Science.gov

Sample records for agents sarin soman

  1. Chemical Warfare Agent Surface Adsorption: Hydrogen Bonding of Sarin and Soman to Amorphous Silica

    DTIC Science & Technology

    2014-03-17

    2014 Figure 1. The structures of the CWAs sarin (red) and soman ( blue ) and five of the most common simulants (black) used to help predict agent chemistry...small transfer chamber located within the confines of a CWA-certified surety fume hood. Within the main chamber, the sample was mounted on a molybdenum ...above 45 kJ/mol, for both agents. In fact, the desorption energy for soman ( blue ) approaches 60 kJ/mol at the lowest coverages. The high activation

  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. Chemical Warfare Agent Surface Adsorption: Hydrogen Bonding of Sarin and Soman to Amorphous Silica.

    PubMed

    Davis, Erin Durke; Gordon, Wesley O; Wilmsmeyer, Amanda R; Troya, Diego; Morris, John R

    2014-04-17

    Sarin and soman are warfare nerve agents that represent some of the most toxic compounds ever synthesized. The extreme risk in handling such molecules has, until now, precluded detailed research into the surface chemistry of agents. We have developed a surface science approach to explore the fundamental nature of hydrogen bonding forces between these agents and a hydroxylated surface. Infrared spectroscopy revealed that both agents adsorb to amorphous silica through the formation of surprisingly strong hydrogen-bonding interactions with primarily isolated silanol groups (SiOH). Comparisons with previous theoretical results reveal that this bonding occurs almost exclusively through the phosphoryl oxygen (P═O) of the agent. Temperature-programmed desorption experiments determined that the activation energy for hydrogen bond rupture and desorption of sarin and soman was 50 ± 2 and 52 ± 2 kJ/mol, respectively. Together with results from previous studies involving other phosphoryl-containing molecules, we have constructed a detailed understanding of the structure-function relationship for nerve agent hydrogen bonding at the gas-surface interface.

  4. Metabolite pharmacokinetics of soman, sarin, and GF in rats and biological monitoring of exposure to toxic organophosphorus agents

    SciTech Connect

    Shih, M.L.; McMonagle, J.D.; Dolzine, T.W.; Gresham, V.C.

    1993-05-13

    This study reports on the pharmacokinetics of the elimination of the metabolites of three toxic organophosphorus compounds (Soman, sarin, and GF). Urine, blood, and lung tissue were collected from rats dosed via subcutaneous route at 75 ug/Kg. Urinary excretion of the metabolite was the major elimination route for these three compounds. The major differences among them were primarily the extent and rate of excretion. The hydrolyzed form, alkylmethylphosphonic acid, was the single major metabolite formed and excreted in urine by a nonsaturable mechanism. Nearly total recoveries of the given doses for sarin and GF in metabolite form were obtained from the urine. The terminal elimination half-lives in urine were 6 and 15 hours for sarin and GF, respectively. Soman metabolite showed a biphasic elimination curve with terminal half-lives of 24 and 14 hours approximately. Soman was excreted at a slower rate with a recovery of only about 60%. Lung was the major organ of accumulation for soman. In blood the toxic agents were concentrated more in red blood cells than in plasma.

  5. The application of the fluoride reactivation process to the detection of sarin and soman nerve agent exposures in biological samples.

    PubMed

    Adams, T K; Capacio, B R; Smith, J R; Whalley, C E; Korte, W D

    2004-02-01

    The fluoride reactivation process was evaluated for measuring the level of sarin or soman nerve agents reactivated from substrates in plasma and tissue from in vivo exposed guinea pigs (Cava porcellus), in blood from in vivo exposed rhesus monkeys (Macaca mulatta), and in spiked human plasma and purified human albumin. Guinea pig exposures ranged from 0.05 to 44 LD50, and reactivated nerve agent levels ranged from 1.0 ng/mL in plasma obtained from 0.05 LD50 sarin-exposed guinea pigs to an average of 147 ng/g in kidney tissue obtained from two 2.0 LD50 soman-exposed guinea pigs. Positive dose-response relationships were observed in all low-level, 0.05 to 0.4 LD50, exposure studies. An average value of 2.4 ng/mL for reactivated soman was determined in plasma obtained from two rhesus monkeys three days after a 2 LD50 exposure. Of the five types of guinea pig tissue studied, plasma, heart, liver, kidney and lung, the lung and kidney tissue yielded the highest amounts of reactivated agent. In similar tissue and with similar exposure procedures, reactivated soman levels were greater than reactivated sarin levels. Levels of reactivated agents decreased rapidly with time while the guinea pig was alive, but decreased much more slowly after death. This latter chemical stability should facilitate forensic retrospective identification. The high level of reactivated agents in guinea pig samples led to the hypothesis that the principal source of reactivated agent came from the agent-carboxylesterase adduct. However, there could be contributions from adducts of the cholinesterases, albumin and fibrous tissue, as well. Quantitative analysis was performed with a GC-MS system using selected ion monitoring of the 99 and 125 ions for sarin and the 99 and 126 ions for soman. Detection levels were as low as 0.5 ng/mL. The assay was precise and easy to perform, and has potential for exposure analysis from organophosphate nerve agents and pesticides in other animal species.

  6. 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.

  7. Quantitation of metabolites of the nerve agents sarin, soman, cyclohexylsarin, VX, and Russian VX in human urine using isotope-dilution gas chromatography-tandem mass spectrometry.

    PubMed

    Barr, John R; Driskell, W J; Aston, Linda S; Martinez, Rodolfo A

    2004-01-01

    Organophosphorus nerve agents are among the most toxic organic compounds known and continue to be a threat for both military and terrorist use. We have developed an isotope-dilution gas chromatography-tandem mass spectrometric (GC-MS-MS) method for quantitating the urinary metabolites of the organophosphorus nerve agents sarin (GB), soman (GD), VX, Russian VX (RVX), and cyclohexylsarin (GF). Urine samples were acidified, extracted into ether-acetonitrile, derivatized by methylation with diazomethane, and analyzed by GC-MS-MS. The limits of detection were less than 1 micro g/L for all analytes.

  8. A Rapid and Sensitive Strip-Based Quick Test for Nerve Agents Tabun, Sarin, and Soman Using BODIPY-Modified Silica Materials.

    PubMed

    Climent, Estela; Biyikal, Mustafa; Gawlitza, Kornelia; Dropa, Tomáš; Urban, Martin; Costero, Ana M; Martínez-Máñez, Ramón; Rurack, Knut

    2016-08-01

    Test strips that in combination with a portable fluorescence reader or digital camera can rapidly and selectively detect chemical warfare agents (CWAs) such as Tabun (GA), Sarin (GB), and Soman (GD) and their simulants in the gas phase have been developed. The strips contain spots of a hybrid indicator material consisting of a fluorescent BODIPY indicator covalently anchored into the channels of mesoporous SBA silica microparticles. The fluorescence quenching response allows the sensitive detection of CWAs in the μg m(-3) range in a few seconds.

  9. Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs.

    PubMed

    Valiyaveettil, Manojkumar; Alamneh, Yonas; Rezk, Peter; Perkins, Michael W; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2011-05-10

    To explore the efficacy of paraoxonase 1 (PON1) as a catalytic bioscavenger, we evaluated human recombinant PON1 (rePON1) expressed in Trichoplusia ni larvae against sarin and soman toxicity using microinstillation inhalation exposure in guinea pigs. Animals were pretreated intravenously with catalytically active rePON1, followed by exposure to 1.2 X LCt₅₀ sarin or soman. Administration of 5 units of rePON1 showed mild increase in the blood activity of the enzyme after 30 min, but protected the animals with a significant increase in survival rate along with minimal signs of nerve agent toxicity. Recombinant PON1 pretreated animals exposed to sarin or soman prevented the reduction of blood O₂ saturation and pulse rate observed after nerve agent exposure. In addition, rePON1 pretreated animals showed significantly higher blood PON1, acetylcholinesterase (AChE), and butyrylcholinesterase activity after nerve agent exposure compared to the respective controls without treatments. AChE activity in different brain regions of rePON1 pretreated animals exposed to sarin or soman were also significantly higher than respective controls. The remaining activity of blood PON1, cholinesterases and brain AChE in PON1 pretreated animals after nerve agent exposure correlated with the survival rate. In summary, these data suggest that human rePON1 protects against sarin and soman exposure in guinea pigs.

  10. Formation of pyrophosphate-like adducts from nerve agents sarin, soman and cyclosarin in phosphate buffer: implications for analytical and toxicological investigations.

    PubMed

    Gäb, Jürgen; John, Harald; Blum, Marc-Michael

    2011-01-15

    Phosphate buffer is frequently used in biological, biochemical and biomedical applications especially when pH is to be controlled around the physiological value of 7.4. One of the prerequisites of a buffer compound among good buffering capacity and pH stability over time is its non-reactivity with other constituents of the solution. This is especially important for quantitative analytical or toxicological assays. Previous work has identified a number of amino alcohol buffers like TRIS to react with G-type nerve agents sarin, soman and cyclosarin to form stable phosphonic diesters. In case of phosphate buffer we were able to confirm not only the rapid hydrolysis of these agents to the respective alkyl methylphosphonates but also the formation of substantial amounts of pyrophosphate-like adducts (phosphorylated methylphosphonates), which very slowly hydrolyzed following zero-order kinetics. This led to a complex mixture of phosphorus containing species with changing concentrations over time. We identified the molecular structure of these buffer adducts using 1D ¹H-³¹P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates of adduct formation are fast enough to compete with hydrolysis in aqueous solution and to yield substantial amounts of buffer adduct over the course of just a couple of minutes. Possible reaction mechanisms are discussed with respect to the formation and subsequent hydrolysis of the pyrophosphate-like compounds as well as the increased rate of hydrolysis of the nerve agent to the corresponding alkyl methylphosphonates. In summary, the use of phosphate buffer for the development of new assays with sarin, soman and cyclosarin is discouraged. Already existing protocols should be carefully reexamined on an individual basis.

  11. Assay techniques for detection of exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide. Technical bulletin

    SciTech Connect

    1996-05-01

    This technical bulletin provides analytical techniques to identify toxic chemical agents in urine or blood samples. It is intended to provide the clinician with laboratory tests to detect exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide.

  12. Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs.

    PubMed

    Valiyaveettil, Manojkumar; Alamneh, Yonas; Rezk, Peter; Biggemann, Lionel; Perkins, Michael W; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2011-03-15

    Human paraoxonase 1 (PON1) has been portrayed as a catalytic bioscavenger which can hydrolyze large amounts of chemical warfare nerve agents (CWNAs) and organophosphate (OP) pesticides compared to the stoichiometric bioscavengers such as butyrylcholinesterase. We evaluated the protective efficacy of purified human and rabbit serum PON1 against nerve agents sarin and soman in guinea pigs. Catalytically active PON1 purified from human and rabbit serum was intravenously injected to guinea pigs, which were 30 min later exposed to 1.2 × LCt₅₀ sarin or soman using a microinstillation inhalation exposure technology. Pre-treatment with 5 units of purified human and rabbit serum PON1 showed mild to moderate increase in the activity of blood PON1, but significantly increased the survival rate with reduced symptoms of CWNA exposure. Although PON1 is expected to be catalytic, sarin and soman exposure resulted in a significant reduction in blood PON1 activity. However, the blood levels of PON1 in pre-treated animals after exposure to nerve agent were higher than that of untreated control animals. The activity of blood acetylcholinesterase and butyrylcholinesterase and brain acetylcholinesterase was significantly higher in PON1 pre-treated animals and were highly correlated with the survival rate. Blood O₂ saturation, pulse rate and respiratory dynamics were normalized in animals treated with PON1 compared to controls. These results demonstrate that purified human and rabbit serum PON1 significantly protect against sarin and soman exposure in guinea pigs and support the development of PON1 as a catalytic bioscavenger for protection against lethal exposure to CWNAs.

  13. A Chromogenic Probe for the Selective Recognition of Sarin and Soman Mimic DFP**

    PubMed Central

    El Sayed, Sameh; Pascual, Lluís; Agostini, Alessandro; Martínez-Máñez, Ramón; Sancenón, Félix; Costero, Ana M; Parra, Margarita; Gil, Salvador

    2014-01-01

    The synthesis, characterization and sensing features of a novel probe 1 for the selective chromogenic recognition of diisopropylfluorophosphate (DFP), a sarin and soman mimic, in 99:1 (v/v) water/acetonitrile and in the gas phase is reported. Colour modulation is based on the combined reaction of phosphorylation of 1 and fluoride-induced hydrolysis of a silyl ether moiety. As fluoride is a specific reaction product of the reaction between DFP and the −OH group, the probe shows a selective colour modulation in the presence of this chemical. Other nerve agent simulants, certain anions, oxidant species and other organophosphorous compounds were unable to induce colour changes in 1. This is one of the very few examples of a selective detection, in solution and in the gas phase, of a sarin and soman simulant versus other reactive derivatives such as the tabun mimic diethylcyanophosphate (DCNP). PMID:25478309

  14. A Chromogenic Probe for the Selective Recognition of Sarin and Soman Mimic DFP.

    PubMed

    El Sayed, Sameh; Pascual, Lluís; Agostini, Alessandro; Martínez-Máñez, Ramón; Sancenón, Félix; Costero, Ana M; Parra, Margarita; Gil, Salvador

    2014-08-01

    The synthesis, characterization and sensing features of a novel probe 1 for the selective chromogenic recognition of diisopropylfluorophosphate (DFP), a sarin and soman mimic, in 99:1 (v/v) water/acetonitrile and in the gas phase is reported. Colour modulation is based on the combined reaction of phosphorylation of 1 and fluoride-induced hydrolysis of a silyl ether moiety. As fluoride is a specific reaction product of the reaction between DFP and the -OH group, the probe shows a selective colour modulation in the presence of this chemical. Other nerve agent simulants, certain anions, oxidant species and other organophosphorous compounds were unable to induce colour changes in 1. This is one of the very few examples of a selective detection, in solution and in the gas phase, of a sarin and soman simulant versus other reactive derivatives such as the tabun mimic diethylcyanophosphate (DCNP).

  15. 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.

  16. Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and vx intoxication. (Reannouncement with new availability information)

    SciTech Connect

    Harris, L.W.; Talbot, B.G.; Lennox, W.J.; Anderson, D.R.; Solana, R.P.

    1991-12-31

    A pretreatment for organophosphorus (OP) anticholinesterase (e. g. , soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts MG/KG, IM tested were akineton 0.25, aprophen 8, trihexyphenidyl 2, atropine 16, azaprophen 51, BENACTYZINE 1.25, cogentin 4, dextromethorphan 7.5, ethopropazine 12, kemadrin 11, MEMANTINE 5, promethazine 5, scopolamine 0.081 AND CONTROL 2. PRGs were given 30 min before soman (60 ug/kg, sc; 2 LD50S) or other OP agents. Animals were then observed and graded for signs of intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs. Pretreatment, physostigmine, anticholinesterases, soman (GD).

  17. 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.

  18. Extension of the transferable potentials for phase equilibria force field to dimethylmethyl phosphonate, sarin, and soman.

    PubMed

    Sokkalingam, Nandhini; Kamath, Ganesh; Coscione, Maria; Potoff, Jeffrey J

    2009-07-30

    The transferable potentials for phase equilibria force field is extended to dimethylmethylphosphonate (DMMP), sarin, and soman by introducing a new interaction site representing the phosphorus atom. Parameters for the phosphorus atom are optimized to reproduce the liquid densities at 303 and 373 K and the normal boiling point of DMMP. Calculations for sarin and soman are performed in predictive mode, without further parameter optimization. Vapor-liquid coexistence curves, critical properties, vapor pressures and heats of vaporization are predicted over a wide range of temperatures with histogram reweighting Monte Carlo simulations in the grand canonical ensemble. Excellent agreement with experiment is achieved for all compounds, with unsigned errors of less than 1% for vapor pressures and normal boiling points and under 5% for heats of vaporization and liquid densities at ambient conditions.

  19. Detection of the organophosphorus nerve agent sarin by a competitive inhibition enzyme immunoassay.

    PubMed

    Zhou, Y X; Yan, Q J; Ci, Y X; Guo, Z Q; Rong, K T; Chang, W B; Zhao, Y F

    1995-01-01

    Two artificial antigens, NalphaNepsilon-di(O,O-diisopropyl) phosphoryl L-lysine (DIP)- bovine serum albumin (BSA) conjugate (DIP-BSA) and DIP-KLH (keyhole limpet hemocyanin), were synthesized. Antibodies against sarin (O-isopropyl methylphosphonofluoridate) were obtained after immunization of rabbits with DIP-KLH conjugate. A competitive inhibition enzyme immunoassay (CIEIA) was developed to detect the organophosphorus nerve agent sarin. The antibody solutions could be inhibited by sarin as low as 10(-6) mol/l, and the standard curve was linear over 3 orders of magnitude. The coefficients of intraassay and interassay variation of this method were 5.4-6.2% (n = 11) and 8.0-9.5% (n = 6) at a sarin concentration range of 10(-3)-10(-6) mol/l, respectively. The recovery of sarin in water samples at the concentration of 5 x 10(-5) mol/l was in the range of 96.8-102.5%. The specificity of the antiserum was assessed by comparing the inhibition induced by sarin with soman, Vx, isopropyl alcohol and isopropyl methyl phosphonic acid. The results showed that less than 5 mmol/l soman, 2 mmol/l Vx, 16 mmol/l isopropyl alcohol and 8 mmol/l isopropyl methyl phosphonic acid did not influence the determination of sarin in water samples.

  20. 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.

  1. Human carboxylesterase 1 stereoselectively binds the nerve agent cyclosarin and spontaneously hydrolyzes the nerve agent sarin.

    PubMed

    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

    2010-04-01

    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 P(R) enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P(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(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.

  2. Protection against soman and sarin exposure by transdermal physostigmine and scopolamine

    SciTech Connect

    Meshulam, Y.; Davidovici, R.; Levy, A.

    1993-05-13

    The purpose of this study was to evaluate the prophylactic efficacy of physostigmine (physo), administered via sustained release (SR) methods, with and without scopolamine, against soman and sarin exposure in guinea-pigs. Transdermal physo pad (3 sq cm/kg; 60-80 ug/sq cm), containing a vehicle based on propionic acid, was applied onto the dorsal back of the animals, 24 hours before exposure to the cholinesterase (ChE) inhibitors. At the time of exposure, physo concentrations in brain and plasma were 3.6 ng/g and 4.1 ng/ml respectively. Brain and whole blood ChE activity were inhibited to 70% and 57% of their original activity. Transdermal physo by itself protected up to 70% of the animals exposed to 1.5 LD(50) of soman or sarin (100% mortality was recorded in the control group). Combining transdermal physo with Scopoderm (by Ciba Geigy Inc.) provided full protection against 1.5 LD(50).

  3. Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman.

    PubMed

    Winkler, Jennifer L; Skovira, Jacob W; Kan, Robert K

    2017-01-01

    Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined

  4. Development of an analytical methodology for Sarin (GB) and Soman (GD) in various military-related wastes.

    SciTech Connect

    O'Neill, H. J.; Brubaker, K. L.; Schneider, J. F.; Sytsma, L. F.; Kimmell, T. A.

    2002-07-12

    The Army requires analytical methods that can detect chemical agents down to the low part-per-billion (ppb) levels in their waste streams in order to meet various state regulations regarding the classification of hazardous waste. Analytical methods were developed for the measurement of sarin (GB) and soman (GD) at ppb levels that involved preconcentration of relatively large volumes (40-150 {mu}l) of a chloroform extract onto a sorbent cartridge, followed by thermal desorption and analysis by GC-flame photometric detection. Certified reporting limits (CRLs) achieved with these methods ranged from 8.3 to 19 ppb for GB and from 1.8 to 5.3 ppb for GD in the three matrices screened. Method detection limits (MDLs) achieved with these methods ranged from 1.7 to 8.2 ppb for GB and from 0.39 to 1.2 ppb for GD. The methods are capable of achieving lower CRLs and MDLs with only minor modification.

  5. EPA Science Matters Newsletter: Chemical Warfare Agent Analytical Standards Facilitate Lab Testing (Published November 2013)

    EPA Pesticide Factsheets

    Learn about the EPA chemists' efforts to develop methods for detecting extremely low concentrations of nerve agents, such as sarin, VX, soman and cyclohexyl sarin, and the blister agent sulfur mustard.

  6. 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.

  7. 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

  8. Detection of the organophosphorus nerve agent soman by an ELISA using monoclonal antibodies.

    PubMed

    Erhard, M H; Kühlmann, R; Szinicz, L; Lösch, U

    1990-01-01

    The development of a specific and sensitive immunologic ELISA detection system for methylphosphonoflouridic acid. 1,2,2-trimethylpropylester (soman) by the use of monoclonal antibodies (MAbs) is described. The monoclonal antibodies F71D7, F71H10, F71B12 and F71H9 originally produced against the soman derivative methyl phosphonic acid, p-aminophenyl 1,2,2-trimethylpropyldiester (MATP) also reacted with soman in a previously developed, direct competitive ELISA. After optimizing the ELISA system by varying the reaction mixture and the solvents for the organophosphate, 5.0 x 10(-7) mol/l soman (80% purity), e.g. 2.5 ng or 2 ng pure soman per 25 microliters test buffer, could be detected after a total test duration of 40 min. A shortening of the incubation time to 10 min resulted in a drop of sensitivity to 1.8 x 10(-6) mol/l soman. Various alcohols which may be used as extraction media for soman from various materials (isopropanol, ethanol and methanol) were shown to inhibit peroxidase activity and thereby reduce the sensitivity of the test. However, the influence of alcohols decreased with the shortening of incubation time. All monoclonal antibodies showed little cross reactivity to sarin and no cross reactivity to tabun and VX. Judging on the reactivity of the MAbs with MATP and soman oxidazed by 1,2-dihydrobenzol, some reactivity with some other (non-toxic) soman analogues containing the same pinacolyl group can be expected. There was no evidence for stereoselectivity of the MAbs tested. Finally, soman could be detected in different biological samples like human serum, goat serum, rabbit serum, chicken serum, milk, and tap water in concentrations between 1.3 x 10(-6) and 2.0 x 10(-6) mol/l.

  9. Functionalized photonic crystal for the sensing of Sarin agents.

    PubMed

    Yan, Chunxiao; Qi, Fenglian; Li, Shuguang; Xu, Jiayu; Liu, Chao; Meng, Zihui; Qiu, Lili; Xue, Min; Lu, Wei; Yan, Zequn

    2016-10-01

    The indiscriminate use of nerve agents by terrorist groups has attracted attention of the scientific communities toward the development of novel sensor technique for these deadly chemicals. A photonic crystal (PhC) hydrogel immobilized with butyrylcholinesterase (BuChE) was firstly prepared for the sensing of Sarin agents. Periodic polystyrene colloidal (240nm) array was embedded inside an acrylamide hydrogel, and then BuChE was immobilized inside the hydrogel matrix via condensation with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3h)-one (DEPBT). It indicated that a total of 3.7 units of BuChE were immobilized onto the PhC hydrogel. The functionalized hydrogel recognized the Sarin agent and then shrunk, thus the diffraction of PhC hydrogel blue shifted significantly, and a limit of detection (LOD) of 10(-15)molL(-1) was achieved.

  10. Selective chromo-fluorogenic detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) with a unique probe based on a boron dipyrromethene (BODIPY) dye.

    PubMed

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

    2014-11-21

    A novel colorimetric probe (P4) for the selective differential detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) was prepared. Probe P4 contains three reactive sites; i.e. (i) a nucleophilic phenol group able to undergo phosphorylation with nerve gases, (ii) a carbonyl group as a reactive site for cyanide; and (iii) a triisopropylsilyl (TIPS) protecting group that is known to react with fluoride. The reaction of P4 with DCNP in acetonitrile resulted in both the phosphorylation of the phenoxy group and the release of cyanide, which was able to react with the carbonyl group of P4 to produce a colour modulation from pink to orange. In contrast, phosphorylation of P4 with DFP in acetonitrile released fluoride that hydrolysed the TIPS group in P4 to yield a colour change from pink to blue. Probe P4 was able to discriminate between DFP and DCNP with remarkable sensitivity; limits of detection of 0.36 and 0.40 ppm for DCNP and DFP, respectively, were calculated. Besides, no interference from other organophosphorous derivatives or with presence of acid was observed. The sensing behaviour of P4 was also retained when incorporated into silica gel plates or onto polyethylene oxide membranes, which allowed the development of simple test strips for the colorimetric detection of DCNP and DFP in the vapour phase. P4 is the first probe capable of colorimetrically differentiating between a Tabun mimic (DCNP) and a Sarin and Soman mimic (DFP).

