulate in low areas. Therefore, the development of a noncorrosive decontaminant, sufficiently viscous to resist dripping from the contaminated surface, is necessary. In the present paper we studied different polysaccharides-thickened fluoride aqueous solutions as noncorrosive decontaminants for rapid and efficient VX degradation to the nontoxic product EMPA (ethyl methylphosphonic acid). Polysaccharides are environmentally benign, natural, and inexpensive. Other known decontaminants cannot be thickened by polysaccharides, due to the sensitivity of the latter toward basic or oxidizing agents. We found that the efficiency of VX degradation in these viscous solutions in terms of kinetics and product identity is similar to that of KF aqueous solutions. Guar gum (1.5 wt %) with 4 wt % KF was chosen for further evaluation. The benign nature, rheological properties, adhering capabilities to different surfaces, and decontamination from a porous matrix were examined. This formulation showed promising properties for implementation as a spray decontaminant for common and sensitive environmental surfaces. PMID:24517492

  1. Analysis of VX nerve agent hydrolysis products in wastewater effluents by ion chromatography with amperometric and conductivity detection.

    PubMed

    Piao, Haishan; Marx, Randall B; Schneider, Steven; Irvine, David A; Staton, John

    2005-09-30

    An analytical method, based on the use of ion chromatography, was developed to monitor the levels of three regulated VX hydrolysis products in the effluent from a biological wastewater treatment process--ethylmethylphosphonic acid, methylphosphonic acid and 2-(diisopropyl)aminoethanethiol. Previous methods have not been applied to wastewater matrices or 2-(diisopropyl)aminoethanethiol. Despite the specificity and sensitivity constraints of this method, it was possible to measure the compounds in bioreactor effluents down to a level substantially below the US Army discharge limit of 0.1% (w/v). Analytical data was confirmed by liquid chromatography-mass spectrometry (LC-MS) at an independent laboratory. PMID:16130773

  2. Enzymatic neutralization of the chemical warfare agent VX: evolution of phosphotriesterase for phosphorothiolate hydrolysis.

    PubMed

    Bigley, Andrew N; Xu, Chengfu; Henderson, Terry J; Harvey, Steven P; Raushel, Frank M

    2013-07-17

    The V-type nerve agents (VX and VR) are among the most toxic substances known. The high toxicity and environmental persistence of VX make the development of novel decontamination methods particularly important. The enzyme phosphotriesterase (PTE) is capable of hydrolyzing VX but with an enzymatic efficiency more than 5 orders of magnitude lower than with its best substrate, paraoxon. PTE has previously proven amenable to directed evolution for the improvement of catalytic activity against selected compounds through the manipulation of active-site residues. Here, a series of sequential two-site mutational libraries encompassing 12 active-site residues of PTE was created. The libraries were screened for catalytic activity against a new VX analogue, DEVX, which contains the same thiolate leaving group of VX coupled to a diethoxyphosphate core rather than the ethoxymethylphosphonate core of VX. The evolved catalytic activity with DEVX was enhanced 26-fold relative to wild-type PTE. Further improvements were facilitated by targeted error-prone PCR mutagenesis of loop-7, and additional PTE variants were identified with up to a 78-fold increase in the rate of DEVX hydrolysis. The best mutant hydrolyzed the racemic nerve agent VX with a value of kcat/Km = 7 × 10(4) M(-1) s(-1), a 230-fold improvement relative to wild-type PTE. The highest turnover number achieved by the mutants created for this investigation was 137 s(-1), an enhancement of 152-fold relative to wild-type PTE. The stereoselectivity for the hydrolysis of the two enantiomers of VX was relatively low. These engineered mutants of PTE are the best catalysts ever reported for the hydrolysis of nerve agent VX. PMID:23789980

  3. Agent neutralization studies III. Detoxification of VX in aqueous persulfate. Final report, May-August 1993

    SciTech Connect

    Hovanec, J.W.; Albizo, J.M.; Henderson, V.D.; Szafraniec, L.L.; Beaudry, W.T.

    1994-06-01

    Aqueous solutions of persulfate salts are frequently used to mineralize organic substrates in the course of total organic carbon analyses. A study has been conducted at the U.S. Army Edgewood Research, Development and Engineering Center to determine whether this approach may be useful to neutralize the nerve agent VX. VX was reacted with aqueous ammonium persulfate at 90 deg C and 70 deg C. The concentration of agent and the acidity of the mixture were varied. 31P-NMR was used to monitor the destruction of VX as well as the formation and degradation of the phosphorus-containing products. A titration procedure using ferrous sulfate and ceric ammonium nitrate was used to monitor the consumption of persulfate. The products formed and their stabilities were found to vary significantly with the acidity of the solution. Nuclear magnetic resonance, Oxidation, VX, Ammonium persulfate, Mineralization, Temperature effects, Chemical agent disposal.

  4. VX

    MedlinePlus

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  5. Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

    PubMed

    Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

    2014-05-01

    In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed. PMID:24676701

  6. Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection.

    PubMed Central

    Munro, N

    1994-01-01

    The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxcity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent releaase, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. Images Figure 2. PMID:9719666

  7. Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: implications for public protection.

    PubMed

    Munro, N

    1994-01-01

    The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. PMID:9719666

  8. Human scalp permeability to the chemical warfare agent VX.

    PubMed

    Rolland, P; Bolzinger, M-A; Cruz, C; Briançon, S; Josse, D

    2011-12-01

    The use of chemical warfare agents such as VX in terrorism act might lead to contamination of the civilian population. Human scalp decontamination may require appropriate products and procedures. Due to ethical reasons, skin decontamination studies usually involve in vitro skin models, but human scalp skin samples are uncommon and expensive. The purpose of this study was to characterize the in vitro permeability to VX of human scalp, and to compare it with (a) human abdominal skin, and (b) pig skin from two different anatomic sites: ear and skull roof, in order to design a relevant model. Based on the VX skin permeation kinetics and distribution, we demonstrated that (a) human scalp was significantly more permeable to VX than abdominal skin and (b) pig-ear skin was the most relevant model to predict the in vitro human scalp permeability. Our results indicated that the follicular pathway significantly contributed to the skin absorption of VX through human scalp. In addition, the hair follicles and the stratum corneum significantly contributed to the formation of a skin reservoir for VX. PMID:21762776

  9. Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection

    SciTech Connect

    Munro, N.B.; Ambrose, K.R.; Watson, A.P. )

    1994-01-01

    The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is not evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agent exposure is the extraordinarily high acute toxicity of these substances. Futhermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. 187 refs., 3 figs., 7 tabs.

  10. Clinical aspects of percutaneous poisoning by the chemical warfare agent VX: effects of application site and decontamination.

    PubMed

    Hamilton, Murray G; Hill, Ira; Conley, John; Sawyer, Thomas W; Caneva, Duane C; Lundy, Paul M

    2004-11-01

    O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) is an extremely toxic organophosphate nerve agent that has been weaponized and stockpiled in a number of different countries, and it has been used in recent terrorist events. It differs from other well-known organophosphate nerve agents in that its primary use is as a contact poison rather than as an inhalation hazard. For this reason, we examined the effects of application site and skin decontamination on VX toxicity in anesthetized domestic swine after topical application. VX applied to the surface of the ear rapidly resulted in signs of toxicity consistent with the development of cholinergic crisis, including apnea and death. VX on the epigastrium resulted in a marked delayed development of toxic signs, reduced toxicity, and reduction in the rate of cholinesterase depression compared with animals exposed on the ear. Skin decontamination (15 minutes post-VX on the ear) arrested the development of clinical signs and prevented further cholinesterase inhibition and death. These results confirm earlier work that demonstrates the importance of exposure site on the resultant toxicity of this agent and they also show that decontamination postexposure has the potential to be an integral and extremely important component of medical countermeasures against this agent. PMID:15605929

  11. Organophosphate nerve agent toxicity in Hydra attenuata.

    PubMed

    Lum, Karin T; Huebner, Henry J; Li, Yingchun; Phillips, Timothy D; Raushel, Frank M

    2003-08-01

    The toxicity for analogues of sarin (GB), soman (GD), and VX was evaluated using Hydra attenuata as a model organism. The organophosphate nerve agent analogue simulants used in this investigation included the following: isopropyl p-nitrophenyl methylphosphonate (for GB); pinacolyl p-nitrophenyl methylphosphonate (for GD); and diisopropyl S-(2-diisopropylaminoethyl)phosphorothioate, diethyl S-(2-diisopropylaminoethyl)phosphorothioate, and diethyl S-(2-trimethylaminoethyl)phosphorothioate (for VX). The toxicity of each organophosphate nerve agent was assessed quantitatively by measuring the minimal effective concentration within 92 h in H. attenuata. There is a positive correlation between the molecular hydrophobicity of the compound and its ability to cause toxicity. Results from this study indicate the potential for application of this assay in the field of organophosphate chemical warfare agent detection, as well as for the prediction of toxicity of structurally similar organophosphate compounds. The minimal effective concentration for two of the VX analogues was 2 orders of magnitude more toxic than the analogue for GD and 4 orders of magnitude more toxic than the analogue for GB. PMID:12924922

  12. Effective, Facile, and Selective Hydrolysis of the Chemical Warfare Agent VX Using Zr6-Based Metal-Organic Frameworks.

    PubMed

    Moon, Su-Young; Wagner, George W; Mondloch, Joseph E; Peterson, Gregory W; DeCoste, Jared B; Hupp, Joseph T; Farha, Omar K

    2015-11-16

    The nerve agent VX is among the most toxic chemicals known to mankind, and robust solutions are needed to rapidly and selectively deactivate it. Herein, we demonstrate that three Zr6-based metal-organic frameworks (MOFs), namely, UiO-67, UiO-67-NH2, and UiO-67-N(Me)2, are selective and highly active catalysts for the hydrolysis of VX. Utilizing UiO-67, UiO-67-NH2, and UiO-67-N(Me)2 in a pH 10 buffered solution of N-ethylmorpholine, selective hydrolysis of the P-S bond in VX was observed. In addition, UiO-67-N(Me)2 was found to catalyze VX hydrolysis with an initial half-life of 1.8 min. This half-life is nearly 3 orders of magnitude shorter than that of the only other MOF tested to date for hydrolysis of VX and rivals the activity of the best nonenzymatic materials. Hydrolysis utilizing Zr-based MOFs is also selective and facile in the absence of pH 10 buffer (just water) and for the destruction of the toxic byproduct EA-2192. PMID:26505999

  13. Screening of nerve agent degradation products by MALDI-TOFMS.

    PubMed

    Shu, You-Ren; Su, An-Kai; Liu, Ju-Tsung; Lin, Cheng-Huang

    2006-07-01

    A novel method for the rapid screening of degradation products derived from nerve agents by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is described. Five standard products were selected as model compounds, including isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA), isobutyl methylphosphonic acid (i-BuMPA), and cyclohexyl methylphosphonic acid (CHMPA), which are degradation products of Sarin (GB), Soman (GD), VX, Russian VX (RVX), and GF, respectively. For comparison, CHCA (alpha-cyano-4-hydroxycinnamic acid) and DCCA (7-(diethylamino)coumarin-3-carboxylic acid) were used as the MALDI-matrix when the third harmonic generation (355 nm) of a Nd:YAG laser and a hydrogen Raman laser (multifrequency laser) were used, respectively. The method permitted the five nerve agent degradation products to be screened rapidly and successfully, suggesting that it has the potential for use as a routine monitoring tool. PMID:16808484

  14. Stereoselective Hydrolysis of Organophosphate Nerve Agents by the Bacterial Phosphotriesterase†

    PubMed Central

    Tsai, Ping-Chuan; Bigley, Andrew; Li, Yingchun; Ghanem, Eman; Cadieux, C. Linn; Kasten, Shane A.; Reeves, Tony E.; Cerasoli, Douglas M.; Raushel, Frank M.

    2010-01-01

    Organophosphorus compounds include many synthetic, neurotoxic substances that are commonly used as insecticides. The toxicity of these compounds is due to their ability to inhibit the enzyme acetylcholine esterase. Some of the most toxic organophosphates have been adapted for use as chemical warfare agents; the most well known are GA, GB, GD, GF, VX and VR. All of these compounds contain a chiral phosphorus center with the SP-enantiomers being significantly more toxic than the RP-enantiomers. Phosphotriesterase (PTE) is an enzyme capable of detoxifying these agents, but the stereochemical preference of the wild-type enzyme is for the RP-enantiomers. A series of enantiomerically pure chiral nerve agent analogues has been developed containing the relevant phosphoryl centers found in GB, GD, GF, VX and VR. Wild-type and mutant forms of PTE have been tested for their ability to hydrolyze this series of compounds. Mutant forms of PTE with significantly enhanced, as well as relaxed or reversed stereoselectivity, have been identified. A number of variants showed dramatically improved kinetic constants for the catalytic hydrolysis of the more toxic SP-enantiomers. Improvements of up to three orders of magnitude relative to the wild type enzyme were observed. Some of these mutants were tested against racemic mixtures of GB and GD. The kinetic constants obtained with the chiral nerve agent analogues accurately predict the improved activity and stereoselectivity against the authentic nerve agents used in this study. PMID:20701311

  15. Metal organic frameworks (MOFs) for degrdation of nerve agent simulant parathion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Parathion, a simulant of nerve agent VX, has been studied for degradation on Fe3+, Fe2+ and zerovalent iron supported on chitosan. Chitosan, a naturally occurring biopolymer derivative of chitin, is a very good adsorbent for many chemicals including metals. Chitosan is used as supporting biopolymer ...

  16. Inhalational exposure to nerve agents.

    PubMed

    Niven, Alexander S; Roop, Stuart A

    2004-03-01

    The respiratory system plays a major role in the pathogenesis of nerve agent toxicity. It is the major route of entry and absorption of nerve agent vapor, and respiratory failure is the most common cause of death follow-ing exposure. Respiratory symptoms are mediated by chemical irritation,muscarinic and nicotinic receptor overstimulation, and central nervous system effects. Recent attacks have demonstrated that most patients with an isolated vapor exposure developed respiratory symptoms almost immediately. Most patients had only mild and transient respiratory effects, and those that did develop significant respiratory compromise did so rapidly. These observations have significant ramifications on triage of patients in a mass-casualty situation, because patients with mild-to-moderate exposure to nerve agent vapor alone do not require decontamination and are less likely to develop progressive symptoms following initial antidote therapy. Limited data do not demonstrate significant long-term respiratory effects following nerve agent exposure and treatment. Provisions for effective respiratory protection against nerve agents is a vital consideration in any emergency preparedness or health care response plan against a chemical attack. PMID:15062227

  17. Relative potency estimates of acceptable residues and reentry intervals after nerve agent release.

    PubMed

    Watson, A P; Jones, T D; Adams, J D

    1992-06-01

    In the event of an unplanned release of a chemical warfare agent during any stage of the Chemical Stockpile Disposal Program, the potential exists for off-post contamination of drinking water, forage crops, grains, garden produce, and livestock. The more persistent agents, such as the organophosphate nerve agent VX, pose the greatest human health concern for reentry. A relative potency approach comparing the toxicity of VX to organophosphate insecticide analogues is developed and used to estimate allowable residues for VX in agricultural products and reentry intervals for public access to contaminated areas. Analysis of mammalian LD50 data by all exposure routes indicates that VX is 10(3) to 10(4) times more toxic than most commercially available organophosphate insecticides. Thus, allowable residues of VX could be considered at concentration levels 10(3) to 10(4) lower than those established for certain insecticides by the U.S. EPA. Evaluation of reentry intervals developed for these organophosphate analogues indicate that, if environmental monitoring cannot reliably demonstrate acceptable levels of VX, restricted access to suspect or contaminated areas may be on the order of weeks to months following agent release. Planning for relocation, mass care centers, and quarantine should take this time period into account. PMID:1376237

  18. Relative potency estimates of acceptable residues and reentry intervals after nerve agent release

    SciTech Connect

    Watson, A.P.; Jones, T.D.; Adams, J.D. )

    1992-06-01

    In the event of an unplanned release of a chemical warfare agent during any stage of the Chemical Stockpile Disposal Program, the potential exists for off-post contamination of drinking water, forage crops, grains, garden produce, and livestock. The more persistent agents, such as the organophosphate nerve agent VX, pose the greatest human health concern for reentry. A relative potency approach comparing the toxicity of VX to organophosphate insecticide analogues is developed and used to estimate allowable residues for VX in agricultural products and reentry intervals for public access to contaminated areas. Analysis of mammalian LD50 data by all exposure routes indicates that VX is 10(3) to 10(4) times more toxic than most commercially available organophosphate insecticides. Thus, allowable residues of VX could be considered at concentration levels 10(3) to 10(4) lower than those established for certain insecticides by the U.S. EPA. Evaluation of reentry intervals developed for these organophosphate analogues indicate that, if environmental monitoring cannot reliably demonstrate acceptable levels of VX, restricted access to suspect or contaminated areas may be on the order of weeks to months following agent release. Planning for relocation, mass care centers, and quarantine should take this time period into account.

  19. Chemical warfare. Nerve agent poisoning.

    PubMed

    Holstege, C P; Kirk, M; Sidell, F R

    1997-10-01

    The threat of civilian and military casualties from nerve agent exposure has become a greater concern over the past decade. After rapidly assessing that a nerve agent attack has occurred, emphasis must be placed on decontamination and protection of both rescuers and medical personnel from exposure. The medical system can become rapidly overwhelmed and strong emotional reactions can confuse the clinical picture. Initially, care should first be focused on supportive care, with emphasis toward aggressive airway maintenance and decontamination. Atropine should be titrated, with the goal of therapy being drying of secretions and the resolution of bronchoconstriction and bradycardia. Early administration of pralidoxime chloride maximizes antidotal efficacy. Benzodiazepines, in addition to atropine, should be administered if seizures develop. Early, aggressive medical therapy is the key to prevention of the morbidity and mortality associated with nerve agent poisoning. PMID:9330846

  20. Modifications to the organophosphorus nerve agent-protein adduct refluoridation method for retrospective analysis of nerve agent exposures.

    PubMed

    Holland, Kerry E; Solano, Maria I; Johnson, Rudolph C; Maggio, Vincent L; Barr, John R

    2008-01-01

    Organophosphorus nerve agents (OPNAs) continue to pose a threat to military personnel and the general public because of their toxicity and their potential use as weapons of mass destruction. An effective method for the detection of human exposure to OPNAs involves the refluoridation of nerve agents adducted to the serum protein butyrylcholinesterase. The regenerated agents are then enriched by solid-phase extraction and quantified by isotope-dilution gas chromatography-mass spectrometry. We have previously reported improvements that resulted in a 10-fold increase in sensitivity. We have now made further changes to the method that include the addition of confirmation ions, the addition of soman (GD) to the assay, the expansion of the linear range, and the elimination of high-volume injection to decrease background noise and run time while improving sensitivity. This report includes the standard operating procedures for this method for tabun, sarin, soman, cyclohexylsarin, and VX and validation studies. The method's limits of detection ranged from 5.5 to 16.5 pg/mL for the G analogue of VX and GD, respectively. Characterization of quality control (QC) materials resulted in an average coefficient of variation of 15.1% for the five analytes in low QC pools and 11.7% in high QC pools. PMID:18269803

  1. Nerve agents: implications for anesthesia providers.

    PubMed

    Hrobak, Paula Kay

    2008-04-01

    Anesthesia providers may be called to treat injuries from chemical weapons or spills, for which prompt treatment is vital. It is therefore important to understand the mechanism of action of nerve agents and the resultant pathophysiology and to be able to quickly recognize the signs and symptoms of nerve agent exposure. This review article addresses the different types of nerve agents that are currently being manufactured as well as the symptomatic and definitive treatment of the patient who presents with acute nerve agent toxicity. This article also reviews the physiology of the neuromuscular junction and the autonomic nervous system receptors that nerve agent toxicity affects. PMID:18478812

  2. Fate of the chemical warfare agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX) on soil following accelerant-based fire and liquid decontamination.

    PubMed

    Gravett, M R; Hopkins, F B; Self, A J; Webb, A J; Timperley, C M; Riches, J R

    2014-08-01

    In the event of alleged use of organophosphorus nerve agents, all kinds of environmental samples can be received for analysis. These might include decontaminated and charred matter collected from the site of a suspected chemical attack. In other scenarios, such matter might be sampled to confirm the site of a chemical weapon test or clandestine laboratory decontaminated and burned to prevent discovery. To provide an analytical capability for these contingencies, we present a preliminary investigation of the effect of accelerant-based fire and liquid decontamination on soil contaminated with the nerve agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX). The objectives were (a) to determine if VX or its degradation products were detectable in soil after an accelerant-based fire promoted by aviation fuel, including following decontamination with Decontamination Solution 2 (DS2) or aqueous sodium hypochlorite, (b) to develop analytical methods to support forensic analysis of accelerant-soaked, decontaminated and charred soil and (c) to inform the design of future experiments of this type to improve analytical fidelity. Our results show for the first time that modern analytical techniques can be used to identify residual VX and its degradation products in contaminated soil after an accelerant-based fire and after chemical decontamination and then fire. Comparison of the gas chromatography-mass spectrometry (GC-MS) profiles of VX and its impurities/degradation products from contaminated burnt soil, and burnt soil spiked with VX, indicated that the fire resulted in the production of diethyl methylphosphonate and O,S-diethyl methylphosphonothiolate (by an unknown mechanism). Other products identified were indicative of chemical decontamination, and some of these provided evidence of the decontaminant used, for example, ethyl 2-methoxyethyl methylphosphonate and bis(2-methoxyethyl) methylphosphonate following decontamination with DS2. Sample preparation

  3. Detoxification of nerve agents by a substituted beta-cyclodextrin: application of a modified biological assay.

    PubMed

    Wille, T; Tenberken, O; Reiter, G; Müller, S; Le Provost, R; Lafont, O; Estour, F; Thiermann, H; Worek, F

    2009-11-30

    Chemical warfare agents (nerve agents) are still available and present a real threat to the population. Numerous in vitro and in vivo studies showed that various nerve agents, e.g. tabun and cyclosarin, are resistant towards standard therapy with atropine and oxime. Based on these facts we applied a modified biological assay for the easy, semi-quantitative testing of the detoxifying properties of the beta-cyclodextrin derivative CD-IBA. Cyclosarin, sarin, tabun and VX were incubated with CD-IBA for 1-50 min at 37 degrees C, then an aliquot was added to erythrocyte acetylcholinesterase (AChE) and the percentage of AChE inhibition was determined. The validity of the assay was confirmed by concomitant quantification of tabun by GC-MS. Different concentrations of cyclosarin were detoxified by CD-IBA in a concentration-dependent velocity. The ability to detoxify various nerve agents decreased in the order cyclosarin>sarin>tabun>VX. Hereby, no detoxification of VX could be detected. Sarin was detoxified in a biphasic reaction with a fast reduction of inhibitory potential in the first phase and a slower detoxification in the second phase. CD-IBA detoxified tabun in a one phase decay and, compared to cyclosarin and sarin, a longer half-life was determined with tabun. The modified biological assay is appropriate for the initial semi-quantitative screening of candidate compounds for the detoxification of nerve agents. The beta-cyclodextrin derivative CD-IBA demonstrated its ability to detoxify different nerve agents. PMID:19800384

  4. In vitro kinetics of nerve agent degradation by fresh frozen plasma (FFP).

    PubMed

    Wille, Timo; Thiermann, Horst; Worek, Franz

    2014-02-01

    Great efforts have been undertaken in the last decades to develop new oximes to reactivate acetylcholinesterase inhibited by organophosphorus compounds (OP). So far, a broad-spectrum oxime effective against structurally diverse OP is still missing, and alternative approaches, e.g. stoichiometric and catalytic scavengers, are under investigation. Fresh frozen plasma (FFP) has been used in human OP pesticide poisoning which prompted us to investigate the in vitro kinetics of OP nerve agent degradation by FFP. Degradation was rapid and calcium-dependent with the G-type nerve agents tabun, sarin, soman and cyclosarin with half-lives from 5 to 28 min. Substantially longer and calcium-independent degradation half-lives of 23-33 h were determined with the V-type nerve agents CVX, VR and VX. However, at all the tested conditions, the degradation of V-type nerve agents was several-fold faster than spontaneous hydrolysis. Albumin did not accelerate the degradation of nerve agents. In conclusion, the fast degradation of G-type nerve agents by FFP might be a promising tool, but would require transfusion shortly after poisoning. FFP does not seem to be suitable for detoxifying relevant agent concentrations in case of human poisoning by V-type nerve agents. PMID:24057572

  5. Novel dual-mode immunomagnetic method for studying reactivation of nerve agent-inhibited butyrylcholinesterase.

    PubMed

    Abney, Carter W; Knaack, Jennifer L S; Ali, Ahmed A I; Johnson, Rudolph C

    2013-05-20

    A novel immunomagnetic method has been developed for the simultaneous measurement of organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BuChE) and free OPNAs in serum. This new approach, deemed dual-mode immunomagnetic analysis (Dual-Mode IMA), combines immunomagnetic separation (IMS) and immunomagnetic scavenging (IMSc) and has been used to measure the effectiveness of cholinesterase reactivators on OPNA-inhibited BuChE in serum. BuChE inhibited by the nerve agent VX, uninhibited BuChE, and unbound VX were measured up to 1 h after the addition of oxime reactivators pralidoxime (2-PAM) and obidoxime. IMS experiments consisted of extracting BuChE and VX-BuChE serum adducts using antibutyrylcholinesterase monoclonal antibodies conjugated to protein-G ferromagnetic particles. In a parallel set of experiments using IMSc, BuChE-coated magnetic beads were used to extract free VX from protein-depleted serum. Adducts from both IMS and IMSc were analyzed using a published IMS liquid chromatography tandem mass spectrometry (IMS-LC-MS/MS) protocol, which has also been demonstrated with other OPNAs. By applying this Dual-Mode IMA approach, 2-PAM was observed to be more potent than obidoxime in reactivating VX-adducted BuChE. VX-BuChE peptide concentrations initially measured at 19.7 ± 0.7 ng/mL decreased over 1 h to 10.6 ± 0.6 ng/mL when reactivated with 2-PAM and 14.4 ± 1.2 ng/mL when reactivated with obidoxime. These experiments also show that previously published IMS-LC-MS/MS analyses are compatible with serum treated with oximes. Dual-Mode IMA is the first immunoaffinity method developed for the simultaneous measurement of OPNA adducted BuChE, unadducted BuChE, and free nerve agent in serum and is a promising new tool for studying reactivator effectiveness on cholinesterases inhibited by nerve agents. PMID:23656164

  6. Emergency department management of nerve agent exposure.

    PubMed

    Pfaff, B L

    1998-01-01

    Nerve agents are toxic chemicals developed for use by the military, but used by terrorists against civilian populations. As threats of terrorism increase, it is possible that health care providers will be confronted with multiple victims of nerve agent exposure. Nerve agents are highly toxic forms of organophosphate poisons that potentially could cause harm to anyone who comes in contact. Emergency personnel need to be familiar with the agents, know how to prepare for encountering and treating victims, and know how to protect all people involved from further poisoning. PMID:9855972

  7. Anticonvulsants for nerve agent-induced seizures: The influence of the therapeutic dose of atropine.

    PubMed

    Shih, Tsung-Ming; Rowland, Tami C; McDonough, John H

    2007-01-01

    Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl)methylphosphonothioate (VX), and O-isobutyl S-(2-diethylamino)ethyl)-methyl phosphonothioate (VR). Animals instrumented for electroencephalogram recording were pretreated with pyridostigmine bromide (0.026 mg/kg i.m.) 30 min before challenge with 2 x LD50 (s.c.) of a nerve agent. In model A, atropine sulfate (2.0 mg/kg i.m.) and pyridine-2-aldoxime methylchloride (2-PAM; 25.0 mg/kg i.m.) were given 1 min after nerve agent challenge, and the tested anticonvulsant was given (i.m.) 5 min after seizure onset. In model B, a lower dose of atropine sulfate (0.1 mg/kg i.m.) was given along with 2-PAM 1 min after nerve agent challenge, and the anticonvulsant was given at seizure onset. With the lower dose of atropine, seizure occurrence increased to virtually 100% for all agents; the time to seizure onset decreased for sarin, cyclosarin, and VX; the signs of nerve agent intoxication were more severe; and coma resulted frequently with cyclosarin. The anticonvulsant ED50 doses for scopolamine or diazepam were, in general, not different between the two models, whereas the anticonvulsant ED50 values of midazolam increased 3- to 17-fold with the lower atropine dose. Seizure termination times were not systematically effected by the different doses of atropine. The order of anticonvulsant effectiveness within each model was scopolamine > or = midazolam > diazepam. The findings indicate that the dose of atropine given as antidotal therapy can significantly influence measures of nerve agent toxicity and responsiveness to anticonvulsant therapy. PMID:17015638

  8. Agent neutralization study IV. VX-caustic peroxide reactions. Final report, August 1993-February 1994

    SciTech Connect

    Hovanec, J.W.; Albizo, J.M.; Henderson, V.D.; Yang, Y.C.

    1994-08-01

    The use of concentrated mixtures of hydrogen peroxide and sodium hydroxide for the chemical neutralization (detoxification) of VX has been examined. The reaction of VX in 4 N sodium hydroxide/11% hydrogen peroxide is rapid and exothermic. Care must be taken to avoid temperature increases which can induce peroxide decomposition. This can be done by controlling the addition of VX to the reaction. (Author).

  9. Resuscitative challenges in nerve agent poisoning.

    PubMed

    Ben Abraham, Ron; Weinbroum, Avi A

    2003-09-01

    The threat of weapons of mass destruction such as nerve agents has become real since last year. The medical community has established protocols for the rapid evacuation and decontamination of affected civilians. However, protocols for resuscitative measures or acute perioperative care in cases of life-saving surgical interventions in toxic-traumatized casualties are still lacking. The database concerning the effects of nerve agent poisoning in humans is limited, and is largely based on reports of unintentional exposures to pesticide organophosphate poisoning and similar chemical substances. In this review, we summarize the knowledge on the possible pharmacological interactions between nerve agents and acute care. PMID:12972890

  10. Evaluation of risk assessment guideline levels for the chemical warfare agents mustard, GB, and VX.

    SciTech Connect

    Hartmann, H.; Environmental Assessment

    2002-06-01

    The U.S. Army has estimated acute lethality guideline levels for inhalation of the chemical warfare agents mustard, GB, and VX. These levels are expressed as dosages measured in milligram-minutes per cubic meter (mg-min/m3). The National Advisory Council has also proposed acute emergency guideline levels (AEGLs) for the agents. The AEGLs are threshold exposure limits for the general public for mild effects, serious adverse effects, and lethality. They are expressed as air concentrations (in units of mg/m3) and are applicable to emergency exposure periods ranging from 10 min to 8 h. The report discusses strengths and deficiencies in the levels, important parameters (i.e., exposure time, breathing rate) that need to be explicitly addressed in deriving the guideline levels, and possible impacts that could result from using AEGLs instead of guideline dosages in future assessments.

  11. Engineering V-type nerve agents detoxifying enzymes using computationally focused libraries.

    PubMed

    Cherny, Izhack; Greisen, Per; Ashani, Yacov; Khare, Sagar D; Oberdorfer, Gustav; Leader, Haim; Baker, David; Tawfik, Dan S

    2013-11-15

    VX and its Russian (RVX) and Chinese (CVX) analogues rapidly inactivate acetylcholinesterase and are the most toxic stockpile nerve agents. These organophosphates have a thiol leaving group with a choline-like moiety and are hydrolyzed very slowly by natural enzymes. We used an integrated computational and experimental approach to increase Brevundimonas diminuta phosphotriesterase's (PTE) detoxification rate of V-agents by 5000-fold. Computational models were built of the complex between PTE and V-agents. On the basis of these models, the active site was redesigned to be complementary in shape to VX and RVX and to include favorable electrostatic interactions with their choline-like leaving group. Small libraries based on designed sequences were constructed. The libraries were screened by a direct assay for V-agent detoxification, as our initial studies showed that colorimetric surrogates fail to report the detoxification rates of the actual agents. The experimental results were fed back to improve the computational models. Overall, five rounds of iterating between experiment and model refinement led to variants that hydrolyze the toxic SP isomers of all three V-agents with kcat/KM values of up to 5 × 10(6) M(-1) min(-1) and also efficiently detoxify G-agents. These new catalysts provide the basis for broad spectrum nerve agent detoxification. PMID:24041203

  12. An attempt to assess functionally minimal acetylcholinesterase activity necessary for survival of rats intoxicated with nerve agents.

    PubMed

    Bajgar, Jiri; Fusek, Josef; Kassa, Jiri; Jun, Daniel; Kuca, Kamil; Hajek, Petr

    2008-09-25

    Acetylcholinesterase (AChE, EC 3.1.1.7) is an important enzyme for cholinergic nerve transmission. The action of toxic organophosphates such as nerve agents is based on AChE inhibition. The death following acute nerve agent poisoning is due to central or peripheral respiratory/cardiac failure. Therefore, the changes in AChE activity following nerve agents acting predominantly on the central (sarin, soman) or peripheral (VX) level were studied. It is known that AChE activity in different structures exists in relative excess. Female Wistar rats intoxicated with sarin, soman, and VX in different doses (0.5-2.0 x LD(50)) were divided into groups of survived and died animals. AChE activities in diaphragm, brain parts (pontomedullar area, frontal cortex, basal ganglia, in some cases other parts of the brain) were determined and the rest of activity (in %) was correlated with survival/death of animals. More precise elucidation of action of nerve agents and the assessment of minimal AChE activity in different organs compatible with the survival of organism poisoned with nerve agents were the aims of this study. PMID:18579126

  13. Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

    PubMed

    Wright, Linnzi K M; Lee, Robyn B; Vincelli, Nicole M; Whalley, Christopher E; Lumley, Lucille A

    2016-01-22

    Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX. PMID:26621540

  14. Identification and characterization of novel catalytic bioscavengers of organophosphorus nerve agents.

    PubMed

    Otto, Tamara C; Scott, Jennifer R; Kauffman, Monika A; Hodgins, Sean M; Ditargiani, Robert C; Hughes, James H; Sarricks, Erin P; Saturday, Greg A; Hamilton, Tracey A; Cerasoli, Douglas M

    2013-03-25

    In an effort to discover novel catalytic bioscavengers of organophosphorus (OP) nerve agents, cell lysates from a diverse set of bacterial strains were screened for their capacity to hydrolyze the OP nerve agents VX, VR, and soman (GD). The library of bacterial strains was identified using both random and rational approaches. Specifically, two representative strains from eight categories of extremophiles were chosen at random. For the rational approach, the protein sequence of organophosphorus hydrolase (OPH) from Brevundimonas diminuta was searched against a non-redundant protein database using the Basic Local Alignment Search Tool to find regions of local similarity between sequences. Over 15 protein sequences with significant sequence similarity to OPH were identified from a variety of bacterial strains. Some of these matches were based on predicted protein structures derived from bacterial genome sequences rather than from bona fide proteins isolated from bacteria. Of the 25 strains selected for nerve agent testing, three bacterial strains had measurable levels of OP hydrolase activity. These strains are Ammoniphilus oxalaticus, Haloarcula sp., and Micromonospora aurantiaca. Lysates from A. oxalaticus had detectable hydrolysis of VR; Haloarcula sp. had appreciable hydrolysis of VX and VR, whereas lysates from M. aurantiaca had detectable hydrolysis of VR and GD. PMID:23041042

  15. Different inhibition of acetylcholinesterase in selected parts of the rat brain following intoxication with VX and Russian VX.

    PubMed

    Hajek, Petr; Bajgar, Jiri; Slizova, Dasa; Krs, Otakar; Kuca, Kamil; Capek, Lukas; Fusek, Josef

    2009-01-01

    Differences between acetylcholinesterase (AChE) inhibition in the brain structures following VX and RVX exposure are not known as well as information on the possible correlation of biochemical and histochemical methods detecting AChE activity. Therefore, inhibition of AChE in different brain parts detected by histochemical and biochemical techniques was compared in rats intoxicated with VX and RVX. AChE activities in defined brain regions 30 min after treating rats with VX and Russian VX intramuscularly (1.0 x LD(50)) were determined by using biochemical and histochemical methods. AChE inhibition was less expressed for RVX, in comparison with VX. Frontal cortex and pontomedullar areas containing ncl. reticularis has been found as the most sensitive areas for the action of VX. For RVX, these structures were determined to be frontal cortex, dorsal septum, and hippocampus, respectively. Histochemical and biochemical results were in good correlation (R(xy) = 0.8337). Determination of AChE activity in defined brain structures was a more sensitive parameter for VX or RVX exposure than the determination of AChE activity in the whole-brain homogenate. This activity represents a "mean" of the activities in different structures. Thus, AChE activity is the main parameter investigated in studies searching for target sites following nerve-agent poisoning contributing to better understanding of toxicodynamics of nerve agents. PMID:19514933

  16. Biocatalytic nerve agent detoxification in fire fighting foams.

    PubMed

    LeJeune, K E; Russell, A J

    1999-03-20

    Current events across the globe necessitate rapid technological advances to combat the epidemic of nerve agent chemical weapons. Biocatalysis has emerged as a viable tool in the detoxification of organophosphorus neurotoxins, such as the chemical weapons VX and sarin. Efficient detoxification of contaminated equipment, machinery, and soils are of principal concern. This study describes the incorporation of a biocatalyst (organophosphorus hydrolase, E.C. 3.1.8.1) into conventional formulations of fire fighting foam. The capacity of fire fighting foams to decrease volatilization of contained contaminants, increase surface wettability, and control the rate of enzyme delivery to large areas makes them useful vehicles for enzyme application at surfaces. The performance of enzyme containing foams has been shown to be not only reproducible but also predictable. An empirical model provides reasonable estimations for the amounts of achievable surface decontamination as a function of the important parameters of the system. Theoretical modeling illustrates that the enzyme-containing foam is capable of extracting agent from the surface and is catalytically active at the foam-surface interface and throughout the foam itself. Biocatalytic foam has proven to be an effective, "environmentally friendly" means of surface and soil decontamination. PMID:10068213

  17. Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

    SciTech Connect

    Hemmert, Andrew C.; Otto, Tamara C.; Wierdl, Monika; Edwards, Carol C.; Fleming, Christopher D.; MacDonald, Mary; Cashman, John R.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

    2010-10-28

    Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P{sub R} enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P{sub S} isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P{sub S} isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

  18. Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

    PubMed Central

    Hemmert, Andrew C.; Otto, Tamara C.; Wierdl, Monika; Edwards, Carol C.; Fleming, Christopher D.; MacDonald, Mary; Cashman, John R.; Potter, Philip M.; Cerasoli, Douglas M.

    2010-01-01

    Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the PR enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the PS isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic PS isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification. PMID:20051531

  19. Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates.

    PubMed

    Meek, Edward C; Chambers, Howard W; Coban, Alper; Funck, Kristen E; Pringle, Ronald B; Ross, Matthew K; Chambers, Janice E

    2012-04-01

    Four nonvolatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates, phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by liquid chromatography-mass spectrometry and nuclear magnetic resonance. NEMP, PIMP, and NIMP were potent inhibitors of rat brain, skeletal muscle, diaphragm, and serum AChE as well as human erythrocyte AChE and serum BuChE in vitro. PIMP was determined to degrade quickly in aqueous solution, making it useful for in vitro assays only, and NEDPA was not a potent inhibitor of AChE or BuChE in vitro; therefore, these two surrogates were not tested in subsequent in vivo studies. Sublethal dosages (yielding about 80% brain AChE inhibition) were determined for both the stable sarin surrogate, NIMP (0.325 mg/kg ip), and the VX surrogate, NEMP (0.4 mg/kg ip), in adult male rats. Time course studies indicated the time to peak brain AChE inhibition for both NIMP and NEMP to be 1 h postexposure. Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality, and the rate of AChE aging was slow, making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents and are useful tools for initial screening of nerve agent oxime therapeutics. PMID:22247004

  20. A high-throughput diagnostic method for measuring human exposure to organophosphorus nerve agents.

    PubMed

    Knaack, Jennifer S; Zhou, Yingtao; Abney, Carter W; Jacob, Justin T; Prezioso, Samantha M; Hardy, Katelyn; Lemire, Sharon W; Thomas, Jerry; Johnson, Rudolph C

    2012-11-01

    An automated high-throughput immunomagnetic separation (IMS) method for diagnosing exposure to the organophosphorus nerve agents (OPNAs) sarin (GB), cyclohexylsarin (GF), VX, and Russian VX (RVX) was developed to increase sample processing capacity for emergency response applications. Diagnosis of exposure to OPNAs was based on the formation of OPNA adducts to butyrylcholinesterase (BuChE). Data reported with this method represent a ratio of the agent-specific BuChE adduct concentration, relative to the total BuChE peptide concentration that provides a nonactivity measurement expressed as percent adducted. All magnetic bead transfer steps and washes were performed using instrumentation in a 96-well format allowing for simultaneous extraction of 86 clinical samples plus reference materials. Automating extractions increased sample throughput 50-fold, as compared to a previously reported manual method. The limits of detection, determined using synthetic peptides, were 1 ng/mL for unadducted BuChE and GB-, GF-, VX-, and RVX-adducted BuChE. The automated method was characterized using unexposed serum and serum pools exposed to GB, GF, VX, or RVX. Variation for the measurement of percent adducted was <12% for all characterized quality control serum pools. Twenty-six (26) serum samples from individuals asymptomatic for cholinesterase inhibitor exposure were analyzed using this method, and no background levels of OPNA exposure were observed. Unexposed BuChE serum concentrations measured using this method ranged from 2.8 μg/mL to 10.6 μg/mL, with an average concentration of 6.4 μg/mL. PMID:23083472

  1. Quantitation of five organophosphorus nerve agent metabolites in serum using hydrophilic interaction liquid chromatography and tandem mass spectrometry

    PubMed Central

    Hamelin, Elizabeth I.; Schulze, Nicholas D.; Shaner, Rebecca L.; Coleman, Rebecca M.; Lawrence, Richard J.; Crow, Brian S.; Jakubowski, E. M.; Johnson, Rudolph C.

    2015-01-01

    Although nerve agent use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. Exposure can be detected through the analysis of the hydrolysis products in urine as well as blood. An analytical method to detect exposure to five nerve agents, including VX, VR (Russian VX), GB (sarin), GD (soman) and GF (cyclosarin), through the analysis of the hydrolysis products, which are the primary metabolites, in serum has been developed and characterized. This method uses solid phase extraction coupled with high performance liquid chromatography for separation and isotopic dilution tandem mass spectrometry for detection. An uncommon buffer of ammonium fluoride was used to enhance ionization and improve sensitivity when coupled with hydrophilic interaction liquid chromatography resulting in detection limits from 0.3–0.5 ng/mL. The assessment of two quality control samples demonstrated high accuracy (101–105%) and high precision (5–8%) for the detection of these five nerve agent hydrolysis products in serum. PMID:24633507

  2. Quantitation of five organophosphorus nerve agent metabolites in serum using hydrophilic interaction liquid chromatography and tandem mass spectrometry.

    PubMed

    Hamelin, Elizabeth I; Schulze, Nicholas D; Shaner, Rebecca L; Coleman, Rebecca M; Lawrence, Richard J; Crow, Brian S; Jakubowski, E M; Johnson, Rudolph C

    2014-08-01

    Although nerve agent use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. Exposure can be detected through the analysis of hydrolysis products in urine as well as blood. An analytical method to detect exposure to five nerve agents, including VX, VR (Russian VX), GB (sarin), GD (soman), and GF (cyclosarin), through the analysis of the hydrolysis products, which are the primary metabolites, in serum has been developed and characterized. This method uses solid-phase extraction coupled with high-performance liquid chromatography for separation and isotopic dilution tandem mass spectrometry for detection. An uncommon buffer of ammonium fluoride was used to enhance ionization and improve sensitivity when coupled with hydrophilic interaction liquid chromatography resulting in detection limits from 0.3 to 0.5 ng/mL. The assessment of two quality control samples demonstrated high accuracy (101-105%) and high precision (5-8%) for the detection of these five nerve agent hydrolysis products in serum. PMID:24633507

  3. Effect of exposure area on nerve agent absorption through skin in vitro.

    PubMed

    Dalton, Christopher; Graham, Stuart; Jenner, John

    2015-12-25

    Diffusion cells are used to determine the penetration of chemicals through skin in vitro. The cells have a limited surface area defined by the edge of the donor chamber. Should the penetrant spread rapidly to this containment limit the penetration rate can be accurately quantified. For the hazard assessment of small droplets of toxic chemicals, such as cholinesterase inhibitors, limiting skin surface spread in vitro could lead to underestimation of percutaneous penetration and hence underestimation of systemic toxicity in vivo. The current study investigated the dependency of the percutaneous penetration of undiluted radiolabelled nerve agents (VX and soman (GD), 10 μl) on skin surface spread (pig and guinea pig) using Franz-type glass diffusion cells with an area available for diffusion of either 2.54 cm(2) or 14.87 cm(2). Both VX and GD spread to the edge of the 2.54 cm(2) cells, but, not the 14.87 cm(2) cells over the study duration. Amounts of VX and GD penetrating pig and guinea pig skin in the 2.54 cm(2) cells were less than in the 14.87 cm(2) cells (except for GD under unoccluded conditions); however, penetration rates expressed per unit area were similar. Artificial limitation of skin surface spread in vitro does not impact percutaneous penetration in vitro as long as penetration is expressed in terms of mass per unit area. PMID:26391143

  4. A structure-activity analysis of the variation in oxime efficacy against nerve agents.

    PubMed

    Maxwell, Donald M; Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k(r2)) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k(r2) decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (>14-fold decrease in PR) than with HI-6 and ICD585 (<3.7-fold decrease in PR). The decrease in oxime PR and k(r2) as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k(r2)[oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy. PMID:18508103

  5. A structure-activity analysis of the variation in oxime efficacy against nerve agents

    SciTech Connect

    Maxwell, Donald M. Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E.

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k{sub r2}) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k{sub r2} decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (> 14-fold decrease in PR) than with HI-6 and ICD585 (< 3.7-fold decrease in PR). The decrease in oxime PR and k{sub r2} as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k{sub r2} {center_dot} [oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy.

  6. An acetylcholinesterase-based chronoamperometric biosensor for fast and reliable assay of nerve agents.

    PubMed

    Pohanka, Miroslav; Adam, Vojtech; Kizek, Rene

    2013-01-01

    The enzyme acetylcholinesterase (AChE) is an important part of cholinergic nervous system, where it stops neurotransmission by hydrolysis of the neurotransmitter acetylcholine. It is sensitive to inhibition by organophosphate and carbamate insecticides, some Alzheimer disease drugs, secondary metabolites such as aflatoxins and nerve agents used in chemical warfare. When immobilized on a sensor (physico-chemical transducer), it can be used for assay of these inhibitors. In the experiments described herein, an AChE- based electrochemical biosensor using screen printed electrode systems was prepared. The biosensor was used for assay of nerve agents such as sarin, soman, tabun and VX. The limits of detection achieved in a measuring protocol lasting ten minutes were 7.41 × 10(-12) mol/L for sarin, 6.31 × 10(-12) mol /L for soman, 6.17 × 10(-11) mol/L for tabun, and 2.19 × 10(-11) mol/L for VX, respectively. The assay was reliable, with minor interferences caused by the organic solvents ethanol, methanol, isopropanol and acetonitrile. Isopropanol was chosen as suitable medium for processing lipophilic samples. PMID:23999806

  7. An Acetylcholinesterase-Based Chronoamperometric Biosensor for Fast and Reliable Assay of Nerve Agents

    PubMed Central

    Pohanka, Miroslav; Adam, Vojtech; Kizek, Rene

    2013-01-01

    The enzyme acetylcholinesterase (AChE) is an important part of cholinergic nervous system, where it stops neurotransmission by hydrolysis of the neurotransmitter acetylcholine. It is sensitive to inhibition by organophosphate and carbamate insecticides, some Alzheimer disease drugs, secondary metabolites such as aflatoxins and nerve agents used in chemical warfare. When immobilized on a sensor (physico-chemical transducer), it can be used for assay of these inhibitors. In the experiments described herein, an AChE- based electrochemical biosensor using screen printed electrode systems was prepared. The biosensor was used for assay of nerve agents such as sarin, soman, tabun and VX. The limits of detection achieved in a measuring protocol lasting ten minutes were 7.41 × 10−12 mol/L for sarin, 6.31 × 10−12 mol/L for soman, 6.17 × 10−11 mol/L for tabun, and 2.19 × 10−11 mol/L for VX, respectively. The assay was reliable, with minor interferences caused by the organic solvents ethanol, methanol, isopropanol and acetonitrile. Isopropanol was chosen as suitable medium for processing lipophilic samples. PMID:23999806

  8. Fluorescent sensors for organophosphorus nerve agent mimics.

    PubMed

    Dale, Trevor J; Rebek, Julius

    2006-04-12

    We present a small molecule sensor that provides an optical response to the presence of an organophosphorus (OP)-containing nerve agent mimic. The design contains three key features: a primary alcohol, a tertiary amine in close proximity to the alcohol, and a fluorescent group used as the optical readout. In the sensor's rest state, the lone pair of electrons of the basic amine quenches the fluorescence of the nearby fluorophore through photoinduced electron transfer (PET). Exposure to an OP nerve agent mimic triggers phosphorylation of the primary alcohol followed rapidly by an intramolecular substitution reaction as the amine displaces the created phosphate. The quaternized ammonium salt produced by this cyclization reaction no longer possesses a lone pair of electrons, and a fluorescence readout is observed as the nonradiative PET quenching pathway of the fluorophore is shut down. PMID:16594648

  9. An anesthesiological approach to nerve agent victims.

    PubMed

    Cosar, Ahmet; Kenar, Levent

    2006-01-01

    The potential use of weapons of mass destruction has recently become a real threat even in the areas of ongoing armed conflicts. Mass casualty victims can suffer from psychological and physical trauma. The exposure of physically injured patients to a toxic substance, in a scenario of mass injury, has recently gained major attention among planners of future protocols for emergency medical services. Because rapid deterioration and multiorgan involvement are to be expected after physical injuries, proper organization and complex but efficient acute medical care systems must be organized and deployed to ensure a maximal number of saved lives. These victims will inevitably require urgent surgical intervention and prolonged perioperative care. Understanding the interdependence between the toxic and traumatic occurrences and the drugs used to prevent or treat nerve agent intoxication (pyridostigmine bromide, a reversible inhibitor of acetylcholinesterase; atropine, a muscarinic receptor antagonist that is one of the on-site, first aid, pharmacological resuscitation drugs; and oxime-like pralidoxime chloride or obidoxime chloride, acetylcholinesterase reactivators) is vital. In addition, the administration of anesthesia and emergency surgery pose further unpredictable threats to the central nervous system, the cardiovascular system, and respiratory function, all of which may be compromised after chemical intoxication and physical trauma. It is noteworthy that information concerning the effects of nerve agent intoxication among human subjects is derived largely from reports of incidents of intentional terrorist attacks or of accidental exposure to organophosphate pesticides, compounds that are chemically related to nerve agents. PMID:16532866

  10. Degradation Kinetics of VX

    SciTech Connect

    Gary S. Groenewold

    2010-12-01

    O-ethyl S-(2-diisopropylaminoethyl)phosphonothiolate (VX) is the most toxic of the conventional chemical warfare agents. It is a persistent compound, an attribute derived from its relative involatility and slow rates of hydrolysis. These properties suggest that VX can linger in an exposed environment for extended periods of time long after the air has cleared. Concern over prolonged risk from VX exposure is exacerbated by the fact that it poses a dermal contact hazard. Hence a detailed understanding of volatilization rates, and degradation pathways and rates occurring in various environments is needed. Historically, volatilization has not been considered to be an important mechanism for VX depletion, but recent studies have shown that a significant fraction of VX may volatilize, depending on the matrix. A significant body of research has been conducted over the years to unravel VX degradation reaction pathways and to quantify the rates at which they proceed. Rigorous measurement of degradation rates is frequently difficult, and thus in many cases the degradation of VX has been described in terms of half lives, while in fewer instances rate constants have been measured. This variable approach to describing degradation kinetics reflects uncertainty regarding the exact nature of the degradation mechanisms. In this review, rates of VX degradation are compared on the basis of pseudo-first order rate constants, in order to provide a basis for assessing likelihood of VX persistence in a given environment. An issue of specific concern is that one VX degradation pathway produces S-2-(diisopropylaminoethyl) methylphosphonothioic acid (known as EA2192), which is a degradation product that retains much of the original toxicity of VX. Consequently degradation pathways and rates for EA2192 are also discussed.

  11. A 10-minute point-of-care assay for detection of blood protein adducts resulting from low level exposure to organophosphate nerve agents.

    PubMed

    VanDine, Robert; Babu, Uma Mahesh; Condon, Peter; Mendez, Arlene; Sambursky, Robert

    2013-03-25

    The OrganoTox test is a rapid, point-of-care assay capable of detecting clinically relevant organophosphate (OP) poisoning after low-level exposure to sarin, soman, tabun, or VX chemical nerve agents. The test utilizes either a finger stick peripheral blood sample or plasma specimen. While high-level nerve agent exposure can quickly lead to death, low-level exposure produces vague, nondescript signs and symptoms that are not easily clinically differentiated from other conditions. In initial testing, the OrganoTox test was used to detect the presence of blood protein-nerve agent adducts in exposed blood samples. In order to mimic the in vivo exposure as closely as possible, nerve agents stored in organic solvents were spiked in minute quantities into whole blood samples. For performance testing, 40 plasma samples were spiked with sarin, soman, tabun, or VX and 10 normal plasma samples were used as the negative control. The 40 nerve agent-spiked plasma samples included 10 replicates of each agent. At the clinically relevant low-level exposure of 10 ng/ml, the OrganoTox test demonstrated 100% sensitivity for soman, tabun, and VX and 80% sensitivity for sarin. The OrganoTox test demonstrated greater than 97% specificity with 150 blood samples obtained from healthy adults. No cross-reactivity or interference from pesticide precursor compounds was found. A rapid test for nerve agent exposure will help identify affected patients earlier in the clinical course and trigger more appropriate medical management in a more timely manner. PMID:23200942

  12. Ultrasonograpy of VX-2 Liver Tumor in Rabbit Treated by High Intensity Focused Ultrasound Combined with Microbubble Contrast Agent

    NASA Astrophysics Data System (ADS)

    Xiaojuan, Ji; Jinqing, Li; Zhibiao, Wang; Jianzhong, Zou; Wenzhi, Chen; Jin, Bai

    2007-05-01

    Objective: To assess the value of sonographic appearance and to investigate the sonographic character of VX-2 liver tumor in rabbit treated by high intensity focused ultrasound (HIFU) combined with microbubble contrast agent. Methods: Forty-five rabbits bearing VX-2 tumors were randomly averagely assigned into three groups. In group A irradiation was sustained until the target region became hyperechoic. In group B therapy was stopped as soon as hyperecho occurred, and in group C irradiation time was prolonged to ensure the occurrence of coagulation necrosis. Results: Exposure duration for tumors treated purely with HIFU was the longest, whilst the use of microbubble contrast agent combined with HIFU shortened the exposure duration significantly. The gross examination and ultrasonogram coagulation necrosis area measurements correlated strongly (r=0.986,P<0.05) in the microbubble-enhanced HIFU group. Conclusion: It was feasible to enhance HIFU therapy with microbubble contrast agent. The characteristic change in the ultrasound images made it possible to assess the enhanced HIFU therapeutic efficacy in order to adjust the treatment program.

  13. Comparison of High Resolution and Tandem Mass Spectrometry for the Analysis of Nerve Agent Metabolites in Urine

    PubMed Central

    Hamelin, Elizabeth I.; Bragg, William; Shaner, Rebecca L.; Swaim, Leigh L.; Johnson, Rudolph C.

    2015-01-01

    Rationale Although use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. High-resolution mass spectrometry (HRMS) was compared to tandem mass spectrometry (MS/MS) analysis for the quantitation of five urinary metabolites specific to VX, Russian VX, soman, sarin and cyclosarin nerve agents. The HRMS method was further evaluated for qualitative screening of metabolites not included in the test panel. Methods Nerve agent metabolites were extracted from urine using solid phase extraction, separated using hydrophilic interaction chromatography and analyzed using both tandem and high resolution mass spectrometry. MS/MS results were obtained using selected reaction monitoring with unit resolution; HRMS results were obtained using a mass extraction window of 10 ppm at a mass resolution of 50,000. The benchtop Orbitrap HRMS instrument was operated in full scan mode, to measure the presence of unexpected agents. Results The assessment of two quality control samples demonstrated high accuracy (99.5-104%) and high precision (2-9%) for both HRMS and MS/MS. Sensitivity, as described by the limit of detection, was overlapping for both detectors (0.2-0.7 ng/mL). Additionally, the HRMS method positively confirmed the presence of a nerve agent metabolite, not included in the test panel, using the accurate mass and relative retention time. Conclusions The precision, accuracy, and sensitivity were comparable between the current MS/MS method and this newly developed HRMS analysis for five nerve agent metabolites. HRMS showed additional capabilities beyond the current method by confirming the presence of a metabolite not included in the test panel. PMID:23821563

  14. VX fate on common matrices: evaporation versus degradation.

    PubMed

    Columbus, Ishay; Waysbort, Daniel; Marcovitch, Itzhak; Yehezkel, Lea; Mizrahi, Dana M

    2012-04-01

    A study of the volatilization rate of the nerve agent VX (O-ethyl S-2-(N,N-diisopropylamino)ethyl methylphosphonothiolate) from various urban matrices in a specially designed climatic chamber (model system) is described. The performance of the model system combined with the analytical procedure produced profiles of vapor concentration obtained from samples of VX dispersed as small droplets on the surfaces of the matrices. The results indicated that the bitumen-containing surfaces such as asphalt blocks and bitumen sheets conserve VX and slow-release part of it over a long period of time. No complete mass balance could be obtained for these surfaces. Influence of environmental and experimental parameters as well as the efficacy of decontamination procedure were also measured. From smooth surface tiles a fast release of VX was measured and almost a complete mass balance was obtained, which characterizes the behavior of inert surfaces. Experiments carried out on concrete blocks showed fast decay of the concentration profile along with a very poor reconstruction of the initial quantity of VX, implying that this matrix degraded VX actively due to its multiple basic catalytic sites. To complement this study, solid-state NMR measurements were compared to add data concerning agent-fate within the matrices. PMID:22413893

  15. Evaluation of Multiple Blood Matrices for Assessment of Human Exposure to Nerve Agents.

    PubMed

    Schulze, Nicholas D; Hamelin, Elizabeth I; Winkeljohn, W Rucks; Shaner, Rebecca L; Basden, Brian J; deCastro, B Rey; Pantazides, Brooke G; Thomas, Jerry D; Johnson, Rudolph C

    2016-04-01

    Biomedical samples may be used to determine human exposure to nerve agents through the analysis of specific biomarkers. Samples received may include serum, plasma, whole blood, lysed blood and, due to the toxicity of these compounds, postmortem blood. To quantitate metabolites resulting from exposure to sarin (GB), soman (GD), cyclosarin (GF), VX and VR, these blood matrices were evaluated individually for precision, accuracy, sensitivity and specificity. Accuracies for these metabolites ranged from 100 to 113% with coefficients of variation ranging from 2.31 to 13.5% across a reportable range of 1-100 ng/mL meeting FDA recommended guidelines for bioanalytical methods in all five matrices. Limits of detection were calculated to be 0.09-0.043 ng/mL, and no interferences were detected in unexposed matrix samples. The use of serum calibrators was also determined to be a suitable alternative to matrix-matched calibrators. Finally, to provide a comparative value between whole blood and plasma, the ratio of the five nerve agent metabolites measured in whole blood versus plasma was determined. Analysis of individual whole blood samples (n = 40), fortified with nerve agent metabolites across the reportable range, resulted in average nerve agent metabolite blood to plasma ratios ranging from 0.53 to 0.56. This study demonstrates the accurate and precise quantitation of nerve agent metabolites in serum, plasma, whole blood, lysed blood and postmortem blood. It also provides a comparative value between whole blood and plasma samples, which can assist epidemiologists and physicians with interpretation of test results from blood specimens obtained under variable conditions. PMID:26861671

  16. Separation and detection of VX and its methylphosphonic acid degradation products on a microchip using indirect laser-induced fluorescence.

    PubMed

    Heleg-Shabtai, Vered; Gratziany, Natzach; Liron, Zvi

    2006-05-01

    The application of indirect LIF (IDLIF) technique for on-chip electrophoretic separation and detection of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate (VX) and its major phosphonic degradation products, ethyl methylphosphonic acid (EMPA) and methylphosphonic acid (MPA) was demonstrated. Separation and detection of MPA degradation products of VX and the nerve agent isopropyl methylphosphonofluoridate (GB) are presented. The negatively charged dye eosin was found to be a good fluorescent marker for both the negatively charged phosphonic acids and the positively charged VX, and was chosen as the IDLIF visualization fluorescent dye. Separation and detection of VX, EMPA, and MPA in a simple-cross microchip were completed within less than a minute, and consumed only a 50 pL sample volume. A characteristic system peak that appeared in all IDLIF electropherograms served as an internal standard that increased the reliability of peak identification. The negative peak of both VX and the MPAs is in agreement with indirect detection theory and with previous reports in the literature. The LOD of VX and EMPA by IDLIF was 30 and 37 microM, respectively. Despite the fact that the detection sensitivity is relatively low, the rapid simultaneous on-chip analysis of both VX and its degradation products as well as the separation and detection of the MPA degradation products of both VX and GB, increases detection reliability and may present a choice when sensitivity is not critical compared with speed and simplicity of the assay. PMID:16703628

  17. Evaluation of standard and alternative methods for the decontamination of VX and HD in chemical agent disposal facilities. Final report, February 1992-February 1993

    SciTech Connect

    Hovanec, J.W.; Szafraniec, L.L.; Albizo, J.M.; Beaudry, W.T.; Henderson, V.D.