  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.

  12. 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.

  13. Non-cholinergic intervention of sarin nerve agent poisoning.

    PubMed

    Sawyer, Thomas W; Mikler, John; Tenn, Catherine; Bjarnason, Stephen; Frew, Robert

    2012-04-11

    The protective effects of selected anesthetic regimens on sarin (GB) were investigated in domestic swine. At 30% oxygen, the toxicity of this agent in isoflurane anesthetized animals (LD(50)=10.1μg/kg) was similar to literature sited values in awake swine (LD(50)=11.8μg/kg) and slightly higher than that of both ketamine (LD(50)=15.6μg/kg) and propofol (LD(50)=15.3μg/kg) anesthetized swine. Use of 100% oxygen in ketamine anesthetized animals resulted in three-fold protective effects compared to 30% oxygen. Use of 100% oxygen in both isoflurane and propofol anesthetized animals, compared to 30% resulted in profound protection against GB poisoning (>33×). There were no differences in the severity of the poisoning or recovery time in animals treated over dose ranges of 10-350μg/kg (isoflurane) or 15-500μg/kg GB (propofol). Survivors of high GB challenges that were revived from propofol anesthetic exhibited no signs of cognitive impairment seven days later. Protective treatments did not attenuate cholinesterase (ChE) inhibition; survivors of otherwise supralethal GB concentrations exhibited very low blood ChE activities. This work indicates that propofol has protective effects against GB, and that oxygen tension may have an important role in treating nerve agent casualties. More importantly, it demonstrates that non-cholinergic protective mechanisms exist that may be exploited in the future development of medical countermeasures against organophosphorous nerve agents.

  14. 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.

  15. Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs.

    PubMed

    Wang, Ying; Oguntayo, Samuel; Wei, Yanling; Wood, Elisa; Brown, Ammon; Jensen, Neil; Auta, James; Guiodotti, Alessandro; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2012-03-01

    The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 μg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

  16. Monoclonal antibodies against soman: Characterization of soman stereoisomers. (Reannouncement with new availability information)

    SciTech Connect

    Lenz, D.E.; Yourick, J.J.; Dawson, J.S.; Scott, J.

    1992-12-31

    Hybridomas were produced which expressed monoclonal anti-soman antibodies as determined by microtiter enzyme-linked-antibody immunoassay (EIA). Each of these antibodies was titrated using a competitive inhibition enzyme immunoassay (CIEIA) with a variety of test ligands. The ligands used included soman (a racemic mixture), sarin, tabun, and each of the four stereoisomers of soman(C+P+, C+P-, C-P+ and C-P-). In all cases the antibodies tested exhibited IC50 values of 10 - 4 - 5 X 10 - 6 M for soman. When sarin or tabun was used as a ligand, the antibodies exhibited no cross reactivity. All of the antibodies cross reacted with the four soman stereoisomers. A second group of hybridomas were produced which expressed monoclonal antibodies against CsPs-soman. These antibodies were used to make preliminary absolute chiral assignments to the four soman stereoisomers. Soman; Antibodies; Stereoisomers; Absolute configuration.

  17. 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

  18. 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.

  19. Acetylcholinesterase-Capped Mesoporous Silica Nanoparticles That Open in the Presence of Diisopropylfluorophosphate (a Sarin or Soman Simulant).

    PubMed

    Pascual, Lluís; Sayed, Sameh El; Martínez-Máñez, Ramón; Costero, Ana M; Gil, Salvador; Gaviña, Pablo; Sancenón, Félix

    2016-11-04

    Mesoporous silica nanoparticles loaded with rhodamine B and capped with acetylcholinesterase are able to be selectively opened and deliver their cargo in the presence of nerve agent simulant diisopropyl fluorophosphate (DFP).

  20. Colorimetric dipstick for assay of organophosphate pesticides and nerve agents represented by paraoxon, sarin and VX.

    PubMed

    Pohanka, Miroslav; Karasova, Jana Zdarova; Kuca, Kamil; Pikula, Jiri; Holas, Ondrej; Korabecny, Jan; Cabal, Jiri

    2010-04-15

    A dipstick for fast assay of nerve agents and organophosphate pesticides was developed. Indicator pH papers were used as detectors. The principle of the assay is based on enzymatic hydrolysis of acetylcholine into acetic acid and choline by acetylcholinesterase. Acidification of the reaction medium due to accumulation of acetic acid was visible. The colour changed from dark red to yellow as the pH indicator recognized pH shift. Presence of an organophosphate pesticide or a nerve agent results in irreversible inhibition of acetylcholinesterase intercepted on the dipstick. The inhibition stops the enzymatic reaction. The inhibition appears as no change of the medium pH. Three compounds were assayed: paraoxon-ethyl as representative organophosphate pesticides and nerve agents sarin and VX. The achieved limit of detection was 5 x 10(-8)M for paraoxon-ethyl and 5 x 10(-9)M for sarin and VX. Dipsticks were found stable for at least one month. Suitability of these dipsticks for routine assay is discussed.

  1. 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.

  2. Potassium Ferrate: A Novel Chemical Warfare Agent Decontaminant

    DTIC Science & Technology

    2004-11-16

    soda . The specific reaction stoichiometry will depend on the type of CWA involved, other oxidizable materials present, etc. In use, excess ferrate...2,2-dichloroethyl ether, Sarin, Soman, mustard and V-nerve agents. The reaction times were as good as or better than commonly accepted...oxidation and hydrolysis reaction (unbalanced) involved in general terms is as follows (written for the CWA Sarin reaction with ferrate), FeO4= + (CH3

  3. Intravenous and inhalation toxicokinetics of sarin stereoisomers in atropinized guinea pigs.

    PubMed

    Spruit, H E; Langenberg, J P; Trap, H C; van der Wiel, H J; Helmich, R B; van Helden, H P; Benschop, H P

    2000-12-15

    We report the first toxicokinetic studies of (+/-)-sarin. The toxicokinetics of the stereoisomers of this nerve agent were studied in anesthetized, atropinized, and restrained guinea pigs after intravenous bolus administration of a dose corresponding to 0.8 LD50 and after nose-only exposure to vapor concentrations yielding 0.4 and 0.8 LCt50 in an 8-min exposure time. During exposure the respiratory minute volume and frequency were monitored. Blood samples were taken for gas chromatographic analysis of the nerve agent stereoisomers and for measurement of the activity of blood acetylcholinesterase (AChE). In all experiments, the concentration of (+)-sarin was below the detection limit (<5 pg/ml). The concentration-time profile of the toxic isomer, i.e., (-)-sarin, after an intravenous bolus was adequately described with a two-exponential equation. (-)-Sarin is distributed ca. 10-fold faster than C(-)P(-)-soman, whereas its elimination proceeds almost 10-fold slower. During nose-only exposure to 0.4 and 0.8 LCt50 of (+/-)-sarin in 8 min, (-)-sarin appeared to be rapidly absorbed. The blood AChE activity decreased during the exposure period to ca. 15 and 70% of control activity, respectively. There were no effects on the respiratory parameters. A significant nonlinearity of the toxicokinetics with dose was observed for the respiratory experiments.

  4. Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

    PubMed Central

    Allgardsson, Anders; Berg, Lotta; Akfur, Christine; Hörnberg, Andreas; Linusson, Anna; Ekström, Fredrik J.

    2016-01-01

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme–sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics. PMID:27140636

  5. Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6.

    PubMed

    Allgardsson, Anders; Berg, Lotta; Akfur, Christine; Hörnberg, Andreas; Worek, Franz; Linusson, Anna; Ekström, Fredrik J

    2016-05-17

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

  6. [Terror in Japan: mass-intoxication with the nerve-agent sarin].

    PubMed

    Solberg, Y; Nachtomi-Shick, O; Shemer, Y; Alcalay, M

    1998-10-01

    During 1994/5 the Japanese civilian population suffered 2 terror attacks by the organophosphorus nerve-agent sarin. In these 2 episodes it is estimated that more than 6000 people were injured, of whom 19 died. The quick and efficient response of the civilian emergency systems to these unforeseen, attacks has to be analyzed by local authorities to determine the best solutions in case of another attack. We summarize the events, and note the emergency system's response, the need for rapid and accurate chemical identification of the toxin, the necessity for decontaminating the casualties and for providing protective gear for rescue units in the contaminated area. We also describe the clinical status of the casualties and outline the mode of therapy applied.

  7. Efficacy of Biperiden and Atropine as Anticonvulsant Treatment for Organophosphorus Nerve Agent Intoxication

    DTIC Science & Technology

    2000-01-01

    3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Efficacy of biperiden and atropine as anticonvulsant treatment For organophosphorus nerve agent...inhibitors, soman, sarin, tabun, GF, VX, anticonvulsants, atropine, biperiden , anticholinergic compounds, convulsions, EEG activity 16. SECURITY... biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication Received: 16 November 1999 /Accepted: 9 February

  8. Activity-Based Protein Profiling Reveals Broad Reactivity of the Nerve Agent Sarin.

    PubMed

    Tuin, Adriaan W; Mol, Marijke A E; van den Berg, Roland M; Fidder, A; van der Marel, Gijs A; Overkleeft, Herman S; Noort, Daan

    2009-04-01

    Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which contains a phosphonofluoridate moiety, a P-Me moiety, and a biotinylated O-alkyl group, and its use in activity-based protein profiling with two relevant biological samples, that is, rhesus monkey liver and cultured human A549 lung cells. In this way, we have unearthed eight serine hydrolases (fatty acid synthase, acylpeptide hydrolase, dipeptidyl peptidase 9, prolyl oligopeptidase, carboxylesterase, long-chain acyl coenzyme A thioesterase, PAF acetylhydrolase 1b, and esterase D/S-formyl glutathione hydrolase) as targets that are modified by the nerve agent sarin. It is also shown that the newly developed probe 3 might find its way into the development of alternative, less laborious purification protocols for human butyrylcholinesterase, a potent bioscavenger currently under clinical investigation as a prophylactic/therapeutic for nerve agent intoxications.

  9. Catalytic soman scavenging by Y337A/F338A acetylcholinesterase mutant assisted with novel site-directed aldoximes

    PubMed Central

    Kovarik, Zrinka; Hrvat, Nikolina Maček; Katalinić, Maja; Sit, Rakesh K.; Paradyse, Alexander; Žunec, Suzana; Musilek, Kamil; Fokin, Valery V.; Taylor, Palmer; Radić, Zoran

    2016-01-01

    Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin and paraoxon inhibition. We here demonstrate that ex vivo, in whole human blood, 1 μM soman was detoxified within 30 minutes when supplemented with 0.5 μM Y337A/F338A AChE and 100 μM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of forty-two pyridinium aldoximes, and five imidazole 2-aldoxime N-propyl pyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2–3 –fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack. PMID:25835984

  10. Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala.

    PubMed

    Prager, Eric M; Pidoplichko, Volodymyr I; Aroniadou-Anderjaska, Vassiliki; Apland, James P; Braga, Maria F M

    2014-09-01

    The recent sarin attack in Syria killed 1429 people, including 426 children, and left countless more to deal with the health consequences of the exposure. Prior to the Syrian chemical assault, nerve agent attacks in Japan left many victims suffering from neuropsychiatric illnesses, particularly anxiety disorders, more than a decade later. Uncovering the neuro-pathophysiological mechanisms underlying the development of anxiety after nerve agent exposure is necessary for successful treatment. Anxiety is associated with hyperexcitability of the basolateral amygdala (BLA). The present study sought to determine the nature of the nerve agent-induced alterations in the BLA, which could explain the development of anxiety. Rats were exposed to soman, at a dose that induced prolonged status epilepticus. Twenty-four hours and 14-days after exposure, neurons from the BLA were recorded using whole-cell patch-clamp techniques. At both the 24h and 14-day post-exposure time-points, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the BLA were reduced, along with reduction in the frequency but not amplitude of miniature IPSCs. In addition, activation of α7-nicotinic acetylcholine receptors, a cholinergic receptor that participates in the regulation of BLA excitability and is involved in anxiety, increased spontaneous excitatory postsynaptic currents (sEPSCs) in both soman-exposed rats and controls, but was less effective in increasing sIPSCs in soman-exposed rats. Despite the loss of both interneurons and principal cells after soman-induced status epilepticus, the frequency of sEPSCs was increased in the soman-exposed rats. Impaired function and cholinergic modulation of GABAergic inhibition in the BLA may underlie anxiety disorders that develop after nerve agent exposure.

  11. Diet Composition Exacerbrates or Attenuates Soman Toxicity in Rats: Implied Metabolic Control of Nerve Agent Toxicity

    DTIC Science & Technology

    2011-01-01

    diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal , or pyruvic acid. Epilep- sia 2007;48:793–800. Greene AE, Todorova MT...12. Kudchodkar BJ, Lacko AG , Dory L, Fungwe TV. Dietary fat modulates serum paraox- onase 1 activity in rats. J Nutr 2000;130:2427–33. Lallement G...restriction on the toxicity of soman in male guinea pigs of different ages . In: Internal report to special projects officer and In-House Labora- tory

  12. Efficient hydrolysis of the chemical warfare nerve agent tabun by recombinant and purified human and rabbit serum paraoxonase 1.

    PubMed

    Valiyaveettil, Manojkumar; Alamneh, Yonas; Biggemann, Lionel; Soojhawon, Iswarduth; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2010-12-03

    Paraoxonase 1 (PON1) has been described as an efficient catalytic bioscavenger due to its ability to hydrolyze organophosphates (OPs) and chemical warfare nerve agents (CWNAs). It is the future most promising candidate as prophylactic medical countermeasure against highly toxic OPs and CWNAs. Most of the studies conducted so far have been focused on the hydrolyzing potential of PON1 against nerve agents, sarin, soman, and VX. Here, we investigated the hydrolysis of tabun by PON1 with the objective of comparing the hydrolysis potential of human and rabbit serum purified and recombinant human PON1. The hydrolysis potential of PON1 against tabun, sarin, and soman was evaluated by using an acetylcholinesterase (AChE) back-titration Ellman method. Efficient hydrolysis of tabun (100 nM) was observed with ∼25-40 mU of PON1, while higher concentration (80-250 mU) of the enzyme was required for the complete hydrolysis of sarin (11 nM) and soman (3 nM). Our data indicate that tabun hydrolysis with PON1 was ∼30-60 times and ∼200-260 times more efficient than that with sarin and soman, respectively. Moreover, the catalytic activity of PON1 varies from source to source, which also reflects their efficiency of hydrolyzing different types of nerve agents. Thus, efficient hydrolysis of tabun by PON1 suggests its promising potential as a prophylactic treatment against tabun exposure.

  13. Translation of Toxicity Data into CW Agent Toxicity Estimates

    DTIC Science & Technology

    2003-07-01

    dosage defined by vapor concentration (C) multiplied by exposure time (T) CTXX -- Lethal or Effective Concentration-Time to XX% exposed Dependence of...kg, young healthy adult males Agents addressed: GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), VX and HD (mustard) Routes of exposure ...use with CW agent exposure scenarios involving healthy adult males Evidence exists that in some mammalian species (ex. rodents) that a significant

  14. Polymer-based lanthanide luminescent sensor for detection of the hydrolysis product of the nerve agent Soman in water.

    PubMed

    Jenkins, A L; Uy, O M; Murray, G M

    1999-01-15

    The techniques of molecular imprinting and sensitized lanthanide luminescence have been combined to create the basis for a sensor that can selectively measure the hydrolysis product of the nerve agent Soman in water. The sensor functions by selectively and reversibly binding the phosphonate hydrolysis product of this agent to a functionality-imprinted copolymer possessing a coordinatively bound luminescent lanthanide ion, Eu3+. Instrumental support for this device is designed to monitor the appearance of a narrow luminescence band in the 610-nm region of the Eu3+ spectrum that results when the analyte is coordinated to the copolymer. The ligand field shifted luminescence was excited using 1 mW of the 465.8-nm line of an argon ion laser and monitored via an optical fiber using a miniature spectrometer. For this configuration, the limit of detection for the hydrolysis product is 7 parts per trillion (ppt) in solution with a linear range from 10 ppt to 10 ppm. Chemical and spectroscopic selectivities have been combined to reduce the likelihood of false positive analyses. Chemically analogous organophosphorus pesticides tested against the sensor have been shown to not interfere with determination.

  15. Lewis acid-assisted detection of nerve agents in water.

    PubMed

    Butala, Rahul R; Creasy, William R; Fry, Roderick A; McKee, Michael L; Atwood, David A

    2015-06-07

    The five-coordinate compound, Salen((t)Bu)Al(Ac), prepared in situ from Salen((t)Bu)AlBr and NH4Ac, forms Lewis acid-base adducts in aqueous solution with the G-type nerve agents, Sarin and Soman, and the VX hydrolysis product, ethylmethylphosphonate (EMPA). The resulting compounds, [Salen((t)Bu)Al(NA)](+)[Ac] (-) (with NA = Sarin, Soman, and EMPA) are sufficiently stable to be identified by ESI-MS. Molecular ion peaks were detected for every compound with little or no fragmentation. The distinctive MS signatures for the [Salen((t)Bu)Al(NA)](+) compounds provide a new technique for identifying nerve agents from aqueous solution. The energetics of the displacement of Ac(-) by the nerve agents to form [Salen((t)Bu)Al(NA)](+)[Ac](-) were determined computationally.

  16. Hydrolysis of DFP and the nerve agent (S)-sarin by DFPase proceeds along two different reaction pathways: implications for engineering bioscavengers.

    PubMed

    Wymore, Troy; Field, Martin J; Langan, Paul; Smith, Jeremy C; Parks, Jerry M

    2014-05-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ("bioscavengers") is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P-F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca(2+), donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds.

  17. Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

    SciTech Connect

    Wymore, Troy W; Langan, Paul; Smith, Jeremy C; Field, Martin J.; Parks, Jerry M

    2014-01-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ( bioscavengers ) is an emerging prophylactic approach to diminishing their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical (QM/MM) umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily due to the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed -propeller folds for more efficient degradation of OP compounds.

  18. Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds along Two Different Reaction Pathways: Implications for Engineering Bioscavengers

    PubMed Central

    2015-01-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (“bioscavengers”) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P–F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds. PMID:24720808

  19. Restoration of soman-blocked neuromuscular transmission in human and rat muscle by the bispyridinium non-oxime MB327 in vitro.

    PubMed

    Seeger, T; Eichhorn, M; Lindner, M; Niessen, K V; Tattersall, J E H; Timperley, C M; Bird, M; Green, A C; Thiermann, H; Worek, F

    2012-04-11

    The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A previous study showed that the di(methanesulfonate) salt of the bispyridinium compound MB327 could restore soman-impaired neuromuscular function in vitro and improve survival of sarin, soman and tabun poisoned guinea pigs in vivo. Here, by using the indirect field stimulation technique, the ability of MB327 to counteract soman-impaired neuromuscular transmission was investigated in human intercostal muscle and rat diaphragm preparations. MB327 restored muscle force in a concentration-dependent manner in both species without reactivating soman-inhibited acetylcholinesterase. The therapeutic effect of MB327 could be washed out, indicating a direct effect at the nicotinic receptor level. Also the ability of MB327 to restore respiratory muscle function could be demonstrated for the first time in rat and human tissue. In combination with previous in vitro and in vivo findings MB327 may be considered a promising compound for the treatment of nerve agent poisoning and further studies are needed to identify optimized drug combinations, concentrations and dosing intervals to provide an effective therapy for OP poisoning.

  20. The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.

    PubMed

    Shih, Tsung-Ming; Guarisco, John A; Myers, Todd M; Kan, Robert K; McDonough, John H

    2011-01-01

    This study examined whether pro-2-PAM, a pro-drug dihydropyridine derivative of the oxime 2-pralidoxime (2-PAM) that can penetrate the brain, could prevent or reverse the central toxic effects of three nerve agents; sarin, cyclosarin, and VX. The first experiment tested whether pro-2-PAM could reactivate guinea pig cholinesterase (ChE) in vivo in central and peripheral tissues inhibited by these nerve agents. Pro-2-PAM produced a dose-dependent reactivation of sarin- or VX-inhibited ChE in both peripheral and brain tissues, but with substantially greater reactivation in peripheral tissues compared to brain. Pro-2-PAM produced 9-25% reactivation of cyclosarin-inhibited ChE in blood, heart, and spinal cord, but no reactivation in brain or muscle tissues. In a second experiment, the ability of pro-2-PAM to block or terminate nerve agent-induced electroencephalographic seizure activity was evaluated. Pro-2-PAM was able to block sarin- or VX-induced seizures (16-33%) over a dose range of 24-32 mg/kg, but was ineffective against cyclosarin-induced seizures. Animals that were protected from seizures showed significantly less weight loss and greater behavioral function 24 h after exposure than those animals that were not protected. Additionally, brains were free from neuropathology when pro-2-PAM prevented seizures. In summary, pro-2-PAM provided modest reactivation of sarin- and VX-inhibited ChE in the brain and periphery, which was reflected by a limited ability to block or terminate seizures elicited by these agents. Pro-2-PAM was able to reactivate blood, heart, and spinal cord ChE inhibited by cyclosarin, but was not effective against cyclosarin-induced seizures.

  1. Synergism of activated carbon and undoped and nitrogen-doped TiO2 in the photocatalytic degradation of the chemical warfare agents soman, VX, and yperite.

    PubMed

    Cojocaru, Bogdan; Neaţu, Stefan; Pârvulescu, Vasile I; Somoghi, Vasile; Petrea, Nicoleta; Epure, Gabriel; Alvaro, Mercedes; Garcia, Hermenegildo

    2009-01-01

    Efficient photocatalytic decomposition of chemical warfare agents is a process that may find application in emergency situations or for the controlled destruction of chemical warfare stockpiles. A series of heterogeneous photocatalysts comprising TiO2-activated carbon or N-TiO2-activated carbon composites exhibit excellent photocatalytic activity to effect the complete decomposition of yperite, soman, and VX in high concentrations. The remarkable photocatalytic activity arises from the synergism between adsorption on active carbon and photoactivity by titania. Nitridation makes the composite also active under visible-light irradiation.

  2. Experimental and theoretical studies of hydrolysis of nerve agent sarin by binuclear zinc biomimetic catalysts

    NASA Astrophysics Data System (ADS)

    Guo, Nan; Zhong, Jin-Yi; Chen, Shi-Lu; Liu, Jing-Quan; Min, Qi; Shi, Rui-Xue

    2015-08-01

    A complex (ZnL1) of 2,2-(2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)bis ((pyridin-2-ylmethyl)azanediyl)diethanol (this ligand is named by L1) functionalized with two Zn(II) centers, has been previously suggested to be a structural model for binuclear zinc phosphotriesterases (PTEs) and proven to be an effective catalyst for the hydrolysis of bis(2,4-dinitrophenyl)phosphate (BDNPP). In this paper, ZnL1 was further found to have a high catalytic activity for the hydrolysis of isopropyl methylphosphonofluoridate (sarin, GB) with kcat/Km = 0.051 s-1 M-1 at 303 K, examined by on-site NMR analysis. The subsequent density functional theory (DFT) calculations indicate that a terminal alkoxide (Ot) bound by Zn may work as a general base to activate a water molecule and then a hydroxide derived from the latter performs the initial nucleophilic attack on the phosphor in GB. Inspired by this mechanism, a new biomimetic catalyst was designed and synthesized by replacing the two pyridines of ZnL1 by hydroxyls, i.e. a complex of two Zn(II) with 2,6-bis((bis(2-hydroxyethyl)amino)methyl)-4-methylphenol (the ligand is named by L2). This replacement was expected to increase the Ot basicity, thereby facilitating the nucleophilic attack and the overall hydrolysis of GB. It was shown that ZnL2 had a very high catalytic efficiency for the hydrolysis of GB, with kcat/Km = 0.11 s-1 M-1 at 303 K and about 90% conversion in 30 min. The following DFT calculations proposed a detailed reaction mechanism of ZnL2 and gave an energy barrier (5.8 kcal M-1) very close to the experimental activation energy (5.6 kcal M-1). In this study, a mechanism-inspired design strategy has been demonstrated to be successful in developing biomimetic catalyst.

  3. LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety

    PubMed Central

    Prager, Eric M.; Figueiredo, Taiza H.; Long, Robert P.; Aroniadou-Anderjaska, Vassiliki; Apland, James P.; Braga, Maria F.M.

    2014-01-01

    Without timely pharmacological treatment, nerve agent exposure can cause a large number of casualties, as occurred in the recent sarin attack in Syria. Nerve agent-induced seizures are initiated due to inhibition of acetylcholinesterase, but they become quickly refractory to muscarinic antagonists, and their suppression by benzodiazepines can be only temporary. Therefore, novel treatments are necessary to stop seizures and prevent brain damage and the resulting long-term behavioral deficits. We have previously shown that LY293558, a GluK1/AMPA receptor antagonist, is a very effective anticonvulsant and neuroprotectant against nerve agent exposure. In the present study, we examined whether the protection against nerve agent-induced seizures and neuropathology conferred by LY293558 translates into protection against pathophysiological alterations in the basolateral amygdala (BLA) and the development of anxiety, which is the most prevalent behavioral deficit resulting from exposure. LY293558 (15 mg/kg) was administered to rats along with atropine and the oxime HI-6, at 20 min after exposure to soman (1.2 x LD50). At 24 h, 7 days, and 30 days after exposure, soman-exposed rats that did not receive LY293558 had reduced but prolonged evoked field potentials in the BLA, as well as increased paired-pulse ratio, suggesting neuronal damage and impaired synaptic inhibition. In contrast, soman-exposed rats that received LY293558 did not differ from controls in these parameters. Similarly, long-term potentiation of synaptic transmission was impaired at 7 days after exposure in the soman-exposed rats that did not receive anticonvulsant treatment, while this impairment was not present in the LY293558-treated rats. Anxiety-like behavior assessed by the open field and acoustic startle response tests was increased in the soman-exposed rats at 30 and 90 days after exposure, while soman-exposed rats treated with LY293558 did not differ from controls. Along with our previous findings

  4. Toxicity studies on agents Gb and Gd (Phase 2): Delayed neuropathy study of soman in SPF white leghorn chickens. Final technical report, July 1985-August 1991

    SciTech Connect

    Bucci, T.J.; Parker, R.M.; Gosnell, P.A.

    1992-05-01

    A dose rangefinding study, a delayed neuropathy study, and a neurotoxic esterase study, were performed in White Leghorn chickens using the organophosphate ester Soman. The hens used for the Rangefinding study were dosed once orally with 500, 250, 100, 50, 25, or 0 microns g/Kg GD, on Day 1. They were pretreated and protected daily through Day 7 with atropine. Surviving hens were euthanized with sodium pentobarbital on Day 21. The maximum tolerated dose (MTD) to be used in the Delayed Neuropathy Study was chosen based upon the rangefinding data. Fifty hens were assigned to a Single Dose Delayed Neuropathy study. Groups of ten hens were given 14.2 (MTD), 7.1 (MTD/2), 3.5 (MTD/4), 0 (negative control) microns/Kg GD or 51 0 mg/Kg tri-ortho-cresyl phosphate (TOCP) (positive control). Rangefinding study. They were evaluated for signs of neurologic toxicity/ataxia. Necropsy examination was performed on all animals. Sections of cerebellum, medulla, spinal cord (cervical, thoracic, and lumbar), both sciatic nerves and their tibial branch were examined microscopically.... Delayed neuropathy; Agents; Soman; Chickens.

  5. Sarin poisoning of a rescue team in the Matsumoto sarin incident in Japan.

    PubMed Central

    Nakajima, T; Sato, S; Morita, H; Yanagisawa, N

    1997-01-01

    OBJECTIVES: A nerve agent sarin (isopropyl methyl phosphonofluoridate) was released in Matsumoto city, Japan, on 27 June 1994. About 600 people were affected by the sarin, including seven who died. Fifty two rescuers engaged in helping the victims and 18 were affected. The aim was to investigate how the rescuers were affected by sarin. METHODS: Health examinations and a questionnaire survey were conducted with all rescuers. RESULTS: A rescuer who was one of the first engaged and who worked for about five hours in areas contaminated with sarin was admitted to hospital after poisoning; the others did not consult doctors although they showed slight muscarinic symptoms. The later the rescuers started their work, the less likely they were to experience symptoms of sarin exposure, and no one starting work 270 minutes after the original release of sarin was affected. The symptoms of exposure included ocular pain, darkness of visual field, nausea, vomiting, headache, rhinorrhea, narrowing of visual field, sore throat, fatigue, and dyspnoea, which were similar to those reported by the citizens who were sarin victims. There were no rescuers who had abnormal physical or neurological signs associated with sarin at the time of the physical examination conducted three weeks after the sarin release. A year after the sarin incident, the symptoms of all the rescuers had resolved. CONCLUSIONS: Rescuers should protect themselves with appropriate clothing, gloves, and a mask to prevent a secondary disaster for at least 24 hours after a similar accident. PMID:9404315

  6. Efficacy assessment of various anticholinergic agents against topical sarin-induced miosis and visual impairment in rats.

    PubMed

    Gore, Ariel; Brandeis, Rachel; Egoz, Inbal; Peri, David; Turetz, Joseph; Bloch-Shilderman, Eugenia

    2012-04-01

    Eye exposure to the organophosphorus (OP) irreversible acetylcholinesterase inhibitor sarin results in long-term miosis and reduction in visual function. Anticholinergic drugs, such as atropine or homatropine, which are used topically in order to counter these effects may produce mydriasis and partial cycloplegia, which may worsen visual performance. This study was aimed to test the efficacy of short-acting anticholinergic drugs against sarin-induced miosis and visual impairment, which will minimally insult vision. Long-Evans rats, exposed topically to various sarin doses from 0 to 10 μg, showed a dose-dependent miosis, which returned to pre-exposure levels within 24-48 h. Tropicamide treatment rapidly widened the miotic effect to a different extent depending on time following treatment and dosage given. Cyclopentolate, however, showed a delayed response that finally widened the pupils in a dose-dependent manner. Atropine treatment showed a rapid widening of the pinpoint pupils exceeding baseline level finally causing mydriasis. Light reflex test showed that the contraction ability of the iris following atropine treatment was impaired, as opposed to the use of tropicamide which facilitated the iris contraction, similar to control. Finally, tropicamide and atropine treatments ameliorated the visual impairment, as opposed to cyclopentolate, which worsened visual performance. Considering that tropicamide treatment against sarin exposure did not cause mydriasis nor did it impair the iris contraction flexibility as a response to light, the use of this drug should be taken into consideration as a first-choice topical treatment against OP intoxication.

  7. Stimulation of Central A1 Adenosine Receptors Suppresses Seizure and Neuropathology in a Soman Nerve Agent Seizure Rat Model

    DTIC Science & Technology

    2014-05-22

    LV’s MTD, the total dose of CPA was buffered in 10 ml of multisol (48.5% H2O, 40% propylene glycol, 10% ethanol , and 1.5% benzyl alcohol ) and adminis...physiologic functions. It is released during normal metabolic activity into the extracel- lular space where it acts on adenosine receptors (ARs) (Ribeiro et al...brain regions following soman intoxication. J Neurochem 54:72–9. Geeraerts T, Vigue B. (2009). Cellular metabolism , temperature and brain injury. Ann

  8. Acute effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate, on cardiovascular parameters in anaesthetized, artificially ventilated rats

    SciTech Connect

    Watanabe, Yoshimasa; Itoh, Takeo; Shiraishi, Hiroaki; Maeno, Yoshitaka; Arima, Yosuke; Torikoshi, Aiko; Namera, Akira; Makita, Ryosuke; Yoshizumi, Masao; Nagao, Masataka

    2013-10-01

    The organophosphorus compound sarin irreversibly inhibits acetylcholinesterase. We examined the acute cardiovascular effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate (BIMP), in anaesthetized, artificially ventilated rats. Intravenous administration of BIMP (0.8 mg/kg; the LD50 value) induced a long-lasting increase in blood pressure and tended to increase heart rate. In rats pretreated with the non-selective muscarinic-receptor antagonist atropine, BIMP significantly increased both heart rate and blood pressure. In atropine-treated rats, hexamethonium (antagonist of ganglionic nicotinic receptors) greatly attenuated the BIMP-induced increase in blood pressure without changing the BIMP-induced increase in heart rate. In rats treated with atropine plus hexamethonium, intravenous phentolamine (non-selective α-adrenergic receptor antagonist) plus propranolol (non-selective β-adrenergic receptor antagonist) completely blocked the BIMP-induced increases in blood pressure and heart rate. In atropine-treated rats, the reversible acetylcholinesterase inhibitor neostigmine (1 mg/kg) induced a transient increase in blood pressure, but had no effect on heart rate. These results suggest that in anaesthetized rats, BIMP induces powerful stimulation of sympathetic as well as parasympathetic nerves and thereby modulates heart rate and blood pressure. They may also indicate that an action independent of acetylcholinesterase inhibition contributes to the acute cardiovascular responses induced by BIMP. - Highlights: • A sarin-like agent BIMP markedly increased blood pressure in anaesthetized rats. • Muscarinic receptor blockade enhanced the BIMP-induced increase in blood pressure. • Ganglionic nicotinic receptor blockade attenuated the BIMP-induced response. • Blockade of α- as well as β-receptors attenuated the BIMP-induced response.

  9. Cardiovascular effects of soman. Annual report Number 2, June 1, 1983-May 31, 1984

    SciTech Connect

    Brezenoff, H.E.

    1984-12-01

    Intravenous (i.v.) injection of soman in the rat produced a rapid and dose-related increase in blood pressure. The dose-response curve was very steep, threshold responses occurring after i.v. injection of 10 ug/kg, and maximum increases of about 50 mmHg occurring after 40 ug/kg. Heart rate also generally increased. An increase in blood pressure also followed injection of soman subcutaneously (s.c.), intramuscularly (i.m.) intraperitoneally (i.p.) and into the cerebral ventricles, although the onset was slower and higher doses were required. The magnitude of the pressor response was correlated with the degree of acetylcholinesterase (AChE) activity in the cortex, hypothalamus and brainstem, but not in the striatum. The pressor response was aborted or prevented by atropine, but not by methylatropine. It also was prevented by phenoxybenzamine. Atropine increased survival following an LD50 dose of soman; phenoxybenzamine prevented the pressor response but did not alter survival rate. Sarin and diisopropylfluorophosphate (DFP) also produced a pressor response following i.v. administration. The effect of sarin was similar to that of soman, although sarin was about 50% less potent. The pressor response to DFP was about 1/20th as potent as soman.

  10. Hydrolysis potential of recombinant human skin and kidney prolidase against diisopropylfluorophosphate and sarin by in vitro analysis.

    PubMed

    Costante, Michael; Biggemann, Lionel; Alamneh, Yonas; Soojhawon, Iswarduth; Short, Radley; Nigam, Savita; Garcia, Gregory; Doctor, Bhupendra P; Valiyaveettil, Manojkumar; Nambiar, Madhusoodana P

    2012-02-01

    Human prolidase (PROL), which has structural homology to bacterial organophosphate acid anhydrolase that hydrolyze organophosphates and nerve agents has been proposed recently as a potential catalytic bioscavenger. To develop PROL as a catalytic bioscavenger, we evaluated the in vitro hydrolysis efficiency of purified recombinant human PROL against organophosphates and nerve agents. Human liver PROL was purified by chromatographic procedures, whereas recombinant human skin and kidney PROL was expressed in Trichoplusia ni larvae, affinity purified and analyzed by gel electrophoresis. The catalytic efficiency of PROL against diisopropylfluorophosphate (DFP) and nerve agents was evaluated by acetylcholinesterase back-titration assay. Partially purified human liver PROL hydrolyzed DFP and various nerve agents, which was abolished by specific PROL inhibitor showing the specificity of hydrolysis. Both the recombinant human skin and kidney PROL expressed in T. ni larvae showed ∼99% purity and efficiently hydrolyzed DFP and sarin. In contrast to human liver PROL, both skin and kidney PROL showed significantly low hydrolyzing potential against nerve agents soman, tabun and VX. In conclusion, compared to human liver PROL, recombinant human skin and kidney PROL hydrolyze only DFP and sarin showing the substrate specificity of PROL from various tissue sources.

  11. Acute effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate, on cardiovascular parameters in anaesthetized, artificially ventilated rats.

    PubMed

    Watanabe, Yoshimasa; Itoh, Takeo; Shiraishi, Hiroaki; Maeno, Yoshitaka; Arima, Yosuke; Torikoshi, Aiko; Namera, Akira; Makita, Ryosuke; Yoshizumi, Masao; Nagao, Masataka

    2013-10-01

    The organophosphorus compound sarin irreversibly inhibits acetylcholinesterase. We examined the acute cardiovascular effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate (BIMP), in anaesthetized, artificially ventilated rats. Intravenous administration of BIMP (0.8mg/kg; the LD50 value) induced a long-lasting increase in blood pressure and tended to increase heart rate. In rats pretreated with the non-selective muscarinic-receptor antagonist atropine, BIMP significantly increased both heart rate and blood pressure. In atropine-treated rats, hexamethonium (antagonist of ganglionic nicotinic receptors) greatly attenuated the BIMP-induced increase in blood pressure without changing the BIMP-induced increase in heart rate. In rats treated with atropine plus hexamethonium, intravenous phentolamine (non-selective α-adrenergic receptor antagonist) plus propranolol (non-selective β-adrenergic receptor antagonist) completely blocked the BIMP-induced increases in blood pressure and heart rate. In atropine-treated rats, the reversible acetylcholinesterase inhibitor neostigmine (1mg/kg) induced a transient increase in blood pressure, but had no effect on heart rate. These results suggest that in anaesthetized rats, BIMP induces powerful stimulation of sympathetic as well as parasympathetic nerves and thereby modulates heart rate and blood pressure. They may also indicate that an action independent of acetylcholinesterase inhibition contributes to the acute cardiovascular responses induced by BIMP.

  12. Capillary gas chromatographic analysis of nerve agents using large volume injections.

    PubMed

    Degenhardt-Langelaan, C E; Kientz, C E

    1996-02-02

    The use of large volume injections has been studied for the verification of intact organophosphorus chemical warfare agents in water samples. As the use of ethyl acetate caused severe detection problems new potential solvents were evaluated. With the developed procedure, the nerve agents sarin, tabun, soman, DFP and VX can be determined in freshly prepared water samples at ppt levels. Except for the nerve agent tabun all other agents added to the water samples were still present after 8 days at 20-60% levels, if the pH of the water sample is adjusted to ca. 5 shortly after sampling and adjusted to pH 7 for analysis.

  13. In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate.

    PubMed

    O'Donnell, John C; McDonough, John H; Shih, Tsung-Ming

    2011-12-01

    Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.

  14. Naloxone Antagonises Soman-induced Central Respiratory Depression in Rats.

    PubMed

    Škrbić, Ranko; Stojiljković, Miloš P; Ćetković, Slavko S; Dobrić, Silva; Jeremić, Dejan; Vulović, Maja

    2016-12-19

    The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonised the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonising respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonises soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors. This article is protected by copyright. All rights reserved.

  15. In vitro reactivation potency of novel symmetrical bis-pyridinium oximes for electric eel acetylcholinesterase inhibited by nerve agent sarin.

    PubMed

    Acharya, Jyotiranjan; Dubey, Devendra Kumar; Kaushik, M P

    2011-12-01

    This communication describes synthesis and in vitro evaluation of a series of novel bis-pyridinium oximes connected by bis-methoxymethyl benzene, 1,4-bis-methoxymethyl (cis)-but-2-ene and 1,4-bis-methoxymethyl but-2-yne linkers as reactivators of sarin inhibited acetylcholinesterase (AChE). The reactivation data of synthesized oximes were compared with those of 2-PAM and obidoxime. The efficacy of oximes such as 1,4-dimethoxy cis-but-2-ene bis-[4,4'-(hydroxyiminomethyl)-pyridinium] dichloride (3g), 1,4-dimethoxy benzene bis-[3,3'-(hydroxyimino-methyl) pyridinium] dichloride (3b) and 1,3-dimethoxy benzene bis-[3,3'-(hydroxy-iminomethyl) pyridinium] dichloride (3e) were found to be more than that of obidoxime in reactivating sarin inhibited AChE. The oxime 3g was able to reactivate 25% of AChE activity in comparison to 20% and 5% reactivation exhibited by 2-PAM and obidoxime respectively at a concentration of 10(-4) M. The pKa of the oximes were determined and correlated with the reactivation potential.

  16. Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents.

    PubMed

    Williams, Nichola H; Harrison, John M; Read, Robert W; Black, Robin M

    2007-09-01

    The organophosphorus nerve agents sarin, soman, cyclosarin and tabun phosphylate a tyrosine residue on albumin in human blood. These adducts may offer relatively long-lived biological markers of nerve agent exposure that do not 'age' rapidly, and which are not degraded by therapy with oximes. Sensitive methods for the detection of these adducts have been developed using liquid chromatography-tandem mass spectrometry. Adducts of all four nerve agents were detected in the blood of exposed guinea pigs being used in studies to improve medical countermeasures. The tyrosine adducts with soman and tabun were detected in guinea pigs receiving therapy 7 days following subcutaneous administration of five times the LD(50) dose of the respective nerve agent. VX also forms a tyrosine adduct in human blood in vitro but only at high concentrations.

  17. (-)-Phenserine Attenuates Soman-Induced Neuropathology

    PubMed Central

    Chen, Jun; Pan, Hongna; Chen, Cynthia; Wu, Wei; Iskandar, Kevin; He, Jeffrey; Piermartiri, Tetsade; Jacobowitz, David M.; Yu, Qian-Sheng; McDonough, John H.; Greig, Nigel H.; Marini, Ann M.

    2014-01-01

    Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy. PMID:24955574

  18. Supralethal poisoning by any of the classical nerve agents is effectively counteracted by procyclidine regimens in rats.

    PubMed

    Myhrer, Trond; Mariussen, Espen; Enger, Siri; Aas, Pål

    2015-09-01

    A treatment regimen consisting of HI-6, levetiracetam, and procyclidine (termed the triple regimen) has previously been shown to work as a universal therapy against soman poisoning in rats, since it has capacities to function as both prophylactic and therapeutic measure. The purpose of the present study was to examine whether the triple regimen may have antidotal efficacy against intoxication by other classical nerve agents than soman. The treatment was given 1 and 5 min after exposure to a supralethal dose of nerve agents, and the results showed that the triple regimen successfully prevented or terminated seizures and preserved the lives of rats exposed to 5×LD50 of soman, sarin, cyclosarin, or VX, but solely 3×LD50 of tabun was managed by this regimen. To meet the particular antidotal requirements of tabun, the triple regimen was reinforced with obidoxime and was made to a quadruple regimen that effectively treated rats intoxicated by 5×LD50 of tabun. The rats recovered very well and the majority gained pre-exposure body weight within 7 days. Neuropathology was seen in all groups regardless of whether the rats seized or not. The most extensive damage was produced by sarin and cyclosarin. Differentiation between the nerve agents' potency to cause lesions was probably seen because the efficacious treatments ensured survival of supralethal poisoning. A combination of 2 oximes and 2 anticonvulsants may be a prerequisite to counteract effectively high levels of poisoning by any classical nerve agent.

  19. Anaerobic toxicity and biodegradability of hydrolysis products of chemical warfare agents.

    PubMed

    Sklyar, V I; Mosolova, T P; Kucherenko, I A; Degtyarova, N N; Varfolomeyev, S D; Kalyuzhnyi, S V

    1999-08-01

    The toxicity and biodegradability of the main hydrolysis products of chemical warfare agents were investigated under methanogenic conditions. Among the tested substances, only MPhA does not have any toxic effect with regard to the aceticlastic methanogenic activity. The toxicity of other compounds varied between moderate (TDG, mercaptoethanol) to strong (ethanolamine, diisobutyl ester of MPhA). Biodegradability tests showed that all the products of chemical detoxification of mustard gas (ethanolamine, ethylene glycol, TDG, mercaptoethanol) can be biomineralized under methanogenic conditions. On the contrary, phosphorus-containing compounds from the chemical detoxification of nerve warfare agents (Sarin, Soman, Vx-gases) are quite persistent under these conditions.

  20. The Oxime Pro-2-PAM Provides Minimal Protection Against the CNS Effects of the Nerve Agents Sarin, Cyclosarin, and VX in Guinea Pigs

    DTIC Science & Technology

    2011-01-01

    Figure 2. Representative micrographs of neuronal damage in CA1 hippocampus (A–D), basolateral (BL) amygdalae (E–H), piriform cortex (I–L) and striatum (M...E) BL amygdala, (I) piriform cortex, and (M) striatum. Although animals that received pro-2-PAM at 1 min after VX or sarin and that had their... piriform cortex (K, sarin; L, VX) and striatum (O, sarin; P, VX). Magnification 200×. A B C D E F G H I J K L M N O P

  1. Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication.

    PubMed

    Shih, T M; McDonough, J H

    2000-05-01

    The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO4 as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO4 admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO4 and observed for seizure termination. The anticonvulsant ED50 of biperiden HCl and atropine SO4 for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED50s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO4 for soman, VR, tabun, GF, sarin, and VX were

  2. [+]-Huperzine A protects against soman toxicity in guinea pigs.

    PubMed

    Wang, Ying; Wei, Yanling; Oguntayo, Samuel; Jensen, Neil; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2011-12-01

    The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood-brain barrier (BBB) to protect against central nervous system damage. [-]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [-]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [-]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD(50) soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.

  3. Rotational Spectrum of Sarin

    NASA Astrophysics Data System (ADS)

    Walker, A. R. Hight; Suenram, R. D.; Samuels, Alan; Jensen, James; Ellzy, Michael W.; Lochner, J. Michael; Zeroka, Daniel

    2001-05-01

    As part of an effort to examine the possibility of using molecular-beam Fourier-transform microwave spectroscopy to unambiguously detect and monitor chemical warfare agents, we report the first observation and assignment of the rotational spectrum of the nerve agent Sarin (GB) (Methylphosphonofluoridic acid 1-methyl-ethyl ester, CAS #107-44-8) at frequencies between 10 and 22 GHz. Only one of the two low-energy conformers of this organophosphorus compound (C4H10FO2P) was observed in the rotationally cold (Trot<2 K) molecular beam. The experimental asymmetric-rotor ground-state rotational constants of this conformer are A=2874.0710(9) MHz, B=1168.5776(4) MHz, C=1056.3363(4) MHz (Type A standard uncertainties are given, i.e., 1σ), as obtained from a least-squares analysis of 74 a-, b-, and c-type rotational transitions. Several of the transitions are split into doublets due to the internal rotation of the methyl group attached to the phosphorus. The three-fold-symmetry barrier to internal rotation estimated from these splittings is 677.0(4) cm-1. Ab initio electronic structure calculations using Hartree-Fock, density functional, and Moller-Plesset perturbation theories have also been made. The structure of the lowest-energy conformer determined from a structural optimization at the MP2/6-311G** level of theory is consistent with our experimental findings.

  4. Histopathologic Changes in the Brain, Heart, and Skeletal Muscle of Rhesus Macaques, Ten Days After Exposure to Soman (An Organophosphorus Nerve Agent)

    DTIC Science & Technology

    2000-04-01

    Jr., Jamie L. Martin, Carlin V. Okerberg, and Edward John Dick, Jr. Background and Purpose: Soman, an organophosphorus, anticholinergic, chemical...lethality. Pharmacol. Biochem. Behav. 54:731-737. 15. Chuaqui, R., and J. Tapia . 1993. Histologie assessment of the age of recent brain infarcts in man

  5. 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.

  6. Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

    SciTech Connect

    Perkins, Michael W.; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Sciuto, Alfred M.; Nambiar, Madhusoodana P.

    2010-06-01

    Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m{sup 3} concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m{sup 3} soman survived, while animals exposed to 841, and 1121 mg/m{sup 3} resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt{sub 50} for soman determined by probit analysis was 827.2 mg/m{sup 3}. A majority of the animals that died at 1121 mg/m{sup 3} developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.

  7. An evaluation of the spectral properties of nerve agents for laser ionization mass spectrometry.

    PubMed

    Imasaka, Tomoko; Imasaka, Totaro

    2014-01-01

    Excitation energies, oscillator strengths, and vacuum-ultraviolet/deep-ultraviolet absorption spectra were calculated for nerve agents, such as sarin, soman, VX, tabun, mustard gas, and analogs. We used time-dependent density functional theory (TD-DFT) methods that included B3LYP combined with basis sets of cc-pVDZ and cc-pVTZ, and ωB97XD with cc-pVTZ. The vertical ionization energies were also calculated for these compounds, in order to collect additional information relative to the optimal pathways for multiphoton ionization in mass spectrometry.

  8. Toxicity studies on Agents GB and GD (Phase 2): 90-day subchronic study of GB (Sarin, Type II) in CD rats. Final report, Jul 85-Aug 91

    SciTech Connect

    Bucci, T.J.; Parker, R.M.