    1993-04-01

    Standard decontaminant formulations, aqueous sodium hydroxide and aqueous sodium hypochlorite, were providing slow and incomplete results when used to decontaminate certain operating facilities at the Johnston Atoll Chemical Agent Disposal System and the Chemical Agent Disposal System (Utah). A study was undertaken to define the capabilities and limitations of using concentrated sodium hydroxide to decontaminate VX, the effect of adding hydrogen peroxide to the sodium hydroxide for the decontamination of VX, the efficacy of aqueous oxone for the decontamination of VX, and the efficacy of oxone in a water/1-methyl-2-pyrrolidinone (MP) mixture for the decontamination of HD. Using aqueous sodium hydroxide alone was not desirable since the formation of toxic EA2192 could not be averted. However, the addition of hydrogen peroxide resulted in effective VX decontamination without EA2192 formation. Aqueous oxone was also found to be effective for both VX and HD. The incorporation of MP did little to improve HD dissolution and reacted with the oxone to reduce the effective usable life of the decontamination solution. Thus, the use of MP in HD decontamination was not recommended.

  18. Detection of nerve agent via perturbation of supramolecular gel formation.

    PubMed

    Hiscock, Jennifer R; Piana, Francesca; Sambrook, Mark R; Wells, Neil J; Clark, Alistair J; Vincent, Jack C; Busschaert, Nathalie; Brown, Richard C D; Gale, Philip A

    2013-10-14

    The formation of tren-based tris-urea supramolecular gels in organic solvents is perturbed by the presence of the nerve agent soman providing a new method of sensing the presence of organophosphorus warfare agents. PMID:23994877

  19. Nanomotors responsive to nerve-agent vapor plumes.

    PubMed

    Singh, Virendra V; Kaufmann, Kevin; Esteban-Fernández de Ávila, Berta; Uygun, Murat; Wang, Joseph

    2016-02-25

    Enzyme-powered nanomotors responsive to the presence of nerve agents in the surrounding atmosphere are employed for remote detection of chemical vapor threats. Distinct changes in the propulsion behavior, associated with the partition of the sarin simulant diethyl chlorophosphate (DCP), offer reliable and rapid detection of the nerve-agent vapor threat. PMID:26824395

  20. Selective enrichment of the degradation products of organophosphorus nerve agents by zirconia based solid-phase extraction.

    PubMed

    Kanaujia, Pankaj K; Pardasani, Deepak; Tak, Vijay; Purohit, Ajay K; Dubey, D K

    2011-09-23

    Selective extraction and enrichment of nerve agent degradation products has been achieved using zirconia based commercial solid-phase extraction cartridges. Target analytes were O-alkyl alkylphosphonic acids and alkylphosphonic acids, the environmental markers of nerve agents such as sarin, soman and VX. Critical extraction parameters such as modifier concentration, nature and volume of washing and eluting solvents were investigated. Amongst other anionic compounds, selectivity in extraction was observed for organophosphorus compounds. Recoveries of analytes were determined by GC-MS which ranged from 80% to 115%. Comparison of zirconia based solid-phase extraction method with anion-exchange solid-phase extraction revealed its selectivity towards phosphonic acids. The limits of detection (LOD) and limit of quantification (LOQ) with selected analytes were achieved down to 4.3 and 8.5 ng mL(-1), respectively, in selected ion monitoring mode. PMID:21862029

  1. CATALYTIC DETOXIFICATION OF NERVE AGENT AND PESTICIDE ORGANOPHOSPHATES BY BUTYRYLCHOLINESTERASE ASSISTED WITH NON-PYRIDINIUM OXIMES

    PubMed Central

    Radić, Zoran; Dale, Trevor; Kovarik, Zrinka; Berend, Suzana; Garcia, Edzna; Zhang, Limin; Amitai, Gabriel; Green, Carol; Radić, Božica; Duggan, Brendan M.; Ajami, Dariush; Rebek, Julius; Taylor, Palmer

    2016-01-01

    SYNOPSIS We present here a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide organophosphates (OPs) catalyzed by purified human butyrylcholinesterase (hBChE) in combination with novel non-pyridinium oxime reactivators. We identified 2-trimethylammonio-6-hydroxybenzaldehyde oxime (TAB2OH) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents, VX and cyclosarin, and the pesticide, paraoxon. It was also functional in reactivation of sarin and tabun inhibited hBChE. A three to five-fold enhancement of in vitro reactivation of VX, cyclosarin and paraoxon inhibited hBChE was observed, when compared to the commonly used N-methylpyridinium aldoxime reactivator, 2PAM. Kinetic analysis showed the enhancement resulted from improved molecular recognition of corresponding OP-hBChE conjugates by TAB2OH. The unique features of TAB2OH stem from an exocyclic quaternary nitrogen and a hydroxyl, both ortho to an oxime group on a benzene ring. pH dependences reveal participation of the hydroxyl (pKa=7.6) forming an additional ionizing nucleophile to potentiate the oxime (pKa=10) at physiological pH. The TAB2OH protective indices in therapy of sarin and paraoxon exposed mice were enhanced by 30% – 60% when they were treated with a combination of TAB2OH and sub-stoichiometric hBChE. These results establish that oxime-assisted catalysis is feasible for OP bioscavenging. PMID:23216060

  2. Fighting nerve agent chemical weapons with enzyme technology.

    PubMed

    LeJeune, K E; Dravis, B C; Yang, F; Hetro, A D; Doctor, B P; Russell, A J

    1998-12-13

    The extreme toxicity of organophosphorous-based compounds has been known since the late 1930s. Starting in the mid-1940s, many nations throughout the world have been producing large quantities of organophosphorous (OP) nerve agents. Huge stockpiles of nerve agents have since developed. There are reportedly more than 200,000 tons of nerve agents in existence worldwide. There is an obvious need for protective clothing capable of guarding an individual from exposure to OP chemical weapons. Also, chemical processes that can effectively demilitarize and detoxify stored nerve agents are in great demand. The new and widely publicized Chemical Weapons Treaty requires such processes to soon be in place throughout the world. Biotechnology may provide the tools necessary to make such processes not only possible, but quite efficient in reducing the nerve agent dilemma. The following paper discusses some of the history in developing enzyme technology against nerve agents. Our laboratory has interest in enhancing the productivity and potential utility of these systems in both demilitarization and decontamination applications. Freeze-dried nerve agent-hydrolyzing enzyme preparations have been shown to be effective in decontaminating gaseous nerve agents. The direct incorporation of nerve agent-hydrolyzing enzymes within cross-linked polyurethane foam matrices during polymer synthesis has been shown to dramatically enhance the productivity of two different enzyme systems. The future goal of such work lies in building a bridge between the clinical application of nerve agent-hydrolyzing enzymes and practical processing techniques that may take advantage of the initial results already achieved in the laboratory. PMID:9928090

  3. Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure.

    PubMed

    Appel, Amanda S; McDonough, John H; McMonagle, Joseph D; Logue, Brian A

    2016-06-21

    Several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure. However, parent nerve agents and known metabolites are generally rapidly excreted from biological matrixes typically used for analysis (i.e., blood, urine, and tissues), limiting the amount of time after an exposure that verification is feasible. In this study, hair was evaluated as a long-term repository of nerve agent hydrolysis products. Pinacolyl methylphosphonic acid (PMPA; hydrolysis product of soman) and isopropyl methylphosphonic acid (IMPA; hydrolysis product of sarin) were extracted from hair samples with N,N-dimethylformamide and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Limits of detection for PMPA and IMPA were 0.15 μg/kg and 7.5 μg/kg and linear ranges were 0.3-150 μg/kg and 7.5-750 μg/kg, respectively. To evaluate the applicability of the method to verify nerve agent exposure well after the exposure event, rats were exposed to soman, hair was collected after approximately 30 days, and stored for up to 3.5 years prior to initial analysis. PMPA was positively identified in 100% of the soman-exposed rats (N = 8) and was not detected in any of the saline treated animals (N = 6). The hair was reanalyzed 5.5 years after exposure and PMPA was detected in 6 of the 7 (one of the soman-exposed hair samples was completely consumed in the analysis at 3.5 years) rat hair samples (with no PMPA detected in the saline exposed animals). Although analysis of CWA metabolites from hair via this technique is not appropriate as a universal method to determine exposure (i.e., it takes time for the hair to grow above the surface of the skin and typical analysis times are >24 h), it complements existing methods and could become the preferred method for verification of exposure if 10 or more days have elapsed after a suspected exposure. PMID:27161086

  4. Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase.

    PubMed

    Coban, Alper; Carr, Russell L; Chambers, Howard W; Willeford, Kenneth O; Chambers, Janice E

    2016-04-25

    Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates. PMID:26965078

  5. Quantification of nerve agent adducts with albumin in rat plasma using liquid chromatography-isotope dilution tandem mass spectrometry.

    PubMed

    Bao, Yi; Liu, Qin; Chen, Jia; Lin, Ying; Wu, Bidong; Xie, Jianwei

    2012-03-16

    A sensitive method for the determination of the organophosphorus nerve agents sarin, soman and VX adducts with tyrosine residue of albumin in rat plasma has been developed and validated using liquid chromatography-isotope dilution tandem mass spectrometry (LC-IDMS/MS). O-(O-Alkyl methylphosphonyl) tyrosine adducts and their deuterated products that were used as the internal standards were synthesised to establish the quantitative isotope-dilution method. Protein purification and solid-phase extraction (SPE) were applied to improve the recovery efficiency, reduce interference and achieve high sensitivity. The method provided a detection limit of 0.01 ng/mL for sarin and soman adducts and 0.05 ng/mL for the VX adduct. The value of the intra-day relative standard deviation over the calibration range was less than 6.16% (n=6), and that of the inter-day was less than 12.7% (n=6). The recovery varied from 86% to 111%. This sensitive method was successfully applied to the analysis of adducts in rat plasma after nerve agent exposure, and the results demonstrated the dose-effect relationships. PMID:22305360

  6. V-type nerve agents phosphonylate ubiquitin at biologically relevant lysine residues and induce intramolecular cyclization by an isopeptide bond.

    PubMed

    Schmidt, Christian; Breyer, Felicitas; Blum, Marc-Michael; Thiermann, Horst; Worek, Franz; John, Harald

    2014-08-01

    Toxic organophosphorus compounds (e.g., pesticides and nerve agents) are known to react with nucleophilic side chains of different amino acids (phosphylation), thus forming adducts with endogenous proteins. Most often binding to serine, tyrosine, or threonine residues is described as being of relevance for toxicological effects (e.g., acetylcholinesterase and neuropathy target esterase) or as biomarkers for post-exposure analysis (verification, e.g., albumin and butyrylcholinesterase). Accordingly, identification of novel protein targets might be beneficial for a better understanding of the toxicology of these compounds, revealing new bioanalytical verification tools, and improving knowledge on chemical reactivity. In the present study, we investigated the reaction of ubiquitin (Ub) with the V-type nerve agents Chinese VX, Russian VX, and VX in vitro. Ub is a ubiquitous protein with a mass of 8564.8 Da present in the extra- and intracellular space that plays an important physiological role in several essential processes (e.g., proteasomal degradation, DNA repair, protein turnover, and endocytosis). Reaction products were analyzed by matrix-assisted laser desorption/ionization-time-of-flight- mass spectrometry (MALDI-TOF MS) and μ-high-performance liquid chromatography online coupled to UV-detection and electrospray ionization MS (μHPLC-UV/ESI MS). Our results originally document that a complex mixture of at least mono-, di, and triphosphonylated Ub adducts was produced. Surprisingly, peptide mass fingerprint analysis in combination with MALDI and ESI MS/MS revealed that phosphonylation occurred with high selectivity in at least 6 of 7 surface-exposed lysine residues that are essential for the biological function of Ub. These reaction products were found not to age. In addition, we herein report for the first time that phosphonylation induced intramolecular cyclization by formation of an isopeptide bond between the ε-amino group of a formerly phosphonylated

  7. Performance of a novel high throughput method for the determination of VX in drinking water samples.

    PubMed

    Knaack, Jennifer S; Zhou, Yingtao; Magnuson, Matthew; Silvestri, Erin; Johnson, Rudolph C

    2013-03-01

    VX (O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate) is a highly toxic organophosphorus nerve agent, and even low levels of contamination in water can be harmful. Measurement of low concentrations of VX in aqueous matrixes is possible using an immunomagnetic scavenging technique and detection using liquid chromatography/tandem-mass spectrometry. Performance of the method was characterized in high-performance liquid chromatography (HPLC)-grade water preserved with sodium omadine, an antimicrobial agent, and sodium thiosulfate, a dechlorinating agent, over eight analytical batches with quality control samples analyzed over 10 days. The minimum reportable level was 25 ng/L with a linear dynamic range up to 4.0 μg/L. The mean accuracies for two quality control samples containing VX at concentrations of 0.250 and 2.00 μg/L were 102 ± 3% and 103 ± 6%, respectively. The stability of VX was determined in five tap water samples representing a range of water quality parameters and disinfection practices over a 91 day period. In preserved tap water samples, VX recovery was between 81 and 92% of the fortified amount, 2.0 μg/L, when analyzed immediately after preparation. Recovery of VX decreased to between 31 and 45% of the fortified amount after 91 days, indicating hydrolysis of VX. However, the preservatives minimized the hydrolysis rate to close to the theoretical limit. The ability to detect low concentrations of VX in preserved tap water 91 days after spiking suggests applicability of this method for determining water contamination with VX and utility during environmental remediation. PMID:23402290

  8. Decomposition of adsorbed VX on activated carbons studied by 31P MAS NMR.

    PubMed

    Columbus, Ishay; Waysbort, Daniel; Shmueli, Liora; Nir, Ido; Kaplan, Doron

    2006-06-15

    The fate of the persistent OP nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) on granular activated carbons that are used for gas filtration was studied by means of 31P magic angle spinning (MAS) NMR spectroscopy. VX as vapor or liquid was adsorbed on carbon granules, and MAS NMR spectra were recorded periodically. The results show that at least 90% of the adsorbed VX decomposes within 20 days or less to the nontoxic ethyl methylphosphonic acid (EMPA) and bis(S-2-diisopropylaminoethane) {(DES)2}. Decomposition occurred irrespective of the phase from which VX was loaded, the presence of metal impregnation on the carbon surface, and the water content of the carbon. Theoretical and practical aspects of the degradation are discussed. PMID:16830567

  9. Decomposition of adsorbed VX on activated carbons studied by {sup 31}P MAS NMR

    SciTech Connect

    Ishay Columbus; Daniel Waysbort; Liora Shmueli; Ido Nir; Doron Kaplan

    2006-06-15

    The fate of the persistent OP nerve agent O-ethyl S-(2-(diisopropylamino)ethyl) methylphosphonothioate (VX) on granular activated carbons that are used for gas filtration was studied by means of 31P magic angle spinning (MAS) NMR spectroscopy. Four types of activated carbon were used, including coal-based BPL. VX as vapor or liquid was adsorbed on carbon granules, and MAS NMR spectra were recorded periodically. The results show that at least 90% of the adsorbed VX decomposes within 20 days or less to the nontoxic ethyl methylphosphonic acid (EMPA) and bis(S-2-diisopropylaminoethane) ((DES){sub 2}). Decomposition occurred irrespective of the phase from which VX was loaded, the presence of metal impregnation on the carbon surface, and the water content of the carbon. Theoretical and practical aspects of the degradation are discussed. 17 refs., 6 figs., 3 tabs.

  10. The therapeutic use of localized cooling in the treatment of VX poisoning.

    PubMed

    Sawyer, T W; Mikler, J; Worek, F; Reiter, G; Thiermann, H; Tenn, C; Weatherby, K; Bohnert, S

    2011-07-01

    The organophosphate (OP) nerve agent VX is a weaponized chemical warfare agent that has also been used by terrorists against civilians. This contact poison produces characteristic signs of OP poisoning, including miosis, salivation, mastication, dysrhythmias and respiratory distress prior to death. Although successful treatment of OP poisoning can be obtained through decontamination and/or oxime reactivation of agent-inhibited cholinesterase, medical countermeasures that increase the therapeutic window for these measures would be of benefit. An anaesthetized swine model was utilized to examine the effects of lethal VX exposure to the skin, followed by cooling the exposure site prior to decontamination or treatment. The cooling was simply accomplished by using crushed ice in grip-seal plastic bags applied to the exposure sites. Cooling of skin exposed to lethal doses of VX significantly increased the window of opportunity for successful decontamination using the Reactive Skin Decontaminant Lotion(®) (RSDL(®)) or treatment with the oxime antidotes HI-6 and 2PAM. Analyses of blood VX levels showed that cooling acted to slow or prevent the entry of VX into the bloodstream from the skin. If the exposure site is known, the simple and non-invasive application of cooling provides a safe means with which to dramatically increase the therapeutic window in which decontamination and/or antidote treatment against VX are life-saving. PMID:21530621

  11. Efficacy of an oximate-based skin decontaminant against organophosphate nerve agents determined in vivo and in vitro.

    PubMed

    Sawyer, T W; Parker, D; Thomas, N; Weiss, M T; Bide, R W

    1991-05-01

    Recent Canadian research efforts have been directed towards the development of a reactive skin decontaminant (RSD) lotion active against classical nerve agents and mustard. The formulation presently under study consists of a 1.25 molal solution of potassium 2,3-butanedione monoximate (KBDO) in polyethylene glycol methylether 550. Although this formulation has shown good efficacy, concern has been expressed as to the potential toxicity of the reaction products of KBDO and organophosphate (OP) nerve agents. This report details the high efficacy of this lotion in inactivating OPs as measured by the systemic toxicity of the OP/RSD mixtures in rats. In addition, primary cultures of chick embryo neurons were also used to test the efficacy of the RSD. By relating the anticholinesterase activity in these cultures of the OP/RSD mixture to that of pure OP standards, a sensitive measure of the value of the RSD in inactivating tabun, sarin, soman and VX was obtained. Experiments with all four nerve agents in this in vitro system provided a good correlation with the in vivo data, and also indicated that the inactivation process was time- and agent-dependent and also related to the ratio of OP to RSD. PMID:2048130

  12. Catalytic bioscavengers in nerve agent poisoning: A promising approach?

    PubMed

    Worek, Franz; Thiermann, Horst; Wille, Timo

    2016-02-26

    The repeated use of the nerve agent sarin against civilians in Syria in 2013 emphasizes the continuing threat by chemical warfare agents. Multiple studies demonstrated a limited efficacy of standard atropine-oxime treatment in nerve agent poisoning and called for the development of alternative and more effective treatment strategies. A novel approach is the use of stoichiometric or catalytic bioscavengers for detoxification of nerve agents in the systemic circulation prior to distribution into target tissues. Recent progress in the design of enzyme mutants with reversed stereo selectivity resulting in improved catalytic activity and their use in in vivo studies supports the concept of catalytic bioscavengers. Yet, further research is necessary to improve the catalytic activity, substrate spectrum and in vivo biological stability of enzyme mutants. The pros and cons of catalytic bioscavengers will be discussed in detail and future requirements for the development of catalytic bioscavengers will be proposed. PMID:26200600

  13. Comparison of selected skin decontaminant products and regimens against VX in domestic swine.

    PubMed

    Bjarnason, S; Mikler, J; Hill, I; Tenn, C; Garrett, M; Caddy, N; Sawyer, T W

    2008-03-01

    An anesthetized domestic swine model was used to compare the efficacy and cross-contamination potential of selected skin decontaminant products and regimens against the chemical warfare agent, VX. Animals topically exposed to 2x, 3x or 5x LD(50) VX showed typical signs of organophosphate nerve agent poisoning, including miosis, salivation, mastication, dysrhythmias, and respiratory distress prior to death. Animals were exposed to 5x LD(50) VX and then decontaminated 45 min later with the reactive skin decontamination lotion (RSDL), Fuller's earth (FE), 0.5% hypochlorite, or soapy water. Survival was 100% when the reactive skin decontamination lotion or FE was utilized, although 50% of Fuller's earth-decontaminated animals exhibited serious signs of VX poisoning. Decontamination of VX-treated animals with 0.5% hypochlorite was less effective but also increased survival. Soapy water was ineffective in preventing lethality. Blood cholinesterase levels were not predictive of clinical outcome in decontaminated animals. The potential of "decontaminated" VX in open wounds to cause poisoning was assessed by vigorously mixing 5x LD(50) VX with the test decontaminants for 5 min and then placing the mixture onto a full-thickness skin wound. Soapy water was ineffective in preventing lethality. Although treatment with dry Fuller's earth prevented death and all signs of organophosphate poisoning, a significant proportion of treated animals decontaminated with Fuller's earth in aqueous suspension exhibited serious signs of organophosphate poisoning, suggesting that live agent may be desorbed from Fuller's earth when it is exposed to a liquid environment. Animals treated with reactive skin decontamination lotion or 0.5% hypochlorite-VX mixtures showed no signs of organophosphate poisoning during the 6- h test period. PMID:18650258

  14. Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity.

    PubMed

    Artursson, Elisabet; Andersson, Per Ola; Akfur, Christine; Linusson, Anna; Börjegren, Susanne; Ekström, Fredrik

    2013-05-01

    Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation. PMID:23376121

  15. Assessment of nerve agent exposure: existing and emerging methods.

    PubMed

    Langenberg, Jan P; van der Schans, Marcel J; Noort, Daan

    2009-07-01

    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 equipment and well-trained personnel and, consequently, they are not very suitable for rapid POC diagnosis. However, new technologies are emerging that allow, among others, immunochemical detection of acetylcholinesterase inhibited by nerve agents. Also, lab-on-a-chip methodologies are under development. It is anticipated that MS methods will be suitable for POC diagnosis within a few years, due to the miniaturization of equipment and the emergence of methodologies that enable mass spectrometric analysis with little sample pretreatment and that are potentially fieldable, such as direct analysis in real time and desorption electrospray ionization MS. PMID:21083135

  16. Bionanoconjugate-based composites for decontamination of nerve agents.

    PubMed

    Borkar, Indrakant V; Dinu, Cerasela Zoica; Zhu, Guangyu; Kane, Ravi S; Dordick, Jonathan S

    2010-01-01

    We have developed enzyme-based composites that rapidly and effectively detoxify simulants of V- and G-type chemical warfare nerve agents. The approach was based on the efficient immobilization of organophosphorus hydrolase onto carbon nanotubes to form active and stable conjugates that were easily entrapped in commercially available paints. The resulting catalytic-based composites showed no enzyme leaching and rendered >99% decontamination of 10 g/m(2) paraoxon, a simulant of the V-type nerve agent, in 30 minutes and >95% decontamination of diisopropylfluorophosphate, a simulant of G-type nerve agent, in 45 minutes. The formulations are expected to be environmentally friendly and to offer an easy to use, on demand, decontamination alternative to chemical approaches for sustainable material self-decontamination. PMID:20859933

  17. Ion chemistry of VX surrogates and ion energetics properties of VX: new suggestions for VX chemical ionization mass spectrometry detection.

    PubMed

    Midey, Anthony J; Miller, Thomas M; Viggiano, A A; Bera, Narayan C; Maeda, Satoshi; Morokuma, Keiji

    2010-05-01

    Room temperature rate constants and product ion branching ratios have been measured for the reactions of numerous positive and negative ions with VX chemical warfare agent surrogates representing the amine (triethylamine) and organophosphonate (diethyl methythiomethylphosphonate (DEMTMP)) portions of VX. The measurements have been supplemented by theoretical calculations of the proton affinity, fluoride affinity, and ionization potential of VX and the simulants. The results show that many proton transfer reactions are rapid and that the proton affinity of VX is near the top of the scale. Many proton transfer agents should detect VX selectively and sensitively in chemical ionization mass spectrometers. Charge transfer with NO(+) should also be sensitive and selective since the ionization potential of VX is small. The surrogate studies confirm these trends. Limits of detection for commercial and research grade CIMS instruments are estimated at 80 pptv and 5 ppqv, respectively. PMID:20384284

  18. Reaction of nerve agents with phosphate buffer at pH 7.

    PubMed

    Creasy, William R; Fry, Roderick A; McGarvey, David J

    2012-07-12

    Chemical weapon nerve agents, including isopropyl methylphosphonofluoridate (GB or Sarin), pinacolyl methylphosphonofluoridate (GD or Soman), and S-(2-diisopropylaminoethyl) O-ethyl methylphosphonothioate (VX), are slow to react in aqueous solutions at midrange pH levels. The nerve agent reactivity increases in phosphate buffer at pH 7, relative to distilled water or acetate buffer. Reactions were studied using (31)P NMR. Phosphate causes faster reaction to the corresponding alkyl methylphosphonic acids, and produces a mixed phosphate/phosphonate compound as an intermediate reaction product. GB has the fastest reaction rate, with a bimolecular rate constant of 4.6 × 10(-3) M(-1)s(-1)[PO(4)(3-)]. The molar product branching ratio of GB acid to the pyro product (isopropyl methylphosphonate phosphate anhydride) is 1:1.4, independent of phosphate concentration, and the pyro product continues to react much slower to form GB acid. The pyro product has two doublets in the (31)P NMR spectrum. The rate of reaction for GD is slower than GB, with a rate constant of 1.26 × 10(-3) M(-1)s(-1) [PO(4)(3-)]. The rate for VX is considerably slower, with a rate constant of 1.39 × 10(-5) M(-1)s(-1) [PO(4)(3-)], about 2 orders of magnitude slower than the rate for GD. The rate constant of the reaction of GD with pyrophosphate at pH 8 is 2.04 × 10(-3) min(-1) at a concentration of 0.0145 M. The rate of reaction for diisopropyl fluorophosphate is 2.84 × 10(-3) min(-1) at a concentration of 0.153 M phosphate, a factor of 4 slower than GD and a factor of 15 slower than GB, and there is no detectable pyro product. The half-lives of secondary reaction of the GB pyro product in 0.153 and 0.046 M solution of phosphate are 23.8 and 28.0 h, respectively, which indicates little or no dependence on phosphate. PMID:22667763

  19. Simultaneous quantification of VX and its toxic metabolite in blood and plasma samples and its application for in vivo and in vitro toxicological studies.

    PubMed

    Reiter, Georg; Mikler, John; Hill, Ira; Weatherby, Kendal; Thiermann, Horst; Worek, Franz

    2011-09-15

    The present study was initiated to develop a sensitive and highly selective method for the simultaneous quantification of the nerve agent VX (O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate) and its toxic metabolite (EA-2192) in blood and plasma samples in vivo and in vitro. For the quantitative detection of VX and EA-2192 the resolution was realized on a HYPERCARB HPLC phase. A specific procedure was developed to isolate both toxic analytes from blood and plasma samples. The limit of detection was 0.1 pg/ml and the absolute recovery of the overall sample preparation procedure was 74% for VX and 69% for EA-2192. After intravenous and percutaneous administration of a supralethal doses of VX in anaesthetised swine both VX and EA-2192 could be quantified over 540 min following exposure. This study is the first to verify the in vivo formation of the toxic metabolite EA-2192 after poisoning with the nerve agent VX. Further toxicokinetic and therapeutic studies are required in order to determine the impact of EA-2192 on the treatment of acute VX poisoning. PMID:21862421

  20. Nerve agent-induced seizures and their pharmacological modulation

    SciTech Connect

    McDonough, J.H.; Shih, T.M.; Adams, N.L.; Koviak, T.A.; Cook, L.A.

    1993-05-13

    Intoxication with nerve agents produces prolonged central nervous system seizures (status epilepticus) that can produce irreversible brain pathology (15). This report summarizes our recent findings regarding the neurotransmitter changes that occur in discrete brain regions as a function of seizure duration and the differential effectiveness of anticholinergic, benzodiazepine and excitatory amino acid (EAA) antagonist drugs in terminating soman-induced seizures when given at different times after seizure onset. These results are discussed in relation to a model we have proposed to explain the sequence of electrophysiological, biochemical and neurochemical events and mechanisms controlling nerve agent-induced seizures.

  1. Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction.

    PubMed

    Farinha, Carlos M; King-Underwood, John; Sousa, Marisa; Correia, Ana Raquel; Henriques, Bárbara J; Roxo-Rosa, Mónica; Da Paula, Ana Carina; Williams, Jonathan; Hirst, Simon; Gomes, Cláudio M; Amaral, Margarida D

    2013-07-25

    Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. We explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR. Our experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR. PMID:23890012

  2. MICROCHIP ENZYMATIC ASSAY OF ORGANOPHOSPHATE NERVE AGENTS. (R830900)

    EPA Science Inventory

    An on-chip enzymatic assay for screening organophosphate (OP) nerve agents, based on a pre-column reaction of organophosphorus hydrolase (OPH), electrophoretic separation of the phosphonic acid products, and their contactless-conductivity detection, is described. Factors affec...

  3. First-principles molecular dynamics simulations of condensed-phase V-type nerve agent reaction pathways and energy barriers.

    PubMed

    Gee, Richard H; Kuo, I-Feng W; Chinn, Sarah C; Raber, Ellen

    2012-03-14

    Computational studies of condensed-phase chemical reactions are challenging in part because of complexities in understanding the effects of the solvent environment on the reacting chemical species. Such studies are further complicated due to the demanding computational resources required to implement high-level ab initio quantum chemical methods when considering the solvent explicitly. Here, we use first-principles molecular dynamics simulations to examine condensed-phase decontamination reactions of V-type nerve agents in an explicit aqueous solvent. Our results include a detailed study of hydrolysis, base-hydrolysis, and nucleophilic oxidation of both VX and R-VX, as well as their protonated counterparts (i.e., VXH(+) and R-VXH(+)). The decontamination mechanisms and chemical reaction energy barriers, as determined from our simulations, are found to be in good agreement with experiment. The results demonstrate the applicability of using such simulations to assist in understanding new decontamination technologies or other applications that require computational screening of condensed-phase chemical reaction mechanisms. PMID:22298156

  4. Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

    PubMed

    Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

    2012-04-01

    The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure. PMID:22240983

  5. Development of a high-throughput screening for nerve agent detoxifying materials using a fully-automated robot-assisted biological assay.

    PubMed

    Wille, T; Thiermann, H; Worek, F

    2010-04-01

    Developing improved medical countermeasures against chemical warfare agents (nerve agents) is urgently needed but time-consuming and costly. Here we introduce a robot-assisted liquid handling system with warming, cooling and incubating facilities to screen the detoxifying properties of biological and chemical materials against nerve agents. Two biological tests were established and plasma from various species, DFPase and three cyclodextrins were used as test materials. In test 1, plasma was mixed with sarin or VX and the inhibitory potency of the incubate was determined with human acetylcholinesterase (AChE) at 0, 30 and 60 min. In test 2, test materials and nerve agents were mixed and incubated. Between 0 and 40 min samples were taken and incubated for 3 min with AChE and the residual AChE inhibition was determined to enable the semi-quantitative evaluation of the detoxification kinetics. The automated assays proved to be highly reproducible. It was possible to pre-select detoxifying reagents with test 1 and to determine more detailed detoxifying kinetics with test 2. In conclusion, the automated assay may be considered as a versatile tool for the high-throughput screening of potential detoxifying materials against different nerve agents. With this two-step assay it is possible to screen effectively for detoxifying materials in a high-throughput system. PMID:19961920

  6. Derivatization of organophosphorus nerve agent degradation products for gas chromatography with ICPMS and TOF-MS detection.

    PubMed

    Richardson, Douglas D; Caruso, Joseph A

    2007-06-01

    Separation and detection of seven V-type (venomous) and G-type (German) organophosphorus nerve agent degradation products by gas chromatography with inductively coupled plasma mass spectrometry (GC-ICPMS) is described. The nonvolatile alkyl phosphonic acid degradation products of interest included ethyl methylphosphonic acid (EMPA, VX acid), isopropyl methylphosphonic acid (IMPA, GB acid), ethyl hydrogen dimethylamidophosphate sodium salt (EDPA, GA acid), isobutyl hydrogen methylphosphonate (IBMPA, RVX acid), as well as pinacolyl methylphosphonic acid (PMPA), methylphosphonic acid (MPA), and cyclohexyl methylphosphonic acid (CMPA, GF acid). N-(tert-Butyldimethylsilyl)-N-methyltrifluroacetamide with 1% TBDMSCl was utilized to form the volatile TBDMS derivatives of the nerve agent degradation products for separation by GC. Exact mass confirmation of the formation of six of the TBDMS derivatives was obtained by GC-time of flight mass spectrometry (TOF-MS). The method developed here allowed for the separation and detection of all seven TBDMS derivatives as well as phosphate in less than ten minutes. Detection limits for the developed method were less than 5 pg with retention times and peak area precisions of less than 0.01 and 6%, respectively. This method was successfully applied to river water and soil matrices. To date this is the first work describing the analysis of chemical warfare agent (CWA) degradation products by GC-ICPMS. PMID:17356819

  7. A review of nerve agent exposure for the critical care physician.

    PubMed

    Leikin, Jerrold B; Thomas, Richard G; Walter, Frank G; Klein, Raymond; Meislin, Harvey W

    2002-10-01

    Nerve agents are discussed. The article discusses their properties, routes of exposure, toxicodynamics, targets of toxicity, and treatment. It is concluded that a focused organized approach to the treatment of nerve agents is key to its successful management. PMID:12394966

  8. Chemical analysis of bleach and hydroxide-based solutions after decontamination of the chemical warfare agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX).

    PubMed

    Hopkins, F B; Gravett, M R; Self, A J; Wang, M; Chua, Hoe-Chee; Hoe-Chee, C; Lee, H S Nancy; Sim, N Lee Hoi; Jones, J T A; Timperley, C M; Riches, J R

    2014-08-01

    Detailed chemical analysis of solutions used to decontaminate chemical warfare agents can be used to support verification and forensic attribution. Decontamination solutions are amongst the most difficult matrices for chemical analysis because of their corrosive and potentially emulsion-based nature. Consequently, there are relatively few publications that report their detailed chemical analysis. This paper describes the application of modern analytical techniques to the analysis of decontamination solutions following decontamination of the chemical warfare agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX). We confirm the formation of N,N-diisopropylformamide and N,N-diisopropylamine following decontamination of VX with hypochlorite-based solution, whereas they were not detected in extracts of hydroxide-based decontamination solutions by nuclear magnetic resonance (NMR) spectroscopy or gas chromatography-mass spectrometry. We report the electron ionisation and chemical ionisation mass spectroscopic details, retention indices, and NMR spectra of N,N-diisopropylformamide and N,N-diisopropylamine, as well as analytical methods suitable for their analysis and identification in solvent extracts and decontamination residues. PMID:24633585

  9. Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection.

    PubMed

    Hodgins, Sean M; Kasten, Shane A; Harrison, Joshua; Otto, Tamara C; Oliver, Zeke P; Rezk, Peter; Reeves, Tony E; Chilukuri, Nageswararao; Cerasoli, Douglas M

    2013-03-25

    Human paraoxonase-1 (HuPON1) has been proposed as a catalytic bioscavenger of organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poisoning using two different paradigms. First, recombinant HuPON1 purified from cabbage loopers (iPON1; Trichoplusia ni) was administered to guinea pigs, followed by exposure to at least 2 times the median lethal dose (LD(50)) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic metabolite of the OP pesticide chlorpyrifos. In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then exposed to sequential doses of GD, VX, or (as reported previously) diazoxon, the toxic metabolite of the OP pesticide diazinon. In both animal models, the exogenously added HuPON1 protected animals against otherwise lethal doses of the OP pesticides but not against the nerve agents. Together, the results support prior modeling and in vitro activity data which suggest that wild-type HuPON1 does not have sufficient catalytic activity to provide in vivo protection against nerve agents. PMID:23123254

  10. Determination of threshold adverse effect doses of percutaneous VX exposure in African green monkeys.

    PubMed

    Genovese, Raymond F; Benton, Bernard J; Oubre, John L; Byers, Christopher E; Jakubowski, E Michael; Mioduszewski, Robert J; Settle, Timothy J; Steinbach, Thomas J

    2011-01-11

    Percutaneous exposure to the chemical warfare nerve agent VX was evaluated in African green monkeys (n=9). Doses of VX (7.5-100 μg/kg) were applied to the skin for 60 min and residual agent was quantified (before decontamination) to estimate the absorbed dose. Monkeys were evaluated for the presence or absence of clinical signs of toxicity and blood was sampled periodically (30 min--12 weeks) following exposure to measure the degree of circulating acetylcholinesterase (AChE) inhibition. Monkeys were also evaluated for behavioral changes from VX exposure using a serial probe recognition (SPR) task. The lowest observable adverse effect level (LOAEL) for the production of major clinical signs was determined to be 42.22 μg/kg (absorbed dose estimate=17.36 μg/kg) and the LOAEL for AChE inhibition was 13.33 μg/kg (absorbed dose estimate=6.53 μg/kg). Behavioral performance was unaffected at doses that, while producing substantial AChE inhibition, did not produce clinical signs. VX represents a substantial threat as a contact hazard and these results complement previous studies using the percutaneous route of exposure with VX and extend the findings to a non-human primate species. PMID:20887765

  11. Hairy skin exposure to VX in vitro: effectiveness of delayed decontamination.

    PubMed

    Rolland, P; Bolzinger, M-A; Cruz, C; Josse, D; Briançon, S

    2013-02-01

    The chemical warfare agents such as VX represent a threat for both military and civilians, which involves an immediate need of effective decontamination systems. Since human scalp is usually unprotected compared to other body regions covered with clothes, it could be a preferential site of exposure in case of terrorist acts. The purpose of this study was to determine if skin decontamination could be efficient when performed more than 1h after exposure. In addition, the impact of hairs in skin contamination was investigated. By using in vitro skin models, we demonstrated that about 75% of the applied quantity of VX was recovered on the skin surface 2h after skin exposition, which means that it is worth decontaminating even if contamination occurred 2h before. The stratum corneum reservoir for VX was quickly established and persistent. In addition, the presence of hairs modified the percutaneous penetration of the nerve agent by binding of VX to hairs. Hair shaft has thus to be taken into account in the decontamination process. Reactive Skin Decontamination Lotion (RSDL) and Fuller's Earth (FE) were active in the skin decontamination 45min post-exposure, but RSDL was more efficient in reducing the amount of VX either in the skin or in the hair. PMID:22926045

  12. Multidimensional conducting polymer nanotubes for ultrasensitive chemical nerve agent sensing.

    PubMed

    Kwon, Oh Seok; Park, Seon Joo; Lee, Jun Seop; Park, Eunyu; Kim, Taejoon; Park, Hyun-Woo; You, Sun Ah; Yoon, Hyeonseok; Jang, Jyongsik

    2012-06-13

    Tailoring the morphology of materials in the nanometer regime is vital to realizing enhanced device performance. Here, we demonstrate flexible nerve agent sensors, based on hydroxylated poly(3,4-ethylenedioxythiophene) (PEDOT) nanotubes (HPNTs) with surface substructures such as nanonodules (NNs) and nanorods (NRs). The surface substructures can be grown on a nanofiber surface by controlling critical synthetic conditions during vapor deposition polymerization (VDP) on the polymer nanotemplate, leading to the formation of multidimensional conducting polymer nanostructures. Hydroxyl groups are found to interact with the nerve agents. Representatively, the sensing response of dimethyl methylphosphonate (DMMP) as a simulant for sarin is highly sensitive and reversible from the aligned nanotubes. The minimum detection limit is as low as 10 ppt. Additionally, the sensor had excellent mechanical bendability and durability. PMID:22545863

  13. Dynamic Contrast-Enhanced MRI Using a Macromolecular MR Contrast Agent (P792): Evaluation of Antivascular Drug Effect in a Rabbit VX2 Liver Tumor Model

    PubMed Central

    Park, Hee Sun; Lee, Jeong Min; Kim, Young Il; Woo, Sungmin; Yoon, Jung Hwan; Choi, Jin-Young; Choi, Byung Ihn

    2015-01-01

    Objective To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. Materials and Methods This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (Ktrans) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. Results P792 group showed a more prominent decrease in Ktrans and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. Conclusion Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent. PMID:26357497

  14. Comparison of latex body paint with wetted gauze wipes for sampling the chemical warfare agents VX and sulfur mustard from common indoor surfaces.

    PubMed

    Hernon-Kenny, Laura A; Behringer, Deborah L; Crenshaw, Michael D

    2016-05-01

    Comparison of solvent-wetted gauze with body paint, a peelable surface sampling media, for the sampling of the chemical warfare agents VX and sulfur mustard from nine surfaces was performed. The nine surfaces sampled are those typical of interior public venues and include smooth, rough, porous, and non-porous surfaces. Overall, solvent-wetted gauze (wipes) performed better for the recovery of VX from non-porous surfaces while body paint (BP) performed better for the porous surfaces. The average percent VX recoveries using wipes and BP, respectively, are: finished wood flooring, 86.2%, 71.4%; escalator handrail, 47.3%, 26.7%; stainless steel, 80.5%, 56.1%; glazed ceramic tile, 81.8%, 44.9%; ceiling tile, 1.77%, 13.1%; painted drywall 7.83%, 21.1%; smooth cement, 0.64%, 10.3%; upholstery fabric, 24.6%, 23.1%; unfinished wood flooring, 9.37%, 13.1%. Solvent-wetted gauze performed better for the recovery of sulfur mustard from three of the relatively non-porous surfaces while body paint performed better for the more porous surfaces. The average percent sulfur mustard recoveries using wipes and BP, respectively, are: finished wood flooring, 30.2%, 2.97%; escalator handrail, 4.40%, 4.09%; stainless steel, 21.2%, 3.30%; glazed ceramic tile, 49.7%, 16.7%; ceiling tile, 0.33%, 11.1%; painted drywall 2.05%, 10.6%; smooth cement, 1.20%, 35.2%; upholstery fabric, 7.63%, 6.03%; unfinished wood flooring, 0.90%, 1.74%. PMID:26990562

  15. Ionization mechanism of the ambient pressure pyroelectric ion source (APPIS) and its applications to chemical nerve agent detection.

    PubMed

    Neidholdt, Evan L; Beauchamp, J L

    2009-11-01

    We present studies of the ionization mechanism operative in the ambient pressure pyroelectric ionization source (APPIS), along with applications that include detection of simulants for chemical nerve agents. It is found that ionization by APPIS occurs in the gas-phase. As the crystal is thermally cycled over a narrow temperature range, electrical discharges near the surface of the crystal produce energetic species which, through reactions with atmospheric molecules, result in reactant ions such as protonated water clusters or clusters of hydroxide and water. Reactant ions can be observed directly in the mass spectrometer. These go on to react with trace neutrals via proton transfer reactions to produce the ions observed in mass spectra, which are usually singly protonated or deprotonated species. Further implicating gas-phase ionization, observed product distributions are highly dependent on the composition of ambient gases, especially the concentration of water vapor and oxygen surrounding the source. For example, basic species such as triethylamine are observed as singly protonated cations at a water partial pressure of 10 torr. At a water pressure of 4 torr, reactive oxygen species are formed and lead to observation of protonated amine oxides. The ability of the APPIS source to detect basic molecules with high proton affinities makes it highly suited for the detection of chemical nerve agents. We demonstrate this application using simulants corresponding to VX and GA (Tabun). With the present source configuration pyridine is detected readily at a concentration of 4 ppm, indicating ultimate sensitivity in the high ppb range. PMID:19682922

  16. Chemical approaches for detection and destruction of nerve agents.

    PubMed

    Ajami, Dariush; Rebek, Julius

    2013-06-28

    Since the introduction of organophosphorus (OP) compounds as nerve agents and pesticides, methods of dealing with their toxicity to humans have been intensely researched. There are studies on sensing, pretreatments, prophylactics, antidotes and therapies. There is some overlap in all of these endeavors because they have to deal with the reactivity of the phosphorus atom in various contexts. The contexts range from large spaces, the thinly spread vapors in the air, to very small spaces in the active sites of enzymes - acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) - that have reacted with the OP agent. PMID:23604461

  17. Detoxification of organophosphate nerve agents by bacterial phosphotriesterase

    SciTech Connect

    Ghanem, Eman; Raushel, Frank M. . E-mail: raushel@tamu.edu

    2005-09-01

    Organophosphates have been widely used as insecticides and chemical warfare agents. The health risks associated with these agents have necessitated the need for better detoxification and bioremediation tools. Bacterial enzymes capable of hydrolyzing the lethal organophosphate nerve agents are of special interest. Phosphotriesterase (PTE) isolated from the soil bacteria Pseudomonas diminuta displays a significant rate enhancement and substrate promiscuity for the hydrolysis of organophosphate triesters. Directed evolution and rational redesign of the active site of PTE have led to the identification of new variants with enhanced catalytic efficiency and stereoselectivity toward the hydrolysis of organophosphate neurotoxins. PTE has been utilized to protect against organophosphate poisoning in vivo. Biotechnological applications of PTE for detection and decontamination of insecticides and chemical warfare agents are developing into useful tools. In this review, the catalytic properties and potential applications of this remarkable enzyme are discussed.

  18. Crystal structures of brain group-VIII phospholipase A2 in nonaged complexes with the organophosphorus nerve agents soman and sarin.

    PubMed

    Epstein, Todd M; Samanta, Uttamkumar; Kirby, Stephen D; Cerasoli, Douglas M; Bahnson, Brian J

    2009-04-21

    Insecticide and nerve agent organophosphorus (OP) compounds are potent inhibitors of the serine hydrolase superfamily of enzymes. Nerve agents, such as sarin, soman, tabun, and VX exert their toxicity by inhibiting human acetycholinesterase at nerve synapses. Following the initial phosphonylation of the active site serine, the enzyme may reactivate spontaneously or through reaction with an appropriate nucleophilic oxime. Alternatively, the enzyme-nerve agent complex can undergo a secondary process, called "aging", which dealkylates the nerve agent adduct and results in a product that is highly resistant to reactivation by any known means. Here we report the structures of paraoxon, soman, and sarin complexes of group-VIII phospholipase A2 from bovine brain. In each case, the crystal structures indicate a nonaged adduct; a stereoselective preference for binding of the P(S)C(S) isomer of soman and the P(S) isomer of sarin was also noted. The stability of the nonaged complexes was corroborated by trypsin digest and electrospray ionization mass spectrometry, which indicates nonaged complexes are formed with diisopropylfluorophosphate, soman, and sarin. The P(S) stereoselectivity for reaction with sarin was confirmed by reaction of racemic sarin, followed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate each stereoisomer. The P(S) stereoisomers of soman and sarin are known to be the more toxic stereoisomers, as they react preferentially to inhibit human acetylcholinesterase. The results obtained for nonaged complexes of group-VIII phospholipase A2 are compared to those obtained for other serine hydrolases and discussed to partly explain determinants of OP aging. Furthermore, structural insights can now be exploited to engineer variant versions of this enzyme with enhanced nerve agent binding and hydrolysis functions. PMID:19271773

  19. Kromoscopy for detection of chemical warfare agents

    NASA Astrophysics Data System (ADS)

    Ewing, Kenneth J.; Sanghera, Jas; Aggarwal, Ishwar D.; Block, Myron J.

    2004-12-01

    The ability of a Kromoscope to discriminate between chemical warfare agent simulants and toxic industrial chemicals is evaluated. The Kromoscope response to the simulants DMMP and DIMP is compared to a pesticide (diazanon) and cyclopentanol. The response of a mid-infrared Kromoscope to the nerve agents VX and GB and the stimulant DF are calculated.

  20. New Chemically Functionalized Nanomaterials for Electrical Nerve Agents Sensors

    NASA Astrophysics Data System (ADS)

    Simonato, Jean-Pierre; Clavaguera, Simon; Carella, Alexandre; Delalande, Michael; Raoul, Nicolas; Lenfant, Stephane; Vuillaume, Dominique; Dubois, Emmanuel

    2011-08-01

    A chemical receptor specific to traces of organophosphorus nerve agents (OPs) has been synthesized and grafted to carbon nanotubes and silicon nanowires in order to make electrical sensors. Our results show that it is possible to detect efficiently sub-ppm traces of OPs with excellent selectivity notably with the use of silicon nanowires by monitoring the Drain-Source current of the SiNW-FET at an optimum back Gate voltage as a function of time. First developments of a prototype have also been realized.

  1. Hydrolysis of VX on concrete: rate of degradation by direct surface interrogation using an ion trap secondary ion mass spectrometer.

    PubMed

    Groenewold, Gary S; Williams, John M; Appelhans, Anthony D; Gresham, Garold L; Olson, John E; Jeffery, Mark T; Rowland, Brad

    2002-11-15

    The nerve agent VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate) is lethal at very low levels of exposure, which can occur by dermal contact with contaminated surfaces. Hence, behavior of VX in contact with common urban or industrial surfaces is a subject of acute interest. In the present study, VX was found to undergo complete degradation when in contact with concrete surfaces. The degradation was directly interrogated at submonolayer concentrations by periodically performing secondary ion mass spectrometry (SIMS) analyses after exposure of the concrete to VX. The abundance of the [VX + H]+ ion in the SIMS spectra was observed to decrease in an exponential fashion, consistent with first-order or pseudo-first-order behavior. This phenomenon enabled the rate constant to be determined at 0.005 min(-1) at 25 degrees C, which corresponds to a half-life of about 3 h on the concrete surface. The decrease in [VX + H]+ was accompanied by an increase in the abundance of the principal degradation product diisopropylaminoethanethiol (DESH), which arises by cleavage of the P-S bond. Degradation to form DESH is accompanied by the formation of ethyl methylphosphonic acid, which is observable only in the negative ion spectrum. A second degradation product was also implicated, which corresponded to a diisopropylvinylamine isomer (perhaps N,N-diisopropyl aziridinium) that arose via cleavage of the S-C bond. No evidence was observed for the formation of the toxic S-2-diisopropylaminoethyl methylphosphonothioic acid. The degradation rate constants were measured at four different temperatures (24-50 degrees C), which resulted in a linear Arrhenius relationship and an activation energy of 52 kJ mol(-1). This value agrees with previous values observed for VX hydrolysis in alkaline solutions, which suggests that the degradation of submonolayer VX is dominated by alkaline hydrolysis within the adventitious water film on the concrete surface. PMID:12487301

  2. Hydrolysis of VX on Concrete: Rate of Degradation by Direct Surface Interrogation using an Ion Trap Secondary Ion Mass Spectrometer

    SciTech Connect

    Groenewold, Gary Steven; Appelhans, Anthony David; Gresham, Garold Linn; Olson, John Eric; Rowland, B.; Williams, j.; Jeffery, M. T.

    2002-09-01

    The nerve agent VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate) is lethal at very low levels of exposure, which can occur by dermal contact with contaminated surfaces. Hence, behavior of VX in contact with common urban or industrial surfaces is a subject of acute interest. In the present study, VX was found to undergo complete degradation when in contact with concrete surfaces. The degradation was directly interrogated at submonolayer concentrations by periodically performing secondary ion mass spectrometry (SIMS) analyses after exposure of the concrete to VX. The abundance of the [VX + H]+ ion in the SIMS spectra was observed to decrease in an exponential fashion, consistent with first-order or pseudo-first-order behavior. This phenomenon enabled the rate constant to be determined at 0.005 min-1 at 25 C, which corresponds to a half-life of about 3 h on the concrete surface. The decrease in [VX + H]+ was accompanied by an increase in the abundance of the principal degradation product diisopropylaminoethanethiol (DESH), which arises by cleavage of the P-S bond. Degradation to form DESH is accompanied by the formation of ethyl methylphosphonic acid, which is observable only in the negative ion spectrum. A second degradation product was also implicated, which corresponded to a diisopropylvinylamine isomer (perhaps N,N-diisopropyl aziridinium) that arose via cleavage of the S-C bond. No evidence was observed for the formation of the toxic S-2-diisopropylaminoethyl methylphosphonothioic acid. The degradation rate constants were measured at four different temperatures (24-50 C), which resulted in a linear Arrhenius relationship and an activation energy of 52 kJ mol-1. This value agrees with previous values observed for VX hydrolysis in alkaline solutions, which suggests that the degradation of submonolayer VX is dominated by alkaline hydrolysis within the adventitious water film on the concrete surface.

  3. Recent advances toward a fiber optic sensor for nerve agent

    NASA Astrophysics Data System (ADS)

    Beshay, Manal; Cordero, Steven R.; Mukamal, Harold; Ruiz, David; Lieberman, Robert A.

    2008-04-01

    We report advances made on the development of a fiber optic nerve agent sensor having its entire length as the sensing element. Upon exposure to sarin gas or its simulant, diisopropyl fluorophosphate, the cladding changes color resulting in an alteration of the light intensity throughput. The optical fiber is multimode and consists of a fused-silica core and a nerve agent sensitive cladding. The absorption characteristics of the cladding affect the fiber's spectral attenuation and limit the length of light guiding fiber that can be deployed continuously. The absorption of the cladding is also dependent on the sensor formulation, which in turn influences the sensitivity of the fiber. In this paper, data related to the trade-off of sensitivity, spectral attenuation, and length of fiber challenged will be reported. The fiber is mass produced using a conventional fiber optic draw tower. This technology could be used to protect human resources and buildings from dangerous chemical attacks, particularly when large areas or perimeters must be covered. It may also be used passively to determine how well such areas have been decontaminated.

  4. Quantification of nerve agent biomarkers in human serum and urine.

    PubMed

    Røen, Bent Tore; Sellevåg, Stig Rune; Lundanes, Elsa

    2014-12-01

    A novel method for rapid and sensitive quantification of the nerve agent metabolites ethyl, isopropyl, isobutyl, cyclohexyl, and pinacolyl methylphosphonic acid has been established by combining salting-out assisted liquid-liquid extraction (SALLE) and online solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS). The procedure allows confirmation of nerve agent exposure within 30 min from receiving a sample, with very low detection limits for the biomarkers of 0.04-0.12 ng/mL. Sample preparation by SALLE was performed in less than 10 min, with a common procedure for both serum and urine. Analyte recoveries of 70-100% were obtained using tetrahydrofuran as extraction solvent and Na2SO4 to achieve phase separation. After SALLE, selective analyte retention was obtained on a ZrO2 column by Lewis acid-base and hydrophilic interactions with acetonitrile/1% CH3COOH (82/18) as the loading mobile phase. The phosphonic acids were backflush-desorbed onto a polymeric zwitterionic column at pH 9.8 and separated by hydrophilic interaction liquid chromatography. The method was linear (R(2) ≥ 0.995) from the limits of quantification to 50 ng/mL, and the within- and between-assay repeatability at 20 ng/mL were below 5% and 10% relative standard deviation, respectively. PMID:25371246

  5. 'Dilute-and-shoot' RSLC-MS-MS method for fast detection of nerve and vesicant chemical warfare agent metabolites in urine.

    PubMed

    Rodin, Igor; Braun, Arcady; Stavrianidi, Andrey; Baygildiev, Timur; Shpigun, Oleg; Oreshkin, Dmitry; Rybalchenko, Igor

    2015-01-01

    A sensitive screening method based on fast liquid chromatography tandem mass-spectrometry (RSLC-MS-MS) has shown the feasibility of separation and detection of low concentration β-lyase metabolites of sulfur mustard and of nerve agent phosphonic acids in urine. The analysis of these compounds is of interest because they are specific metabolites of the chemical warfare agents (CWAs), sulfur mustard (HD), sarin (GB), soman (GD), VX and Russian VX (RVX). The 'dilute-and-shoot' RSLC-MS-MS method provides a sensitive and direct approach for determining CWA exposure in non-extracted non-derivatized samples from urine. Chromatographic separation of the metabolites was achieved using a reverse phase column with gradient mobile phases consisting of 0.5% formic acid in water and acetonitrile. Identification and quantification of species were achieved using electrospray ionization-tandem mass-spectrometry monitoring two precursor-to-product ion transitions for each compound. The method demonstrates linearity over at least two orders of magnitude and had detection limits of 0.5 ng/mL in urine. PMID:25326204

  6. Timing of decontamination and treatment in case of percutaneous VX poisoning: a mini review.

    PubMed

    Joosen, Marloes J A; van der Schans, Marcel J; Kuijpers, Willem C; van Helden, Herman P M; Noort, Daan

    2013-03-25

    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 injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4× LD50 VX in IPA. The results showed that RSDL decontamination at 15 min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90 min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment. PMID:23085122

  7. Early quantification of the therapeutic efficacy of the vascular disrupting agent, CKD-516, using dynamic contrast-enhanced ultrasonography in rabbit VX2 liver tumors

    PubMed Central

    2014-01-01

    Purpose: To evaluate the usefulness of dynamic contrast-enhanced ultrasonography (DCE-US) in the early quantification of hemodynamic change following administration of the vascular disrupting agent (VDA) CKD-516 using a rabbit VX2 liver tumor model. Methods: This study was approved by our institutional animal care and use committee. Eight VX2 liver-tumor-bearing rabbits were treated with intravenous CKD-516, and all underwent DCE-US using SonoVue before and again 2, 4, 6, and 24 hours following their treatment. The tumor perfusion parameters were obtained from the time-intensity curve of the DCE-US data. Repeated measures analysis of variance was performed to assess any significant change in tumor perfusion over time. Relative changes in the DCE-US parameters between the baseline and follow-up assessments were correlated with the relative changes in tumor size over the course of seven days using Pearson correlation. Results: CKD-516 treatment resulted in significant changes in the DCE-US parameters, including the peak intensity, total area under the time-intensity curve (AUCtotal), and AUC during wash-out (AUCout) over time (P<0.05). Pairwise comparison tests revealed that the AUCtotal and AUC during wash-in (AUCin) seen on the two-hour follow-up were significantly lower than the baseline values (P<0.05). However, none of early changes in the DCE-US parameters until 24-hour follow-up showed a significant correlation with the relative changes in tumor size during seven days after CKD-516 treatment. Conclusion: Our results suggest that a novel VDA (CKD-516) can cause disruption of tumor perfusion as early as two hours after treatment and that the therapeutic effect of CKD-516 treatment can be effectively quantified using DCE-US. PMID:24936491

  8. Comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in the rabbit

    SciTech Connect

    Koplovitz, I.; Stewart, J.R.

    1994-12-31

    This study compared the efficacy of H16 and 2-PAM against nerve agent (soman tabun sarin and VX) -induced lethality in the atropinesterase-free rabbits pretreated with vehicle (controls) or pyridostigmine. Treatment was administered at signs or 2 min after agent challenge and consisted ofoxime (l00umol/lkg) + atropine 13 mg(kg) (alone or together with diazepam). Twenty-four-h LD50 values were calculated for soman- and tabun-intoxicated animals, whereas 24-h survival was noted in animals given 10 LD50s of sarin or VX. In pyridostigmine and control rabbits intoxicated with soman and treated with oxime + atropine (alone or together with diazepam), HI6 was 35 times more effective than 2-PAM. In contrast 1116 was less effective than 2-PAM against tabun poisoning. In pyridostigmine-pretreated animals exposed to tabun, efficacy was increased more than 3-fold when compare to tabun-challenged animals treated with atropine + H16 alone. Both oximes were highly effective against satin and VX. These findings suggest that Hifi could replace 2-PAM as therapy for nerve agent poisoning because it is superior to 2-PAM against soman, and when used in pyridostigmine-pretreated animals it affords excellent protection against all four nerve agents when used in combination with atropine (alone or together with diazepam) therapy.

  9. Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents.

    PubMed

    Trovaslet-Leroy, Marie; Musilova, Lucie; Renault, Frédérique; Brazzolotto, Xavier; Misik, Jan; Novotny, Ladislav; Froment, Marie-Thérèse; Gillon, Emilie; Loiodice, Mélanie; Verdier, Laurent; Masson, Patrick; Rochu, Daniel; Jun, Daniel; Nachon, Florian

    2011-09-25

    Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we

  10. Screening of carbonaceous nanoporous materials for capture of nerve agents.

    PubMed

    Kowalczyk, Piotr; Gauden, Piotr A; Terzyk, Artur P; Neimark, Alexander V

    2013-01-01

    A strategy for combined experimental and computational screening of candidate carbonaceous materials for capturing highly volatile nerve agents at ambient temperature using physisorption. Based on theoretical calculations of Henry constants and zero-coverage adsorption enthalpies for sarin and DMMP (its common stimulant) adsorbed in model slit-shaped carbon pores at 298 K, we found the following. Slit-shaped carbon pores with pore width ~0.5 nm are optimal for agent adsorption due to strong confinement of adsorbed molecules. Agent adsorption enthalpy at zero coverage computed for optimal pore width is very high and reaches ~83 kJ mol(-1). Widening of pore width above ~1 nm results in a significant decrease of the Henry constant and zero-coverage adsorption enthalpy (~44 kJ mol(-1)). Polydispersity of studied candidate carbonaceous materials strongly affects adsorption capacity for DMMP under the operating conditions. The optimal carbonaceous adsorbent, pitch-based P7 activated carbon fiber, adsorbed ~100 μg g(-1) DMMP at 0.03 μg m(-3). Commercial Norit activated carbon adsorbed only ~20 μg g(-1) DMMP at 0.03 μg m(-3). Surprisingly, a small shift of the pore size distribution towards wider micropores has a great impact on agent adsorption. Because the adsorption enthalpies computed at zero coverage weakly dependent on pore size, the heat released during agent adsorption is similar for all studied candidate adsorbents (i.e.~55-60 kJ mol(-1)). PMID:23165364

  11. [The nerve agent sarin: history, clinical manifestations, and treatment].

    PubMed

    Yanagisawa, Nobuo

    2014-05-01

    Organic phosphate pesticides were used worldwide after World War II and experiences on poisoning and treatment have been accumulated. An organic phosphate "nerve agent" Sarin was used in two terrorist attacks in Japan in the 1990s. Sarin effects on humans were well documented in these two incidents. Sarin gas inhalation caused instantaneous death by respiratory arrest in several victims in Matsumoto. Severely injured victims presenting with coma and generalized convulsion were resuscitated and recovered rapidly without sequelae. Miosis and blurred-dark vision, ocular pain, copious secretions from respiratory and gastrointestinal tract (muscarinic effects), and headache were common in severely to slightly affected victims. Plasma cholinesterase (ChE) activity decreased in parallel with the severity of signs and symptoms in victims. Oximes, atropine sulphate, diazepam, and ample intravenous infusion were effective treatments. Follow-up examinations on victims were conducted up to 10 years in Matsumoto, and 5 years in Tokyo. No neurological sequelae or abnormalities were observed after 1 year, except for a few EEG abnormalities or delay in sensory nerve conduction velocity. Posttraumatic stress disorder (PTSD) was observed in several of the victims in the 5-year follow up, irrespective of the severity of poisoning at Matsumoto. Psychological symptoms continue in victims of both incidents. PMID:24807372

  12. Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs.