    1992-01-01

    A two-phase Dose Range findng study and a 90-Day Subchronic study were conducted in CD rats using the organophosphate ester Sarin (Agent GB, Type II, CAS Number 107-44-8). The highest dose level without lethality in the second phase of the range finding study was designated the maximum tolerated dose (MTD). The doses selected for the subchronic study were the MTD (300 micron GBII/Kg/day), MTD/2 (150micron GBII/Kg/day), MTD/4 (75micron GBII/Kg/day), and a vehicle control . Forty-eight male and forty-eight female CD rats were randomly allocated at 11 -1 2 weeks of age into four treatment groups (1 2 per sex per group). The animals were gavaged Monday through Friday for 13 weeks and euthanized with carbon dioxide at the beginning of the fourteenth week. Animals were observed daily for clinical signs of toxicity and were weighed weekly. The rats were bled (6 rat/sex/dose) during weeks -1, 1, 3, 7, and at necropsy. Necropsy examination was performed on all animals. Microscopic evaluation was performed on all high-dose and control animals and on those tissues of lower dose animals that were abnormal at necropsy. All gross lesions and all animals dying or removed early received histological examination. A cause of death or morbidity for animals removed before the end of the study, determined from histopathological examination, was established in four cases. There were several statistically significant effects in the clinical chemistry and hematology data. These effects were scattered among the treatment groups and were not numerous enough to develop a pattern of organ toxicity.

  9. Toxicity studies on Agents GB and GD (Phase 2): 90-day subchronic study of GB (Sarin, Type I) in CD rats. Final report, Jul 85-Aug 91

    SciTech Connect

    Bucci, T.J.; Parker, R.M.; Crowell, J.A.; Thurman, J.D.; Gosnell, P.A.

    1991-08-01

    A two-phase Dose Range finding study and a 90-Day Subchronic study were conducted in CD rats using the organophosphate ester Sarin (Agent GB, Type I, CAS Number 107-44-8). The highest dose level without lethality in the second phase of the range finding study was designated the maximum tolerated dose (MTD). The doses selected for the subchronic study were the MTD (300 micron GBI/Kg/day), MTD/2 (150, micron GBI/Kg/day), MTD/4 (75 micron GBI/Kg/day), and a vehicle control (O micron /Kg/day). Forty-eight male and forty-eight female CD rats were randomly allocated at 11-12 weeks of age into four treatment groups (12 per sex per group). The animals were gavaged Monday through Friday for 13 weeks and euthanized with carbon dioxide at the beginning of the fourteenth week. Animals were observed daily for clinical signs of toxicity and were weighed weekly. The rats were bled (6 rats/sex/dose) during weeks -1, 1, 3, 7, and at necropsy. Necropsy examination was performed on all animals. Microscopic evaluation was performed on all high-dose and control animals, and on those tissues of lower dose animals that were abnormal at necropsy. All gross lesions and all animals dying or removed early received histological examination. A cause of death or morbidity for animals removed before the end of the study, determined from histopathological examination, was established in four of the eight cases. There were several statistically significant effects in the clinical chemistry and hematology data. These effects were scattered among the treatment groups and were not numerous enough to develop a pattern of organ toxicity.

  10. 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.

  11. Quantitation of organophosphorus nerve agent metabolites in human urine using isotope dilution gas chromatography-tandem mass spectrometry.

    PubMed

    Driskell, W Jack; Shih, Ming; Needham, Larry L; Barr, Dana B

    2002-01-01

    An isotope dilution gas chromatography-tandem mass spectrometric (GC-MS-MS) method was developed for quantitating the urinary metabolites of the organophosphorus nerve agents sarin, soman, tabun (GA), VX, and GF. Urine samples were concentrated by codistillation with acetonitrile, derivatized by methylation with diazomethane, and analyzed by GC-MS-MS. The limits of detection were less than 4 microg/L for all the analytes except for the GA metabolite, which had a limit of detection of less than 20 microg/L.

  12. Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

    PubMed Central

    2014-01-01

    Background Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Results Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Conclusion Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the

  13. Crystal Structures of Human Group-VIIA Phospholipase A2 Inhibited by Organophosphorus Nerve Agents Exhibit Non-aged Complexes ☆,☆☆

    PubMed Central

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

    2009-01-01

    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 PR and PS stereoisomers at the P-chiral center. The tabun complex displayed only the PR 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

  14. The development of immunoassays for detection of chemical warfare agents

    SciTech Connect

    Lenz, D.E.

    1995-06-01

    With the advent of enzyme linked immunoabsorbant assays (ELISA) and monoclonal antibodies in the last two decades, there has been considerable effort devoted to the development of antibodies to detect and quantify low molecular weight toxic substances in environmental or biological fluids. Polyclonal antibodies against paraoxon (the toxic metabolite of parathion) were reported as capable of detecting paraoxon in body fluids at a level of 10{sup -9} M ({approximately}260 pg/mL) when used in a competitive inhibition enzyme immunoassay (CIEIA). Monoclonal antibodies developed against a structural analogue of the chemical warfare agent soman were capable of detecting soman in buffer solutions at a level of 10{sup -6} M ({approximately}180 ng/mL). In addition, these antibodies were highly specific for soman even in the presence of its major hydrolysis product. Subsequent studies with antisoman monoclonal antibodies reported an extension of the level of sensitivity to -80 ng/mL. Furthermore these antibodies did not cross react with other chemical warfare nerve agents such as sarin or tabun. In all cases, the time for a confirmatory test was two hours or less. Immunoassays for T-2 micotoxins have also been reported with a minimal detection range of 2 pg/assay to 50 ng/assay for the polyclonal and monoclonal T-2 antibodies respectively. These antibodies offer a sensitive, rapid and low cost approach to the diagnosis or detection of the presence of toxic chemical substances.

  15. Measurement of breakthrough volumes of volatile chemical warfare agents on a poly(2,6-diphenylphenylene oxide)-based adsorbent and application to thermal desorption-gas chromatography/mass spectrometric analysis.

    PubMed

    Kanamori-Kataoka, Mieko; Seto, Yasuo

    2015-09-04

    To establish adequate on-site solvent trapping of volatile chemical warfare agents (CWAs) from air samples, we measured the breakthrough volumes of CWAs on three adsorbent resins by an elution technique using direct electron ionization mass spectrometry. The trapping characteristics of Tenax(®) TA were better than those of Tenax(®) GR and Carboxen(®) 1016. The latter two adsorbents showed non-reproducible breakthrough behavior and low VX recovery. The specific breakthrough values were more than 44 (sarin) L/g Tenax(®) TA resin at 20°C. Logarithmic values of specific breakthrough volume for four nerve agents (sarin, soman, tabun, and VX) showed a nearly linear correlation with the reciprocals of their boiling points, but the data point of sulfur mustard deviated from this linear curve. Next, we developed a method to determine volatile CWAs in ambient air by thermal desorption-gas chromatography (TD-GC/MS). CWA solutions that were spiked into the Tenax TA(®) adsorbent tubes were analyzed by a two-stage TD-GC/MS using a Tenax(®) TA-packed cold trap tube. Linear calibration curves for CWAs retained in the resin tubes were obtained in the range between 0.2pL and 100pL for sarin, soman, tabun, cyclohexylsarin, and sulfur mustard; and between 2pL and 100pL for VX and Russian VX. We also examined the stability of CWAs in Tenax(®) TA tubes purged with either dry or 50% relative humidity air under storage conditions at room temperature or 4°C. More than 80% sarin, soman, tabun, cyclohexylsarin, and sulfur mustard were recovered from the tubes within 2 weeks. In contrast, the recoveries of VX and Russian VX drastically reduced with storage time at room temperature, resulting in a drop to 10-30% after 2 weeks. Moreover, we examined the trapping efficiency of Tenax TA(®) adsorbent tubes for vaporized CWA samples (100mL) prepared in a 500mL gas sampling cylinder. In the concentration range of 0.2-2.5mg/m(3), >50% of sarin, soman, tabun, cyclohexylsarin, and HD were

  16. Vibrational overtone stretching transitions in sarin

    NASA Astrophysics Data System (ADS)

    Petryk, Michael W. P.

    2006-10-01

    The CH stretching overtone transitions of the nerve agent sarin (O-isopropyl methylphosphonofluoridate) are of interest to the standoff detection of chemical warfare agents, as many of these transitions occur near regions where small, efficient, portable diode lasers (originally developed for use in the telecommunications industry) operate. However, the interpretation of experimental vibrational overtone spectra is often difficult, and the computational simulation of overtone transitions in a molecule is challenging. Presented herein are the simulated CH overtone stretching transitions in sarin. Spectral regions are simulated from overtone transition energies and intensities, both of which are calculated within the harmonically coupled anharmonic oscillator (HCAO) model. Data for HCAO calculations are obtained from ab initio calculations, without any recourse to experimental data.

  17. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

    SciTech Connect

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.; Xu, Fadi; Russell, Robert G.; Sopori, Mohan L.

    2014-01-15

    Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily.

  18. Inhalation toxicokinetics of soman stereoisomers in the atropinized guinea pig with nose-only exposure to soman vapor.

    PubMed

    Langenberg, J P; Spruit, H E; van der Wiel, H J; Trap, H C; Helmich, R B; Bergers, W W; van Helden, H P; Benschop, H P

    1998-07-01

    The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were studied in anesthetized, atropinized guinea pigs for nose-only exposure to soman vapor. During exposure the respiratory minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the concentrations of nerve agent stereoisomers and for measurement of the progressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4-0.8 LCt50 of C(+/-)P(+/-)-soman. Concentrations of the P(-)-isomers increased rapidly during exposure, up to several nanograms per milliliter of blood. Mathematical equations describing the concentration-time courses of the P(-)-isomers were obtained by nonlinear regression. The kinetics were mathematically described as a discontinuous process, with a monoexponential equation for the exposure period and a two-exponential equation for the postexposure period. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer, presumably due to preferential covalent binding at as yet unidentified binding sites. The terminal half-life observed after nose-only exposure is longer than that observed after an equitoxic iv bolus administration, which suggests the presence of a depot in the upper respiratory tract from which absorption continues after termination of the exposure. Two types of nonlinearity of the toxicokinetics were observed, i.e., with dose and with exposure time. The AChE activity was rapidly inhibited during exposure to the nerve agent vapor. There were no soman-related effects on RMV and RF. The toxicokinetics of the soman stereoisomers observed for nose-only exposure are compared with those determined for iv bolus and sc administration.

  19. Stereoselective Syntheses of Soman Analog

    DTIC Science & Technology

    1993-04-28

    AD-A283 855 AD_ _ _ _ CONTRACT NO: DAMDl7-88-C-8021 0 / TITLE: STEREOSELECTIVE SYNTHESES OF SOMAN ANALOG SUBTITLE: Synthesis of Pentacoordinate...SUPPLEMENTARY NOTES SUBTITLE: Synthesis of Pentacoordinate Phosphorus Compounds, "Bait and Switch" Compounds, and Soman Simulants as Hapten. for Production of...simulant. We reporit a detailed study on the synthesis , isolation and characterization of the four pure enantiomners; of [(S or R)-4 -amino-2,2-diniethyl-2

  20. 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

  1. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: effects of epinephrine and oxygen therapies.

    PubMed

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G; Xu, Fadi; Russell, Robert G; Sopori, Mohan L

    2014-01-15

    Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD50 sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD50 sarin-exposed animals were administered the bronchodilator epinephrine, >90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50 sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin.

  2. Bioanalysis of the enantiomers of (+/-)-sarin using automated thermal cold-trap injection combined with two-dimensional gas chromatography.

    PubMed

    Spruit, H E; Trap, H C; Langenberg, J P; Benschop, H P

    2001-01-01

    A fully automated multidimensional gas chromatographic system with thermal desorption injection and alkali flame detection was developed for analysis of the enantiomers of the nerve agent (+/-)-sarin. The chiral stationary phase was CP Cyclodex B on which the sarin enantiomers were completely resolved. The absolute detection limit was 2.5 pg per enantiomer. The method is intended to be used for the analysis of the sarin enantiomers in biological samples. For this purpose, sarin was isolated from guinea pig blood via solid-phase extraction. Deuterated sarin was used as internal standard. Stabilization of sarin in the blood sample by acidification and addition of an excess of a competitive organophosphorus compound (neopentyl sarin) appeared to be essential. The absolute recovery of the extraction procedure was 60%, whereas the recovery relative to the internal standard was 100%.

  3. The effects of repeated low-dose sarin exposure

    SciTech Connect

    Shih, T.-M. . E-mail: tsungming.a.shih@us.army.mil; Hulet, S.W.; McDonough, J.H.

    2006-09-01

    This project assessed the effects of repeated low-dose exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the established LD{sub 5} dose of sarin (42 {mu}g/kg, s.c.). The animals were assessed for changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels, neurobehavioral reactions to a functional observational battery (FOB), cortical electroencephalographic (EEG) power spectrum, and intrinsic acetylcholine (ACh) neurotransmitter (NT) regulation over the 2 weeks of sarin exposure and for up to 12 days postinjection. No guinea pig receiving 0.3, 0.4 or 0.5 x LD{sub 5} of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline, while seizures were evident in animals receiving 0.6 x LD{sub 5} of sarin as early as the second day; subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD{sub 5} sarin showed obvious signs of cholinergic toxicity; overall, 2 of 13 animals receiving 0.5 x LD{sub 5} sarin died before all 10 injections were given, and there was a significant increase in the angle of gait in the animals that lived. By the 10th day of injection, the animals receiving saline were significantly easier to remove from their cages and handle and significantly less responsive to an approaching pencil and touch on the rump in comparison with the first day of testing. In contrast, the animals receiving 0.4 x LD{sub 5} sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared with the first day. The 0.5 x LD{sub 5} sarin animals also failed to show any significant changes to the approach and touch responses and did not adjust to handling or removal from the cage from the first day of injections to the last day of handling. Thus, the guinea pigs receiving the 0

  4. Polyclonal antibody to soman-tyrosine

    PubMed Central

    Li, Bin; Duysen, Ellen G.; Froment, Marie-Thérèse; Masson, Patrick; Nachon, Florian; Jiang, Wei; Schopfer, Lawrence M.; Thiele, Geoffrey M.; Klassen, Lynell W.; Cashman, John; Williams, Gareth R.; Lockridge, Oksana

    2013-01-01

    Soman forms a stable, covalent bond with tyrosine 411 of human albumin, with tyrosines 257 and 593 in human transferrin, and with tyrosine in many other proteins. The pinacolyl group of soman is retained, suggesting that pinacolyl methylphosphonate bound to tyrosine could generate specific antibodies. Tyrosine in the pentapeptide RYGRK was covalently modified with soman simply by adding soman to the peptide. The phosphonylated-peptide was linked to keyhole limpet hemocyanin, and the conjugate was injected into rabbits. The polyclonal antiserum recognized soman-labeled human albumin, soman-mouse albumin, and soman human transferrin, but not non-phosphonylated control proteins. The soman-labeled tyrosines in these proteins are surrounded by different amino acid sequences, suggesting that the polyclonal recognizes soman-tyrosine independent of the amino acid sequence. Antiserum obtained after 4 antigen injections over a period of 18 weeks was tested in a competition ELISA where it had an IC50 of 10−11 M. The limit of detection on Western blots was 0.01 μg (15 picomoles) of soman-labeled albumin. In conclusion, a high-affinity, polyclonal antibody that specifically recognizes soman adducts on tyrosine in a variety of proteins has been produced. Such an antibody could be useful for identifying secondary targets of soman toxicity. PMID:23469927

  5. Role of Immunogen Design in Induction of Soman-Specific Monoclonal Antibodies

    DTIC Science & Technology

    2005-01-01

    CH3 H 0 2. Methods and materials S oman (a) AH3 LH, LH 2.1. Hybridomas _H The monoclonal antibodies CCI-IIA4 (CC1) and BE2- KLH IA1O (BE2) were...Inhibitors Structures CC1 #2-ID)8.2 BE2 CH3 H V Soman (GD) CH3 -! -L - F >1000 0.2 100 AH3 tAH, AH3 H Y Sarin (GB) CH3• -0P-F N.I. 10 N.I. AH3 dH, CCH Soran

  6. Interactions of sarin with polyelectrolyte membranes: a molecular dynamics simulation study.

    PubMed

    Lee, Ming-Tsung; Vishnyakov, Aleksey; Gor, Gennady Yu; Neimark, Alexander V

    2013-01-10

    Nanostructured polyelectrolyte membranes (PEMs), which are widely used as permselective diffusion barriers in fuel cell technologies and electrochemical processing, are considered as protective membranes suitable for blocking warfare toxins, including water-soluble nerve agents such as sarin. In this article, we examine the mechanisms of sorption and diffusion of sarin in hydrated PEMs by means of atomistic molecular dynamics simulations. Three PEMs are considered: Nafion, sulfonated polystyrene (sPS) that forms the hydrophilic subphase of segregated sPS-polyolefin block copolymers, and random sPS-polyethylene copolymer. We found that sarin concentrates at the interface between the hydrophilic and hydrophobic subphases of hydrated Nafion acting as a surfactant. In hydrated sPS, where the scale of water-polymer segregation is much smaller (1-2 nm), sarin also interacts favorably with hydrophobic and hydrophilic components. Water diffusion slows as the sarin content increases despite the overall increase in solvent content, which suggests that sarin and water have somewhat different pathways through the segregated membrane. Upon replacement of counterions of monovalent potassium with those of divalent calcium, sarin diffusion slows but remains substantial in all ionomers considered, especially at high sarin concentrations. The behavior of sarin is similar to that of its common simulant, dimethyl methylphosphonate.

  7. 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.

  8. Prehospital management of sarin nerve gas terrorism in urban settings: 10 years of progress after the Tokyo subway sarin attack.

    PubMed

    Tokuda, Yasuharu; Kikuchi, Makiko; Takahashi, Osamu; Stein, Gerald H

    2006-02-01

    Chemical agents have been used previously in wartime on numerous occasions, from World War I to the Gulf War. In 1994 and 1995, sarin nerve gas was used first in peacetime as a weapon of terrorism in Japan. The Tokyo subway sarin attack was the first large-scale disaster caused by nerve gas. A religious cult released sarin gas into subway commuter trains during morning rush hour. Twelve passengers died and about 5500 people were harmed. Sarin is a highly toxic nerve agent that can be fatal within minutes to hours. It causes the clinical syndrome of cholinergic hyperstimulation by inhibition of the crucial enzyme acetylcholinesterase. Therapy of nerve agent toxicity is divided into three categories, decontamination, respiratory support, and antidotes. All of these therapies may be given simultaneously. This article reviews toxicology and management of this acute chemical emergency. To help minimize the possible catastrophic impact on the public, we make several recommendations based on analysis of the Tokyo subway sarin attack and systematically review the current scientific literature.

  9. Aerosolized scopolamine protects against microinstillation inhalation toxicity to sarin in guinea pigs.

    PubMed

    Che, Magnus M; Chanda, Soma; Song, Jian; Doctor, Bhupendra P; Rezk, Peter E; Sabnekar, Praveena; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2011-07-01

    Sarin is a volatile nerve agent that has been used in the Tokyo subway attack. Inhalation is predicted to be the major route of exposure if sarin is used in war or terrorism. Currently available treatments are limited for effective postexposure protection against sarin under mass casualty scenario. Nasal drug delivery is a potential treatment option for mass casualty under field conditions. We evaluated the efficacy of endotracheal administration of muscarinic antagonist scopolamine, a secretion blocker which effectively crosses the blood-brain barrier for protection against sarin inhalation toxicity. Age and weight matched male Hartley guinea pigs were exposed to 677.4 mg/m³ or 846.5 mg/ m³ (1.2 × LCt₅₀) sarin by microinstillation inhalation exposure for 4 min. One minute later, the animals exposed to 846.5 mg/ m³ sarin were treated with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 h for efficacy evaluation. The results showed that treatment with scopolamine increased the survival rate from 20% to 100% observed in untreated sarin-exposed animals. Behavioral symptoms of nerve agent toxicity including, convulsions and muscular tremors were reduced in sarin-exposed animals treated with scopolamine. Sarin-induced body weight loss, decreased blood O₂ saturation and pulse rate were returned to basal levels in scopolamine-treated animals. Increased bronchoalveolar lavage (BAL) cell death due to sarin exposure was returned to normal levels after treatment with scopolamine. Taken together, these data indicate that postexposure treatment with aerosolized scopolamine prevents respiratory toxicity and protects against lethal inhalation exposure to sarin in guinea pigs.

  10. Enzymatic detoxification of chemical warfare agents: immobilization of the enzyme for material surfaces. Final report

    SciTech Connect

    Rajan, K.S.

    1991-01-01

    The objective of this research is to investigate feasibility of immobilizing squid-type DFPase on fabrics such as nylon, polyester, cotton and polyester-cotton blends and on polyethylene glycol. Large quantities (about 15,000 units) on of the enzyme was prepared from the hepatopancreas tissues of East Coast (ECHP) and West Coast (WCHP) squid belonging to the species, Loligo Pealii and Loligo Opalescens. The purified enzyme preparations were characterized by their activities against diisopropylphosphorofluoridate (DFP), isopropylmethylphosphonofluoridate (SARIN) and pinacolylmethyl phosphonofluoridate (SOMAN) and their kinetic constants (KM and VMAX). The enzyme-immobilization study included the exploration of different preactivation methods involving treatment with (1) glutaraldehyde, (2) triethyloxoniumtetrafluoroborate (TTFB), (3) tresylchloride, (4) isocyanide, (5) cyanuric chloride and (6) KMnO4-oxidation. Results of examination of the DFPase-immobilized matrices showed agent-specific activities (DFP, SOMAN and SARIN) in the range 3.5 to 17.7 units/gram. A number of them retained up to 90% of their initial enzyme activity over a 90-day period. This is indicative of a good potential for this technical approach squid-type DFPase.

  11. Gene Expression Profiling of Rat Hippocampus Following Exposure to the Acetylcholinesterase Inhibitor Soman

    DTIC Science & Technology

    2009-01-01

    from seizure-related damage , and thus, neurodegeneration of soman- sensitive brain areas is a potential postexposure outcoVle. We performed gene...2009. 14. ABSTRACT See reprint. 15. SUBJECT TERMS Acetylcholinesterase, nerve agents, soman, neurodegeneration , gene expression profiling...Kniffin,:j: Christina P. Tompkins,:j: Tracey A. Hamilton,:j: and Robert K. Kan:j: Cell and Molecular Biology Branch, and Comparative Pathology

  12. Analogues with fluorescent leaving groups for screening and selection of enzymes that efficiently hydrolyze organophosphorus nerve agents.

    PubMed

    Briseño-Roa, Luis; Hill, Jim; Notman, Stuart; Sellers, David; Smith, Andy P; Timperley, Christopher M; Wetherell, Janet; Williams, Nichola H; Williams, Gareth R; Fersht, Alan R; Griffiths, Andrew D

    2006-01-12

    Enzymes that efficiently hydrolyze highly toxic organophosphorus nerve agents could potentially be used as medical countermeasures. As sufficiently active enzymes are currently unknown, we synthesized twelve fluorogenic analogues of organophosphorus nerve agents with the 3-chloro-7-oxy-4-methylcoumarin leaving group as probes for high-throughput enzyme screening. This set included analogues of the pesticides paraoxon, parathion, and dimefox, and the nerve agents DFP, tabun, sarin, cyclosarin, soman, VX, and Russian-VX. Data from inhibition of acetylcholinesterase, in vivo toxicity tests of a representative analogue (cyclosarin), and kinetic studies with phosphotriesterase (PTE) from Pseudomonas diminuta, and a mammalian serum paraoxonase (PON1), confirmed that the analogues mimic the parent nerve agents effectively. They are suitable tools for high-throughput screens for the directed evolution of efficient nerve agent organophosphatases.

  13. 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.

  14. Identification of chemical warfare agents using a portable microchip-based detection device

    NASA Astrophysics Data System (ADS)

    Petkovic-Duran, K.; Swallow, A.; Sexton, B. A.; Glenn, F.; Zhu, Y.

    2011-12-01

    Analysis of chemical warfare agents (CWAs) and their degradation products is an important verification component in support of the Chemical Weapons Convention and urgently demanding rapid and reliable analytical methods. A portable microchip electrophoresis (ME) device with contactless conductivity (CCD) detection was developed for the in situ identification of CWA and their degradation products. A 10mM MES/His, 0.4mM CTAB - based separation electrolyte accomplished the analysis of Sarin (GB), Tabun( GA) and Soman (GD) in less than 1 min, which is the fastest screening of nerve agents achieved with portable ME and CCD based detection methods to date. Reproducibility of detection was successfully demonstrated on simultaneous detection of GB (200ppm) and GA (278ppm). Reasonable agreement for the four consecutive runs was achieved with the mean peak time for Sarin of 29.15s, and the standard error of 0.58s or 2%. GD and GA were simultaneously detected with their degradation products methylphosphonic acid (MPA), pinacolyl methylphosphonic acid (PMPA) and O-Ethyl Phosphorocyanidate (GAHP and GAHP1) respectively. The detection limit for Sarin was around 35ppb. To the best of our knowledge this is the best result achieved in microchip electrophoresis and contactless conductivity based detection to date.

  15. Pre- and post-treatment effect of physostigmine on soman-inhibited human erythrocyte and muscle acetylcholinesterase in vitro

    SciTech Connect

    Herkert, N.M.; Schulz, S.; Wille, T.; Thiermann, H.; Hatz, R.A.; Worek, F.

    2011-05-15

    Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by decarbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors.

  16. Protection of rhesus monkeys against Soman and prevention of performance decrement by pretreatment with acetylcholinesterase. (Reannouncement with new availability information)

    SciTech Connect

    Maxwell, D.M.; Castro, C.A.; De La Hoz, D.M.; Gentry, M.K.; Gold, M.B.

    1992-12-31

    The ability of acetylcholinesterase from fetal bovine serum (FBS AChE) to protect against soman, a highly toxic organophosphorus (OP) compound, was tested in rhesus monkeys. Intravenous administration of FBS AChE produced a minimal behavioral effect on the serial probe recognition task, a sensitive test of cognitive function and short-term memory. Pharmacokinetic studies of injected FBS AChE indicated a plasma half-life of 40 hr for FBS AChE in monkeys. Both in vitro and in vivo titration of FBS AChE with soman produced a 1:1 stoichiometry between organophosphate-inhibited FBS AChE and the cumulative dose of the toxic stereoisomers of soman. Administration of FBS AChE protected monkeys against the lethal effects of up to 2.7 LD50 of soman and prevented any signs of organophosphate intoxication, e.g., excessive secretions, respiratory depression, muscle fasciculations, or convulsions. In addition, monkeys pretreated with FBS AChE were devoid of any behavioral incapacitation after soman challenge, as measured by the serial probe recognition task. Compared to the current multicomponent drug treatment against soman, which does not prevent the signs or the behavioral deficits resulting from OP intoxication, use of FBS AChE as a single pretreatment drug provides significantly effective protection against both the lethal and the behavioral effects of soman.... Pretreatment, Nonhuman primate, Performance decrements, Acetylcholinesterase, Soman, Nerve agents.

  17. Ppb detection of Sarin surrogate in liquid solutions

    NASA Astrophysics Data System (ADS)

    Hamel, Matthieu; Hamoniaux, Jennifer; Rocha, Licinio; Normand, Stéphane

    2013-05-01

    Sarin, a well-known chemical warfare agent, is toxic for concentrations as low as 0.03 ppm in the air (Immediately Dangerous to Life or Health value). A technology providing "on the field" detection could be fluorescence spectroscopy. This presentation shows a sensitive method for the detection of Diethyl Chlorophosphate (DCP), a Sarin surrogate, which provides in a few seconds a turn-off fluorescence response of the sensor for ppb levels of DCP. For instance, a I/I0 = 0.68 (fluorescence quenching) was obtained when the sensor was exposed to 16 ppb of DCP.

  18. Delayed behavioral and endocrine effects of sarin and stress exposure in mice.

    PubMed

    Mach, Mojmir; Grubbs, Robert D; Price, William A; Nagaoka, Maya; Dubovický, Michal; Lucot, James B

    2008-03-01

    The organophosphorus agent sarin is a potent inhibitor of acetylcholinesterase. Experiments tested the influence of exposure to low doses of sarin along with psychological stress on delayed behavioral and endocrine changes in mice. Motor activity, acoustic startle response (ASR), pre-pulse inhibition (PPI) of ASR, activity of cholinesterase in blood and catecholamine levels in adrenals were evaluated after low dose sarin exposure (3 x 0.4 LD50 subcutaneously) combined with chronic intermittent stress in C57BL/6J mice. While sarin alone produced depression of motor activity, no interaction of the stress with sarin exposure was observed. Cholinesterase activity was significantly reduced 24 h after exposure to sarin; however, the basal activity was re-established 3 weeks later. The combination of low dose sarin exposure and stress produced delayed behavioral change manifested as excessive grooming together with endocrine alterations in adrenals 7 weeks after exposure. The size of the adrenals in the combined exposure group was increased and the concentration of catecholamines was significantly decreased. In conclusion, these findings indicate that sarin in low doses is more dangerous when combined with shaker stress inducing delayed behavioral and endocrine changes.

  19. 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.

  20. Measurements of chemical warfare agent degradation products using an electrophoresis microchip with contactless conductivity detector.

    PubMed

    Wang, Joseph; Pumera, Martin; Collins, Greg E; Mulchandani, Ashok

    2002-12-01

    This paper reports on a microfluidic device for the screening of organophosphonate nerve agent degradation products. The miniaturized system relies on an efficient chip-based separation of alkyl methylphosphonic acids (breakdown products of Sarin, Soman, and VX nerve agents) followed by their sensitive contactless conductivity detection. Experimental parameters relevant to the separation and detection processes have been optimized to yield high sensitivity (with 48-86 microg L(-1) detection limits), fast response (50 s for a three alkyl methylphosphonic acid mixture), high precision (RSD = 3.8-5.0%), and good linearity (over the 0.3-100 mg L(-1) range). Applicability to natural (river) water samples is demonstrated. The new microsystem offers promise for monitoring degradation products of chemical warfare agents, with advantages of speed/warning, efficiency, portability, sample size, and cost compared to conventional ion chromatography or capillary electrophoresis systems.

  1. Biodegradation of the hydrolysis product of Sarin

    SciTech Connect

    Zhang, Y.; Autenrieth, R.L.; Bonner, J.S.

    1995-12-31

    Sarin (isopropyl methylphosphonofluoridate) is a highly toxic chemical warfare agent which must be destroyed in an {open_quotes}essentially irreversible manner{close_quotes} as specified by the 1993 Chemical Weapons Convention. The destruction process usually involves two major steps: (1) destruction of the chemical warfare agents; (2) mineralization of the neutralization products to reach a waste stream that is environmentally acceptable. Under extreme pH, Sarin can easily be hydrolyzed to a much less toxic compound, isopropyl methylphosphonic acid (IMPA), leaving the fluoride either as an acid or ion. This study was designed to determine whether the Sarin neutralization product, IMPA, is susceptible to biodegradation. Five bacterial cultures were prepared and acclimated. APG swamp microorganisms and soil extract microorganisms degraded IMPA at the highest rates. Four reactor types were chosen to study the effect of the presence of PO{sub 4}{sup 3}{sup -} on IMPA degradation using the APG swamp microorganisms. Results showed that the PO{sub 4}{sup 3}{sup -} was preferentially used by the bacteria. The formation of phosphate in the reactors due to IMPA degradation was also determined for three concentrations of IMPA. Phosphate did not appear in the reactors until 48 hours. For a 0.36mM concentration, all IMPA was transformed to PO{sub 4}{sup 3}{sup -} after 248 hours. At higher concentrations, extra time was required to convert the IMPA. Further experiments are being conducted to determine kinetic parameters and to compare the performance of the free cells versus the immobilized cells in IMPA degradation.

  2. 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.

  3. Alterations in brain glutathione homeostasis induced by the nerve gas soman.

    PubMed

    Klaidman, Lori K; Adams, James D; Cross, Robert; Pazdernik, Thomas L; Samson, Fred

    2003-01-01

    Public awareness of the dangers of chemical and biological warfare has been heightened in recent times. In particular, chemical nerve agents such as soman and its analogs have been developed and used in war as well as recent incidents, such as in Iraq and Japan. Soman, a rapid acting acetylcholinesterase inhibitor, produces a status epilepticus that leads to extensive neuropathology in vulnerable brain regions (eg, piriform cortex and hippocampus). This study was undertaken to determine whether oxidative mechanisms are involved in brain pathology during soman toxicity. Intracellular thiols such as glutathione (GSH) and protein sulfhydryls (PrSH) are among the most critical antioxidants used to combat oxidative stress. Here we report that during the seizure phase (1 h post soman exposure), PrSH levels in piriform cortex and hippocampus were decreased without changes in glutathione (GSH) levels. However, by 24 h post soman exposure (pathology phase), GSH levels were decreased by nearly 50% in the piriform cortex with a corresponding decrease in PrSH groups. The shift to a more oxidized thiol status indicates that oxygen free radicals likely participate in the neuropathology associated with soman-induced seizures.

  4. Skin decontamination with mineral cationic carrier against sarin determined in vivo.

    PubMed

    Vucemilović, Ante; Hadzija, Mirko; Jukić, Ivan

    2009-06-01

    Our Institute's nuclear, biological, and chemical defense research team continuously investigates and develops preparations for skin decontamination against nerve agents. In this in vivo study, we evaluated skin decontamination efficacy against sarin by a synthetic preparation called Mineral Cationic Carrier (MCC) with known ion exchange, absorption efficacy and bioactive potential. Mice were treated with increasing doses of sarin applied on their skin, and MCC was administered immediately after contamination. The results showed that decontamination with MCC could achieve therapeutic efficacy corresponding to 3 x LD(50) of percutaneous sarin and call for further research.

  5. The development of immunoassays for detection of chemical warfare agents

    SciTech Connect

    Lenz, D.E.; Brimfield, A.A.; Cook, L.

    1996-10-01

    With the advent of enzyme linked immunoabsorbent assays (ELISA) and monoclonal antibodies in the last two decades, there has been considerable effort devoted to the development of antibodies to detect and quantify low molecular weight toxic substances in environmental or biological fluids. Polyclonal antibodies against paraoxon (the toxic metabolite of parathion) were capable of detecting paraoxon in body fluids at a level of 10{sup -9} M ({approximately}260 pg/mL) when used in a competitive inhibition enzyme immunoassay (CIEIA). Monoclonal antibodies developed against a structural analogue of the chemical warfare agent soman were capable of detection soman in buffer solutions at a level of 10{sup -6} M ({approximately}180 ng/mL). In addition these antibodies were found to be highly specific for soman even in the presence of its major hydrolysis product. Subsequent studies with antisoman monoclonal antibodies extended the level of sensitivity to {approximately}80 ng/mL. Furthermore these antibodies did not cross react with other chemical warfare nerve agents such as sarin or tabun. In all cases, the time for a confirmatory test was two hours or less. Immunoassays for T-2 micotoxins have also been reported with a minimal detection range of 2 pg/assay to 50 ng/assay for the polyclonal and monoclonal T-2 antibodies respectively. These reagents offer a sensitive, rapid and low cost approach to the diagnosis or detection of the presence of toxic chemical substances. More recent efforts have focussed on developing antibodies specific for sulfur mustard a highly reactive vesicating agent.

  6. Determination of trace amounts of chemical warfare agent degradation products in decontamination solutions with NMR spectroscopy.

    PubMed

    Koskela, Harri; Rapinoja, Marja-Leena; Kuitunen, Marja-Leena; Vanninen, Paula

    2007-12-01

    Decontamination solutions are used for an efficient detoxification of chemical warfare agents (CWAs). As these solutions can be composed of strong alkaline chemicals with hydrolyzing and oxidizing properties, the analysis of CWA degradation products in trace levels from these solutions imposes a challenge for any analytical technique. Here, we present results of application of nuclear magnetic resonance spectroscopy for analysis of trace amounts of CWA degradation products in several untreated decontamination solutions. Degradation products of the nerve agents sarin, soman, and VX were selectively monitored with substantially reduced interference of background signals by 1D 1H-31P heteronuclear single quantum coherence (HSQC) spectrometry. The detection limit of the chemicals was at the low part-per-million level (2-10 microg/mL) in all studied solutions. In addition, the concentration of the degradation products was obtained with sufficient confidence with external standards.

  7. 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.

  8. An in vitro and in vivo evaluation of the efficacy of recombinant human liver prolidase as a catalytic bioscavenger of chemical warfare nerve agents.

    PubMed

    Rezk, Peter E; Zdenka, Pierre; Sabnekar, Praveena; Kajih, Takwen; Mata, David G; Wrobel, Chester; Cerasoli, Douglas M; Chilukuri, Nageswararao

    2015-01-01

    In this study, we determined the ability of recombinant human liver prolidase to hydrolyze nerve agents in vitro and its ability to afford protection in vivo in mice. Using adenovirus containing the human liver prolidase gene, the enzyme was over expressed by 200- to 300-fold in mouse liver and purified to homogeneity by affinity and gel filtration chromatography. The purified enzyme hydrolyzed sarin, cyclosarin and soman with varying rates of hydrolysis. The most efficient hydrolysis was with sarin, followed by soman and by cyclosarin {apparent kcat/Km [(1.9 ± 0.3), (1.7 ± 0.2), and (0.45 ± 0.04)] × 10(5 )M(-1 )min(-1), respectively}; VX and tabun were not hydrolyzed by the recombinant enzyme. The enzyme hydrolyzed P (+) isomers faster than the P (-) isomers. The ability of recombinant human liver prolidase to afford 24 hour survival against a cumulative dose of 2 × LD50 of each nerve agent was investigated in mice. Compared to mice injected with a control virus, mice injected with the prolidase expressing virus contained (29 ± 7)-fold higher levels of the enzyme in their blood on day 5. Challenging these mice with two consecutive 1 × LD50 doses of sarin, cyclosarin, and soman resulted in the death of all animals within 5 to 8 min from nerve agent toxicity. In contrast, mice injected with the adenovirus expressing mouse butyrylcholinesterase, an enzyme which is known to afford protection in vivo, survived multiple 1 × LD50 challenges of these nerve agents and displayed no signs of toxicity. These results suggest that, while prolidase can hydrolyze certain G-type nerve agents in vitro, the enzyme does not offer 24 hour protection against a cumulative dose of 2 × LD50 of G-agents in mice in vivo.

  9. Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman-Induced Seizures

    DTIC Science & Technology

    2008-01-01

    23, 2008) Abstract: This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when...significantly slower. Midazolam was effective in treating soman-induced seizures when given by all three routes, but with differences in potency and speed of...subset of anticonvulsant or antiepileptic drugs. Benzodiazepines are typically the most effective class of compounds and are used as the first drug of

  10. Pathways for the Oxidation of Sarin in Urban Atmospheres

    SciTech Connect

    Gerald E. Streit; James E. Bossert; Jeffrey S. Gaffney; Jon Reisner; Laurie A. McNair; Michael Brown; Scott Elliott

    1998-11-01

    Terrorists have threatened and carried out chemicalhiological agent attacks on targets in major cities. The nerve agent sarin figured prominently in one well-publicized incident. Vapors disseminating from open containers in a Tokyo subway caused thousands of casualties. High-resolution tracer transport modeling of agent dispersion is at hand and will be enhanced by data on reactions with components of the urban atmosphere. As a sample of the level of complexity currently attainable, we elaborate the mechanisms by which sarin can decompose in polluted air. A release scenario is outlined involving the passage of a gas-phase agent through a city locale in the daytime. The atmospheric chemistry database on related organophosphorus pesticides is mined for rate and product information. The hydroxyl,radical and fine-mode particles are identified as major reactants. A review of urban air chernistry/rnicrophysics generates concentration tables for major oxidant and aerosol types in both clean and dirty environments. Organic structure-reactivity relationships yield an upper limit of 10-1' cm3 molecule-' S-* for hydrogen abstraction by hydroxyl. The associated midday loss time scale could be as little as one hour. Product distributions are difficult to define but may include nontoxic organic oxygenates, inorganic phosphorus acids, sarin-like aldehydes, and nitrates preserving cholinergic capabilities. Agent molecules will contact aerosol surfaces in on the order of minutes, with hydrolysis and side-chain oxidation as likely reaction channels.

  11. SERS-based ultrasensitive detection of organophosphorus nerve agents via substrate's surface modification.

    PubMed

    Zhao, Qian; Liu, Guangqiang; Zhang, Hongwen; Zhou, Fei; Li, Yue; Cai, Weiping

    2017-02-15

    Highly efficient detection of the organicphosphor nerve agents such as sarin and soman, based on surface enhanced Raman scattering (SERS) effect, has been in challenge due to their weak adsorption property on coin metals. In this paper, a new strategy is presented to achieve the SERS-based ultrasensitive detection of sarin-simulated agent methanephosphonic acid (MPA) via the surface modification of SERS-substrates. The Au-coated Si nanocone array is surface-modified with 2-aminoethanethiol and used as SERS-substrate for detection of MPA. It has been shown that the modified substrate could preferentially capture MPA molecules in the solution with coupling agent and induce amidation reaction. The reaction products are still bound or anchor on the substrate's surface. The MPA molecules can thus be detected by Raman spectral measurement of the solution-soaked SERS-substrate. The minimum detection level is down to ∼1ppb. The Raman peak intensity versus the MPA concentration is subject to a linear double logarithmic relation from ∼1ppb to ∼1000ppm, which is attributed to Freundlich adsorption of MPA on the surface-modified SERS substrate. This study provides a new way for the highly efficient SERS-based detection of the organophosphorus nerve agents and some other target molecules weakly interacted with metal substrates.

  12. Hand-held analyser based on microchip electrophoresis with contactless conductivity detection for measurement of chemical warfare agent degradation products

    NASA Astrophysics Data System (ADS)

    Duran, Karolina-Petkovic; Zhu, Yonggang; Chen, Chuanpin; Swallow, Anthony; Stewart, Robert; Hoobin, Pam; Leech, Patrick; Ovenden, Simon

    2008-12-01

    This paper reports on the development of a hand-held device for on-site detection of organophosphonate nerve agent degradation products. This field-deployable analyzer relies on efficient microchip electrophoresis separation of alkyl methylphosphonic acids and their sensitive contactless conductivity detection. Miniaturized, low-powered design is coupled with promising analytical performance for separating the breakdown products of chemical warfare agents such as Soman, Sarin and VX . The detector has a detection limit of about 10 μg/mL and has a good linear response in the range 10-300 μg/mL concentration range. Applicability to environmental samples is demonstrated .The new hand-held analyzer offers great promise for converting conventional ion chromatography or capillary electrophoresis sophisticated systems into a portable forensic laboratory for faster, simpler and more reliable on-site screening.

  13. 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.

  14. Quantitative Infrared Spectra of Vapor Phase Chemical Agents

    SciTech Connect

    Sharpe, Steven W.; Johnson, Timothy J.; Chu, P M.; Kleimeyer, J; Rowland, Brad; Gardner, Patrick J.

    2003-04-21

    Quantitative high resolution (0.1 cm -1) infrared spectra have been acquired for a number of pressure broadened (101.3 KPa N2), vapor phase chemicals including: Sarin (GB), Soman (GD), Tabun (GA), Cyclosarin (GF), VX, nitrogen mustard (HN3), sulfur mustard (HD) and Lewisite (L).

  15. Conformational Variability of Organophosphorus Hydrolase upon Soman and Paraoxon Binding

    SciTech Connect

    Gomes, Diego Eb; Lins, Roberto D.; Pascutti, Pedro G.; Lei, Chenghong; Soares, Thereza A.

    2011-12-31

    The bacterial enzyme organophosphorus hydrolase (OPH) exhibits both catalytic and substrate promiscuity. It hydrolyzes bonds in a variety of phosphotriester (P-O), phosphonothioate (P-S), phosphofluoridate (P-F) and phosphonocyanate (F-CN) compounds. However, its catalytic efficiency varies markedly for different substrates, limiting the broad-range application of OPH as catalyst in the bioremediation of pesticides and chemical war agents. In the present study, pK{sub a} calculations and multiple explicit-solvent molecular dynamics (MD) simulations were performed to characterize and contrast the structural dynamics of OPH bound to two substrates hydrolyzed with very distinct catalytic efficiencies: the nerve agent soman (O-pinacolyl-methyl-phosphonofluoridate) and the pesticide paraoxon (diethyl p-nitrophenyl phosphate). pK{sub a} calculations for the substrate-bound and unbound enzyme showed a significant pK{sub a} shift from standard values ({Delta}pK{sub a} = {+-} 3 units) for residues 254His and 275Arg. MD simulations of the doubly protonated 254His revealed a dynamic hydrogen bond network connecting the catalytic residue 301Asp via 254His to 232Asp, 233Asp, 275Arg and 235Asp, and is consistent with a previously postulated proton relay mechanism to ferry protons away from the active site with substrates that do not require activation of the leaving group. Hydrogen bonds between 301Asp and 254His were persistent in the OPH-paraoxon complex but not in the OPH-soman one, suggesting a potential role for such interaction in the more efficient hydrolysis of paraoxon over soman by OPH. These results are in line with previous mutational studies of residue 254His, which led to an increase of the catalytic efficiency of OPH over soman yet decreased its efficiency for paraoxon. In addition, comparative analysis of the molecular trajectories for OPH bound to soman and paraoxon suggests that binding of the latter facilitates the conformational transition of OPH from the

  16. The Effects of Repeated Low-Dose Sarin Exposure

    DTIC Science & Technology

    2005-08-01

    this report, the investigators complied with the regulations and standards of the Animal Welfare Act and adhered to the principles of the Guide for...the Care and Use of Laboratory Animals (NRC 1996). The use of trade names does not constitute an official endorsement or approval of the use of...exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with

  17. 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.

  18. Evaluation of cognitive and biochemical effects of low-level exposure to sarin in rhesus and African green monkeys.

    PubMed

    Genovese, Raymond F; Oubre, John L; Jakubowski, E Michael; Fleming, Patrick J; Saxena, Ashima; Rockwood, Gary A; Tipparaju, Prasanthi; Willmore, Catherine B

    2007-02-28

    We investigated the potential of low-level exposures to the chemical warfare nerve agent, sarin, to produce adverse effects. Rhesus (Macaca mulatta) and African green monkeys (Chlorocebus acthiops) were trained on a serial probe recognition (SPR) task before IM administration of a low-level concentration (5.87 microg/kg or 2.93 microg/kg) of sarin. Blood was sampled before agent administration and at various times following administration. Sarin administration did not disrupt performance on the SPR task in either species. Major dependent measures characterizing performance (accuracy, number of completed trials per session, average choice response time) were largely unaffected on the day sarin was administered as well as on subsequent testing sessions occurring over several weeks following administration. Analyses of red blood cell (RBC) and plasma samples revealed that sarin administration produced a substantial degree of inhibition of circulating acetylcholinesterase (AChE) in RBC fractions and butyrylcholinesterase (BChE) in plasma fractions, which only slowly recovered. In this regard, AChE activity was inhibited to a greater extent than BChE activity. Blood samples were also evaluated for regenerated sarin, which was found in RBC and plasma fractions in both species and showed orderly elimination functions. More sarin was regenerated from RBC fractions than from plasma fractions. Elimination of regenerated sarin was much slower in RBC than plasma and exceeded the expected time of AChE aging, suggesting the presence of additional sarin binding sites. In general, effects were similar in both species. Taken together, our results show that while the concentrations of sarin administered were clearly biochemically active, they were below those that are required to produce a disruption of behavioral performance.

  19. Neuroimmune Effects of Inhaling Low Dose Sarin

    DTIC Science & Technology

    2008-02-01

    system Because two of the Japanese sarin terrorism survivors succumbed to Legionella infection nearly two years after the sarin exposure (Kamimura...lung organism, Legionella . However, our results indicated that both adaptive (antibody and T cell receptor-mediated responses) as well inflammatory...H. Niino, K. Saitoh, and A. Saitoh. 1998. Legionella pneumonia caused by aspiration of hot spring water after sarin exposure. Nihon. Kokyuki. Gakkai

  20. Modelling aerosol processes related to the atmospheric dispersion of sarin.

    PubMed

    Kukkonen, J; Riikonen, K; Nikmo, J; Jäppinen, A; Nieminen, K

    2001-08-17

    We have developed mathematical models for evaluating the atmospheric dispersion of selected chemical warfare agents (CWA), including the evaporation and settling of contaminant liquid droplets. The models and numerical results presented may be utilised for designing protection and control measures against the conceivable use of CWA's. The model AERCLOUD (AERosol CLOUD) was extended to treat two nerve agents, sarin and VX, and the mustard agent. This model evaluates the thermodynamical evolution of a five-component aerosol mixture, consisting of two-component droplets together with the surrounding three-component gas. We have performed numerical computations with this model on the evaporation and settling of airborne sarin droplets in characteristic dispersal and atmospheric conditions. In particular, we have evaluated the maximum radii (r(M)) of a totally evaporating droplet, in terms of the ambient temperature and contaminant vapour concentration. The radii r(M) range from approximately 15-80 microm for sarin droplets for the selected ambient conditions and initial heights. We have also evaluated deposition fractions in terms of the initial droplet size.