    PubMed

    Nambiar, Madhusoodana P; Wright, Benjamin S; Rezk, Peter E; Smith, Kelvin B; Gordon, Richard K; Moran, Theodore S; Richards, Shannon M; Sciuto, Alfred M

    2006-01-01

    Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the

  13. Multi-encoded rugate porous silicon as nerve agents sensors.

    PubMed

    Jang, Seunghyun; Kim, Jihoon; Koh, Youngdae; Ko, Young Chun; Woo, Hee-Gweon; Sohn, Honglae

    2007-11-01

    The nanostructured rugate porous silicons (PSi) containing multiple photonic band gaps have been generated by an electrochemical etching through applying a composite waveform summed three computer-generated pseudo-sinusoidal current waveforms. They exhibit three sharp photonic band gaps in the optical reflectivity spectrum, corresponding to the each of the sine components varied from 0.42, 0.36, and 0.30 Hz, with a spacing of 0.06 Hz between each sine component. The sensing experiments using multi-encoded rugate PSi for the detection of nerve agents such as triethyl phosphate (TEP), diethyl chlorophosphate (DCP), dimethyl methylphosphonate (DMMP), and diethyl ethylphosphonate (DEEP) have been achieved. Capillary condensation in the pores causes the reflectivity of rugate PSi to shift to longer wavelengths due to an increase in refractive indices of the porous medium. PMID:18047116

  14. Field deployable EEG monitor for nerve agent casualties.

    PubMed

    McDonnall, Daniel; Hiatt, Scott; Yatsenko, Dimitri; Guillory, K Shane

    2009-01-01

    Early recognition and aggressive management of seizure activity is important in the treatment of patients with nerve agent exposure. However, these patients can experience non-convulsive seizures that are difficult to identify without EEG monitoring. In this paper, we discuss the development and testing of a low-cost, field-deployable device that records and displays patient EEG trends over time. The device is optimized for early levels of care for military and mass casualty patients until they can be relocated to medical facilities with more comprehensive monitoring. The device also records pulse oximetry and acceleration information, and patient data are available for later analysis and improvement of treatment protocols. PMID:19964118

  15. Enhanced Stability of Blood Matrices Using a Dried Sample Spot Assay to Measure Human Butyrylcholinesterase Activity and Nerve Agent Adducts

    PubMed Central

    Perez, Jonas W.; Pantazides, Brooke G.; Watson, Caroline M.; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2015-01-01

    Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intra-spot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and >90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intra-spot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10-times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intra-spot variability without the need to control for initial sample volume, and enhances analyte stability. PMID:25955132

  16. Behavioral efficacy of diazepam against nerve agent exposure in rhesus monkeys. (Reannouncement with new availability information)

    SciTech Connect

    Castro, C.A.; Larsen, T.; Finger, A.V.; Solana, R.P.; McMaster, S.B.

    1991-12-31

    The possibility that nerve agents will be used on the battlefield is real. The traditional therapy against nerve agent exposure consists of pyridostigmine pretreatment and atropine-pralidoxime chloride therapy administered after nerve agent exposure. This therapy regimen is extremely effective in preventing mortality in laboratory animals exposed to multilethal concentrations of nerve agent, yet these animals often display convulsions, brain damage, and behavioral incapacitation. We report here that the addition of diazepam to the traditional therapy for nerve agent (soman) exposure not only decreases the incidence of convulsions, but also attenuates the cognitive impairments of rhesus monkeys trained on a Serial Probe Recognition (SPR) task. Monkeys which received diazepam treatment required only 6 days before their performance on the SPR task returned to presoman exposure levels, compared to nondiazepamtreated monkeys which required 15 days. Moreover, only 1 out of the 5 monkeys which received diazepain treatment suffered tonic-clonic convulsions; in contrast all 5 monkeys which did not receive diazepam treatment experienced severe convulsive episodes. These results suggest that diazepam would be an excellent adjunct to traditional nerve agent therapy to facilitate behavioral recovery from nerve agent intoxication that might be encountered by US military personnel on the battlefield or accidental organophosphate poisoning encountered in industrial or agricultural accidents. Serial probe recognition task, diazepam, nerve agents, soman convulsions, rhesus monkeys, cognition, organophosphate.

  17. Cholinergic symptoms due to nerve agent attack: a strategy for management.

    PubMed

    Schecter, William P

    2004-09-01

    This article provides a brief history of nerve agent development and use and discusses the pharmacology, symptoms, signs, and treatment of nerve agent exposure. In addition, this article discusses the challenges of mass-casualty triage, decontamination, resuscitation, and intensive care. PMID:15325720

  18. Novel reversible and selective nerve agent simulant detection in conjunction with superoxide "turn-on" probing.

    PubMed

    Jang, Yoon Jeong; Murale, Dhiraj P; Churchill, David G

    2014-04-01

    Herein, we present fluorescein as a reversible fluorescent sensor for nerve agent simulants diethylchlorophosphate (DCP), diethyl methylphosphonate (DEMP), and diethyl cyanophosphonate (DECP). The superoxide allows for an "off-on" mechanism to regenerate fluorescein. The order of decrease in fluorescence intensity for nerve agent simulants is DCP > DEMP ≫ DECP. PMID:24558644

  19. Detection of VX contamination in soil through solid-phase microextraction sampling and gas chromatography/mass spectrometry of the VX degradation product bis(diisopropylaminoethyl)disulfide.

    PubMed

    Hook, Gary L; Kimm, Gregory; Koch, David; Savage, Paul B; Ding, Bangwei; Smith, Philip A

    2003-04-11

    A solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) sampling and analysis method was developed for bis(diisopropylaminoethyl)disulfide (a degradation product of the nerve agent VX) in soil. A 30-min sampling time with a polydimethylsiloxane-coated fiber and high temperature alkaline hydrolysis allowed detection with 1.0 microg of VX spiked per g of agricultural soil. The method was successfully used in the field with portable GC-MS instrumentation. This method is relatively rapid (less than 1 h), avoids the use of complex preparation steps, and enhances analyst safety through limited use of solvents and decontamination of the soil before sampling. PMID:12735457

  20. Differentiated NSC-34 cells as an in vitro cell model for VX.

    PubMed

    Kanjilal, Baishali; Keyser, Brian M; Andres, Devon K; Nealley, Eric; Benton, Betty; Melber, Ashley A; Andres, Jaclynn F; Letukas, Valerie A; Clark, Offie; Ray, Radharaman

    2014-10-01

    The US military has placed major emphasis on developing therapeutics against nerve agents (NA). Current efforts are hindered by the lack of effective in vitro cellular models to aid in the preliminary screening of potential candidate drugs/antidotes. The development of an in vitro cellular model to aid in discovering new NA therapeutics would be highly beneficial. In this regard, we have examined the response of a differentiated hybrid neuronal cell line, NSC-34, to the NA VX. VX-induced apoptosis of differentiated NSC-34 cells was measured by monitoring the changes in caspase-3 and caspase-9 activity post-exposure. Differentiated NSC-34 cells showed an increase in caspase-3 activity in a manner dependent on both time (17-23 h post-exposure) and dose (10-100 nM). The maximal increase in caspase-3 activity was found to be at 20-h post-exposure. Caspase-9 activity was also measured in response to VX and was found to be elevated at all concentrations (10-100 nM) tested. VX-induced cell death was also observed by utilizing annexin V/propidium iodide flow cytometry. Finally, VX-induced caspase-3 or -9 activities were reduced with the addition of pralidoxime (2-PAM), one of the current therapeutics used against NA toxicity, and dizocilpine (MK-801). Overall the data presented here show that differentiated NSC-34 cells are sensitive to VX-induced cell death and could be a viable in vitro cell model for screening NA candidate therapeutics. PMID:25045830

  1. Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig.

    PubMed

    Snider, Thomas H; Babin, Michael C; Jett, David A; Platoff, Gennady E; Yeung, David T

    2016-01-01

    Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl2. The 24-hr median lethal dose (LD50) for the four by intramuscular (IM) injection and the median effective dose (ED50) were determined. In the ED50 study, male guinea pigs clipped of hair received 2x LD50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED90) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 µmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl2. Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED90 < 149 µmol/kg against all three topical OPs tested. PMID:27432237

  2. Investigation of the persistence of nerve agent degradation analytes on surfaces through wipe sampling and detection with ultrahigh performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Willison, Stuart A

    2015-01-20

    The persistence of chemical warfare nerve agent degradation analytes on surfaces is important, from indicating the presence of nerve agent on a surface to guiding environmental restoration of a site after a release. Persistence was investigated for several chemical warfare nerve agent degradation analytes on indoor surfaces and presents an approach for wipe sampling of surfaces, followed by wipe extraction and liquid chromatography-tandem mass spectrometry detection. Commercially available wipe materials were investigated to determine optimal wipe recoveries. Tested surfaces included porous/permeable (vinyl tile, painted drywall, and wood) and largely nonporous/impermeable (laminate, galvanized steel, and glass) surfaces. Wipe extracts were analyzed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). UPLC provides a separation of targeted degradation analytes in addition to being nearly four times faster than high-performance liquid chromatography, allowing for greater throughput after a large-scale contamination incident and subsequent remediation events. Percent recoveries from nonporous/impermeable surfaces were 60-103% for isopropyl methylphosphonate (IMPA), GB degradate; 61-91% for ethyl methylphosphonate (EMPA), VX degradate; and 60-98% for pinacolyl methylphosphonate (PMPA), GD degradate. Recovery efficiencies for methyl phosphonate (MPA), nerve agent degradate, and ethylhydrogen dimethylphosphonate (EHDMAP), GA degradate, were lower, perhaps due to matrix effects. Diisopropyl methylphosphonate, GB impurity, was not recovered from surfaces. The resulting detection limits for wipe extracts were 0.065 ng/cm(2) for IMPA, 0.079 ng/cm(2) for MPA, 0.040 ng/cm(2) for EMPA, 0.078 ng/cm(2) for EHDMAP, and 0.013 ng/cm(2) for PMPA. The data indicate that laboratories may hold wipe samples for up to 30 days prior to analysis. Target analytes were observed to persist on surfaces for at least 6 weeks. PMID:25495198

  3. Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

    PubMed Central

    Hemmert, Andrew C.; Otto, Tamara C.; Chica, Roberto A.; Wierdl, Monika; Edwards, Jonathan S.; Lewis, Steven L.; Edwards, Carol C.; Tsurkan, Lyudmila; Cadieux, C. Linn; Kasten, Shane A.; Cashman, John R.; Mayo, Stephen L.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  4. Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.

    PubMed

    Hemmert, Andrew C; Otto, Tamara C; Chica, Roberto A; Wierdl, Monika; Edwards, Jonathan S; Lewis, Steven M; Lewis, Steven L; Edwards, Carol C; Tsurkan, Lyudmila; Cadieux, C Linn; Kasten, Shane A; Cashman, John R; Mayo, Stephen L; Potter, Philip M; Cerasoli, Douglas M; Redinbo, Matthew R

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  5. Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates.

    PubMed

    Chambers, Janice E; Meek, Edward C; Bennett, Joshua P; Bennett, W Shane; Chambers, Howard W; Leach, C Andrew; Pringle, Ronald B; Wills, Robert W

    2016-01-01

    Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures. PMID:26705700

  6. Flexible carbon nanotube sensors for nerve agent simulants

    NASA Astrophysics Data System (ADS)

    Cattanach, Kyle; Kulkarni, Rashmi D.; Kozlov, Mikhail; Manohar, Sanjeev K.

    2006-08-01

    Chemiresistor-based vapour sensors made from network films of single-walled carbon nanotube (SWNT) bundles on flexible plastic substrates (polyethylene terephthalate, PET) can be used to detect chemical warfare agent simulants for the nerve agents Sarin (diisopropyl methylphosphonate, DIMP) and Soman (dimethyl methylphosphonate, DMMP). Large, reproducible resistance changes (75-150%), are observed upon exposure to DIMP or DMMP vapours, and concentrations as low as 25 ppm can be detected. Robust sensor response to simulant vapours is observed even in the presence of large equilibrium concentrations of interferent vapours commonly found in battle-space environments, such as hexane, xylene and water (10 000 ppm each), suggesting that both DIMP and DMMP vapours are capable of selectively displacing other vapours from the walls of the SWNTs. Response to these interferent vapours can be effectively filtered out by using a 2 µm thick barrier film of the chemoselective polymer polyisobutylene (PIB) on the SWNT surface. These network films are composed of a 1-2 µm thick non-woven mesh of SWNT bundles (15-30 nm diameter), whose sensor response is qualitatively and quantitatively different from previous studies on individual SWNTs, or a network of individual SWNTs, suggesting that vapour sorption at interbundle sites could be playing an important role. This study also shows that the line patterning method used in device fabrication to obtain any desired pattern of films of SWNTs on flexible substrates can be used to rapidly screen simulants at high concentrations before developing more complicated sensor systems.

  7. Preparation and performance of a colorimetric biosensor using acetylcholinesterase and indoxylacetate for assay of nerve agents and drugs

    PubMed Central

    Vlcek, Vitezslav

    2014-01-01

    Different toxic compounds can target the cholinergic nervous system. Acetylcholinesterase (AChE; EC 3.1.1.7) is one of the most crucial components of the cholinergic nervous system and thus many of the toxins interact with this enzyme. As to inhibitors, nerve agents used as chemical warfare, some insecticides, and drugs influencing the cholinergic system are common examples of AChE inhibitors. Once inhibited by a neurotoxic compound, a serious cholinergic crisis can occur. On the other hand, sensitivity of AChE to the inhibition can be used for analytical purposes. In this study, a simple disposable biosensor with AChE as a recognition element was devised. AChE was immobilized onto a cellulose matrix and indoxylacetate was used as a chromogenic substrate. The enzyme reaction was assessed by the naked eye using arbitrary units and pyridostigmine, tacrine, paraoxon, carbofuran, soman and VX were assayed as selected inhibitors. A good stability of the biosensors was found, with no aging over a quarter of a year and minimal sensitivity to the interference of organic solvents. The limit of detection ranged from 10 to 100 nmol/L for the compounds tested with a sample volume of 40 µL. PMID:26109903

  8. Preparation and performance of a colorimetric biosensor using acetylcholinesterase and indoxylacetate for assay of nerve agents and drugs.

    PubMed

    Pohanka, Miroslav; Vlcek, Vitezslav

    2014-12-01

    Different toxic compounds can target the cholinergic nervous system. Acetylcholinesterase (AChE; EC 3.1.1.7) is one of the most crucial components of the cholinergic nervous system and thus many of the toxins interact with this enzyme. As to inhibitors, nerve agents used as chemical warfare, some insecticides, and drugs influencing the cholinergic system are common examples of AChE inhibitors. Once inhibited by a neurotoxic compound, a serious cholinergic crisis can occur. On the other hand, sensitivity of AChE to the inhibition can be used for analytical purposes. In this study, a simple disposable biosensor with AChE as a recognition element was devised. AChE was immobilized onto a cellulose matrix and indoxylacetate was used as a chromogenic substrate. The enzyme reaction was assessed by the naked eye using arbitrary units and pyridostigmine, tacrine, paraoxon, carbofuran, soman and VX were assayed as selected inhibitors. A good stability of the biosensors was found, with no aging over a quarter of a year and minimal sensitivity to the interference of organic solvents. The limit of detection ranged from 10 to 100 nmol/L for the compounds tested with a sample volume of 40 µL. PMID:26109903

  9. Detoxification of VX by Chloramine-B. Final report, August 1989-April 1992

    SciTech Connect

    Yang, Y.C.; Szafraniec, L.L.; Beaudry, W.T.; Ward, J.R.

    1993-07-01

    At ambient temperature, the nerve agent O-ethyl S-2(diisopropylamino)ethyl methylphosphonothiolate (VX), can be detoxified in an aqueous solution of Chloramine-B CAB, C6H5SQ2N(Cl)Na only in the presence of sufficient acid (pH 3). The thiolo sulfur is first attacked by the reactive species, benzene chlorosulfonamide, to form a chlorosulfonium ion intermediate followed by hydrolysis and substitution reactions with the sulfonamide anion at the P-S bond. These reactions produce strongly acidic products, which further accelerate the initial reaction. Consequently, one of the acidic hydrolysis products of VX, the toxic S-2-(diisopropylamino)ethyl methylphosphonothioic acid (EA 2192) reacts with CAB instantaneously. This acid-catalyzed mechanism is similar to that reported for bivalent sulfides; direct attack by active chlorine is considered insignificant. A neutral VX analog, O,S-diethyl methylphoshonothiolate, reacts with CAB rapidly in H20 with an initial pH of 8.9 but requires the addition of 0.006 N (H+) for the reaction to occur in D20. By comparison, bivalent sulfides are more reactive than the phosphonothiolates, in general, and can be rapidly oxidized in both H20 and D20, even at high pH values. Chloramine-B, VX, Bivalent sulfide, Benzenechlorosulfonamide, Thiolo sulfur, Phosphonothiolate.

  10. Task 89-07: Evaluation of the in vitro efficacy of candidate pretreatment and treatment (pt) compounds against vesicants and nerve agents. Final report, January 1990-January 1993

    SciTech Connect

    Hobson, D.W.; Blank, J.A.; Starner, R.A.

    1993-10-01

    MREF Task 89-07 encompassed four vesicant assays and four nerve agent assays. The four vesicant assays evaluated the candidate P and T compound solubility limitations, direct cytotoxic effects, efficacy against HD-induced cellular nicotinamide adenine dinucleotide (NAD+) depletion, and efficacy against HD-induced cytotoxicity. Normal human epidermal cells (NHEKs) were used to evaluate candidate PT compound efficacy against HD-induced NAD+ depletion, and peripheral blood mononuclear leukocytes (PBMC) were used in direct cytotoxicity and HD-induced cytotoxicity assays. The four nerve agent assays assessed candidate PT compound direct inhibitory effects on acetylcholinesterase (AChE) activity, candidate PT compound efficacy in reactivating Tabun (GA) - and O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-inhibited A ThE, and candidate PT compound efficacy in slowing the aging rate of Soman (GD) inhibited AChE. All nerve agent and vesicant assays with the exception of the direct cytotoxicity and HD-induced cytotoxicity assays were initially established under MREF Task 88-36. The direct cytotoxicity and HD-induced cytotoxicity assays were transitioned to the MREF from USAMRICD and validated for use in routine screening procedures, including the generation of control database values, under Task 89-07. Solubility data were obtained for 37 compounds submitted for evaluation in the vesicant assays. Thirty-five of these compounds were evaluated for direct cytotoxicity, and their effect against HD-induced cytotoxicity, while 13 compound is were evaluated for efficacy against HD-induced NAD+ depletion. AChE reactivation, ACHE aging, ACHE inhibition, In vitro, Cytotoxicity , Vesicant assays, Nerve ag.

  11. Cyclodextrines as functional agents for decontamination of the skin contaminated by nerve agents.

    PubMed

    Cabal, Jirí; Kuca, Kamil; Sevelová-Bartosová, Lucie; Dohnal, Vlastimil

    2004-01-01

    Three decontamination solutions of beta-cyclodextrines were prepared. Their abilities to decontamine rat skin contamined with nerve agent soman were tested. Decontamination efficacy of the tested cyclodextrine solutions was compared with the same decontamination means but without the cyclodextrines. The efficacy of tested decontaminants was evaluated by the assessment of the ID50 values. Two decontamination prescriptions with cyclodextrines (tetraborate buffer and tetraborate buffer with acetone) do not show significantly better decontamination efficacies in comparison with prescriptions without cyclodextrines. Only in case of aqueous solution of 2-aminoethanol the addition of beta-cyclodextrine resulted in significant increase (32%) in decontamination efficacy. PMID:15446361

  12. Analysis of nerve agents using capillary electrophoresis and laboratory-on-a-chip technology.

    PubMed

    Pumera, Martin

    2006-04-28

    The nerve agents belong among the most toxic compounds produced by human kind. While they have been used very sporadically until now, typically in local conflicts or by local terrorists groups, the global increase in terrorist activity in the recent years has generated tremendous demand for innovative tools capable of detecting nerve agents. Fast, sensitive and reliable detection of nerve agents in the field is very important issue in present days. Capillary electrophoresis (CE) offers great possibilities for sensitive detection of these harmful compounds as well as incorporation in mobile laboratory and it proved to have capability to detect nerve agent breakdown products in real environmental samples. Laboratory-on-a-chip format offers great possibilities to create portable, field deployable, rapidly responding and potentially disposable device, allowing security forces to make the important decision regarding the safety of civilians. This article overviews the conventional capillary electrophoretic and laboratory-on-a-chip techniques for analysis of degradation products of G-type and V-type nerve agents. It discusses diverse strategies of detection of different nerve agents breakdown products, which are corresponding to their parental nerve agents. It also overviews possibilities and challenges for analysis of the real samples. PMID:16530776

  13. Flexible carbon nanotube sensors for nerve agent simulants.

    PubMed

    Cattanach, Kyle; Kulkarni, Rashmi D; Kozlov, Mikhail; Manohar, Sanjeev K

    2006-08-28

    Chemiresistor-based vapour sensors made from network films of single-walled carbon nanotube (SWNT) bundles on flexible plastic substrates (polyethylene terephthalate, PET) can be used to detect chemical warfare agent simulants for the nerve agents Sarin (diisopropyl methylphosphonate, DIMP) and Soman (dimethyl methylphosphonate, DMMP). Large, reproducible resistance changes (75-150%), are observed upon exposure to DIMP or DMMP vapours, and concentrations as low as 25 ppm can be detected. Robust sensor response to simulant vapours is observed even in the presence of large equilibrium concentrations of interferent vapours commonly found in battle-space environments, such as hexane, xylene and water (10 000 ppm each), suggesting that both DIMP and DMMP vapours are capable of selectively displacing other vapours from the walls of the SWNTs. Response to these interferent vapours can be effectively filtered out by using a 2 µm thick barrier film of the chemoselective polymer polyisobutylene (PIB) on the SWNT surface. These network films are composed of a 1-2 µm thick non-woven mesh of SWNT bundles (15-30 nm diameter), whose sensor response is qualitatively and quantitatively different from previous studies on individual SWNTs, or a network of individual SWNTs, suggesting that vapour sorption at interbundle sites could be playing an important role. This study also shows that the line patterning method used in device fabrication to obtain any desired pattern of films of SWNTs on flexible substrates can be used to rapidly screen simulants at high concentrations before developing more complicated sensor systems. PMID:21727548

  14. Role of glutamatergic system in nerve agent intoxication

    SciTech Connect

    Blanchet, G.; Lallement, G.; Carpentier, P.; De Groot, D.; Bodjarian, N.

    1993-05-13

    Our recent studies concerning soman-induced seizures mechanisms and subsequent brain damage are reviewed. (1) Seizure activity was associated with transient increases of extracellular concentrations of acetylcholine (ACh) and with long-lasting releases of glutamate (Glu) in all limbic areas studied. (2) Preventive intraseptal application of atropine abolished the hippocampal increases of extracellular AChi and Glu indicating a key role of septum in triggering seizure activity. (3) Early increases of hippocampal AMPA receptor binding occurred before activation of NMDA receptors. (4) Pretreatment with NBQX, an antagonist of AMPA receptor, prevented convulsions and brain damage even without atropine. In the same conditions, no protection was afforded by TCP, a non-competitive antagonist of the NMDA receptor. (5) On the contrary, in the presence of pyridostigmine and atropine, TCP blocked the seizures induced by 2 x LD50 of soman. The anticonvulsant potency of TCP was particularly obvious when administered curatively. (6) Mossy fibers sprouting takes place in the supragranular-molecular layers of rat hippocampus long after brain injury associated with abnormal neuronal excitability. (7) Altogether, it appears that an AMPA component is involved in combination with cholinergic mechanisms in initiating seizures. A subsequent and long-lasting recruitment of NMDA receptors is then essential in sustaining the seizures. New anticonvulsant and neuroprotective approaches using Glu antagonists against nerve agents intoxication are discussed.

  15. Pyridostigmine used as a nerve agent pretreatment under wartime conditions. (Reannouncement with new availability information)

    SciTech Connect

    Keeler, J.R.; Hurst, C.G.; Dunn, M.A.

    1991-08-07

    During Operation Desert Storm there was a credible threat of chemical warfare even though there was never actual use of chemical agents. Intelligence reports indicated that the Iraqi chemical arsenal contained nerve, vesicant, and blood agents. Nerve agents are organophosphorus inhibitors of acetylcholinesterase, such as sarin and tabun. The vesicants are skin blistering compounds, such as mustards and arsenicals, while blood agents are the cyanides, inhibitors of cytochrome oxidase. The US Armed Force`s approach to the medical management of actual or anticipated nerve agent injuries employs a regimen that consists of pretreatment with pyridostigmine bromide tablets prior to nerve agent exposure followed by atropine citrate and pralidoxime chloride by autoinjector intramuscularly on actual exposure. Proper administration of this drug combination provides significantly increased survival after lethal exposures to nerve agents above that provided by atropine and pralidoxime therapy alone. The recent addition of pyridostigmine to the US therapeutic regimen for nerve agent poisoning was based on efficacy data in animals and safety studies in humans.

  16. Determination of nerve agent metabolites in human urine by isotope-dilution gas chromatography-tandem mass spectrometry after solid phase supported derivatization.

    PubMed

    Lin, Ying; Chen, Jia; Yan, Long; Guo, Lei; Wu, Bidong; Li, Chunzheng; Feng, Jianlin; Liu, Qin; Xie, Jianwei

    2014-08-01

    A simple and sensitive method has been developed and validated for determining ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA), isobutyl methylphosphonic acid (iBuMPA), and pinacolyl methylphosphonic acid (PMPA) in human urine using gas chromatography-tandem mass spectrometry (GC-MS/MS) coupled with solid phase derivatization (SPD). These four alkyl methylphosphonic acids (AMPAs) are specific hydrolysis products and biomarkers of exposure to classic organophosphorus (OP) nerve agents VX, sarin, RVX, and soman. The AMPAs in urine samples were directly derivatized with pentafluorobenzyl bromide on a solid support and then extracted by liquid-liquid extraction. The analytes were quantified with isotope-dilution by negative chemical ionization (NCI) GC-MS/MS in a selected reaction monitoring (SRM) mode. This method is highly sensitive, with the limits of detection of 0.02 ng/mL for each compound in a 0.2 mL sample of human urine, and an excellent linearity from 0.1 to 50 ng/mL. It is proven to be very suitable for the qualitative and quantitative analyses of degradation markers of OP nerve agents in biomedical samples. PMID:24633564

  17. Fluorescent discrimination between traces of chemical warfare agents and their mimics.

    PubMed

    Díaz de Greñu, Borja; Moreno, Daniel; Torroba, Tomás; Berg, Alexander; Gunnars, Johan; Nilsson, Tobias; Nyman, Rasmus; Persson, Milton; Pettersson, Johannes; Eklind, Ida; Wästerby, Pär

    2014-03-19

    An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds. PMID:24597942

  18. Chromo-fluorogenic BODIPY-complexes for selective detection of V-type nerve agent surrogates.

    PubMed

    Barba-Bon, Andrea; Costero, Ana María; Gil, Salvador; Sancenón, Félix; Martínez-Máñez, Ramón

    2014-11-11

    Two new Eu(3+) and Au(3+) BODIPY-complexes capable of chromo-fluorogenically detecting micromolar concentrations of V-type nerve agent surrogates by a simple displacement assay are described. PMID:25233370

  19. Chromogenic and fluorogenic detection of a nerve agent simulant with a rhodamine-deoxylactam based sensor.

    PubMed

    Wu, Xuanjun; Wu, Zhisheng; Han, Shoufa

    2011-11-01

    A chromogenic and fluorogenic detection of a nerve agent simulant was developed based on diethyl chlorophosphate triggered tandem phosphorylation and intramolecular cyclization of N-(rhodamine B)-deoxylactam-2-aminoethanol. PMID:21952323

  20. REMOTE BIOSENSOR FOR IN SITU MONITORING OF ORGANOPHOSPHATE NERVE AGENTS. (R823663)

    EPA Science Inventory

    A remote electrochemical biosensor for field monitoring of organophosphate nerve agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a submersible amperometric probe design. This combination resu...

  1. Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse (II): effects of some currently used skin decontaminants (RSDL and Fuller's earth) against liquid sulphur mustard and VX exposure.

    PubMed

    Taysse, L; Dorandeu, F; Daulon, S; Foquin, A; Perrier, N; Lallement, G; Breton, P

    2011-06-01

    Using the hairless mouse screening model presented in the companion paper(1) the aim of this study was to assess two skin decontaminating systems: Fuller's earth (FE) and Reactive Skin Decontamination Lotion (RSDL) against two extremely toxic chemical warfare agents that represent a special percutaneous hazard, sulphur mustard (SM) and O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX). Five minutes after being exposed on the back to either 2 µL of neat sulphur mustard or 50 µg.kg(-1) of diluted VX, mice were decontaminated. Both systems were able to reduce blisters 3 days after SM exposure. However, RSDL was found to be more efficient than FE in reducing the necrosis of the epidermis and erosion. In the case of VX exposure, RSDL, whatever the ratio of decontaminant to toxicant used (RSDL 10, 20, 50), was not able to sufficiently prevent the inhibition of plasma cholinesterases taken as a surrogate marker of exposure and toxicity. Only FE reduced significantly the ChE inhibition. Some of these observations are different from our previous results obtained in domestic swine and these changes are thus discussed in the perspective of using SKH-1 hairless mice for the initial in vivo screening of decontaminants. PMID:20534641

  2. The birth of nerve agent warfare: lessons from Syed Abbas Foroutan.

    PubMed

    Newmark, Jonathan

    2004-05-11

    The author reviewed Farsi-language articles published recently by Dr. Syed Abbas Foroutan, which constitute the only firsthand clinical descriptions of battlefield nerve agent casualties in the world literature, and the author compares his comments with US and North Atlantic Treaty Organization (NATO) chemical casualty care doctrine. Foroutan's lessons learned reassure us that a robust medical evacuation system, coupled with timely and appropriate medical care of nerve agent poisoning, will save many more lives on future battlefields. PMID:15136687

  3. Determination of S-2-(N,N-diisopropylaminoethyl)- and S-2-(N,N-diethylaminoethyl) methylphosphonothiolate, nerve agent markers, in water samples using strong anion-exchange disk extraction, in vial trimethylsilylation, and gas chromatography-mass spectrometry analysis.