  1. Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

    PubMed

    Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

    2010-12-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity.

  2. Soman Increases Neuronal COX-2 Levels: Possible Link between Seizures and Protracted Neuronal Damage

    PubMed Central

    Angoa-Pérez, Mariana; Kreipke, Christian W.; Thomas, David M.; Van Shura, Kerry E.; Lyman, Megan; McDonough, John H.; Kuhn, Donald M.

    2010-01-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. PMID:20600289

  3. Metal-ion catalyzed oxidation of a G-agent simulant by oxone. Final report Oct 89-Dec 90

    SciTech Connect

    Leslie, D.R.; Ward, J.R.

    1992-07-01

    By means of the ability of oxone to oxidize sulphur, oxone has been shown to be a rapid decontaminant for mustard or VX. G-agents, such as sarin or soman, are difficult to oxidize, and all means to decontaminate sarin or soman are based on hydrolysis. To see if oxone might have utility as a general decontaminant, experiments were run to see if the ability of oxone to destroy organophosphorus esters could be enhanced with transition-metal catalysts. Hydrolysis of the G-agent simulant diisopropyl methylphosphonate (DIMP) was promoted in oxone solution by the presence of such low valent metal ions as cobalt (II), chromium (III), or manganese (II). The reaction is initiated by radical formation from decomposition of HO-SO3. Radical chains may be terminated by dimerization of S04-, other reactions forming 02, or by reduction of the radical to S04= by low valent metal ion. The radical can also reduce the oxidized metal ion back to the original low valent state, thereby providing a path for turnover of the metal ion. The relatively slow rate and the potential for contaminants in field application that could react with the SO4- radicals make it unlikely that metal ion catalysis of oxone decomposition will prove to be a useful decontaminant. Decontamination, NMR, Chemical agents, Metal-ion catalysis, Chromium (III), DIMP, Oxone, Kinetics. This paper describes the effect of a crystal field, according to site symmetry, upon the magnetic quantum-level structure of an atomic ion, as expressed in electric dipole transitions (a corresponding treatment for magnetic dipole transitions, in the original German, is not included). Crystal field Magnetic quantum numbers Atomic ion.

  4. Cholinesterases as scavengers for organophosphorus compounds: protection of primate performance against soman toxicity.

    PubMed

    Doctor, B P; Blick, D W; Caranto, G; Castro, C A; Gentry, M K; Larrison, R; Maxwell, D M; Murphy, M R; Schutz, M; Waibel, K

    1993-06-01

    The present treatment for poisoning by organophosphates consists of multiple drugs such as carbamates, antimuscarinics, and reactivators in pre- and post-exposure modalities. Recently an anticonvulsant, diazapam, has been included as a post-exposure drug to reduce convulsions and increase survival. Most regimens are effective in preventing lethality from organophosphate exposure but do not prevent toxic effects and incapacitation observed in animals and likely to occur in humans. Use of enzymes such as cholinesterases as pretreatment drugs for sequestration of highly toxic organophosphate anticholinesterases and alleviation of side effects and performance decrements was successful in animals, including non-human primates. Pretreatment of rhesus monkeys with fetal bovine serum acetylcholinesterase protected them against lethal effects of soman (up to 5 LD50) and prevented signs of OP toxicity. Monkeys pretreated with fetal bovine serum acetylcholinesterase were devoid of behavioral incapacitation after soman exposure, as measured by serial probe recognition or primate equilibrium platform performance tasks. Use of acetylcholinesterase as a single pretreatment drug provided greater protection against both lethal and behavioral effects of potent organophosphates than current multicomponent drug treatments that prevent neither signs of toxicity nor behavioral deficits. Although use of cholinesterases as single pretreatment drugs provided complete protection, its use for humans may be limited, since large quantities will be required, due to the approximately 1:1 stoichiometry between organophosphate and enzyme. Bisquaternary oximes, particularly HI-6, have been shown to reactivate organophosphate-inhibited acetylcholinesterase at a rapid rate. We explored the possibility that enzyme could be continually reactivated in animals pretreated with fetal bovine serum acetylcholinesterase, followed by an appropriate dose of reactivator, and challenged with repeated doses of

  5. Multiple exposures to sarin vapor result in parasympathetic dysfunction in the eye but not the heart.

    PubMed

    Dabisch, Paul A; To, Filip; Kerut, Edmund K; Horsmon, Michael S; Mioduszewski, Robert J

    2007-09-01

    Several studies in conscious animals have reported parasympathetic dysfunction in the eyes following exposure to cholinesterase inhibitors. Given the similarities between the autonomic innervation in the eye and the heart, it is possible that parasympathetic dysfunction could also occur in the heart. Therefore, the present study assessed time domain indices of heart rate variability in conscious rats surgically implanted with telemetric transmitters to investigate the hypothesis that multiple exposures to the nerve agent sarin would result in muscarinic receptor desensitization and parasympathetic dysfunction in the heart. Animals exposed to sarin vapor on multiple occasions developed parasympathetic dysfunction in the eye characterized by an attenuated response to light and a diminished miotic response to sarin vapor exposure. However, the same dose of sarin vapor failed to produce any effects on either time domain indices of HRV or the magnitude of the tachycardia induced by atropine, suggesting that autonomic control in the heart was not affected. It is possible that the dose of sarin used in the present study was insufficient to inhibit cardiac acetylcholinesterase (AChE). Additional studies utilizing higher doses of sarin may be able to inhibit cardiac AChE, producing overstimulation of cardiac muscarinic receptors, ultimately resulting in desensitization and parasympathetic dysfunction.

  6. A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

    PubMed Central

    Fattebert, Jean-Luc; Emigh, Aiyana

    2015-01-01

    Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures. PMID:25874456

  7. A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

    DOE PAGES

    Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; ...

    2015-04-13

    Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

  8. A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

    SciTech Connect

    Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; Fattebert, Jean -Luc; Emigh, Aiyana; Lightstone, Felice C.; Salsbury , Jr, Freddie

    2015-04-13

    Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.

  9. Detection of the sarin hydrolysis product in formalin-fixed brain tissues of victims of the Tokyo subway terrorist attack.

    PubMed

    Matsuda, Y; Nagao, M; Takatori, T; Niijima, H; Nakajima, M; Iwase, H; Kobayashi, M; Iwadate, K

    1998-06-01

    One of the hydrolysis products of sarin (isopropyl methylphosphonofluoridate) was detected in formalin-fixed brain tissues of victims poisoned in the Tokyo subway terrorist attack. Part of this procedure, used for the detection of sarin hydrolysis products in erythrocytes of sarin victims, has been described previously. The test materials were four individual cerebellums, which had been stored in formalin fixative for about 2 years. Sarin-bound acetylcholinesterase (AChE) was solubilized from these cerebellums, purified by immunoaffinity chromatography, and digested with trypsin. Then the sarin hydrolysis products bound to AChE were released by alkaline phosphatase digestion, subjected to trimethylsilyl derivatization (TMS), and detected by gas chromatography-mass spectrometry. Peaks at m/z 225 and m/z 240, which are indicative of TMS-methylphosphonic acid, were observed within the retention time range of authentic methylphosphonic acid. However, no isopropyl methylphosphonic acid was detected in the formalin-fixed cerebellums of these 4 sarin victims, probably because the isopropoxy group of isopropyl methylphosphonic acid underwent chemical hydrolysis during storage. This procedure will be useful for the forensic diagnosis of poisoning by protein-bound, highly toxic agents, such as sarin, which are easily hydrolysed. This appears to be the first time that intoxication by a nerve agent has been demonstrated by analyzing formalin-fixed brains obtained at autopsy.

  10. Chemical Warfare Agent Degradation and Decontamination

    SciTech Connect

    Talmage, Sylvia Smith; Watson, Annetta Paule; Hauschild, Veronique; Munro, Nancy B; King, J.

    2007-02-01

    The decontamination of chemical warfare agents (CWA) from structures, environmental media, and even personnel has become an area of particular interest in recent years due to increased homeland security concerns. In addition to terrorist attacks, scenarios such as accidental releases of CWA from U.S. stockpile sites or from historic, buried munitions are also subjects for response planning. To facilitate rapid identification of practical and effective decontamination approaches, this paper reviews pathways of CWA degradation by natural means as well as those resulting from deliberately applied solutions and technologies; these pathways and technologies are compared and contrasted. We then review various technologies, both traditional and recent, with some emphasis on decontamination materials used for surfaces that are difficult to clean. Discussion is limited to the major threat CWA, namely sulfur mustard (HD, bis(2-chloroethyl)sulfide), VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate), and the G-series nerve agents. The principal G-agents are GA (tabun, ethyl N,N-dimethylphosphoramidocyanidate), GB (sarin, isopropyl methylphosphonofluoridate), and GD (soman, pinacolyl methylphosphonofluoridate). The chemical decontamination pathways of each agent are outlined, with some discussion of intermediate and final degradation product toxicity. In all cases, and regardless of the CWA degradation pathway chosen for decontamination, it will be necessary to collect and analyze pertinent environmental samples during the treatment phase to confirm attainment of clearance levels.

  11. Soman

    MedlinePlus

    ... CDC.gov . Specific Hazards Bioterrorism A-Z Anthrax (Bacillus anthracis) Arenaviruses Treatment & Infection Control Specimen Submission & Lab Testing Education & Training Related Bioterrorism Resources Bacillus anthracis (Anthrax) Botulism (Clostridium botulinum toxin) Brucella species ( ...

  12. Detection of DNT, TNT, HF, and nerve agents using photoluminescence and interferometry from a porous silicon chip

    NASA Astrophysics Data System (ADS)

    Sailor, Michael J.; Trogler, William C.; Content, Stephane; Letant, Sonia; Sohn, Honglae; Fainman, Yeshaiahu; Shames, Paul E.

    2000-07-01

    Porous silicon chips have been used to detect vapors of explosives and a simulant for the nerve agents Sarin, Soman, and GF using two different transduction modes: reflectivity and photoluminescence. Detection of nitroaromatic compounds is achieved by monitoring the photoluminescence of a nanocrystalline porous Si film on exposure to the analyte of interest in a flowing air stream. Photoluminescence is quenched on exposure to the nitroaromatic. Detection limits of 2 ppb and 1 ppb were observed for 2,4-dinitrotoluene, and 2,4,6-trinitrotoluene, respectively (exposure times of 5 min for each, in air). Specificity for detection is achieved in a two-channel system using catalytic oxidation of the nitroaromatic.

  13. Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.

    PubMed

    Curtin, Bryan F; Seetharam, Karthik I; Dhoieam, Pilin; Gordon, Richard K; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2008-04-01

    Current advances in enzyme bioscavenger prophylactic therapy against chemical warfare nerve agent (CWNA) exposure are moving towards the identification of catalytic bioscavengers that can degrade large doses of organophosphate (OP) nerve agents without self destruction. This is a preferred method compared to therapy with the purified stoichiometric bioscavenger, butyrylcholinesterase, which binds OPs 1:1 and would thus require larger doses for treatment. Paraoxonase-1 (PON-1) is one such catalytic bioscavenger that has been shown to hydrolyze OP insecticides and contribute to detoxification in animals and humans. Here we investigated the effects of a common red wine ingredient, Resveratrol (RSV), to induce the expression of PON-1 in the human hepatic cell line HC04 and evaluated the protection against CWNA simulants. Dose-response curves showed that a concentration of 20 microM RSV was optimal in inducing PON-1 expression in HC04 cells. RSV at 20 microM increased the extracellular PON-1 activity approximately 150% without significantly affecting the cells. Higher doses of RSV were cytotoxic to the cells. Resveratrol also induced PON-1 in the human lung cell line A549. RSV pre-treatment significantly (P = 0.05) protected the hepatic cells against exposure to 2x LD(50) of soman and sarin simulants. However, lung cells were protected against soman simulant exposure but not against sarin simulant exposure following RSV treatment. In conclusion, these studies indicate that dietary inducers, such as RSV, can up-regulate PON-1, a catalytic bioscavenger, which can then hydrolyze and protect against CWNA-induced toxicity, providing a prospective new method to protect against CWNA exposure.

  14. Identification of new binding sites of human transferrin incubated with organophosphorus agents via Q Exactive LC-MS/MS.

    PubMed

    Sun, Fengjuan; Ding, Junjie; Yu, Huilan; Gao, Runli; Wang, Hongmei; Pei, Chengxin

    2016-06-01

    Organophosphorus agents (OPs) like sarin, VX, or soman could inhibit acetylcholinesterase activity and cause poisoning. OPs could bind many proteins, such as butyrylcholinesterase and albumin, and the adducts formed could identify the exposure. In this paper, we studied human transferrin, which was one of the proteins that could be labeled by OPs. Pure human transferrin was incubated with an overdose of organophosphorus agents, including sarin, soman, VX, tabun, cyclosarin, ethyl tabun, and propyl tabun, and then additional OPs was removed through dialysis. Trypsin was used to cleave the OP-treated proteins and Q Exactive liquid chromatography tandem mass spectrometry (Q Exactive LC-MS/MS) was used to identify them. The present study set out to accomplish two goals. The first goal was to find a good method for identifying multiple binding sites on a given protein through Q Exactive LC-MS/MS. The second goal was to investigate the labeled peptides when transferrin was incubated with a numerous molar excess of OPs. Results showed that tyrosine, lysine, and serine formed covalent bonds with OPs. Twenty OP-labeled sites were found: ten tyrosine sites (including two reported sites), seven lysine sites, and three serine sites. Characteristic fragments for labeled-tyrosine and labeled-lysine adducts were summarized in detail. In conclusion, the method by Q Exactive LC-MS/MS using in this present work is a good way to diagnose exposure to OPs accurately when the binding sites of OPs are uncertain. Novel modified peptides and the characteristic ions found in this work could help investigators assess exposure to OPs.

  15. Neuroprotective mechanisms activated in non-seizing rats exposed to sarin.

    PubMed

    Te, Jerez A; Spradling-Reeves, Kimberly D; Dillman, James F; Wallqvist, Anders

    2015-08-27

    Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures.

  16. Low-dose sarin exposure produces long term changes in brain neurochemistry of mice.

    PubMed

    Oswal, Dhawal P; Garrett, Teresa L; Morris, Mariana; Lucot, James B

    2013-01-01

    Sarin is a toxic organophosphorus (OP) nerve agent that has been reported to cause long-term alterations in behavioral and neuropsychological processes. The present study was designed to investigate the effect of low dose sarin exposure on the monoamine neurotransmitter systems in various brain regions of mice. The rationale was to expand our knowledge about the noncholinergic neurochemical alterations associated with low dose exposure to this cholinesterase inhibitor. We analyzed the levels of monoamines and their metabolites in different brain areas after exposure of male C57BL/6 mice to a subclinical dose of sarin (0.4 LD50). Mice did not show any signs of cholinergic toxicity or pathological changes in brain tissue. At 1, 4 and 8 weeks post-sarin exposure brains were collected for neurochemical analysis. A significant decrease in the dopamine (DA) turnover, as measured by the metabolite to parent ratio, was observed in the frontal cerebral cortex (FC) at all time points tested. DA turnover was significantly increased in the amygdala at 4 weeks but not at 1 or 8 weeks after exposure. The caudate nucleus displayed a decrease in DA turnover at 1 week but no significant change was observed at 4 and 8 weeks suggesting a reversible effect. In addition to this, serotonin (5-HT) levels were transiently altered at various time points in all the brain regions studied (increase in FC, caudate nucleus and decrease in amygdala). Since there were no signs of cholinergic toxicity or cell death after sarin exposure, different non-cholinergic mechanisms may be involved in regulating these effects. Our results demonstrate that non-symptomatic dose of OP nerve agent sarin has potent long-term, region-specific effects on the monoaminergic neurotransmitter systems. Data also suggests differential effects of sarin on the various DA projections. These neurochemical alterations could be associated with long term behavioral and neuropsychological changes associated with low dose OP

  17. Pyridostigmine protects the soman challenged visual system

    SciTech Connect

    Kirby, A.W.; Townsend, A.T.; Evans, G.; Clarke, T.; Pope, C.

    1993-05-13

    The studies described here were designed to evaluate the protective action of pyridostigmine (pyrido) on visual processing following a soman challenge to fully anesthetized adult cats. The visual evoked response (VER) was used as our response measure, and all drugs were given i.v. Following soman, VERs in the adult cat show a preferential loss in low spatial frequency information which is dose dependent, and can be reversed with atropine. In our preparation, a single dose of 4 ug/kg soman given i.v. results in about 80% inhibition of blood cholinesterase (ChE) and 80-90% reduction in the VER. There is no spontaneous recovery of either parameter over the next 24 hours. Pretreatment with pyrido greatly alters the effect of 4 ug/kg soman. Enough pyrido to inhibit 60% blood ChE caused no change in the VER. After soman, ChE activity recovered to about 60% (40% inhibition) within several hours. Over the same period of time, VER reduction recovered to about 30% inhibition rather than 80% without pyrido.

  18. Blood and bronchoalveolar lavage fluid acetylcholinesterase levels following microinstillation inhalation exposure to sarin in Guinea pigs.

    PubMed

    Che, Magnus M; Conti, Michele; Boylan, Megan; Sciuto, Alfred M; Gordon, Richard K; Nambiar, Madhusoodana P

    2008-07-01

    We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m(3)) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt(50) for sarin using the microinstillation technique was determined to be close to 677.4 mg/m(3). Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m(3) sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m(3) sarin exposure but a marginal inhibition at 169.3 mg/m(3). In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m(3) in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m(3) and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.

  19. Neurophysiologic effects of chemical agent hydrolysis products on cortical neurons in vitro.

    PubMed

    Pancrazio, J J; Keefer, E W; Ma, W; Stenger, D A; Gross, G W

    2001-06-01

    The neurophysiologic effects of chemical agent hydrolysis products were examined on cultured cortical neurons using multielectrode array (MEA) recording and the whole-cell patch clamp technique. Measurement of neuronal network extracellular potentials showed that the primary hydrolysis product of soman, pinacolyl methylphosphonic acid (PMPA), inhibited network mean burst and spike rates with an EC50 of approximately 2 mM. In contrast, the degradation product of sarin, isopropyl methylphosphonic acid (IMPA), and the final common hydrolysis product of both soman and sarin, methylphosphonic acid (MPA), failed to affect neuronal network behavior at concentrations reaching 5 mM. Closer examination of the effects of PMPA (2 mM) on discriminated extracellular units revealed that mean spike amplitude was slightly diminished to 95 +/- 1% (mean +/- S.E.M., n = 6, P < 0.01) of control. Whole-cell patch clamp records under current clamp mode also showed a PMPA-induced depression of the firing rate of spontaneous action potentials (APs) to 36 +/- 6% (n = 5, P < 0.001) of control. In addition, a minor depression with exposure to PMPA was observed in spontaneous and evoked AP amplitude to 93 +/- 3% (n = 5, P < 0.05) of control with no change in either the baseline membrane potential or input resistance. Preliminary voltage clamp recordings indicated a reduction in the occurrence of spontaneous inward currents with application of PMPA. These findings suggest that PMPA, unlike MPA or IMPA, may more readily interfere with one or more aspects of excitatory synaptic transmission. Furthermore, the data demonstrate that the combination of extracellular microelectrode array and patch clamp recording techniques facilitates analysis of compounds with neuropharmacologic effects.

  20. The combination of donepezil and procyclidine protects against soman-induced seizures in rats

    SciTech Connect

    Haug, Kristin Huse . E-mail: k.h.haug@medisin.uio.no; Myhrer, Trond; Fonnum, Frode

    2007-04-15

    Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of Brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6x LD{sub 50}) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.

  1. 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.

  2. Gastrointestinal acetylcholinesterase activity following endotracheal microinstillation inhalation exposure to sarin in guinea pigs.

    PubMed

    Chanda, Soma; Song, Jian; Rezk, Peter; Sabnekar, Praveena; Doctor, Bhupendra P; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2010-09-06

    The goal of this study was to assess acetylcholinesterase (AChE) inhibition at different regions of the gastrointestinal (GI) tract following inhalation exposure to nerve agent sarin. Seven major regions of the GI tract were removed from saline control animals (n=3) and 677.4 mg/m(3) sarin-exposed animals at 4h (n=4) and 24h (n=4) post-exposure. AChE activity was determined in blood and homogenized tissue supernatant by specific Ellman's assay using Iso-OMPA, a BChE inhibitor, and expressed as activity/optical density of hemoglobin for blood and activity/mg protein for tissues. Our data showed that the AChE activity was significantly decreased for groups both 4h and 24h post-sarin exposure. Among the seven chosen regions of the guinea pig GI tract, duodenum showed the highest AChE activity in control animals. The AChE activity was significantly decreased in the stomach (p=0.03), duodenum (p=0.029), jejunum (p=0.006), and ileum (p=0.006) 4h following sarin exposure. At 24h post-sarin exposure the AChE activity of duodenum (p=0.029) and ileum (p=0.006) was significantly inhibited. Esophagus showed no inhibition following sarin exposure at both 4h and 24h groups. These results suggest that the AChE activity is different in different regions of the GI tract and highest levels of AChE inhibition following sarin exposure were seen in regions exhibiting higher overall AChE activity and cholinergic function.

  3. Microwave spectroscopy of chemical warfare agents: prospects for remote sensing

    NASA Astrophysics Data System (ADS)

    Samuels, Alan C.; Jensen, James O.; Suenram, Richard D.; Hight Walker, Angela R.; Woolard, Dwight L.

    1999-07-01

    The high level of interest in the sensor development community in millimeter wave technology development demonstrates the potential for several multipurpose applications of millimeter wave sensors. The potential for remote sensing of hazardous chemical materials based on their millimeter wave rotational signatures is yet another possible applications, offering certain distinct advantages over FTIR remote sensing. The high specificity of the rotational spectra to the molecular structures affords the capability of detecting chemical warfare (CW) agents and degradation products in complex mixtures including water vapor and smoke, an important consideration in military applications. Furthermore, the rotational modes are not complicated by electronic or vibrational transitions, reducing the potential for false alarms. We have conducted microwave spectroscopic measurements on two CW nerve agents (sarin and soman) and one blister agent (H-mustard). The assignment of the observed band furnishes us with an extremely accurate tool for predicting the rotational spectrum of these agents at any arbitrary frequency. By factoring in the effects of pressure (Lorentzian broadening and intensity reduction), we present the predicted spectral signatures of the CW agents in the 80 - 300 GHz region. This frequency regime is important for atmospheric monitoring as it exploits the wide bandwidth capability of millimeter wave sensors as well as the atmospheric windows that occur in this region.

  4. How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

    PubMed Central

    2015-01-01

    Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

  5. Mesoporous iron–manganese oxides for sulphur mustard and soman degradation

    SciTech Connect

    Štengl, Václav; Grygar, Tomáš Matys; Bludská, Jana; Opluštil, František; Němec, Tomáš

    2012-12-15

    Graphical abstract: Display Omitted Highlights: ► New nanodispersive materials based on Fe and Mn oxides for degradations of warfare agents. ► The best activities for the degradation of sulphur mustard (97.9% in 64 min) and soman (97.9% in 64 min). ► One pot synthesis with friendly transformed to industrial conditions. -- Abstract: Substituted iron(III)–manganese(III, IV) oxides, ammonio-jarosite and birnessite, were prepared by a homogeneous hydrolysis of potassium permanganate and iron(III) sulphate with 2-chloroacetamide and urea, respectively. Synthesised oxides were characterised using Brunauer–Emmett–Teller (BET) surface area and Barrett–Joiner–Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM). The oxides were taken for an experimental evaluation of their reactivity against sulphur mustard (HD) and soman (GD). When ammonio-jarosite formation is suppressed by adding urea to the reaction mixture, the reaction products are mixtures of goethite, schwertmannite and ferrihydrite, and their degradation activity against soman considerably increases. The best activities for the degradation of sulphur mustard (97.9% in 64 min) and soman (97.9% in 64 min) were observed for FeMn{sub 7}5 with 32.6 wt.% Fe (36.8 wt.% Mn) and FeMn{sub 3}7U with 60.8 wt.% Fe (10.1 wt.% Mn) samples, respectively.

  6. Screening for sarin in air and water by solid-phase microextraction-gas chromatography-mass spectrometry.

    PubMed

    Schneider, J F; Boparai, A S; Reed, L L

    2001-10-01

    A method of screening air and water samples for the chemical-warfare agent Sarin is developed using solid-phase microextraction (SPME)-gas chromatography (GC)-mass spectrometry (MS). The SPME field kit sampler is ideal for collecting air and water samples in the field and transporting samples safely to the laboratory. The sampler also allows the sample to be introduced into the GC-MS system without further sample preparation. Results of the tests with Sarin using the SPME technique indicate that a sample collection time of 5 min is sufficient to detect 100 ng/L of Sarin in air. For water samples, Sarin is detected at a concentration of 12 microg/mL or higher. This method is ideal for screening samples for quick response situations.

  7. Screening for sarin in air and water by solid-phase microextraction-gas chromatography/mass spectrometry.

    SciTech Connect

    Schneider, J. F.; Boparai, A. S.; Reed, L. L.

    2001-10-01

    A method of screening air and water samples for the chemical-warfare agent Sarin is developed using solid-phase microextraction (SPME)-gas chromatography (GC)-mass spectrometry (MS). The SPME field kit sampler is ideal for collecting air and water samples in the field and transporting samples safely to the laboratory. The sampler also allows the sample to be introduced into the GC-MS system without further sample preparation. Results of the tests with Sarin using the SPME technique indicate that a sample collection time of 5 min is sufficient to detect 100 ng/L of Sarin in air. For water samples, Sarin is detected at a concentration of 12 {mu}g/mL or higher. This method is ideal for screening samples for quick response situations.

  8. Chromogenic detection of Sarin by discolouring decomplexation of a metal coordination complex.

    PubMed

    Ordronneau, Lucie; Carella, Alexandre; Pohanka, Miroslav; Simonato, Jean-Pierre

    2013-10-11

    An innovative chromogenic sensing concept based on decomplexation of a tris-(bipyridine)iron(II) coordination complex has been developed for the detection of organophosphorus nerve agents. It was evaluated both on a simulant and real Sarin in vapour and liquid phases.

  9. The Effects of Repeated Low-Dose Sarin Exposure

    DTIC Science & Technology

    2006-01-01

    subcutaneous. "" Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and...placing the animal on its back and recording the time it took for the was used to separate ACh and choline. A " biosensor " was created by coating a guinea...nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the

  10. Sarin

    MedlinePlus

    ... CDC.gov . Specific Hazards Bioterrorism A-Z Anthrax (Bacillus anthracis) Arenaviruses Treatment & Infection Control Specimen Submission & Lab Testing Education & Training Related Bioterrorism Resources Bacillus anthracis (Anthrax) Botulism (Clostridium botulinum toxin) Brucella species ( ...

  11. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by Soman. (Reannouncement with new availability information)

    SciTech Connect

    Sparenborg, S.; Brennecke, L.H.; Jaax, N.K.; Braitman, D.J.

    1992-12-31

    The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a post treatment (30, 100 or 300 micron g/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Post treatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity....Seizure-related brain damage, Organophosphorus compound, Nerve agent, Cholinesterase inhibition, Excitotoxicity, Guinea pig.

  12. Quantification of organophosphorus nerve agent metabolites using a reduced-volume, high-throughput sample processing format and liquid chromatography-tandem mass spectrometry.

    PubMed

    Swaim, Leigh L; Johnson, Rudolph C; Zhou, Yingtao; Sandlin, Chris; Barr, John R

    2008-01-01

    A reduced-volume, high-throughput analytical method has been developed for the quantification of organophosphorus (OP) nerve agent metabolites in human urine. Metabolites of soman, sarin, cyclohexyl-sarin, VX, and Russian-VX were quantified down to a lowest reportable limit of 1 ng/mL in human urine. One hundred microliter urine samples were preconcentrated using normal-phase 96-well solid-phase extraction silica sorbent beds. Dual-column hydrophilic interaction liquid chromatography was applied in a 2.5-min isocratic separation followed by negative electrospray isotope-dilution multiple-reaction-monitoring mass spectrometry. Method validation included the characterization of two synthetic urine pools, relative recovery experiments, and calculation of the method limit of detection. All liquid handling steps were processed in a high-density 96-well format, including sample aliquoting, extraction, dry-down, and reconstitution. This allows up to 3840 unknown samples, plus calibrators and quality control materials, to be prepared on a single liquid handler in a 24-h period. In a public health emergency involving OP-nerve agents, this method provides the sample preparation and analytical capacity to respond rapidly to a large number of patient samples.

  13. Structural analogs of huperzine A improve survival in guinea pigs exposed to soman.

    PubMed

    Gunosewoyo, Hendra; Tipparaju, Suresh K; Pieroni, Marco; Wang, Ying; Doctor, Bhupendra P; Nambiar, Madhusoodana P; Kozikowski, Alan P

    2013-03-01

    Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2×LD(50).

  14. New bispyridinium oximes: in vitro and in vivo evaluation of their biological efficiency in soman and tabun poisoning.

    PubMed

    Berend, Suzana; Vrdoljak, Ana Lucić; Radić, Bozica; Kuca, Kamil

    2008-09-25

    Improving the efficacy of antidotal treatment of poisonings with nerve agents is still a challenge for the scientific community. This study investigated the interactions of four bispyridinium oximes with human erythrocyte acetylcholinesterase (AChE) and their effects on soman- and tabun-poisoned mice. Oximes HI-6 and TMB-4 were used for comparison. These oximes inhibited AchE with inhibitory potency (IC(50)) ranging from 0.02 to 1.0 mM. The best reactivating potency (%R) was obtained with K074, when AChE was inhibited by tabun. The protective potency (P(50)) of all oximes in human erythrocyte AChE inhibited by soman and tabun could not be determined. In tabun-poisoned mice very good antidotal efficacy was obtained with K027, K048, and K074, which makes them interesting for future investigation. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.

  15. Treatment with endotracheal therapeutics after sarin microinstillation inhalation exposure increases blood cholinesterase levels in guinea pigs.

    PubMed

    Che, Magnus M; Song, Jian; Oguntayo, Samuel; Doctor, Bhupendra P; Rezk, Peter; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2012-05-01

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4 mg/m(3) or 846.5 mg/m(3) (1.2 LCt(50)) sarin for 4 min using a microinstillation inhalation exposure technique and treated 1 min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24 h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45-60%) compared to sarin-exposed animals (p < 0.05). Similarly, treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p < 0.05). BChE activity was increased after treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases.

  16. Being prepared: emergency treatment following a nerve agent release.

    PubMed

    Bailey, Abby M; Baker, Stephanie N; Baum, Regan A; Chandler, Hannah E; Weant, Kyle A

    2014-01-01

    Nerve agents are extremely toxic and are some of the most lethal substances on earth. This group of chemicals consists of sarin, cyclosarin, soman, tabun, VX, and VR. It is currently unknown how many countries possess these chemicals and in what quantities. These agents work through altering the transmission and breakdown of acetylcholine by binding to, and inactivating, acetylcholinesterase. This results in an uncontrolled and overwhelming stimulation of both muscarinic and nicotinic receptors. Receptor activation at these sites can lead to a wide variety of clinical symptoms, with death frequently resulting from pulmonary edema. Antidotal therapy in this setting largely consists of atropine, pralidoxime, and benzodiazepines, all of which must be administered emergently to limit the progression of symptoms and prevent the enzyme inactivation from becoming permanent. This article reviews the mechanism of action of the nerve agents and their effects on the human body, the currently available therapies to mitigate their impact, and important therapeutic considerations for health care practitioners in the emergency department.

  17. Cardiovascular effects of soman. Annual report, June 1, 1982-May 31, 1983

    SciTech Connect

    Brezenoff, H.E.

    1983-09-01

    The primary objective of this contract is to study the cardiovascular effects of the organophosphate acetylcholinesterase (ACHe) inhibitor soman in the rat. During the first year we established the assays for brain acetylcholine (ACh) and AChE as routine procedures in the laboratory. Baseline levels of ACh in cortex, hippocampus, hypothalamus, and striatum averaged 16.4, 28.1, 32.3 and 71.3 nmoles/g tissue, respectively, while AChE activity in these region averaged 3.5, 5.2, 6.1 and 40.8 micromoles substrate hydrolyzed/g tissue/min. Construction of the dilute agent laboratory and subsequent delivery of soman occupied virtually the entire first year. In the interim, we used physostigmine and neostigmine as tools to examine cholinergic mechanisms in the locus ceruleus (LC) which might contribute to the pressor effects of AChE inhibitors. Injection of neostigmine or carbachol into the LC increased blood pressure. The pressor effect of neostigmine, but not of carbachol, was potentiated in the caudal LC by prior injection of the alpha-2 adrenergic receptor agonist clonidine. Lesioning the LC did not block the pressor response to intravenous injection of physostigmine. Preliminary experiments with soman demonstrate that this agent also increases blood pressure following i.v. administration.

  18. Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration.

    PubMed

    van der Schans, Marcel J; Lander, Brenda J; van der Wiel, Herma; Langenberg, Jan P; Benschop, Hendrik P

    2003-08-15

    In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(+/-)P(+/-)-soman and (+/-)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (+/-)-VX. A validated method was developed to determine blood levels of (+/-)-VX by means of achiral gas chromatography at blood levels > or =10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels > or =1 ng/ml by using chiral HPLC in combination with off-line gas chromatographic analysis. In order to obtain basic information on the toxicokinetics of (+/-)-VX, i.e., under conditions of 100% bioavailability, the blood levels of this agent were measured in hairless guinea pigs at iv doses corresponding with 1 and 2 LD50. The derived AUCs indicate a reasonable linearity of the toxicokinetics with dose. Also, the toxicokinetics in marmoset primates was studied at an absolute iv dose corresponding with 1 LD50 in the hairless guinea pig which led to approximately the same levels of (+/-)-VX in blood as observed at 2 LD50 in the hairless guinea pig. Finally, the toxicokinetics of (+/-)-VX were measured in hairless guinea pigs via the most relevant porte d' entrée for this agent, which is the percutaneous route at a dose corresponding with 1 LD50 (pc). Large variations were observed between individual animals in the rate of penetration of (+/-)-VX and in concomitant progression of AChE inhibition in blood of these animals. Blood levels of (+/-)-VX increased gradually over a 6-h period of time. After a 7-h penetration period, the total AUC corresponded with 2.5% bioavailability relative to iv administration. In contrast with the G-agents C(+/-)P(+/-)-soman and (+/-)-sarin, stereospecificity in the sequestration of the two enantiomers of (+/-)-VX is not a prominent phenomenon. It appears that (+/-)-VX is substantially more persistent in vivo than the two G-agents. This persistence may undermine the efficacy of pretreatment with carbamates of percutaneous

  19. Cholinergic and noradrenergic triggers' in soman induced convulsions

    SciTech Connect

    Shipley, M.T.; Zimmer, L.; Ennis, M.; Etri, M.

    1993-05-13

    Considerable evidence suggests that soman induced seizure's are initiated in the piriform cortex (PC). Consistent with this, PC is the most frequent site of neuropathology in soman treated rats and other species. Previous studies in this laboratory have shown that convulsive doses of soman cause the rapid induction of the immediate early gene protein product, Fos, in piriform cortex (PC). Fos is known to be expressed when neurons undergo sustained excitatory activity. Following soman, Fos is selectively expressed by neurons in layers II Ill of PC. These neurons are known to send excitatory projections to the hippocampus and to thalamus and neocortex. Thus, we have suggested that soman may initially cause seizure activity in layer II-III PC neurons; this seizure activity could then spread to the hippocampus and neocortex. Consistent with this hypothesis, we have observed that Fos is expressed in hippocampus, thalamus and neocortex subsequent to its expression in PC.

  20. 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.

  1. Sarin experiences in Japan: acute toxicity and long-term effects.

    PubMed

    Yanagisawa, N; Morita, H; Nakajima, T

    2006-11-01

    Two terrorist attacks with the nerve agent Sarin affected citizens in Matsumoto and Tokyo, Japan in 1994 and 1995, killing 19 and injuring more the 6000. Sarin, a very potent organophosphate nerve agent, inhibits acetylcholinesterase (AchE) activity within the central, peripheral, and autonomic nervous systems. Acute and long-term Sarin effects upon humans were well documented in these two events. Sarin gas inhalation caused instantaneous death by respiratory arrest in 4 victims in Matsumoto. In Tokyo, two died in station yards and another ten victims died in hospitals within a few hours to 3 months after poisoning. Six victims with serum ChE below 20% of the lowest normal were resuscitated from cardiopulmonary arrest (CPA) or coma with generalized convulsion. Five recovered completely and one remained in vegetative state due to anoxic brain damage. EEG abnormalities persisted for up to 5 years. Miosis and copious secretions from the respiratory and GI tracts (muscarinic effects) were common in severely to slightly affected victims. Weakness and twitches of muscles (nicotinic effects) appeared in severely affected victims. Neuropathy and ataxia were observed in small number (less than 10%) of victims, which findings disappeared between 3 days and 3 months. Leukocytosis and high serum CK levels were common. Hyperglycemia, ketonuria, low serum triglyceride, hypopotassemia were observed in severely affected victims, which abnormalities were attributed to damage of the adrenal medulla. Oximes, atropine sulphate, diazepam and ample intravenous infusion were effective treatments. Pralidoxime iodide IV reversed cholinesterase and symptoms quickly even if administered 6 h after exposure. Post Traumatic Stress Disorder (PTSD) was less than 8% after 5 years. However, psychological symptoms continue in victims of both incidents. In summary, both potent toxicity and quick recovery from critical ill conditions were prominent features. Conventional therapies proved effective in

  2. Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates.

    PubMed

    Chambers, Janice E; Meek, Edward C; Chambers, Howard W

    2016-06-01

    Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood-brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood-brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain.

  3. Neuroimmune Effects of Inhaling Low Dose Sarin

    DTIC Science & Technology

    2005-02-01

    ORGANIZA TION Lovelace Respiratory Research Institute REPORT NUMBER Albuquerque, New Mexico 87108-5127 E-Mail: msopori@lrri . org 9. SPONSORING...J.C., 1958. Effects in man of the anticholinesterase tation. andconducting rearchG using anima the iara nd ses- ocompound sarin (isopropyl

  4. Studies of the action of chemical agents on the heart. Annual report, February 1985-February 1986

    SciTech Connect

    Hassler, G.R.; Moutvic, R.R.

    1986-03-01

    This report describes initial studies to determine the subchronic effect of Soman and Sarin, on the electrical, mechanical, and neurochemical properties of the heart. Two different animal models are under development. The electrophysiologic and hemodynamic aspects of survival doses of chemical agent are begin studied in the dog. Two chronically instrumented dog models have been developed. The first is a hemodynamic dog model in which long-term measurements of left and right heart pressures, aortic flow, coronary flow as well as epicardial electrocardiograms, are monitored. The animals will be monitored at baseline and for one month following exposure in survival of a chemical-warfare-agent insult. These animals are stressed via treadmill exercise. The electrophysiology dog model consists of chronically implanted electrodes for performance of repetitive ventricular response stimulation, His bundle recording, and ECG analysis. Measurements are made prior to, and for one month following, exposure to survivable doses of CW agent. This dog model is further probed by sequential administration of various pharmacologic agents designed to study the autonomic status of the heart. All dogs and a limited number of the guinea pigs will be continuously monitored for occurrence of arrhythmic events utilizing Holter monitoring technology. The guinea pig neurochemical studies will include acetylcholines, choline acetyltransferase activity, QNB binding, choline uptake, norepinephrine levels and turnover, and norepinephrine uptake experiments.

  5. Fourier transform microwave spectroscopy of chemical-warfare agents and their synthetic precursors

    NASA Astrophysics Data System (ADS)

    Hight Walker, Angela R.; Suenram, Richard D.; Samuels, Alan C.; Jensen, James O.; Woolard, Dwight L.; Wiebach, W.

    1999-01-01

    Fourier-transform microwave (FTMW) spectroscopy is an established is an established technique for observing the rotational spectra of molecules and complexes in molecular beams. Scientists at the National Institute of Standards and Technology (NIST) are adapting this measurement technology for applications in analytical chemistry. Presently, FTMW spectroscopy is being used to investigate chemical-warfare agents and their synthetic precursors. A FTMW spectroscopy facility has been established at a surety laboratory at the Edgewood Research, Development, and Engineering Center, where the capabilities exist for handling these deadly warfare agents. Here, the rotational spectra of Sarin, Soman and DF have been observed and assigned. Also, microwave spectroscopic studies of less toxic precursors such as pinacolyl alcohol, isopropyl alcohol, and thiodiglycol have been carried out at NIST. Tests will be undertaken to assess the potential of using FTMW spectroscopy for detecting trace amounts of chemical-warfare agents and precursors in air. A database of rotational transition frequencies is being compiled for use in conjunction with a FTMW spectrometer to unambiguously detect and monitor chemical weapons. The sensitivity and resolution of FTMW spectroscopy of FTMW spectroscopy suggest that the technique may offer real-time, unequivocal identification of chemical-warfare agents at trace vapor concentrations in air.

  6. Blaptica dubia as sentinels for exposure to chemical warfare agents - a pilot study.

    PubMed

    Worek, Franz; Seeger, Thomas; Neumaier, Katharina; Wille, Timo; Thiermann, Horst

    2016-11-16

    The increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents a continuing threat to our societies. Early warning and detection is a key component for effective countermeasures against such deadly agents. Presently available and near term solutions have a number of major drawbacks, e.g. lack of automated, remote warning and detection of primarily low volatile chemical warfare agents. An alternative approach is the use of animals as sentinels for exposure to toxic chemicals. To overcome disadvantages of vertebrates the present pilot study was initiated to investigate the suitability of South American cockroaches (Blaptica dubia) as warning system for exposure to chemical warfare nerve and blister agents. Initial in vitro experiments with nerve agents showed an increasing inhibitory potency in the order tabun - cyclosarin - sarin - soman - VX of cockroach cholinesterase. Exposure of cockroaches to chemical warfare agents resulted in clearly visible and reproducible reactions, the onset being dependent on the agent and dose. With nerve agents the onset was related to the volatility of the agents. The blister agent lewisite induced signs largely comparable to those of nerve agents while sulfur mustard exposed animals exhibited a different sequence of events. In conclusion, this first pilot study indicates that Blaptica dubia could serve as a warning system to exposure of chemical warfare agents. A cockroach-based system will not detect or identify a particular chemical warfare agent but could trigger further actions, e.g. specific detection and increased protective status. By designing appropriate boxes with (IR) motion sensors and remote control (IR) camera automated off-site warning systems could be realized.

  7. Mesoporous titanium-manganese dioxide for sulphur mustard and soman decontamination

    SciTech Connect

    Stengl, Vaclav; Bludska, Jana; Oplustil, Frantisek; Nemec, Tomas

    2011-11-15

    Highlights: {yields} New nano-dispersive materials for warfare agents decontamination. {yields} 95% decontamination activities for sulphur mustard. {yields} New materials base on titanium and manganese oxides. -- Abstract: Titanium(IV)-manganese(IV) nano-dispersed oxides were prepared by a homogeneous hydrolysis of potassium permanganate and titanium(IV) oxo-sulphate with 2-chloroacetamide. Synthesised samples were characterised using Brunauer-Emmett-Teller (BET) surface area and Barrett-Joiner-Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), and scanning electron microscopy (SEM). These oxides were taken for an experimental evaluation of their reactivity with sulphur mustard (HD or bis(2-chloroethyl)sulphide) and soman (GD or (3,3'-dimethylbutan-2-yl)-methylphosphonofluoridate). Mn{sup 4+} content affects the decontamination activity; with increasing Mn{sup 4+} content the activity increases for sulphur mustard and decreases for soman. The best decontamination activities for sulphur mustard and soman were observed for samples TiMn{sub 3}7 with 18.6 wt.% Mn and TiMn{sub 5} with 2.1 wt.% Mn, respectively.

  8. Safety of administration of human butyrylcholinesterase and its conjugates with soman or VX in rats.

    PubMed

    Genovese, Raymond F; Sun, Wei; Johnson, Christina C; Ditargiani, Robert C; Doctor, Bhupendra P; Saxena, Ashima

    2010-05-01

    We evaluated the effects of conjugated enzyme-nerve agent product resulting from the inhibition of bioscavenger human serum butyrylcholinesterase (Hu BChE) by nerve agents soman or VX. Rats were trained on a multiple Fixed-Ratio 32, Extinction 30 sec. (FR32, Ext30) schedule of food reinforcement and then injected (i.m.) with Hu BChE (30 mg/kg), equivalent amounts of Hu BChE-soman conjugate (GDC), Hu BChE-VX conjugate, oxotremorine (OXO) (0.316 mg/kg) or vehicle (n = 8, each group). On the day of injection and on 10 subsequent daily sessions, performance was evaluated on the FR32, Ext30 schedule. Neither conjugates nor Hu BChE produced a performance deficit under the schedule. OXO produced a substantial decrease in responding on the day of administration, with complete recovery observed on subsequent sessions. None of the treatments affected circulating acetylcholinesterase (AChE) activity when evaluated 24-72 hr after injection. The dose of Hu BChE produced a 20,000-fold increase above baseline in circulating BChE activity. Pathological evaluation of organ systems approximately 2 weeks following administration of conjugates or Hu BChE alone did not show toxicity. Taken together, these results suggest that Hu BChE - nerve agent conjugates produced following bioscavenger protection against nerve agents soman and VX do not appear to be particularly toxic. These results add to the safety assessment of Hu BChE as a bioscavenger countermeasure against nerve agent exposure.

  9. NBQX and TCP prevent soman-induced hippocampal damage

    SciTech Connect

    Lallement, G.; Carpentier, P.; Pernot-Marino, I.; Baubichon, D.; Blanchet, G.

    1993-05-13

    In a previous investigation we demonstrated that the measurement of w3 (peripheral-type benzodiazepine) binding site densities could be of widespread applicability in the localization and quantification of soman-induced damage in the central nervous system. We thus used this marker to assess, in mouse hippocampus, the neuroprotective activity against soman-induced brain damage of NBQX and TCP which are respective antagonists of non-NMDA and NMDA glutamatergic receptors. Injection of NBQX at 20 or 40 mg/kg 5 min prior to soman totally prevented the neuronal damage. Comparatively, TCP had neuroprotective efficacy when administered at l mg/kg 5 min prior to soman followed by a reinjection 1 hour after. These results demonstrate that both NBQX and TCP afford a satisfactory neuroprotection against soman-induced brain damage. Since it is known that the neuropathology due to soman is closely seizure-related, it is likely that the neuroprotective activities of NBQX and TCP are related to the respective roles of non-NMDA and NMDA receptors in the onset and maintenance of soman-induced seizures.

  10. DNA fragmentation in leukocytes following repeated low dose sarin exposure in guinea pigs.

    PubMed

    Dave, J R; Connors, R A; Genovese, R F; Whipple, R A; Chen, R W; DeFord, S M; Moran, A V; Tortella, E C

    2007-11-01

    The objective of this study was to determine levels of DNA fragmentation in blood leukocytes and parietal cortex from guinea pigs following repeated low-level exposure to the chemical warfare nerve agent (CWNA) sarin. Guinea pigs were injected (s.c.) once a day for 10 days with saline, or 0.1, 0.2, or 0.4 LD50 (50% mean lethal dose) sarin dissolved in sterile physiological saline. Blood and parietal cortex was collected after injection at 0, 3, and 17 days recovery and evaluated for DNA fragmentation using single-cell gel electrophoresis (Comet assay). Cells were imaged using comet analysis software and three parameters of DNA fragmentation measured: tail length, percent DNA in the tail, and tail moment arm. Repeated low-dose exposure to sarin produced a dose-dependent response in leukocytes at 0 and 3 days post-exposure. There was a significant increase in all measures of DNA fragmentation at 0.2 and 0.4 LD50, but not at 0.1 LD50. There was no significant increase in DNA fragmentation in any of the groups at 17 days post-exposure. Sarin did not produce a systematic dose-dependent response in parietal cortex at any of the time points. However, significant increases in DNA fragmentation at 0.1 and 0.4 LD50 were observed at 0 and 3 days post-exposure. All measures of DNA fragmentation in both leukocytes and neurons returned to control levels by 17 days post-exposure, indicating a small and non-persistent increase in DNA fragmentation following repeated low-level exposure to sarin.

  11. Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity.

    PubMed

    Katalan, Shahaf; Lazar, Shlomi; Brandeis, Rachel; Rabinovitz, Ishai; Egoz, Inbal; Grauer, Ettie; Bloch-Shilderman, Eugenia; Raveh, Lily

    2013-02-01

    Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.

  12. Interaction of Exposure Concentration and Duration in Determining Acute Toxic Effects of Sarin Vapor in Rats

    DTIC Science & Technology

    2002-01-01

    effects occur in the rat and 2) develop models for predicting dose - response effects of low CW agent concentrations as a function of exposure duration. Sarin...effective concentrations for lethality (LC50) and miosis (EC50) in 50% of the exposed population and corresponding dose - response slopes were determined for...exposure duration (i.e., the CT for 50% lethality exposed population and corresponding dose - response slope was not constant over time). A plot of Log (LCt50

  13. Effects of soman on visual processing

    SciTech Connect

    Townsend, A.T.; Clarke, T.; Evans, G.; Pope, C.; Tomberlin, J.