    PubMed

    Subramaniam, Raja; Åstot, Crister; Juhlin, Lars; Nilsson, Calle; Östin, Anders

    2012-03-16

    Since the establishment of the Chemical Weapons Convention in 1997, the development of analytical methods for unambiguous identification of large numbers of chemicals related to chemical warfare agents has attracted increased interest. The analytically challenging, zwitterionic S-2-(N,N-diisopropylaminoethyl) methylphosphonothiolate (EA-2192), a highly toxic degradation marker of the nerve agent VX, has been reported to resist trimethylsilylation or to result in an unacceptably high limit of detection in GC-MS analysis. In the present study, the problem is demonstrated to be associated with the presence of salt, which hinders trimethysilylation. EA-2192 was extracted from aqueous samples by use of a strong anion-exchange disk, derivatized as a trimethylsilyl derivative via in vial solid-phase trimethylsilylation and identified by GC-MS. The limits of detection were 10 ng/mL and 100 ng/mL (in a water sample) for SIM and SCAN mode respectively. The analytical method was found to be repeatable with relative standard deviation <10%. The performance of the method was evaluated using a proficiency test sample and environmental samples (spiked river water and Baltic Bay water) and compared with the commonly used evaporation-silylation method. The disk method displayed good tolerance to the presence of salt and the spiked EA-2192 was conclusively identified in all matrices. In addition, the applicability of the method was further demonstrated for other selected hydrolysis products of VX and Russian VX, namely S-2-(N,N-diethylaminoethyl) methylphosphonothiolate, ethyl methylphosphonic acid, methylphosphonic acid, and isobutyl methylphosphonic acid. For the synthesis of reference compounds, EA-2192 and its analog from degradation of the Russian VX isomer, the present methods were improved by using a polymer-bound base, resulting in >90% purity based on (1)H NMR. Based on the current results and earlier work on alkylphosphonic acids using the same method, we conclude that the

  4. Characterization of chemical agent transport in paints.

    PubMed

    Willis, Matthew P; Gordon, Wesley; Lalain, Teri; Mantooth, Brent

    2013-09-15

    A combination of vacuum-based vapor emission measurements with a mass transport model was employed to determine the interaction of chemical warfare agents with various materials, including transport parameters of agents in paints. Accurate determination of mass transport parameters enables the simulation of the chemical agent distribution in a material for decontaminant performance modeling. The evaluation was performed with the chemical warfare agents bis(2-chloroethyl) sulfide (distilled mustard, known as the chemical warfare blister agent HD) and O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), an organophosphate nerve agent, deposited on to two different types of polyurethane paint coatings. The results demonstrated alignment between the experimentally measured vapor emission flux and the predicted vapor flux. Mass transport modeling demonstrated rapid transport of VX into the coatings; VX penetrated through the aliphatic polyurethane-based coating (100 μm) within approximately 107 min. By comparison, while HD was more soluble in the coatings, the penetration depth in the coatings was approximately 2× lower than VX. Applications of mass transport parameters include the ability to predict agent uptake, and subsequent long-term vapor emission or contact transfer where the agent could present exposure risks. Additionally, these parameters and model enable the ability to perform decontamination modeling to predict how decontaminants remove agent from these materials. PMID:23872337

  5. Nerve agent detection using networks of single-walled carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Novak, J. P.; Snow, E. S.; Houser, E. J.; Park, D.; Stepnowski, J. L.; McGill, R. A.

    2003-11-01

    We report the use of carbon nanotubes as a sensor for chemical nerve agents. Thin-film transistors constructed from random networks of single-walled carbon nanotubes were used to detect dimethyl methylphosphonate (DMMP), a simulant for the nerve agent sarin. These sensors are reversible and capable of detecting DMMP at sub-ppb concentration levels, and they are intrinsically selective against interferent signals from hydrocarbon vapors and humidity. We provide additional chemical specificity by the use of filters coated with chemoselective polymer films. These results indicate that the electronic detection of sub-ppb concentrations of nerve agents and potentially other chemical warfare agents is possible with simple-to-fabricate carbon nanotube devices.

  6. A liquid chromatography tandem mass spectrometric method on in vitro nerve agents poisoning characterization and reactivator efficacy evaluation by determination of specific peptide adducts in acetylcholinesterase.

    PubMed

    Yan, Long; Chen, Jia; Xu, Bin; Guo, Lei; Xie, Yan; Tang, Jijun; Xie, Jianwei

    2016-06-10

    The terroristic availability of highly toxic nerve agents (NAs) highlights the necessity for a deep understanding of their toxicities and effective medical treatments. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method for a characterization of the NAs poisoning and an evaluation on the efficacy of reactivators in in vitro was developed for the first time. After exposure to sarin or VX and pepsin digestion, the specific peptides of acetylcholinesterase (AChE) in a purified status, i.e. undecapeptide "GESAGAASVGM" in free, unaged, or aged status was identified and quantified. A key termination procedure is focused to make the reaction system "frozen" and precisely "capture" the poisoning, aging and spontaneous reactivation status of AChE, and the abundance of such specific peptides can thus be simultaneously measured. In our established method, as low as 0.72% and 0.84% inhibition level of AChE induced by 0.5nM sarin and VX can be detected from the measurement of peptide adducts, which benefits a confirmation of NAs exposure, especially at extremely low levels. Comparing with conventional colorimetric Ellman assays, our method provides not only enzyme activity and inhibition rate, but also the precise poisoning status of NAs exposed AChE. Based on the full information provided by this method, the efficacy of reactivators, such as HI-6, obidoxime and pralidoxime, in the typical treatment of NAs poisoned AChE in in vitro was further evaluated. Our results showed that this method is a promising tool for the characterization of NAs poisoning and the evaluation of reactivator efficacy. PMID:27179675

  7. Nerve agent intoxication: Recent neuropathophysiological findings and subsequent impact on medical management prospects

    SciTech Connect

    Collombet, Jean-Marc

    2011-09-15

    This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3 months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents. - Highlights: > This review focuses on neuropathophysiology following nerve agent poisoning in mice. > Extensive data on long-term neuropathology and related inflammation are provided here. > Delayed self-repair attempts encountered in lesioned rodent brains are also described. > Cell therapy is considered as a valuable treatment against nerve agent intoxication.

  8. Analysis of nerve agent metabolites from nail clippings by liquid chromatography tandem mass spectrometry.

    PubMed

    Appel, Amanda S; Logue, Brian A

    2016-09-15

    While several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure, these methods are generally limited in the amount of time after an exposure that markers of exposure can be detected (due to rapid metabolism from biological matrices). In this study, a method for the analysis of nerve agent hydrolysis products from nail clippings was developed to allow evaluation of nails as a long-term repository of these markers. Pinacolyl methylphosphonic acid (PMPA) and isopropyl methylphosphonic acid (IMPA) were extracted from nail samples with N,N-dimethylformamide and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Limits of detection for PMPA and IMPA were 0.3μg/kg and 7.5μg/kg and linear ranges were 0.75-300μg/kg and 30-1500μg/kg, respectively. Precision was within 10% and 8% for PMPA and IMPA, respectively, and accuracy was 100±12% for both analytes. The approach presented here is complementary to current methods for nerve agent exposure verification, and should allow for long-term determination of nerve agent poisoning. PMID:27474780

  9. Efficient heterogeneous and environmentally friendly degradation of nerve agents on a tungsten-based POM.

    PubMed

    Mizrahi, Dana M; Saphier, Sigal; Columbus, Ishay

    2010-07-15

    Common (chemical warfare agent) CWA decontaminants exhibit harsh and corrosive characteristics, and are harmful to the environment. In the course of our quest for active sorbents as efficient decontaminants, Keggin-type polyoxometalate (POM) (NH(4))(3)PW(12)O(40) was tested for oxidative degradation of CWAs. Although oxidation did not take place, sarin (GB) and VX were smoothly decontaminated to non-toxic products within 1 and 10 days, respectively. Degradation was carried out directly on the powder, eliminating the need for solvents. Mustard gas (HD), whose degradation is highly dependent on oxidation, was not decontaminated by this POM. Solid state MAS NMR ((31)P and (13)C) was utilized both for POM characterization and for decontamination studies monitoring. PMID:20363072

  10. Fiber-optic-based surface plasmon resonance (SPR) sensors for the detection of toxic nerve agents

    NASA Astrophysics Data System (ADS)

    Prakash, Anna M. C.; Kim, Yoon-Chang; Banerji, Soame; Masson, Jean-Francois; Booksh, Karl S.

    2004-03-01

    Analytical instruments capable of detecting nerve agents in battlefield conditions where speed, accuracy and ease of operation are a must in today's military. Fast detection and decontamination of nerve agents in very low concentrations is the primary focus of our research. The method presented here focuses on optimizing polymer stabilized sensing elements on the surface of SPR fiber-optic probes. A number of polymers & polymer supported metal complexes capable of reversibly binding to the species of interest & which have robust operation in hostile environments are incorporated with the fiber optic sensing elements. An optical technique, such as Surface Plasmon Resonance (SPR), better suited to rapid data collection without sample pretreatment is employed. The approach using polymer-based optical fibers with off-the-shelf SPR system components has been tested for the detection of Pinacolyl methylphosphonate (PMP), a simulant for nerve agent Soman. Surface initiated polymeric sensors have higher sensitivity toward detecting PMP than bulk-polymerized sensors.

  11. Nerve agent analogs that produce authentic soman, sarin, tabun, and cyclohexyl methylphosphonate-modified human butyrylcholinesterase

    PubMed Central

    Gilley, Cynthia; MacDonald, Mary; Nachon, Florian; Schopfer, Lawrence M.; Zhang, Jun; Cashman, John R.; Lockridge, Oksana

    2009-01-01

    The goal was to test 14 nerve agent model compounds of soman, sarin, tabun, and cyclohexyl methylphosphonofluoridate (GF) for their suitability as substitutes for true nerve agents. We wanted to know whether the model compounds would form the identical covalent adduct with human butyrylcholinesterase that is produced by reaction with true nerve agents. Nerve agent model compounds containing thiocholine or thiomethyl in place of fluorine or cyanide were synthesized as Sp and Rp stereoisomers. Purified human butyrylcholinesterase was treated with a 45-fold molar excess of nerve agent analog at pH 7.4 for 17 h at 21°C. The protein was denatured by boiling and digested with trypsin. Aged and non-aged active site peptide adducts were quantified by MALDI-TOF mass spectrometry of the tryptic digest mixture. The active site peptides were isolated by HPLC and analyzed by MALDI-TOF-TOF mass spectrometry. Serine 198 of butyrylcholinesterase was covalently modified by all 14 compounds. Thiocholine was the leaving group in all compounds that had thiocholine in place of fluorine or cyanide. Thiomethyl was the leaving group in the GF thiomethyl compounds. However, sarin thiomethyl compounds released either thiomethyl or isopropyl, while soman thiomethyl compounds released either thiomethyl or pinacolyl. Thiocholine compounds reacted more rapidly with butyrylcholinesterase than thiomethyl compounds. Labeling with the model compounds resulted in aged adducts that had lost the O-alkyl group (O-ethyl for tabun, O-cyclohexyl for GF, isopropyl for sarin, and pinacolyl for soman) in addition to the thiocholine or thiomethyl group. The nerve agent model compounds containing thiocholine, and the GF thiomethyl analog were found to be suitable substitutes for true soman, sarin, tabun, and GF in terms of the adduct they produced with human butyrylcholinesterase. However, the soman and sarin thiomethyl compounds yielded two types of adducts, one of which was thiomethyl phosphonate, a

  12. Evaluation of oxime efficacy in nerve agent poisoning: Development of a kinetic-based dynamic model

    SciTech Connect

    Worek, Franz . E-mail: FranzWorek@Bundeswehr.org; Szinicz, Ladislaus; Eyer, Peter; Thiermann, Horst

    2005-12-15

    The widespread use of organophosphorus compounds (OP) as pesticides and the repeated misuse of highly toxic OP as chemical warfare agents (nerve agents) emphasize the necessity for the development of effective medical countermeasures. Standard treatment with atropine and the established acetylcholinesterase (AChE) reactivators, obidoxime and pralidoxime, is considered to be ineffective with certain nerve agents due to low oxime effectiveness. From obvious ethical reasons only animal experiments can be used to evaluate new oximes as nerve agent antidotes. However, the extrapolation of data from animal to humans is hampered by marked species differences. Since reactivation of OP-inhibited AChE is considered to be the main mechanism of action of oximes, human erythrocyte AChE can be exploited to test the efficacy of new oximes. By combining enzyme kinetics (inhibition, reactivation, aging) with OP toxicokinetics and oxime pharmacokinetics a dynamic in vitro model was developed which allows the calculation of AChE activities at different scenarios. This model was validated with data from pesticide-poisoned patients and simulations were performed for intravenous and percutaneous nerve agent exposure and intramuscular oxime treatment using published data. The model presented may serve as a tool for defining effective oxime concentrations and for optimizing oxime treatment. In addition, this model can be useful for the development of meaningful therapeutic animal models.

  13. Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis

    SciTech Connect

    Worek, F. . E-mail: FranzWorek@Bundeswehr.org; Eyer, P.; Aurbek, N.; Szinicz, L.; Thiermann, H.

    2007-03-15

    The availability of highly toxic organophosphorus (OP) warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents, e.g. soman and cyclosarin. This led to the synthesis and investigation of numerous oximes in the past decades. Reactivation of OP-inhibited AChE is considered to be the most important reaction of oximes. Clinical data from studies with pesticide-poisoned patients support the assumption that the various reactions between AChE, OP and oxime, i.e. inhibition, reactivation and aging, can be investigated in vitro with human AChE. In contrast to animal experiments such in vitro studies with human tissue enable the evaluation of oxime efficacy without being affected by species differences. In the past few years numerous in vitro studies were performed by different groups with a large number of oximes and methods were developed for extrapolating in vitro data to different scenarios of human nerve agent poisoning. The present status in the evaluation of new oximes as antidotes against nerve agent poisoning will be discussed.

  14. Augmentation of Chemotherapeutic Infusion Effect by TSU-68, an Oral Targeted Antiangiogenic Agent, in a Rabbit VX2 Liver Tumor Model

    SciTech Connect

    Kim, Hyo-Cheol; Chung, Jin Wook Choi, Seung Hong; Im, Seock-Ah; Yamasaki, Yasundo; Jun, Suryoung; Jae, Hwan Jun; Park, Jae Hyung

    2012-02-15

    Purpose: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. Methods: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. Results: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). Conclusions: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.

  15. Rapid and highly selective chromogenic detection of nerve agents with a cleft-shaped host.

    PubMed

    Kumar, Vinod; Kaushik, Mahabir Parshad

    2011-12-21

    A new chromogenic protocol has been developed for rapid and selective detection of nerve agents like tabun. The chemsensor displayed a drastic color change from its colorless solution to yellow instantaneously with an 89 nm bathochromic shift. No inference of other chemical warfare agents and its mimics was observed either with the naked-eye or by UV-Vis spectroscopy. The development of a portable chemosensor kit for tabun demonstrates its practical application in real-time monitoring. PMID:22013586

  16. Fluorogenic and chromogenic probe for rapid detection of a nerve agent simulant DCP.

    PubMed

    Wu, Wei-hui; Dong, Jun-jun; Wang, Xin; Li, Jian; Sui, Shao-hui; Chen, Gao-yun; Liu, Ji-wei; Zhang, Ming

    2012-07-21

    A fluorogenic and visual probe was devised to detect diethyl chlorophosphate (DCP), a nerve agent simulant. The probe, N-(rhodamine B)-lactam-2-aminoethanol (RB-AE), undergoes oxazoline formation following phosphorylation in the presence of DCP, which gives rapid and clear fluorescence and color change in the assay solutions. PMID:22624148

  17. Long-term neuropathological and behavioral impairments after exposure to nerve agents.

    PubMed

    Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Apland, James P; Prager, Eric M; Pidoplichko, Volodymyr I; Miller, Steven L; Braga, Maria F M

    2016-06-01

    One of the deleterious effects of acute nerve agent exposure is the induction of status epilepticus (SE). If SE is not controlled effectively, it causes extensive brain damage. Here, we review the neuropathology observed after nerve agent-induced SE, as well as the ensuing pathophysiological, neurological, and behavioral alterations, with an emphasis on their time course and longevity. Limbic structures are particularly vulnerable to damage by nerve agent exposure. The basolateral amygdala (BLA), which appears to be a key site for seizure initiation upon exposure, suffers severe neuronal loss; however, GABAergic BLA interneurons display a delayed death, perhaps providing a window of opportunity for rescuing intervention. The end result is a long-term reduction of GABAergic activity in the BLA, with a concomitant increase in spontaneous excitatory activity; such pathophysiological alterations are not observed in the CA1 hippocampal area, despite the extensive neuronal loss. Hyperexcitability in the BLA may be at least in part responsible for the development of recurrent seizures and increased anxiety, while hippocampal damage may underlie the long-term memory impairments. Effective control of SE after nerve agent exposure, such that brain damage is also minimized, is paramount for preventing lasting neurological and behavioral deficits. PMID:27002925

  18. FIBER-OPTIC BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS. (R823663)

    EPA Science Inventory

    A fiber-optic enzyme biosensor for the direct measurement of organophosphate nerve
    agents
    was developed. The basic element of this biosensor is organophosphorus hydrolase
    immobilized on a nylon membrane and attached to the common end of a bifurcated optical fiber
    bundle....

  19. Polynorbornene derived 8-hydroxyquinoline paper strips for ultrasensitive chemical nerve agent surrogate sensing.

    PubMed

    Sarkar, Santu; Shunmugam, Raja

    2014-08-11

    The detection of nerve agent simulants is achieved by the photoinduced electron transfer (PET) mechanism. A "turn-on" fluorescence response upon phosphorylation at 8-hydroxyquinoline of norbornene-based triazolyl functionalized 8-hydroxyquinoline () followed by intramolecular rearrangement provides very intense green emission. The detection limit of polymer () coated paper strips is 25 ppb with instantaneous response. PMID:24948420

  20. BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS. 1. POTENTIOMETRIC ENZYME ELECTRODE. (R823663)

    EPA Science Inventory

    A potentiometric enzyme electrode for the direct measurement of organophosphate (OP)
    nerve agents was developed. The basic element of this enzyme electrode was a pH electrode
    modified with an immobilized organophosphorus hydrolase (OPH) layer formed by cross-linking
    OPH ...

  1. The reactivating and therapeutic efficacy of oximes to counteract Russian VX poisonings.

    PubMed

    Kassa, Jiri; Jun, Daniel; Kuca, Kamil

    2006-01-01

    Russian VX (O-isobutyl-S-(2-diethylaminoethyl)methylphosphonothioate) is the structural analogue of VX agent. It differs from VX agent (O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate) by two alkyl groups. The potency of currently available oximes (pralidoxime, obidoxime, HI-6) to reactivate Russian VX-inhibited acetylcholinesterase and to eliminate Russian VX-induced acute toxic effects was evaluated using in vivo methods. In vivo determined percentage of reactivation of Russian VX-inhibited blood and brain acetylcholinesterase in poisoned rats shows that HI-6 seems to be the most efficacious reactivator of Russian VX-inhibited acetylcholinesterase among currently used oximes in the peripheral compartment, whereas no difference between reactivating efficacy of all tested oximes was observed in the central compartment. The oxime HI-6 was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in Russian VX-poisoned mice among all studied oximes. Thus, the oxime HI-6 seems to be the most suitable oxime for the antidotal treatment of acute poisonings with Russian VX as in the case of VX, sarin, cyclosarin, and soman poisonings. PMID:16940011

  2. Nerve agent analogues that produce authentic soman, sarin, tabun, and cyclohexyl methylphosphonate-modified human butyrylcholinesterase.

    PubMed

    Gilley, Cynthia; MacDonald, Mary; Nachon, Florian; Schopfer, Lawrence M; Zhang, Jun; Cashman, John R; Lockridge, Oksana

    2009-10-01

    The goal was to test 14 nerve agent model compounds of soman, sarin, tabun, and cyclohexyl methylphosphonofluoridate (GF) for their suitability as substitutes for true nerve agents. We wanted to know whether the model compounds would form the identical covalent adduct with human butyrylcholinesterase that is produced by reaction with true nerve agents. Nerve agent model compounds containing thiocholine or thiomethyl in place of fluorine or cyanide were synthesized as Sp and Rp stereoisomers. Purified human butyrylcholinesterase was treated with a 45-fold molar excess of nerve agent analogue at pH 7.4 for 17 h at 21 degrees C. The protein was denatured by boiling and was digested with trypsin. Aged and nonaged active site peptide adducts were quantified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry of the tryptic digest mixture. The active site peptides were isolated by HPLC and analyzed by MALDI-TOF-TOF mass spectrometry. Serine 198 of butyrylcholinesterase was covalently modified by all 14 compounds. Thiocholine was the leaving group in all compounds that had thiocholine in place of fluorine or cyanide. Thiomethyl was the leaving group in the GF thiomethyl compounds. However, sarin thiomethyl compounds released either thiomethyl or isopropyl, while soman thiomethyl compounds released either thiomethyl or pinacolyl. Thiocholine compounds reacted more rapidly with butyrylcholinesterase than thiomethyl compounds. Labeling with the model compounds resulted in aged adducts that had lost the O-alkyl group (O-ethyl for tabun, O-cyclohexyl for GF, isopropyl for sarin, and pinacolyl for soman) in addition to the thiocholine or thiomethyl group. The nerve agent model compounds containing thiocholine and the GF thiomethyl analogue were found to be suitable substitutes for true soman, sarin, tabun, and GF in terms of the adduct that they produced with human butyrylcholinesterase. However, the soman and sarin thiomethyl compounds

  3. Microfluidic chip with optical sensor for rapid detection of nerve agent Sarin in water samples

    NASA Astrophysics Data System (ADS)

    Tan, Hsih Yin; Nguyen, Nam-Trung; Loke, Weng Keong; Tan, Yong Teng

    2007-12-01

    The chemical warfare agent Sarin is an organophosphate that is highly toxic to humans as they can act as cholinesterase inhibitors, that disrupts neuromuscular transmission. As these nerve agents are colorless, odorless and highly toxic, they can be introduced into drinking water as a means of terrorist sabotage. Hence, numerous innovative devices and methods have been developed for rapid detection of these organophosphates. Microfluidic technology allows the implementation of fast and sensitive detection of Sarin. In this paper, a micro-total analysis systems (TAS), also known as Lab-on-a-chip, fitted with an optical detection system has been developed to analyze the presence of the nerve agent sarin in water samples. In the present set-up, inhibition of co-introduced cholinesterase and water samples containing trace amounts of nerve agent sarin into the microfluidic device was used as the basis for selective detection of sarin. The device was fabricated using polymeric micromachining with PMMA (poly (methymethacrylate)) as the substrate material. A chromophore was utilized to measure the activity of remnant cholinesterase activity, which is inversely related to the amount of sarin present in the water samples. Comparisons were made between two different optical detection techniques and the findings will be presented in this paper. The presented measurement method is simple, fast and as sensitive as Gas Chromatography.

  4. Estimated Chemical Warfare Agent Surface Clearance Goals for Remediation Pre-Planning

    SciTech Connect

    Dolislager, Frederick; Bansleben, Dr. Donald; Watson, Annetta Paule

    2010-01-01

    Health-based surface clearance goals, in units of mg/cm2, have been developed for the persistent chemical warfare agents sulfur mustard (HD) and nerve agent VX as well as their principal degradation products. Selection of model parameters and critical receptor (toddler child) allow calculation of surface residue estimates protective for the toddler child, the general population and adult employees of a facilty that has undergone chemical warfare agent attack.

  5. Solid supported in situ derivatization extraction of acidic degradation products of nerve agents from aqueous samples.

    PubMed

    Chinthakindi, Sridhar; Purohit, Ajay; Singh, Varoon; Tak, Vijay; Dubey, D K; Pardasani, Deepak

    2014-09-12

    This study deals with the solid supported in situ derivatization extraction of acidic degradation products of nerve agents present in aqueous samples. Target analytes were alkyl alkylphosphonic acids and alkylphosphonic acids, which are important environmental signatures of nerve agents. The method involved tert-butyldimethylchlorosilane mediated in situ silylation of analytes on commercially available diatomaceous solid phase extraction cartridges. Various parameters such as derivatizing reagent, its concentration, reaction time, temperature and eluting solvent were optimized. Recoveries of the analytes were determined by GC-MS which ranged from 60% to 86%. The limits of detection (LOD) and limit of quantification (LOQ) with selected analytes were achieved down to 78 and 213ngmL(-1) respectively, in selected ion monitoring mode. The successful applicability of method was also demonstrated on samples of biological origin such as plasma and to the samples received in 34th official proficiency test conducted by the Organization for Prohibition the of Chemical Weapons. PMID:25103280

  6. A rhodamine-deoxylactam based sensor for chromo-fluorogenic detection of nerve agent simulant.

    PubMed

    Wu, Zhisheng; Wu, Xuanjun; Yang, Yuhui; Wen, Ting-bin; Han, Shoufa

    2012-10-15

    N-(rhodamine B)-deoxylactam-5-amino-1-pentanol (dRB-APOH) was designed and prepared as the chromo-fluorogenic sensor for detection of a nerve agent simulant via analyte triggered tandem phosphorylation and opening of the intramolecular deoxylactam. The successful detection of diethyl chlorophosphate suggests the utility of rhodamine-deoxylactams as the chromo-fluorogenic signal reporting platform for design of sensors targeting reactive chemical species via various chemistries. PMID:22995618

  7. Chemical warfare nerve agents. A review of cardiopulmonary pathophysiology and resuscitation. Technical report

    SciTech Connect

    Franz, D.R.

    1986-12-01

    The purpose of this document is to provide the medical research community with a digest of the open and internal literature related to cardiopulmonary pathophysiology, resuscitation, and animal modeling of chemical warfare nerve agent intoxication. Though not comprehensive, this review makes available to the reader a cross section of what research was done in this small but important part of the medical chemical defense research program between World War II and the early 1980's.

  8. A near infrared colorimetric and fluorometric probe for organophosphorus nerve agent mimics by intramolecular amidation.

    PubMed

    Hu, Xiao-Xiao; Su, Yue-Ting; Ma, Yun-Wei; Zhan, Xin-Qi; Zheng, Hong; Jiang, Yun-Bao

    2015-10-21

    A near infrared probe for sensitive colorimetric and fluorimetric detection of nerve agent mimics, DCP and DCNP, was reported based on the activation of a carboxylic acid group by the mimics to conduct an intramolecular amidation reaction in the heptamethine chromophore, where its absorption or excitation maximum wavelength could be greatly red-shifted by attenuating the electron-donating ability of the amine group in the bridgehead site of heptamethine cyanine. PMID:26323249

  9. Highly selective detection of nerve-agent simulants with BODIPY dyes.

    PubMed

    Barba-Bon, Andrea; Costero, Ana M; Gil, Salvador; Harriman, Anthony; Sancenón, Félix

    2014-05-19

    Two chromo-fluorogenic probes, each based on the boron dipyrromethene core, have been developed for the detection of nerve-agent mimics. These chemosensors display both a color change and a significant enhancement of fluorescence in the presence of diethylcyanophosphonate (DCNP) and diisopropylfluorophosphate (DFP). No interference from other organophosphorus compounds or acids has been observed. Two portable chemosensor kits have been developed and tested to demonstrate its practical application in real-time monitoring. PMID:24700454

  10. Technology assessment for the determination of chemical agent vapors in demilitarization facilities: Final report

    SciTech Connect

    Maskarinec, M.P.; Wise, M.B.; Buchanan, M.V.

    1987-01-01

    A survey of analytical methods for the determination of chemical agents GB, VX, and HD was made. HD, or mustard, is bis-2-chloroethyl sulfide, and is classified as a blishtering agent. GB, or Sarin, is isopropyl methyl phosphonofluoridate. VX is O-ethyl-S-(2-diisopropylaminoethyl)methylphosphonothioate. Both GB and VX are nerve agents. Included were methods capable of providing for monitoring requirements at the time weighted average (TWA) and allowable stack concentration (ASC) levels in near real time. A review of the currently used automatic continuous air monitoring system (ACAMS) was made as well as a review of the recently developed atmospheric pressure ionization mass spectrometry (APIMS). This report recommends a strategy for research and development for near term and medium term improvement of the overall monitoring program. 12 refs., 1 tab.

  11. Choice of approaches in developing novel medical countermeasures for nerve agent poisoning.

    PubMed

    Myhrer, Trond; Aas, Pål

    2014-09-01

    During the establishment of a research branch, all relevant matters encountered will be of interest to study. After having acquired a body of basal knowledge, it becomes possible to derive ideas or hypotheses for further elaboration of information. The purpose of the present study was to show that therapies for nerve agent poisoning based on specific neuropharmacological approaches can have greater probability for being successful than treatment regimens based on fragmental research or serendipitous discoveries. By following the guidelines for research in experimental epilepsy, neuronal target areas for nerve agents have been identified through lesion studies, and critical receptors for pharmacological treatment have been specified through microinfusion studies of rats. Subsequent experimentations have shown that the results achieved from microinfusion studies are transferable to systemic administration. It is demonstrated that a treatment regimen developed through the novel approach is more efficacious than regimens derived from conventional research on countermeasures. A therapy consisting of HI-6, levetiracetam, and procyclidine that has been worked out along the new lines, exerts powerful anticonvulsant capacity and appears to have universal utility as a stand-alone therapy against soman intoxication in rats. It would be of great interest to examine whether the latter findings can be expanded to other animal species than rats and other classical nerve agents than soman. PMID:24820435

  12. Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects.

    PubMed

    Collombet, Jean-Marc

    2011-09-15

    This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents. PMID:21791221

  13. Optimal choice of acetylcholinesterase reactivators for antidotal treatment of nerve agent intoxication.

    PubMed

    Bajgar, Jirí

    2010-01-01

    The studies dealing with mechanism of organophosphates (OP)/nerve agent action, prophylaxis and treatment of intoxications is a very hot topic at present. Though the research is very intensive, unfortunately, up to now, there is not universal or significantly better reactivator sufficiently effective against all nerve agents/OP when compared with presently available oximes (pralidoxime, methoxime, obidoxime, trimedoxime, HI-6). The use of the most effective reactivator (HI-6) using simple type of autoinjector (e.g. ComboPen) is strictly limited because of decomposition of HI-6 in solution. Thanks to better solubility it is clear that another salt of HI-6 (dimethanesulfonate, HI-6 DMS) is more convenient for the use as antidote against nerve agents in the autoinjector than HI-6 chloride (Cl). It was clearly demonstrated that reactivation potency of HI-6 DMS in comparison with HI-6 Cl in vivo was the same and bioavailability of HI-6 DMS is better than that of HI-6 Cl. Three chambered autoinjector allows administration of all three antidotes (atropine, reactivator, diazepam) simultaneously. Moreover, the content of chambers can be changed according to proposed requirements. Possible way to solve the problem of universal reactivator could be the use of two reactivators. Three chambered autoinjector is an ideal device for this purpose. PMID:21400978

  14. General guidelines for medically screening mixed population groups potentially exposed to nerve or vesicant agents

    SciTech Connect

    Watson, A.P.; Munro, N.B.; Sidell, F.R.; Leffingwell, S.S.

    1992-01-01

    A number of state and local planners have requested guidance on screening protocols and have expressed interest in sampling body fluids from exposed or potentially exposed individuals as a means of estimating agent dose. These guidelines have been developed to provide a clear statement that could be used by state and local emergency response personnel in the event of a nerve or vesicant agent incident resulting in off-post contamination; maximum protection from harm is the goal. The assumption is that any population group so exposed would be heterogeneous for age, gender, reproductive status, and state of health.

  15. Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase

    PubMed Central

    Barakat, Nora H.; Zheng, Xueying; Gilley, Cynthia B.; MacDonald, Mary; Okolotowicz, Karl; Cashman, John R.; Vyas, Shubham; Beck, Jeremy M.; Hadad, Christopher M.; Zhang, Jun

    2009-01-01

    Both G- and V-type nerve agents possess a center of chirality about phosphorus. The Sp-enantiomers are generally more potent inhibitors than their Rp-counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the Sp and Rp stereoisomers of two series of G-type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G-type agents, except that thiomethyl (CH3-S-) and thiocholine ((CH3)3NCH2CH2-S-) groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD; and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the Sp enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between Sp and Rp enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogs were much more potent than the corresponding thiomethyl analogs. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., Sp > Rp), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed. PMID:19715346

  16. Selective opening of nanoscopic capped mesoporous inorganic materials with nerve agent simulants; an application to design chromo-fluorogenic probes.

    PubMed

    Candel, Inmaculada; Bernardos, Andrea; Climent, Estela; Marcos, M Dolores; Martínez-Máñez, Ramón; Sancenón, Félix; Soto, Juan; Costero, Ana; Gil, Salvador; Parra, Margarita

    2011-08-01

    A hybrid nanoscopic capped mesoporous material, that is selectively opened in the presence of nerve agent simulants, has been prepared and used as a probe for the chromo-fluorogenic detection of these chemicals. PMID:21691625

  17. Development of pretreatment compounds against nerve-gas agents. Annual report (Final), 16 May 88-30 Sep 90

    SciTech Connect

    Carroll, F.I.; Abraham, P.

    1990-09-30

    The U. S. Army Medical Research and Development Command is interested in research directed toward the development of countermeasures to chemical warfare (CW) agents such as the nerve gas poison soman. Soman and other nerve gas poisons are extremely potent cholinesterase inhibitors. This inhibition leads to a buildup of excess acetylcholine resulting in over-stimulation of both the peripheral and central nervous system and can lead to death. Standard therapy for organophosphate nerve agent poisoning is based on co-administration of an anticholinergic agent such as atropine to antagonize the effects of accumulated acetylcholine and a cholinesterase reactivator such as 2-PAM to dephosphorylate the inhibited enzyme. However, since many problems remain in the treatment of organophosphate nerve agent poisoning, there is considerable interest and need to develop new pretreatment and treatment drugs, particularly for soman poisoning.

  18. A FRET-based ratiometric fluorescent and colorimetric probe for the facile detection of organophosphonate nerve agent mimic DCP.

    PubMed

    Xuan, Weimin; Cao, Yanting; Zhou, Jiahong; Wang, Wei

    2013-11-18

    A FRET ratiometric fluorescent probe enabling a fast and highly sensitive response to OP nerve agent mimic DCP within 1 min and with as low as 0.17 ppm concentration detection limit has been developed. Moreover, the probe exhibits noticeable color changes under UV light and even with the naked eye. It is also demonstrated that it can detect both liquid and gas nerve agents. PMID:24080856

  19. Nanoparticle-Based Electrochemical Immunosensor for the Detection of Phosphorylated Acetylcholinesterase: An Exposure Biomarker of Organophosphate Pesticides and Nerve AgentsOrganophosphate Pesticides and Nerve Agents

    SciTech Connect

    Liu, Guodong; Wang, Jun; Barry, Richard C.; Petersen, Catherine E.; Timchalk, Charles; Gassman, Paul L.; Lin, Yuehe

    2008-11-01

    A nanoparticle-based electrochemical immunosensor has been developed for the detection of phosphorylated acetylcholinesterase (AChE) adducts, which is a potential exposure biomarker for organophosphate pesticides (OP) and chemical warfare nerve agent exposures. Zirconia nanoparticles (ZrO2 NPs) were used as selective sorbents to capture the phosphorylated AChE adduct, and quantum dots (ZnS@CdS, QDs) were used as tags to label monoclonal anti-AChE antibody to track the immunorecognition events. The sandwich-like immunoreactions were performed among the ZrO2 NPs, which were pre-coated on a screen printed electrode (SPE) by electrodeposition, phosphorylated AChE and QD-anti-AChE. The captured QD tags were determined on the SPE by electrochemical stripping analysis of its metallic component (cadmium) after an acid-dissolution step. Paraoxon was used as a model OP insecticide to prepare the phosphorylated AChE adduct to demonstrate the proof of principle for this sensor technology. The paraoxon-AChE adduct was characterized by Fourier Transform Infrared Spectrum, and the binding affinity of anti-AChE to the paraoxon-AChE was validated with an enzyme-linked immunosorbent assay. The parameters (e.g., amount of ZrO2 NP, QD-anti-AChE concentration,) that govern the electrochemical response of immunosensors were optimized. The voltammetric response of the immunosensor is highly linear over the range of 10 pM to 4 nM paraoxon-AChE, and the limit of detection is estimated to be 8 pM. This new nanoparticle-based electrochemical immunosensor thus provides a sensitive and quantitative tool for biomonitoring exposure to OP pesticides and nerve agents.

  20. Anticholinesterase (DFP) toxicity antagonism by chronic donepezil: a potential nerve agent treatment.

    PubMed

    Janowsky, David S; Davis, John M; Overstreet, David H

    2005-08-01

    Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity. PMID:16054679

  1. Simultaneous Measurement of Tabun, Sarin, Soman, Cyclosarin, VR, VX, and VM Adducts to Tyrosine in Blood Products by Isotope Dilution UHPLC-MS/MS

    PubMed Central

    Crow, Brian S.; Pantazides, Brooke G.; Quiñones-González, Jennifer; Garton, Joshua W.; Carter, Melissa D.; Perez, Jonas W.; Watson, Caroline M.; Tomcik, Dennis J.; Crenshaw, Michael D.; Brewer, Bobby N.; Riches, James R.; Stubbs, Sarah J.; Read, Robert W.; Evans, Ronald A.; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2015-01-01

    This work describes a new specific, sensitive, and rapid stable isotope dilution method for the simultaneous detection of the organophosphorus nerve agents (OPNAs) tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), VR, VX, and VM adducts to tyrosine (Tyr). Serum, plasma, and lysed whole blood samples (50 µL) were prepared by protein precipitation followed by digestion with Pronase. Specific Tyr adducts were isolated from the digest by a single solid phase extraction (SPE) step, and the analytes were separated by reversed-phase ultra high performance liquid chromatography (UHPLC) gradient elution in less than 2 min. Detection was performed on a triple quadrupole tandem mass spectrometer using time-triggered selected reaction monitoring (SRM) in positive electrospray ionization (ESI) mode. The calibration range was characterized from 0.100–50.0 ng/mL for GB– and VR– Tyr and 0.250–50.0 ng/mL for GA–, GD–, GF–, and VX/VM–Tyr (R2 ≥ 0.995). Inter- and intra-assay precision had coefficients of variation of ≤17 and ≤10%, respectively, and the measured concentration accuracies of spiked samples were within 15% of the targeted value for multiple spiking levels. The limit of detection was calculated to be 0.097, 0.027, 0.018, 0.074, 0.023, and 0.083 ng/mL for GA–, GB–, GD–, GF–, VR–, and VX/VM–Tyr, respectively. A convenience set of 96 serum samples with no known nerve agent exposure was screened and revealed no baseline values or potential interferences. This method provides a simple and highly specific diagnostic tool that may extend the time postevent that a confirmation of nerve agent exposure can be made with confidence. PMID:25286390

  2. Simultaneous measurement of tabun, sarin, soman, cyclosarin, VR, VX, and VM adducts to tyrosine in blood products by isotope dilution UHPLC-MS/MS.

    PubMed

    Crow, Brian S; Pantazides, Brooke G; Quiñones-González, Jennifer; Garton, Joshua W; Carter, Melissa D; Perez, Jonas W; Watson, Caroline M; Tomcik, Dennis J; Crenshaw, Michael D; Brewer, Bobby N; Riches, James R; Stubbs, Sarah J; Read, Robert W; Evans, Ronald A; Thomas, Jerry D; Blake, Thomas A; Johnson, Rudolph C

    2014-10-21

    This work describes a new specific, sensitive, and rapid stable isotope dilution method for the simultaneous detection of the organophosphorus nerve agents (OPNAs) tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), VR, VX, and VM adducts to tyrosine (Tyr). Serum, plasma, and lysed whole blood samples (50 μL) were prepared by protein precipitation followed by digestion with Pronase. Specific Tyr adducts were isolated from the digest by a single solid phase extraction (SPE) step, and the analytes were separated by reversed-phase ultra high performance liquid chromatography (UHPLC) gradient elution in less than 2 min. Detection was performed on a triple quadrupole tandem mass spectrometer using time-triggered selected reaction monitoring (SRM) in positive electrospray ionization (ESI) mode. The calibration range was characterized from 0.100-50.0 ng/mL for GB- and VR-Tyr and 0.250-50.0 ng/mL for GA-, GD-, GF-, and VX/VM-Tyr (R(2) ≥ 0.995). Inter- and intra-assay precision had coefficients of variation of ≤17 and ≤10%, respectively, and the measured concentration accuracies of spiked samples were within 15% of the targeted value for multiple spiking levels. The limit of detection was calculated to be 0.097, 0.027, 0.018, 0.074, 0.023, and 0.083 ng/mL for GA-, GB-, GD-, GF-, VR-, and VX/VM-Tyr, respectively. A convenience set of 96 serum samples with no known nerve agent exposure was screened and revealed no baseline values or potential interferences. This method provides a simple and highly specific diagnostic tool that may extend the time postevent that a confirmation of nerve agent exposure can be made with confidence. PMID:25286390

  3. Ultraviolet Raman spectra and cross-sections of the G-series nerve agents.

    PubMed

    Christesen, Steven D; Pendell Jones, Jay; Lochner, Joseph M; Hyre, Aaron M

    2008-10-01

    Ultraviolet (UV) Raman spectroscopy is being applied to the detection of chemical agent contamination of natural and man-made surfaces. In support of these efforts, we have measured the UV Raman signatures of the G-series nerve agents GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), and the agent simulant diisopropyl methylphosphonate (DIMP) at 248 nm and 262 nm, as well as taking their UV Raman and UV absorption cross-sections. Of these chemicals, only GA exhibits any significant pre-resonance enhancement. We also show that reduction of the excitation wavelength from 262 nm to 248 nm effectively shifts the Raman spectrum away from a substantial sample fluorescence background, implying a significant improvement in detection capability. PMID:18926015

  4. Detrimental influences of intraluminally-administered sclerotic agents on surrounding tissues and peripheral nerves: An experimental study

    PubMed Central

    Fujiki, Masahide; Kurita, Masakazu; Ozaki, Mine; Kawakami, Hayato; Kaji, Nobuyuki; Takushima, Akihiko; Harii, Kiyonori

    2012-01-01

    The minimally-invasive nature of sclerotherapy makes it one of the first treatment options for venous malformations, although treatment-related complications, such as peripheral nerve paralysis, have been reported in some clinical cases. However, no studies of the aetiology of the detrimental effects of intraluminally-administered sclerotic agents on the surrounding tissues, including the peripheral nerves, have yet been published. This study therefore investigated the influences of intraluminally-administered sclerotic agents on the tissues surrounding the injection site using a newly-developed rat femoral vein model. Using this model, the effects of absolute ethanol, 5% ethanolamine oleate, and 1% polidocanol were compared histologically with those of normal saline controls. Fluorescein isothiocyanate-conjugated agents were administered and the leakage of sclerotic agents through the venous wall was evaluated by fluorescence microscopy. Damage to the adjacent femoral nerve was quantitatively evaluated by counting the numbers of axons in cross-sections. All the sclerotic agents caused vascular wall injuries and leakage into the surrounding tissues. The number of axons in the femoral nerve was significantly reduced following administration of absolute ethanol or 5% ethanolamine oleate, compared with normal saline. The results of this study suggest that sclerotic agents commonly leak out the vascular lumen, and some agents can cause adjacent nerve injury. It is important to be aware of this type of complication of sclerotherapy for venous malformations when selecting appropriate therapeutic interventions. PMID:22686430

  5. Lab-on-a-chip for rapid electrochemical detection of nerve agent Sarin.

    PubMed

    Tan, Hsih Yin; Loke, Weng Keong; Nguyen, Nam-Trung; Tan, Swee Ngin; Tay, Nam Beng; Wang, Wei; Ng, Sum Huan

    2014-04-01

    This paper reports a lab-on-a-chip for the detection of Sarin nerve agent based on rapid electrochemical detection. The chemical warfare agent Sarin (C₄H₁₀FO₂P, O-isopropyl methylphosphonofluoridate) is a highly toxic organophosphate that induces rapid respiratory depression, seizures and death within minutes of inhalation. As purified Sarin is colourless, odourless, water soluble and a easily disseminated nerve agent, it has been used as a weapon in terrorist or military attacks. To ascertain whether potable water supplies have been adulterated with this extremely potent poison, an inexpensive, sensitive and easy to use portable test kit would be of interest to first responders investigating such attacks. We report here an amperometric-based approach for detecting trace amounts of Sarin in water samples using a screen-printed electrode (SPE) integrated in a microfluidic chip. Enzymatic inhibition was obtained by exposing the immobilised biosensor in the microfluidic platform to Sarin in water samples. With the aid of cobalt phthalocyanine modified SPE, the device could detect Sarin at part-per-billion levels with concentration as low as 1 nM. The detection method reported here represents a significant improvement over the authors'previous optical-based detection method. PMID:24288016

  6. Molecular Dynamics of Organophosphorous Hydrolases Bound to the Nerve Agent Soman

    SciTech Connect

    Soares, Thereza A.; Osman, Mohamed A.; Straatsma, TP

    2007-07-01

    The organophosphorous hydrolase (OPH) from Pseudomonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. The potential use of this enzyme for the detection and detoxification of warfare nerve agents has spurred efforts to engineer mutants of enhanced catalytic activity and modified stereospecificity towards the most toxic forms of organophosphate nerve agents. Molecular dynamics simulations of the wild-type OPH and the complexes between the wild-type and the triple-mutant H254G/H257W/L303R forms and the substrate SpSc-soman have been carried out to enhance our molecular level understanding of its reaction mechanism. Comparison of the three simulations indicate that substrate binding induces conformational changes of the loops near the active site, suggesting an induced-fit mechanism. Likewise, the coordination of the zinc cations in the active site of the enzyme differs between the free enzyme and the complexes. In the absence of the substrate, the more exposed b-zinc is hexa-coordinated and the less exposed a-zinc is penta-coordinated. In the presence of the substrate, the b- zinc atom can be both penta- or hexa-coordinated while the a-zinc atom is tetra-coordinated. In addition, binding energies were calculated from electrostatic properties obtained by solution of the Poisson-Boltzmann equation combined with a surface area-dependent apolar contribution. The calculations indicate that the binding of SpSc-soman to OPH is driven by nonpolar interactions while electrostatic interactions determine binding specificity. These results provide a qualitative, molecular-level explanation for 2 the three-fold increase in catalytic efficiency of the triple-mutant towards SpSc-soman. Keywords: organophosphorous hydrolase, phosphotriesterase, nerve agents, soman, molecular dynamics, Poisson-Boltzmann equation, continuum electrostatics, metalloprotein.

  7. Nonconventional terror--the anesthesiologist's role in a nerve agent event.

    PubMed

    Talmor, Daniel

    2007-03-01

    The structure and biologic action of nerve agents is similar to organophosphates, commonly used as insecticides. Acetylcholine accumulation and binding to the cholinergic receptor site stimulates the affected organs producing a predictable set of clinical symptoms. Treatment of the affected patients will include decontamination, respiratory and hemodynamic support, as well as specific antidotes. The multiple casualties that may be expected present additional logistical and organizational problems. The specific skills of anesthesiologists will make them invaluable members of the care team in such a chemical mass casualty event. PMID:17400165

  8. Integration of metal oxide nanobelts with microsystems for nerve agent detection

    NASA Astrophysics Data System (ADS)

    Yu, Choongho; Hao, Qing; Saha, Sanjoy; Shi, Li; Kong, Xiangyang; Wang, Z. L.

    2005-02-01

    We have assembled tin dioxide nanobelts with low-power microheaters for detecting dimethyl methylphosphonate (DMMP), a nerve agent simulant. The electrical conductance of a heated nanobelt increased for 5% upon exposure to 78 parts per billion DMMP in air. The nanobelt conductance recovered fully quickly after the DMMP was shut off, suggesting that the single-crystal nanobelt was not subject to poisoning often observed in polycrystalline metal oxide sensors. While the sensitivity can be improved via doping nanobelts with catalytic additives, directed assembly or growth of nanobelts on microsystems will potentially allow for the large-scale fabrication of nanosensor arrays.

  9. Low-power microsensors for explosives and nerve warfare agents using silicon nanodots and nanowires

    NASA Astrophysics Data System (ADS)

    Sailor, Michael J.; Trogler, William C.; Letant, Sonia; Sohn, Honglae; Content, Stephane; Schmedake, Thomas A.; Gao, Jun; Zmolek, Peter; Link, Jamie R.; Fainman, Yeshaiahu; Xu, Fang; Shames, Paul E.

    2001-09-01

    Nanocrystalline porous silicon films (nanodots) and polymeric silicon wires (nanowires) have been used to detect chemicals in gas and liquid phase. Transduction mechanisms using quantum confinement derived photoluminescence and optical reflectivity have been used. Photoluminescence intensity is modulated by energy or electron transfer induced quenching, and a shift of the Fabry-Perot reflectivity fringes from thin nanocrystalline films occurs upon molecular absorption. Examples of irreversible detection and reversible sensing modes for explosives, nerve warfare agents, and various odors of commercial interest will be provided. A catalyst can be incorporated into the nanomaterials to provide specificity for the analyte of interest.

  10. Detection of nerve agents using proton transfer reaction mass spectrometry with ammonia as reagent gas.

    PubMed

    Ringer, Joachim M

    2013-01-01

    The chemical warfare agents (CWA) Sarin, Soman, Cyclosarin and Tabun were characterised by proton transfer mass spectrometry (PTRMS). It was found that PTRMS is a suitable technique to detect nerve agents highly sensitively, highly selectively and in near real-time. Methods were found to suppress molecule fragmentation which is significant under PTRMS hollow cathode ionisation conditions. In this context, the drift voltage (as one of the most important system parameters) was varied and ammonia was introduced as an additional chemical reagent gas. Auxiliary chemicals such as ammonia affect ionisation processes and are quite common in context with detectors for CWAs based on ion mobility spectrometry (IMS). With both, variation of drift voltage and ammonia as the reagent gas, fragmentation can be suppressed effectively. Suppression of fragmentation is crucial particularly concerning the implementation of an algorithm for automated agent identification in field applications. On the other hand, appearance of particular fragments might deliver additional information. Degradation and rearrangement products of nerve agents are not distinctive for the particular agent but for the chemical class they belong to. It was found that switching between ammonia doped and ordinary water ionisation chemistry can easily be performed within a few seconds. Making use of this effect it is possible to switch between fragment and molecular ion peak spectra. Thus, targeted fragmentation can be used to confirm identification based only on single peak detection. PTRMS turned out to be a promising technique for future CWA detectors. In terms of sensitivity, response time and selectivity (or confidence of identification, respectively) PTRMS performs as a bridging technique between IMS and GC-MS. PMID:24308198

  11. Comparison of 2-PAM and pro-2-PAM containing treatment regimens as antagonists of nerve agent-induced lethality and incapacitation. Final report, June 1981-December 1985

    SciTech Connect

    Talbot, B.G.; Harris, L.W.; Lennox, W.J.; Anderson, D.A.; Green, M.D.

    1986-09-01

    In vivo, (2-Puridine Aldoxine Methioidide) reactivates phosphonylated acetylcholinesterase AChE peripherally, but is effective in restoring AChE centrally because the quaternary nitrogen atom of 2-PAM prevents penetration of the brain. The problem was solved by the synthesis of the 1,6-dihyropyridine derivative of 2-PAM, pro-2-PAM (PP). Functional brain AChE is related to return to control performance on an accelerating rotarod (ARR) in animals intoxicated with soman. There should be a difference in the time to recovery of control ARR performance between PP- and 2-PAM-treated, sarin-intoxicated animals. In the present work, an ARR decrement free dosage (DFD) of each of these oximes (30 mg/kg, im) in combination with DFD of atropine (A) and mecamylamine (M) (0.79 mg/kg each, im) was used as pretreatment against sarin-induced deficit. The same antidotes were given pre-and post- intoxication (as pretreatment and therapy) to anatagonize sarin-induced lethality; the PP containing antidote provided significantly greater protection than that by the 2-PAM antidote which in turn provided significant protection over control. Neither antidote when given as pretreatment and therapy provided protection above control against soman-induced physical incapacitation, but they were equally effective in antagonizing VX-induced physical incapacitation. The reversal of sarin-induced physical debilitation reflects the central actions of PP and supports the notion that functional brain AChE activity is essential for rapid recovery from the debilitating effeclts on nerve agents.

  12. Portable Analytical Systems for On-Site Diagnosis of Exposure to Pesticides and Nerve Agents

    SciTech Connect

    Lin, Yuehe; Wang, Jun; Liu, Guodong; Timchalk, Chuck

    2009-12-01

    In this chapter, we summarize recent work in our laboratory on the development of sensitive portable analytical systems for use in on-site detection of exposure to organophosphate (OP) pesticides and chemical nerve agents. These systems are based on various nanomaterials functioning as transducers; recognition agents or labels and various elelectrochemical/immunoassay techniques. The studied nanomaterials included functionalized carbon nanotubes (CNT), zirconia nanoparticles (NPs) and quantum dots (QDs). Three biomarkers e.g. the free OPs, metabolites of OPs and protein-OP adducts in biological matrices have been employed for biomonitoring of OP exposure with our developed system. It has been found that the nanomaterial-based portable analytical systems have high sensitivity for the detection of the biomarkers, which suggest that these technologies offer great promise for the rapid and on-site detection and evaluation of OP exposure.

  13. Detection of nerve agents and biological molecules using embedded piezoresistive microcantilever sensors.

    NASA Astrophysics Data System (ADS)

    Porter, Timothy; Vail, Tim; Wooley, Amanda

    2008-03-01

    Embedded piezoresistive microcantilever (EPM) sensors have been used in the detection of a variety of analyte species. EPM sensors utilize a tiny piezoresistive microcantilever partially embedded into a sensing material to produce a sensing element that is compact, simple, resistant to movement and shock, and suitable for remote sensing applications. In the current project, we have used sensing materials comprised of an immobilizing polymer functionalized with either target enzymes or antibodies to detect two biological agents, bacillus globigi (BG) and Diisopropyl fluorophosphate (DFP). DFP is an organophosphate used as a simulant for organophosphate nerve agents, while BG is a large bacterial spore used as a simulant for other bacterial spores such as bacillus anthracis. Sensing results are presented for both types of EPM sensors.

  14. Chiral Separation of G-type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

    PubMed Central

    Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

    2014-01-01

    Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(–) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(–) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. Chirality 26:817–824, 2014. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc. PMID:25298066

  15. Behavioral side effects in rats treated with acetylcholinesterase inhibitors suggested used as prophylactics against nerve agents.

    PubMed

    Myhrer, Trond; Enger, Siri; Aas, Pål

    2010-05-01

    Acetylcholinesterase inhibitors in combination with an anticholinergic, particularly anticholinergics with antiglutamatergic properties, can effectively protect against nerve agent-induced seizures and lethality. The objective of the present study was to examine potential behavioral side effects of the anticholinesterases physostigmine (0.1mg/kg), galantamine (3mg/kg), huperzine (0.5mg/kg), and donepezil (2.5mg/kg) alone or each drug in combination with anticholinergic procyclidine (3mg/kg). The results showed that rats injected intraperitoneally with galantamine displayed a mild cognitive deficit in terms of reduced preference for novelty that was similarly found among animals treated with procyclidine combined with either galantamine or donepezil. Locomotor activity and rearing were radically depressed in all groups treated with anticholinesterases as well as in combination with procyclidine. Reductions in activity were most prominent for rats injected with galantamine alone. Equalizing effects of cholinesterase inhibitors and anticholinergics were absent in the present context. Findings from previous studies that both systemic and local (amygdala) application of physostigmine cause increased fear-motivated freezing response in rats, may explain the marked reductions in activity among the present rats. In view of these findings, use of anticholinesterases (crossing the blood-brain barrier) as prophylactics against nerve agents must be carefully examined to avoid severe side effects. PMID:20184916

  16. A lab-on-a-chip for detection of nerve agent sarin in blood.

    PubMed

    Tan, Hsih Yin; Loke, Weng Keong; Tan, Yong Teng; Nguyen, Nam-Trung

    2008-06-01

    Sarin (C(4)H(10)FO(2)P,O-isopropyl methylphosphonofluoridate) is a colourless, odourless and highly toxic phosphonate that acts as a cholinesterase inhibitor and disrupts neuromuscular transmission. Sarin and related phosphonates are chemical warfare agents, and there is a possibility of their application in a military or terrorist attack. This paper reports a lab-on-a-chip device for detecting a trace amount of sarin in a small volume of blood. The device should allow early detection of sarin exposure during medical triage to differentiate between those requiring medical treatment from mass psychogenic illness cases. The device is based on continuous-flow microfluidics with sequential stages for lysis of whole blood, regeneration of free nerve agent from its complex with blood cholinesterase, protein precipitation, filtration, enzyme-assisted reaction and optical detection. Whole blood was first mixed with a nerve gas regeneration agent, followed by a protein precipitation step. Subsequently, the lysed product was filtered on the chip in two steps to remove particulates and fluoride ions. The filtered blood sample was then tested for trace levels of regenerated sarin using immobilised cholinesterase on the chip. Activity of immobilised cholinesterase was monitored by the enzyme-assisted reaction of a substrate and reaction of the end-product with a chromophore. Resultant changes in chromophore-induced absorbance were recorded on the chip using a Z-shaped optical window. Loss of enzyme activity obtained prior and after passage of the treated blood sample, as shown by a decrease in recorded absorbance values, indicates the presence of either free or regenerated sarin in the blood sample. The device was fabricated in PMMA (polymethylmethacrylate) using CO(2)-laser micromachining. This paper reports the testing results of the different stages, as well as the whole device with all stages in the required assay sequence. The results demonstrate the potential use of a

  17. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for detection and identification of albumin phosphylation by organophosphorus pesticides and G- and V-type nerve agents.

    PubMed

    John, Harald; Breyer, Felicitas; Thumfart, Jörg Oliver; Höchstetter, Hans; Thiermann, Horst

    2010-11-01

    Toxic organophosphorus compounds (OPC), e.g., pesticides and nerve agents (NA), are known to phosphylate distinct endogenous proteins in vivo and in vitro. OPC adducts of butyrylcholinesterase and albumin are considered to be valuable biomarkers for retrospective verification of OPC exposure. Therefore, we have detected and identified novel adducts of human serum albumin (HSA) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Pure albumin and plasma were incubated with numerous pesticides and NA of the V- and G-type in different molar ratios. Samples were prepared either by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by in-gel enzymatic cleavage using endoproteinase Glu-C (Glu-C) or by combining highly albumin-selective affinity extraction with ultrafiltration followed by reduction, carbamidomethylation, and enzymatic cleavage (Glu-C) prior to MALDI-TOF MS analysis. Characteristic mass shifts for phosphylation revealed tyrosine adducts at Y(411) (Y(401)KFQNALLVRY(411)TKKVPQVSTPTLVE(425)), Y(148) and Y(150) (I(142)ARRHPY(148)FY(150)APE(153), single and double labeled), and Y(161) (L(154)LFFAKRY(161)KAAFTE(167)) produced by original NA (tabun, sarin, soman, cyclosarin, VX, Chinese VX, and Russian VX) as well as by chlorpyrifos-oxon, diisopropyl fluorophosphate (DFP), paraoxon-ethyl (POE), and profenofos. MALDI-MS/MS of the single-labeled I(142)-E(153) peptide demonstrated that Y(150) was phosphylated with preference to Y(148). Aged albumin adducts were not detected. The procedure described was reproducible and feasible for detection of adducts at the most reactive Y(411)-residue (S/N ≥ 3) when at least 1% of total albumin was labeled. This was achieved by incubating plasma with molar HSA/OPC ratios ranging from approximately 1:0.03 (all G-type NA, DFP, and POE) to 1:3 (V-type NA, profenofos). Relative signal intensity of the Y(411) adduct correlated well with the spotted relative

  18. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure.

    PubMed

    Halbrook, R S; Shugart, L R; Watson, A P; Munro, N B; Linnabary, R D

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release. PMID:1399773

  19. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    SciTech Connect

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.; Munro, N.B.; Linnabary, R.D. )

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.

  20. Immobilization of Russian VX skin depots by localized cooling: implications for decontamination and medical countermeasures.

    PubMed

    Mikler, J; Tenn, C; Worek, F; Reiter, G; Thiermann, H; Garrett, M; Bohnert, S; Sawyer, T W

    2011-09-25

    The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD₅₀ for VR topically applied on the ear was 100 μg/kg. Treatment of VR exposed animals (5 × LD₅₀) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective. PMID:21704135

  1. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

    PubMed

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L

    2016-01-01

    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period. PMID:26829110

  2. The noncontact detection of nerve agent simulants on U.S. military CARC

    NASA Astrophysics Data System (ADS)

    Petryk, Michael W. P.

    2009-05-01

    The non-contact detection of chemical warfare agent simulants is achieved in the condensed phase using polarization modulation infrared reflection-absorption spectroscopy (PMIRRAS). The G-series nerve agent simulants, trimethyl phosphate (TMP) and triethyl phosphate (TEP), are detected on US military chemical agent resistant coating (CARC) using PMIRRAS. Optimal detector angles for PMIRRAS are determined, as are absorption features which can be used to distinguish between the spectral contributions of the substrate (CARC) and the analyte (TMP or TEP). Ab initio calculations carried out at the B3LYP / 6-31G(d,p) level of theory and basis set are used to predict the most stable simulant conformations, and their harmonic (unscaled) vibrational frequencies. Ab initio vibrational frequency data is used to explain the existence of both upward-oriented and downward-oriented PMIRRAS absorption features in terms of molecular orientation at a surface and the orientation of the dipole derivative vector of a given vibrational mode.

  3. Improving the promiscuous nerve agent hydrolase activity of a thermostable archaeal lactonase.

    PubMed

    Merone, Luigia; Mandrich, Luigi; Porzio, Elena; Rossi, Mosé; Müller, Susanne; Reiter, Georg; Worek, Franz; Manco, Giuseppe

    2010-12-01

    The thermostable Phosphotriesterase-Like Lactonase from Sulfolobus solfataricus (SsoPox) hydrolyzes lactones and, at a lower rate, neurotoxic organophosphorus compounds. The persistent demand of detoxification tools in the field of agricultural wastes and restoring of conditions after terrorist acts prompted us to exploit SsoPox as a "starter" to evolve its ancillary nerve agents hydrolytic capability. A directed evolution strategy yielded, among several variants, the single mutant W263F with k(cat) and specificity constant against paraoxon 16- and 6-fold enhanced, respectively, compared to the wild type. Furthermore, a phenomenon of enzyme activation by SDS has been observed, which allowed to increase those values 150- and 28-fold, respectively. The activity of SsoPox against the deadly nerve gas Cyclosarin has been reported for the first time and proved to be substantially unaffected for variant W263F. Finally, outperforming efficiency of W263F was demonstrated, under severe stressing conditions, with respect to the best known phosphotriesterase PTE from Brevundimonas diminuta. PMID:20667718

  4. Single treatment of VX poisoned guinea pigs with the phosphotriesterase mutant C23AL: Intraosseous versus intravenous injection.

    PubMed

    Wille, Timo; Neumaier, Katharina; Koller, Marianne; Ehinger, Christina; Aggarwal, Nidhi; Ashani, Yacov; Goldsmith, Moshe; Sussman, Joel L; Tawfik, Dan S; Thiermann, Horst; Worek, Franz

    2016-09-01

    The recent attacks with the nerve agent sarin in Syria reveal the necessity of effective countermeasures against highly toxic organophosphorus compounds. Multiple studies provide evidence that a rapid onset of antidotal therapy might be life-saving but current standard antidotal protocols comprising reactivators and competitive muscarinic antagonists show a limited efficacy for several nerve agents. We here set out to test the newly developed phosphotriesterase (PTE) mutant C23AL by intravenous (i.v.), intramuscular (i.m.; model for autoinjector) and intraosseous (i.o.; model for intraosseous insertion device) application in an in vivo guinea pig model after VX challenge (∼2LD50). C23AL showed a Cmax of 0.63μmolL(-1) after i.o. and i.v. administration of 2mgkg(-1) providing a stable plasma profile up to 180min experimental duration with 0.41 and 0.37μmolL(-1) respectively. The i.m. application of C23AL did not result in detectable plasma levels. All animals challenged with VX and subsequent i.o. or i.v. C23AL therapy survived although an in part substantial inhibition of erythrocyte, brain and diaphragm AChE was detected. Theoretical calculation of the time required to hydrolyze in vivo 96.75% of the toxic VX enantiomer is consistent with previous studies wherein similar activity of plasma containing catalytic scavengers of OPs resulted in non-lethal protection although accompanied with a variable severity of cholinergic symptoms. The relatively low C23AL plasma level observed immediately after its i.v. or i.o load, point at a possible volume of distribution greater than the guinea pig plasma content, and thus underlines the necessity of in vivo experiments in antidote research. In conclusion the i.o. application of PTE is efficient and resulted in comparable plasma levels to the i.v. application at a given time. Thus, i.o. vascular access systems could improve the post-exposure PTE therapy of nerve agent poisoning. PMID:27397758

  5. Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides.

    PubMed

    McCarren, Hilary S; McDonough, John H

    2016-06-01

    Organophosphorus pesticides (OPs) and nerve agents (NAs) are highly toxic chemicals that pose a significant threat to human health worldwide. These compounds induce status epilepticus (SE) by irreversibly blocking the ability of acetylcholinesterase to break down acetylcholine at neural synapses. Animal models of organophosphate-induced SE are a crucial resource for identifying new anticonvulsant therapies. Here, we describe the development of various animal models of SE induced by NA or OP exposure. Experiments in nonhuman primates, rats, mice, and guinea pigs have helped to identify novel therapeutic targets in the central nervous system, with particular success at modulating GABAergic and glutamatergic receptors. The anticonvulsants identified by NA- and OP-induced SE models are well poised for fast advancement into clinical development, and their potential utility in the broader field of epilepsy should make them all the more attractive for commercial pursuit. PMID:27258770

  6. Impurity Profiling to Match a Nerve Agent to Its Precursor Source for Chemical Forensics Applications

    SciTech Connect

    Fraga, Carlos G.; Perez Acosta, Gabriel A.; Crenshaw, Michael D.; Wallace, Krys; Mong, Gary M.; Colburn, Heather A.

    2011-10-31

    Chemical forensics is an emerging field in homeland security that aims to attribute a weaponized toxic chemical or related material to its source. Herein, for the first time, trace impurities originating from a chemical precursor were used to match a synthesized nerve agent to its precursor source. Specifically, multiple batches of sarin and its intermediate were synthesized from two commercial stocks of methylphosphonic dichloride (DC) and were then matched by impurity profiling to their DC stocks from out of five possible stocks. This was possible because each DC stock had a unique impurity profile that, for the tested stocks, persisted through synthesis, decontamination, and sample preparation. This work may form a basis for using impurity profiling to help find and prosecute perpetrators of chemical attacks.

  7. Nucleotide sequence of a gene encoding an organophosphorus nerve agent degrading enzyme from Alteromonas haloplanktis.

    PubMed

    Cheng, T; Liu, L; Wang, B; Wu, J; DeFrank, J J; Anderson, D M; Rastogi, V K; Hamilton, A B

    1997-01-01

    Organophosphorus acid anhydrolases (OPAA) catalyzing the hydrolysis of a variety of toxic organophosphorus cholinesterase inhibitors offer potential for decontamination of G-type nerve agents and pesticides. The gene (opa) encoding an OPAA was cloned from the chromosomal DNA of Alteromonas haloplanktis ATCC 23821. The nucleotide sequence of the 1.7 -kb DNA fragment contained the opa gene (1.3 kb) and its flanking region. We report structural and functional similarity of OPAAs from A. haloplanktis and Alteromonas sp JD6.5 with the enzyme prolidase that hydrolyzes dipeptides with a prolyl residue in the carboxyl-terminal position. These results corroborate the earlier conclusion that the OPAA is a type of X-Pro dipeptidase, and that X-Pro could be the native substrate for such an enzyme in Alteromonas cells. PMID:9079288

  8. Detoxification of organophosphorus pesticides and nerve agents through RSDL: efficacy evaluation by (31)P NMR spectroscopy.

    PubMed

    Elsinghorst, Paul W; Worek, Franz; Koller, Marianne

    2015-03-01

    Intoxication by organophosphorus compounds, especially by pesticides, poses a considerable risk to the affected individual. Countermeasures involve both medical intervention by means of antidotes as well as external decontamination to reduce the risk of dermal absorption. One of the few decontamination options available is Reactive Skin Decontamination Lotion (RSDL), which was originally developed for military use. Here, we present a (31)P NMR spectroscopy based methodology to evaluate the detoxification efficacy of RSDL with respect to a series of organophosphorus pesticides and nerve agents. Kinetic analysis of the obtained NMR data provided degradation half-lives proving that RSDL is also reasonably effective against organophosphorus pesticides. Unexpected observations of different RSDL degradation patterns are presented in view of its reported oximate-catalyzed mechanism of action. PMID:25597861

  9. Gas sensor based on nano ZSM-5 zeolite films for the nerve agent simulant dimethylmethylphosphonate detection

    NASA Astrophysics Data System (ADS)

    Xie, Haifen; Ting, Yu; Sun, Xiaoxiang; Jia, Zhou; Huang, Yiping

    2004-12-01

    The piezoelectric sensor device coated with nanosize ZSM-5 zeolite films has beem fabricated. The Nerve agent simulant Dimethylmethylphosphonate has been tested with this piezoelectric sensor devices. The frequency shifts to time at 1 ppm, 5ppm and 20ppm DMMP are examined respectively. The minimum detection concentration of 1ppm DMMP has been obtained in the N2 at 293K. 1 ppm is lower than the EC50 concentration value (where EC50 is the airborne concentration sufficient to induce severe effects in 50% of those exposed for 30 min). The frequency sensitivity was found to be about 60HZ / ppm. The effect of acetone on the ZSM-5 zeolite film was also investigated for the selectivity test. Using principle component analysis (PCA), we can qualify and quantify these testing gases.

  10. Trapping of organophosphorus chemical nerve agents in water with amino acid functionalized baskets.

    PubMed

    Ruan, Yian; Dalkiliç, Erdin; Peterson, Paul W; Pandit, Aroh; Dastan, Arif; Brown, Jason D; Polen, Shane M; Hadad, Christopher M; Badjić, Jovica D

    2014-04-01

    We prepared eleven amino-acid functionalized baskets and used (1) H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 Å(3) ) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 Å(3) ). The binding interaction (Ka ) was found to vary with the size of substituent groups at the basket's rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host-guest interaction, as described with the Verloop's B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future. PMID:24616086

  11. Good manufacturing practice: manufacturing of a nerve agent antidote nanoparticle suspension.

    PubMed

    Clark, Andrew P-Z; Dixon, Hong; Cantu, Norma L; Cabell, Larry A; McDonough, Joe A

    2013-01-01

    We have established a current good manufacturing practice (GMP) manufacturing process to produce a nanoparticle suspension of 1,1'-methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) in cottonseed oil (CSO) as a nerve agent antidote for a Phase 1 clinical trial. Bis-pyridinium oximes such as MMB4 were previously developed for emergency treatment of organophosphate nerve agent intoxication. Many of these compounds offer efficacy superior to monopyridinium oximes, but they have poor thermal stability due to hydrolytic cleavage in aqueous solution. We previously developed a nonaqueous nanoparticle suspension to improve the hydrothermal stability, termed Enhanced Formulation (EF). An example of this formulation technology is a suspension of MMB4 DMS nanoparticles in CSO. Due to the profound effect of particle size distribution on product quality and performance, particle size must be controlled during the manufacturing process. Therefore, a particle size analysis method for MMB4 DMS in CSO was developed and validated to use in support of good laboratory practice/GMP development and production activities. Manufacturing of EF was accomplished by milling MMB4 DMS with CSO and zirconia beads in an agitator bead mill. The resulting bulk material was filled into 5-mL glass vials at a sterile fill facility and terminally sterilized by gamma irradiation. The clinical lot was tested and released, a Certificate of Analysis was issued, and a 3-year International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stability study started. The drug product was placed in storage for Phase 1 clinical trial distribution. A dose delivery uniformity study was undertaken to ensure that the correct doses were delivered to the patients in the clinic. PMID:23929446

  12. Nerve Agent Exposure Elicits Site-Specific Changes in Protein Phosphorylation in Mouse Brain

    PubMed Central

    Zhu, Hongwen; O’Brien, Jennifer J.; O’Callaghan, James P.; Miller, Diane B.; Zhang, Qiang; Rana, Minal; Tsui, Tiffany; Peng, Youyi; Tomesch, John; Hendrick, Joseph P.; Wennogle, Lawrence P; Snyder, Gretchen L.

    2010-01-01

    Organophosphorus (OP) compounds cause toxic symptoms, including convulsions, coma, and death, as the result of irreversible inhibition of acetylcholinesterase (AChE). The development of effective treatments to block these effects and attenuate long-term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions. We employed a candidate method (called CNSProfile™) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound, diisopropyl fluorophosphate (DFP). Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of DFP-treated mice; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho-specific antibodies. DFP exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL/6 and FVB mice. DFP treatment significantly altered phosphorylation at regulatory residues on glutamate receptors, including Serine897 (S897) of the NR1 NMDA receptor. NR1 phosphorylation was bi-directionally regulated after DFP in striatum versus hippocampus. NR1 phosphorylation was reduced in striatum, but elevated in hippocampus, compared with controls. DARPP-32 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate, Threonine75 (T75). Phencynonate hydrochloride, a muscarinic cholinergic antagonist, prevented seizure-like behaviors and the observed changes in phosphorylation induced by DFP. The data reveal region-specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure-like behavior and which are reversed by the muscarinic receptor blockade. This approach identifies specific targets for nerve agents, including substrates for Cdk5 kinase, which may be the basis for new anti-convulsant therapies. PMID:20423708

  13. Tailoring the Pore Size and Functionality of UiO-Type Metal-Organic Frameworks for Optimal Nerve Agent Destruction.

    PubMed

    Peterson, Gregory W; Moon, Su-Young; Wagner, George W; Hall, Morgan G; DeCoste, Jared B; Hupp, Joseph T; Farha, Omar K

    2015-10-19

    Evaluation of UiO-66 and UiO-67 metal-organic framework derivatives as catalysts for the degradation of soman, a chemical warfare agent, showed the importance of both the linker size and functionality. The best catalysts yielded half-lives of less than 1 min. Further testing with a nerve agent simulant established that different rate-assessment techniques yield similar values for degradation half-lives. PMID:26431370

  14. Determination of VX-G analogue in red blood cells via gas chromatography-tandem mass spectrometry following an accidental exposure to VX.

    PubMed

    McGuire, Jeffrey M; Taylor, James T; Byers, Christopher E; Jakubowski, Edward M; Thomson, Sandra M

    2008-01-01

    A sensitive method for determining exposure to the chemical warfare agent VX is described in which the biomarker ethyl methylphosphonofluoridate (VX-G) is measured in red blood cells (RBCs) following treatment with fluoride ion using isotope-dilution gas chromatography-tandem mass spectrometry. The analyte was isolated via solid-phase extraction and detected using ammonia chemical ionization in the multiple reaction monitoring mode. A good linear relationship was obtained in the quantitative concentration range of 4 ng/mL to 1000 ng/mL with an absolute detection limit of < 1 pg on column. The method has been applied to the analysis of RBCs from a laboratory worker accidentally exposed to VX vapor. Detection and quantitation of VX-G were possible in samples taken as late as 27 days following exposure. PMID:18269797

  15. GC-MS and LC-MS analysis of nerve agents in body fluids: intra-laboratory verification test using spiked plasma and urine samples.

    PubMed

    Koller, Marianne; Becker, Christian; Thiermann, Horst; Worek, Franz

    2010-05-15

    The purpose of this study was to check the applicability of different analytical methods for the identification of unknown nerve agents in human body fluids. Plasma and urine samples were spiked with nerve agents (plasma) or with their metabolites (urine) or were left blank. Seven random samples (35% of all samples) were selected for the verification test. Plasma was worked up for unchanged nerve agents and for regenerated nerve agents after fluoride-induced reactivation of nerve agent-inhibited butyrylcholinesterase. Both extracts were analysed by GC-MS. Metabolites were extracted from plasma and urine, respectively, and were analysed by LC-MS. The urinary metabolites and two blank samples could be identified without further measurements, plasma metabolites and blanks were identified in six of seven samples. The analysis of unchanged nerve agent provided five agents/blanks and the sixth agent after further investigation. The determination of the regenerated agents also provided only five clear findings during the first screening because of a rather noisy baseline. Therefore, the sample preparation was extended by a size exclusion step performed before addition of fluoride which visibly reduced baseline noise and thus improved identification of the two missing agents. The test clearly showed that verification should be performed by analysing more than one biomarker to ensure identification of the agent(s). PMID:20061191

  16. Direct derivatization and gas chromatography-tandem mass spectrometry identification of nerve agent biomarkers in urine samples.

    PubMed

    Subramaniam, Raja; Östin, Anders; Nilsson, Calle; Åstot, Crister

    2013-06-01

    Rapid determination of nerve agent biomarkers at low-ppb levels in urine samples was achieved by direct derivatization and sample analysis using gas chromatography-tandem mass spectrometry. The studied biomarkers were alkylphosphonic acids (APAs), as they are specific hydrolysis products of organophosphorus nerve agents that can be used to verify nerve agent exposure. The sample preparation technique employed involves rapid direct derivatization (5min) of acidified urine samples (25μL) using a highly fluorinated phenyldiazomethane reagent [1-(diazomethyl)-3,5-bis(trifluoromethyl)benzene]. The derivatization conditions were optimized using statistical experimental design and multivariate data analysis. The APA derivatives were analyzed by GC-MS and MS/MS using negative ion chemical ionization. The selectivity and sensitivity of analyses performed by low and high resolution single ion monitoring MS-mode were compared with those performed by multiple reaction monitoring MS/MS-mode. The MS/MS technique offered the greatest sensitivity and selectivity of the tested mass spectrometric techniques, with limits of detection ranging from 0.5 to 1ng APAs/mL of urine. The method's robustness was evaluated using urine samples from the OPCW 2nd biomedical confidence building exercise and all APAs present in the samples were conclusively identified. The method thus offers excellent performance and is viable for the simultaneous trace determination of a wide range of nerve agent markers. PMID:23603296

  17. AMPEROMETRIC THICK-FILM STRIP ELECTRODES FOR MONITORING ORGANOPHOSPHATE NERVE AGENTS BASED ON IMMOBILIZED ORGANOPHOSPHORUS HYDROLASE. (R823663)

    EPA Science Inventory

    An amperometric biosensor based on the immobilization of organophosphorus hydrolase
    (OPH) onto screen-printed carbon electrodes is shown useful for the rapid, sensitive, and low-cost
    detection of organophosphate (OP) nerve agents. The sensor relies upon the sensitive and ra...

  18. Detection and classification of organophosphate nerve agent simulants using support vector machines with multiarray sensors.

    PubMed

    Sadik, Omowunmi; Land, Walker H; Wanekaya, Adam K; Uematsu, Michiko; Embrechts, Mark J; Wong, Lut; Leibensperger, Dale; Volykin, Alex

    2004-01-01

    The need for rapid and accurate detection systems is expanding and the utilization of cross-reactive sensor arrays to detect chemical warfare agents in conjunction with novel computational techniques may prove to be a potential solution to this challenge. We have investigated the detection, prediction, and classification of various organophosphate (OP) nerve agent simulants using sensor arrays with a novel learning scheme known as support vector machines (SVMs). The OPs tested include parathion, malathion, dichlorvos, trichlorfon, paraoxon, and diazinon. A new data reduction software program was written in MATLAB V. 6.1 to extract steady-state and kinetic data from the sensor arrays. The program also creates training sets by mixing and randomly sorting any combination of data categories into both positive and negative cases. The resulting signals were fed into SVM software for "pairwise" and "one" vs all classification. Experimental results for this new paradigm show a significant increase in classification accuracy when compared to artificial neural networks (ANNs). Three kernels, the S2000, the polynomial, and the Gaussian radial basis function (RBF), were tested and compared to the ANN. The following measures of performance were considered in the pairwise classification: receiver operating curve (ROC) Az indices, specificities, and positive predictive values (PPVs). The ROC Az) values, specifities, and PPVs increases ranged from 5% to 25%, 108% to 204%, and 13% to 54%, respectively, in all OP pairs studied when compared to the ANN baseline. Dichlorvos, trichlorfon, and paraoxon were perfectly predicted. Positive prediction for malathion was 95%. PMID:15032529

  19. Advances in toxicology and medical treatment of chemical warfare nerve agents

    PubMed Central

    2012-01-01

    Organophosphorous (OP) Nerve agents (NAs) are known as the deadliest chemical warfare agents. They are divided into two classes of G and V agents. Most of them are liquid at room temperature. NAs chemical structures and mechanisms of actions are similar to OP pesticides, but their toxicities are higher than these compounds. The main mechanism of action is irreversible inhibition of Acetyl Choline Esterase (AChE) resulting in accumulation of toxic levels of acetylcholine (ACh) at the synaptic junctions and thus induces muscarinic and nicotinic receptors stimulation. However, other mechanisms have recently been described. Central nervous system (CNS) depression particularly on respiratory and vasomotor centers may induce respiratory failure and cardiac arrest. Intermediate syndrome after NAs exposure is less common than OP pesticides poisoning. There are four approaches to detect exposure to NAs in biological samples: (I) AChE activity measurement, (II) Determination of hydrolysis products in plasma and urine, (III) Fluoride reactivation of phosphylated binding sites and (IV) Mass spectrometric determination of cholinesterase adducts. The clinical manifestations are similar to OP pesticides poisoning, but with more severity and fatalities. The management should be started as soon as possible. The victims should immediately be removed from the field and treatment is commenced with auto-injector antidotes (atropine and oximes) such as MARK I kit. A 0.5% hypochlorite solution as well as novel products like M291 Resin kit, G117H and Phosphotriesterase isolated from soil bacterias, are now available for decontamination of NAs. Atropine and oximes are the well known antidotes that should be infused as clinically indicated. However, some new adjuvant and additional treatment such as magnesium sulfate, sodium bicarbonate, gacyclidine, benactyzine, tezampanel, hemoperfusion, antioxidants and bioscavengers have recently been used for OP NAs poisoning. PMID:23351280

  20. Fragmentation pathways and structural characterization of 14 nerve agent compounds by electrospray ionization tandem mass spectrometry.

    PubMed

    Housman, Kathleen J; Swift, Austin T; Oyler, Jonathan M

    2015-03-01

    Organophosphate nerve agents (OPNAs) are some of the most widely used and proliferated chemical warfare agents. As evidenced by recent events in Syria, these compounds remain a serious military and terrorist threat to human health because of their toxicity and the ease with which they can be used, produced and stored. There are over 2,000 known, scheduled compounds derived from common parent structures with many more possible. To address medical, forensic, attribution, remediation and other requirements, laboratory systems have been established to provide the capability to analyze 'unknown' samples for the presence of these compounds. Liquid chromatography/mass spectrometric methods have been validated and are routinely used in the analysis of samples for a very limited number of these compounds, but limited data exist characterizing the electrospray ionization (ESI) and mass spectrometric fragmentation pathways of the compound families. This report describes results from direct infusion ESI/MS, ESI/MS(2) and ESI/MS(3) analysis of 14 G and V agents, the major OPNA families, using an AB Sciex 4000 QTrap. Using a range of conditions, spectra were acquired and characteristic fragments identified. The results demonstrated that the reproducible and predictable fragmentation of these compounds by ESI/MS, ESI/MS(2) and ESI/MS(3) can be used to describe systematic fragmentation pathways specific to compound structural class. These fragmentation pathways, in turn, may be useful as a predictive tool in the analysis of samples by screening and confirmatory laboratories to identify related compounds for which authentic standards are not readily available. PMID:25519457

  1. Advances in toxicology and medical treatment of chemical warfare nerve agents.

    PubMed

    Moshiri, Mohammd; Darchini-Maragheh, Emadodin; Balali-Mood, Mahdi

    2012-01-01

    Organophosphorous (OP) Nerve agents (NAs) are known as the deadliest chemical warfare agents. They are divided into two classes of G and V agents. Most of them are liquid at room temperature. NAs chemical structures and mechanisms of actions are similar to OP pesticides, but their toxicities are higher than these compounds. The main mechanism of action is irreversible inhibition of Acetyl Choline Esterase (AChE) resulting in accumulation of toxic levels of acetylcholine (ACh) at the synaptic junctions and thus induces muscarinic and nicotinic receptors stimulation. However, other mechanisms have recently been described. Central nervous system (CNS) depression particularly on respiratory and vasomotor centers may induce respiratory failure and cardiac arrest. Intermediate syndrome after NAs exposure is less common than OP pesticides poisoning. There are four approaches to detect exposure to NAs in biological samples: (I) AChE activity measurement, (II) Determination of hydrolysis products in plasma and urine, (III) Fluoride reactivation of phosphylated binding sites and (IV) Mass spectrometric determination of cholinesterase adducts. The clinical manifestations are similar to OP pesticides poisoning, but with more severity and fatalities. The management should be started as soon as possible. The victims should immediately be removed from the field and treatment is commenced with auto-injector antidotes (atropine and oximes) such as MARK I kit. A 0.5% hypochlorite solution as well as novel products like M291 Resin kit, G117H and Phosphotriesterase isolated from soil bacterias, are now available for decontamination of NAs. Atropine and oximes are the well known antidotes that should be infused as clinically indicated. However, some new adjuvant and additional treatment such as magnesium sulfate, sodium bicarbonate, gacyclidine, benactyzine, tezampanel, hemoperfusion, antioxidants and bioscavengers have recently been used for OP NAs poisoning. PMID:23351280

  2. Development of an autonomous detector for sensing of nerve agents based on functionalized silicon nanowire field-effect transistors.

    PubMed

    Clavaguera, Simon; Raoul, Nicolas; Carella, Alexandre; Delalande, Michael; Celle, Caroline; Simonato, Jean-Pierre

    2011-10-15

    The ability to detect minute traces of chemical warfare agents is mandatory both for military forces and homeland security. Various detectors based on different technologies are available but still suffer from serious drawbacks such as false positives. There is still a need for the development of innovative reliable sensors, in particular for organophosphorus nerve agents like Sarin. We report herein on the fabrication of a portable, battery-operated, microprocessor-based prototype sensor system relying on silicon nanowire field-effect transistors for the detection of nerve agents. A fast, supersensitive and highly selective detection of organophosphorus molecules is reported. The results show also high selectivity in complex mixtures and on contaminated materials. PMID:21962681

  3. Development and application of acute exposure guideline levels (AEGLs) for chemical warfare nerve and sulfur mustard agents.

    PubMed

    Watson, Annetta; Opresko, Dennis; Young, Robert; Hauschild, Veronique

    2006-01-01

    Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios. PMID:16621779

  4. Development and Application of Acute Exposure Guideline Levels (AEGLs) for Chemical Warfare Nerve and Sulfur Mustard Agents.

    SciTech Connect

    Watson, Annetta Paule; Opresko, Dennis M; Young, Robert A; Hauschild, Veronique

    2006-01-01

    Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios.

  5. Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

    SciTech Connect

    Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi; Cerasoli, Douglas M.; Bahnson, Brian J.

    2009-09-02

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{sub R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

  6. Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.

    PubMed

    Samanta, Uttamkumar; Kirby, Stephen D; Srinivasan, Prabhavathi; Cerasoli, Douglas M; Bahnson, Brian J

    2009-08-15

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents. PMID:19394314

  7. Continuum Model for Decontamination of Chemical Warfare Agent from a Rubbery Polymer using the Maxwell-Stefan Formulation

    NASA Astrophysics Data System (ADS)

    Varady, Mark; Bringuier, Stefan; Pearl, Thomas; Stevenson, Shawn; Mantooth, Brent

    Decontamination of polymers exposed to chemical warfare agents (CWA) often proceeds by application of a liquid solution. Absorption of some decontaminant components proceed concurrently with extraction of the CWA, resulting in multicomponent diffusion in the polymer. In this work, the Maxwell-Stefan equations were used with the Flory-Huggins model of species activity to mathematically describe the transport of two species within a polymer. This model was used to predict the extraction of the nerve agent O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate (VX) from a silicone elastomer into both water and methanol. Comparisons with experimental results show good agreement with minimal fitting of model parameters from pure component uptake data. Reaction of the extracted VX with sodium hydroxide in the liquid-phase was also modeled and used to predict the overall rate of destruction of VX. Although the reaction proceeds more slowly in the methanol-based solution compared to the aqueous solution, the extraction rate is faster due to increasing VX mobility as methanol absorbs into the silicone, resulting in an overall faster rate of VX destruction.

  8. Percutaneous toxicity and decontamination of soman, VX, and paraoxon in rats using detergents.

    PubMed

    Misík, Jan; Pavliková, Růžena; Kuča, Kamil

    2013-06-01

    Highly toxic organophosphorus compounds (OPs) were originally developed for warfare or as agricultural pesticides. Today, OPs represent a serious threat to military personnel and civilians. This study investigates the in vivo decontamination of male Wistar rats percutaneously exposed to paraoxon and two potent nerve agents--soman (GD) and VX. Four commercial detergents were tested as decontaminants--Neodekont(TM), Argos(TM), Dermogel(TM), and FloraFree(TM). Decontamination performed 2 min after exposure resulted in a higher survival rate in comparison with non-decontaminated controls. The decontamination effectiveness was expressed as protective ratio (PR, median lethal dose of agent in decontaminated animals divided by the median lethal dose of agent in untreated animals). The highest decontamination effectiveness was consistently achieved with Argos(TM) (PR=2.3 to 64.8), followed by Dermogel(TM) (PR=2.4 to 46.1). Neodekont(TM) and FloraFree(TM) provided the lowest decontamination effectiveness, equivalent to distilled water (PR=1.0 to 43.2). PMID:23819929

  9. Pediatric nerve agent poisoning: medical and operational considerations for emergency medical services in a large American city.

    PubMed

    Foltin, George; Tunik, Michael; Curran, Jennifer; Marshall, Lewis; Bove, Joseph; van Amerongen, Robert; Cherson, Allen; Langsam, Yedidyah; Kaufman, Bradley; Asaeda, Glenn; Gonzalez, Dario; Cooper, Arthur

    2006-04-01

    Most published recommendations for treatment of pediatric nerve agent poisoning are based on standard resuscitation doses for these agents. However, certain medical and operational concerns suggest that an alternative approach may be warranted for treatment of children by emergency medical personnel after mass chemical events. (1) There is evidence both that suprapharmacological doses may be warranted and that side effects from antidote overdosage can be tolerated. (2) There is concern that many emergency medical personnel will have difficulty determining both the age of the child and the severity of the symptoms. Therefore, the Regional Emergency Medical Advisory Committee of New York City and the Fire Department, City of New York, Bureau of Emergency Medical Services, in collaboration with the Center for Pediatric Emergency Medicine of the New York University School of Medicine and the Bellevue Hospital Center, have developed a pediatric nerve agent antidote dosing schedule that addresses these considerations. These doses are comparable to those being administered to adults with severe symptoms and within limits deemed tolerable after inadvertent nerve agent overdose in children. We conclude that the above approach is likely a safe and effective alternative to weight-based dosing of children, which will be nearly impossible to attain under field conditions. PMID:16651913

  10. Intrinsic optical fiber sensor for sensing organophosphate nerve agent using the modified cladding approach

    NASA Astrophysics Data System (ADS)

    Bansal, Lalitkumar; El-Sherif, Mahmoud

    2004-03-01

    The concept of modified cladding based sensors represents the largest class of intrinsic fiber optic chemical sensors. In this design, the passive cladding of the optical fiber is replaced by an active coating, called modified cladding. The analyte in this case diffuses into the coating and induces changes in the absorbance, fluorescence, or some other spectroscopic property of the modified cladding, the coating acts as a chemo-chromic transducer and sensing takes place by intensity modulation. This design i.e. of the coating based sensors, has found enormous applicability in the realm of chemical and biochemical sensing which also includes environmental monitoring and detection of chemical warfare agents. In this paper, the development of an intrinsic fiber optic sensor for detection of organophosphate dimethyl-methyl phoshopnate (DMMP) is presented. DMMP is a chemical precursor to the nerve agent sarin. The chemo-chromic transducer material used as a modified coating on the fiber core is NDSA (Naphthalene disulphonic acid) doped polypyrrole. This coating material shows conductivity and absorbance change when exposed to DMMP. The fabrication of the sensor device is a three step process which involves (a) etching a small section of the optical fiber to expose the core, (b) coating the etched section of the optical fiber with the polymer, (c) integration of sensor components and testing. Thin film characterization is done using the UV-Vis spectrophotometer on in-situ coated films of polypyrrole on a glass substrate to check for absorbance change upon exposure to DMMP. The development procedure is presented next and encouraging results are discussed.