    1993-05-13

    We have demonstrated previously that diisopropylfluorophosphate (DFP) causes a preferential loss of low spatial frequency information in the visual evoked response (VER) of the adult cat. The effect is dose related, can be reversed with atropine, is closely related to acetylcholinesterase (AChE) activity, and shows spontaneous recovery to baseline conditions over 15-20 hours without recovery of AChE activity. After DFP, dopamine (DA) turnover increases and there are consistent changes in gamma-aminobutyric acid (GABA), and muscarinic, DA, and GABA receptors in visual cortex. The experiments described here were designed to investigate the effect of soman on visual processing in the adult cat. The VER was used as our response measure, and all drugs were given i.v. Following soman (1-5 ug/kg), there is a preferential loss to low spatial frequencies in the VER. The loss is dose related, can be reversed with atropine, seems closely linked to AChE activity, but shows no tendency for spontaneous recovery over the next 24 hours. There is no consistent change in DA turnover in visual cortex; however, changes in GABA and the already mentioned receptor populations are similar to those seen after DFP.

  14. Removal of Sarin Aerosol and Vapor by Water Sprays

    SciTech Connect

    Brockmann, John E.

    1998-09-01

    Falling water drops can collect particles and soluble or reactive vapor from the gas through which they fall. Rain is known to remove particles and vapors by the process of rainout. Water sprays can be used to remove radioactive aerosol from the atmosphere of a nuclear reactor containment building. There is a potential for water sprays to be used as a mitigation technique to remove chemical or bio- logical agents from the air. This paper is a quick-look at water spray removal. It is not definitive but rather provides a reasonable basic model for particle and gas removal and presents an example calcu- lation of sarin removal from a BART station. This work ~ a starting point and the results indicate that further modeling and exploration of additional mechanisms for particle and vapor removal may prove beneficial.

  15. 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.

  16. SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides.

    PubMed

    Gorecki, Lukas; Korabecny, Jan; Musilek, Kamil; Malinak, David; Nepovimova, Eugenie; Dolezal, Rafael; Jun, Daniel; Soukup, Ondrej; Kuca, Kamil

    2016-12-01

    Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

  17. Screening organophosphorus nerve agent degradation products in pesticide mixtures by GC-ICPMS.

    PubMed

    Richardson, Douglas D; Caruso, Joseph A

    2007-10-01

    Gas chromatography inductively coupled plasma mass spectrometry (GC-ICPMS) was utilized for the analysis of four organophosphorus nerve agent degradation products in the presence of mixtures of common organophosphorus pesticides. The first degradation products of sarin (isopropyl methylphosphonic acid, GB acid), cyclosarin (cyclohexyl methylphosphonic acid, GF acid), and soman (pinacolyl methylphosphonic acid) as well as their common final hydrolysis product methyl phosphonic acid were utilized throughout these experiments. Due to the non-volatile nature of these alkyl phosphonic acid degradation products, derivatization was performed to generate the volatile tert-butyl dimethylsilyl species. Degraded organophosphorus pesticide standards were obtained for acephate, chlorpyrifos, dichlorvos, ethion, and parathion ethyl. Mixtures consisting of three pesticides in the presence of a single nerve agent degradation product were prepared. GC-ICPMS allowed for the separation and detection of all four degradation products in the presence of pesticide mixtures in just over 12 minutes. This is the first study analyzing pesticides as interfering species for analysis of nerve agent degradation products by GC-ICPMS.

  18. Chemical warfare agent detection in complex environments with comprehensive two-dimensional gas chromatography

    NASA Astrophysics Data System (ADS)

    Reichenbach, Stephen E.; Ni, Mingtian; Kottapalli, Visweswara; Visvanathan, Arvind; Ledford, Edward B., Jr.; Oostdijk, John; Trap, Henk C.

    2003-08-01

    Comprehensive two-dimensional gas chromatography (GCxGC) is an emerging technology for chemical separation that provides an order-of-magnitude increase in separation capacity over traditional gas chromatography. GCxGC separates chemical species with two capillary columns interfaced by two-stage thermal desorption. Because GCxGC is comprehensive and has high separation capacity, it can perform multiple traditional analytical methods with a single analysis. GCxGC has great potential for a wide variety of environmental sensing applications, including detection of chemical warfare agents (CWA) and other harmful chemicals. This paper demonstrates separation of nerve agents sarin and soman from a matrix of gasoline and diesel fuel. Using a combination of an initial column separating on the basis of boiling point and a second column separating on the basis of polarity, GCxGC clearly separates the nerve agents from the thousands of other chemicals in the sample. The GCxGC data is visualized, processed, and analyzed as a two-dimensional digital image using a software system for GCxGC image processing developed at the University of Nebraska - Lincoln.

  19. Miniaturized low-cost ion mobility spectrometer for fast detection of chemical warfare agents.

    PubMed

    Zimmermann, Stefan; Barth, Sebastian; Baether, Wolfgang K M; Ringer, Joachim

    2008-09-01

    Ion mobility spectrometry (IMS) is a well-known method for detecting hazardous compounds in air. Typical applications are the detection of chemical warfare agents, highly toxic industrial compounds, explosives, and drugs of abuse. Detection limits in the low part per billion range, fast response times, and simple instrumentation make this technique more and more popular. In particular, there is an increasing demand for miniaturized low-cost IMS for hand-held devices and air monitoring of public areas by sensor networks. In this paper, we present a miniaturized aspiration condenser type ion mobility spectrometer for fast detection of chemical warfare agents. The device is easy to manufacture and allows single substance identification down to low part per billion-level concentrations within seconds. The improved separation power results from ion focusing by means of geometric constraints and fluid dynamics. A simple pattern recognition algorithm is used for the identification of trained substances in air. The device was tested at the German Armed Forces Scientific Institute for Protection Technologies-NBC-Protection. Different chemical warfare agents, such as sarin, tabun, soman, US-VX, sulfur mustard, nitrogen mustard, and lewisite were tested. The results are presented here.

  20. Efficacy of liquid and foam decontamination technologies for chemical warfare agents on indoor surfaces.

    PubMed

    Love, Adam H; Bailey, Christopher G; Hanna, M Leslie; Hok, Saphon; Vu, Alex K; Reutter, Dennis J; Raber, Ellen

    2011-11-30

    Bench-scale testing was used to evaluate the efficacy of four decontamination formulations on typical indoor surfaces following exposure to the liquid chemical warfare agents sarin (GB), soman (GD), sulfur mustard (HD), and VX. Residual surface contamination on coupons was periodically measured for up to 24h after applying one of four selected decontamination technologies [0.5% bleach solution with trisodium phosphate, Allen Vanguard Surface Decontamination Foam (SDF™), U.S. military Decon Green™, and Modec Inc. and EnviroFoam Technologies Sandia Decontamination Foam (DF-200)]. All decontamination technologies tested, except for the bleach solution, performed well on nonporous and nonpermeable glass and stainless-steel surfaces. However, chemical agent residual contamination typically remained on porous and permeable surfaces, especially for the more persistent agents, HD and VX. Solvent-based Decon Green™ performed better than aqueous-based bleach or foams on polymeric surfaces, possibly because the solvent is able to penetrate the polymer matrix. Bleach and foams out-performed Decon Green for penetrating the highly polar concrete surface. Results suggest that the different characteristics needed for an ideal and universal decontamination technology may be incompatible in a single formulation and a strategy for decontaminating a complex facility will require a range of technologies.

  1. Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure.

    PubMed

    Pan, Hongna; Piermartiri, Tetsade C B; Chen, Jun; McDonough, John; Oppel, Craig; Driwech, Wafae; Winter, Kristin; McFarland, Emylee; Black, Katelyn; Figueiredo, Taiza; Grunberg, Neil; Marini, Ann M

    2015-12-01

    Exposure to nerve agents results in severe seizures or status epilepticus caused by the inhibition of acetylcholinesterase, a critical enzyme that breaks down acetylcholine to terminate neurotransmission. Prolonged seizures cause brain damage and can lead to long-term consequences. Current countermeasures are only modestly effective against the brain damage supporting interest in the evaluation of new and efficacious therapies. The nutraceutical alpha-linolenic acid (LIN) is an essential omega-3 polyunsaturated fatty acid that has a wide safety margin. Previous work showed that a single intravenous injection of alpha-linolenic acid (500 nmol/kg) administered before or after soman significantly protected against soman-induced brain damage when analyzed 24h after exposure. Here, we show that administration of three intravenous injections of alpha-linolenic acid over a 7 day period after soman significantly improved motor performance on the rotarod, enhanced memory retention, exerted an anti-depressant-like activity and increased animal survival. This dosing schedule significantly reduced soman-induced neuronal degeneration in four major vulnerable brain regions up to 21 days. Taken together, alpha-linolenic acid reduces the profound behavioral deficits induced by soman possibly by decreasing neuronal cell death, and increases animal survival.

  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.

  3. 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

  4. Kinetics of sarin (GB) following a single sublethal inhalation exposure in the guinea pig.

    PubMed

    Whalley, Christopher E; McGuire, Jeffrey M; Miller, Dennis B; Jakubowski, Edward M; Mioduszewski, Robert J; Thomson, Sandra A; Lumley, Lucille A; McDonough, John H; Shih, Tsung-Ming A

    2007-06-01

    To improve toxicity estimates from sublethal exposures to chemical warfare nerve agents (CWNA), it is necessary to generate mathematical models of the absorption, distribution, and elimination of nerve agents. However, current models are based on representative data sets generated with different routes of exposure and in different species and are designed to interpolate between limited laboratory data sets to predict a wide range of possible human exposure scenarios. This study was performed to integrate CWNA sublethal toxicity data in male Duncan Hartley guinea pigs. Specific goal was to compare uptake and clearance kinetics of different sublethal doses of sarin (either 0.1 x or 0.4 x LC50) in blood and tissues of guinea pigs exposed to agent by acute whole-body inhalation exposure after the 60-min LC50 was determined. Arterial catheterization allowed repeated blood sampling from the same animal at various time periods. Blood and tissue levels of acetylcholinesterase, butyrylcholinesterase, and regenerated sarin (rGB) were determined at various time points during and following sarin exposure. The following pharmacokinetic parameters were calculated from the graph of plasma or RBC rGB concentration versus time: time to reach the maximal concentration; maximal concentration; mean residence time; clearance; volume of distribution at steady state; terminal elimination-phase rate constant; and area under plasma concentration time curve extrapolated to infinity using the WinNonlin analysis program 5.0. Plasma and RBC t(1/2) for rGB was also calculated. Data will be used to develop mathematical model of absorption and distribution of sublethal sarin doses into susceptible tissues.

  5. Comparison of status epilepticus models induced by pilocarpine and nerve agents - a systematic review of the underlying aetiology and adopted therapeutic approaches.

    PubMed

    Tang, F R; Loke, W K; Ling, E A

    2011-01-01

    Among potential radiological, nuclear, biological and chemical weapons, cholinergic nerve agents from chemical weapons remain a realistic terrorist threat due to its combination of high lethality, demonstrated use and relative abundance of un-destroyed stockpiles in various militaries around the world. While current fielded antidotes are able to mitigate acute poisoning, effective neuroprotection in the field remains a challenge amongst subjects with established status epilepticus following nerve agent intoxication. Due to ethical, safety and surety issues, extensive preclinical and clinical research on cholinergic nerve agents is not possible. This may have been a contributory factor for the slow progress in uncovering new neuroprotectants for nerve agent casualties with established status epilepticus. To overcome this challenge, comparative research with surrogate chemicals that produce similar hypercholinergic toxicity but with less security concerns would be a useful approach forward. In this paper, we will systemically compare the mechanism of seizure generation, propagation and the subsequent clinical, hematologic, and metabolic, biochemical, neuroinflammatory changes and current therapeutic approaches reported in pilocarpine, soman, and sarin models of seizures. This review will be an important first step in closing this knowledge gap among different closely related models of seizures and neurotoxicity. Hopefully, it will spur further efforts in using surrogate cholinergic models by the wider scientific community to expedite the development of a new generation of antidotes that are better able to protect against delayed neurological effects inflicted by nerve agents.

  6. The sources, fate, and toxicity of chemical warfare agent degradation products.

    PubMed Central

    Munro, N B; Talmage, S S; Griffin, G D; Waters, L C; Watson, A P; King, J F; Hauschild, V

    1999-01-01

    We include in this review an assessment of the formation, environmental fate, and mammalian and ecotoxicity of CW agent degradation products relevant to environmental and occupational health. These parent CW agents include several vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD), and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and Lewisite; four nerve agents (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)); and the blood agent cyanogen chloride. The degradation processes considered here include hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly address decontamination but not combustion processes. Because CW agents are generally not considered very persistent, certain degradation products of significant persistence, even those that are not particularly toxic, may indicate previous CW agent presence or that degradation has occurred. Of those products for which there are data on both environmental fate and toxicity, only a few are both environmentally persistent and highly toxic. Major degradation products estimated to be of significant persistence (weeks to years) include thiodiglycol for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl phosphonic acid, and possibly S-(2-diisopropylaminoethyl) methylphosphonothioic acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a closely related contaminant of GB, diisopropyl methylphosphonate, are also persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess high mammalian toxicity. Unlike other CW agents, sulfur mustard agents (e.g., HD) are somewhat persistent; therefore, sites or conditions involving potential HD contamination should include an

  7. Case report: Long-term cognitive sequelae of sarin exposure.

    PubMed

    Loh, Yince; Swanberg, Margaret M; Ingram, M Victoria; Newmark, Jonathan

    2010-03-01

    The long-term sequelae of acute sarin exposure are not well understood. The largest clinical cohort resulted from the 1994 and 1995 attacks in Japan. Observers noted mostly psychiatric sequelae, with a high prevalence of post-traumatic stress disorder (PTSD). We describe neurocognitive findings that may represent sequelae of low-level sarin exposure in Iraq.

  8. Neurobehavioral teratogenicity of sarin in an avian model.

    PubMed

    Yanai, Joseph; Pinkas, Adi; Seidler, Frederic J; Ryde, Ian T; Van der Zee, Eddy A; Slotkin, Theodore A

    2009-01-01

    Nerve gas organophosphates like sarin are likely to be used in urban terrorism, leading to widespread exposures of pregnant women and young children. Here, we established a model for sarin neurobehavioral teratogenicity in the developing chick so as to explore the consequences of apparently subtoxic sarin exposure and the mechanisms underlying synaptic and behavioral deficits. Chicken eggs were injected with sarin (2, 6 and 12 microg/kg) on incubation days 2 and 6, treatments that did not decrease hatching and did not evoke dysmorphology. After hatching the chicks were tested for filial imprinting and neurochemical markers known to be critical for imprinting. Imprinting was reduced at 2 and 6 microg/kg but not at the highest dose. Acetylcholinesterase and choline acetyltransferase were unaffected but sarin reduced the concentration of the high-affinity choline transporter, the rate-limiting factor in acetylcholine utilization. The concentration of PKC isoforms was assessed in the imprinting-related intermediate part of the medial hyperstriatum ventrale, the region most closely associated with cholinergic function in imprinting behavior. Sarin reduced the concentration of all isoforms (alpha, beta, gamma) with a similar, biphasic dose-response curve to that seen for behavioral performance, a relationship noted in previous work with organophosphate pesticides. Our results indicate that otherwise subtoxic exposures to sarin produce neurodevelopmental deficits; since we utilized a chick model, which is devoid of maternal confounds that are present in mammalian development, the adverse effects of sarin are mediated directly in the developing organism.

  9. Isotope dilution LC/MS/MS for the detection of nerve agent exposure in urine.

    PubMed

    Ciner, Frederic L; McCord, Carla E; Plunkett, Roy W; Martin, Michael F; Croley, Timothy R

    2007-02-01

    Organophosphorus nerve agents (OPNA), chemically related to and derived from organophosphate insecticides, constitute a clear and present threat to both military and civilian targets. Military regimes and terrorist organizations have demonstrated the will and ability to produce mass casualties by dispersing organophosphorus nerve agents, which, in turn could terrorize populations and overwhelm healthcare systems. A high throughput, robust and sensitive analytical protocol has been developed for the quantitation of the urinary metabolites of sarin (GB), soman (GD), VX, Russian VX (RVX) and cyclohexylsarin (GF) utilizing solid phase extraction (SPE) followed by High Performance Liquid Chromatography (HPLC)-isotope dilution tandem mass spectrometry (LC/MS/MS). The method has demonstrated linearity and reproducibility (1-200 ng/mL) for all analytes and has a Limit of Quantitation (LOQ)< or =0.5 ng/mL for all analytes (S/N> or =10/1). The method was validated by performing 20 individual analyses over 10 days by five scientists with all values falling within two standard deviations of the mean.

  10. 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

  11. Chiral separation of G-type chemical warfare nerve agents via analytical supercritical fluid chromatography.

    PubMed

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

    2014-12-01

    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.

  12. Characterization of a phosphodiesterase capable of hydrolyzing EA 2192, the most toxic degradation product of the nerve agent VX.

    PubMed

    Ghanem, Eman; Li, Yingchun; Xu, Chengfu; Raushel, Frank M

    2007-08-07

    Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a nonspecific diesterase that enables Escherichia coli to utilize alkyl phosphodiesters, such as diethyl phosphate, as the sole phosphorus source. The catalytic properties of GpdQ were determined, and the best substrate found was bis(p-nitrophenyl) phosphate with a kcat/Km value of 6.7 x 10(3) M-1 s-1. In addition, the E. aerogenes diesterase was tested as a catalyst for the hydrolysis of a series of phosphonate monoesters which are the hydrolysis products of the highly toxic organophosphonate nerve agents sarin, soman, GF, VX, and rVX. Among the phosphonate monoesters tested, the hydrolysis product of rVX, isobutyl methyl phosphonate, was the best substrate with a kcat/Km value of 33 M-1 s-1. The ability of GpdQ to hydrolyze the phosphonate monoesters provides an alternative selection strategy in the search of enhanced variants of the bacterial phosphotriesterase (PTE) for the hydrolysis of organophosphonate nerve agents. This investigation demonstrated that the previously reported activity of GpdQ toward the hydrolysis of methyl demeton-S is due to the presence of a diester contaminant in the commercial material. Furthermore, it was shown that GpdQ is capable of hydrolyzing a close analogue of EA 2192, the most toxic and persistent degradation product of the nerve agent VX.

  13. Using Metal Complex Ion-Molecule Reactions in a Miniature Rectilinear Ion Trap Mass Spectrometer to Detect Chemical Warfare Agents

    NASA Astrophysics Data System (ADS)

    Graichen, Adam M.; Vachet, Richard W.

    2013-06-01

    The gas-phase reactions of a series of coordinatively unsaturated [Ni(L)n]y+ complexes, where L is a nitrogen-containing ligand, with chemical warfare agent (CWA) simulants in a miniature rectilinear ion trap mass spectrometer were investigated as part of a new approach to detect CWAs. Results show that upon entering the vacuum system via a poly(dimethylsiloxane) (PDMS) membrane introduction, low concentrations of several CWA simulants, including dipropyl sulfide (simulant for mustard gas), acetonitrile (simulant for the nerve agent tabun), and diethyl phosphite (simulant for nerve agents sarin, soman, tabun, and VX), can react with metal complex ions generated by electrospray ionization (ESI), thereby providing a sensitive means of detecting these compounds. The [Ni(L)n]2+ complexes are found to be particularly reactive with the simulants of mustard gas and tabun, allowing their detection at low parts-per-billion (ppb) levels. These detection limits are well below reported exposure limits for these CWAs, which indicates the applicability of this new approach, and are about two orders of magnitude lower than electron ionization detection limits on the same mass spectrometer. The use of coordinatively unsaturated metal complexes as reagent ions offers the possibility of further tuning the ion-molecule chemistry so that desired compounds can be detected selectively or at even lower concentrations.

  14. Using metal complex ion-molecule reactions in a miniature rectilinear ion trap mass spectrometer to detect chemical warfare agents.

    PubMed

    Graichen, Adam M; Vachet, Richard W

    2013-06-01

    The gas-phase reactions of a series of coordinatively unsaturated [Ni(L)n](y+) complexes, where L is a nitrogen-containing ligand, with chemical warfare agent (CWA) simulants in a miniature rectilinear ion trap mass spectrometer were investigated as part of a new approach to detect CWAs. Results show that upon entering the vacuum system via a poly(dimethylsiloxane) (PDMS) membrane introduction, low concentrations of several CWA simulants, including dipropyl sulfide (simulant for mustard gas), acetonitrile (simulant for the nerve agent tabun), and diethyl phosphite (simulant for nerve agents sarin, soman, tabun, and VX), can react with metal complex ions generated by electrospray ionization (ESI), thereby providing a sensitive means of detecting these compounds. The [Ni(L)n](2+) complexes are found to be particularly reactive with the simulants of mustard gas and tabun, allowing their detection at low parts-per-billion (ppb) levels. These detection limits are well below reported exposure limits for these CWAs, which indicates the applicability of this new approach, and are about two orders of magnitude lower than electron ionization detection limits on the same mass spectrometer. The use of coordinatively unsaturated metal complexes as reagent ions offers the possibility of further tuning the ion-molecule chemistry so that desired compounds can be detected selectively or at even lower concentrations.

  15. In situ determination of nerve agents in various matrices by portable capillary electropherograph with contactless conductivity detection.

    PubMed

    Kubáň, Petr; Seiman, Andrus; Makarõtševa, Natalja; Vaher, Merike; Kaljurand, Mihkel

    2011-05-06

    Rapid, efficient and robust methods for sampling and extracting genuine nerve agents sarin, soman and VX were developed for analyzing these compounds on various solid matrices, such as concrete, tile, soil and vegetation. A portable capillary electrophoretic (CE) system with contactless conductometric detection was used for the in situ analysis of the extracted samples. A 7.5 mM MES/HIS-based separation electrolyte accomplished the analysis of target analytes in less than 5 min. The overall duration of the process including instrument start-up, sample extraction and analysis was less than 10 min, which is the fastest screening of nerve agents achieved with liquid phase separation methods to date. The procedure can easily be performed by a person in a protective suit and is therefore suitable for real-life applications. The CE results were validated by an independent GC-MS method and a satisfactory correlation was obtained. The use of a proper sampling strategy with two internal standards and "smart" data-processing software can overcome the low reproducibility of CE. This has a significant impact on the potential acceptance of portable CE instrumentation for the detection and analysis of genuine chemical warfare agents (CWA).

  16. Neurology and neuropathology of Soman-induced brain injury: an overview.

    PubMed Central

    Petras, J M

    1994-01-01

    Battlefield use of nerve agents poses serious medical threats to combat troops and to civilians in the immediate or adjacent environment. The experiments reported herein were carried out in the 1980s to help to define both the neurological and neuropathological consequences of exposure to the organophosphate nerve agent Soman. These data contributed to the scientific foundation for a program of drug development to find agents that would prevent or reduce the risk of injury to the central nervous system and specifically pointed to the importance of including an anticonvulsant in the treatment of agent exposure. Since these experiments were conducted, research efforts have continued to improve pretreatment and treatment, such as the inclusion of the anticonvulsant diazepam in the medical treatment of exposed personnel. Images Fig. 1. Fig. 2. Fig. 3. PMID:8169578

  17. Domestic Preparedness Program: Phase 2 Sarin (GB) and Distilled Sulfur Mustard (HD) Vapor Challenge Testing of Commercial Self-Contained Breathing Apparatus Facepieces

    DTIC Science & Technology

    2005-03-01

    GB Mustard HD Self-Contained Breathing Apparatus Sarin Chemical Agent Breakthrough SCBA Agent Challenge Testing ...emergency escape breathing apparatus. 3. CHEMICAL AGENT TESTING 3.1 Chemical Agent Testing Equipment. 3.1.1 Vapor Generator. The GB and HD vapors were... agent seeped inside the other two within 4 min. For all three tests , the North Model 821 resisted HD for 60 min and GB for 25, 28, and 32 min.

  18. Quantitative proteomic analysis of the brainstem following lethal sarin exposure.

    PubMed

    Meade, Mitchell L; Hoffmann, Andrea; Makley, Meghan K; Snider, Thomas H; Schlager, John J; Gearhart, Jeffery M

    2015-06-22

    The brainstem represents a major tissue area affected by sarin organophosphate poisoning due to its function in respiratory and cardiovascular control. While the acute toxic effects of sarin on brainstem-related responses are relatively unknown, other brain areas e.g., cortex or cerebellum, have been studied more extensively. The study objective was to analyze the guinea pig brainstem toxicology response following sarin (2×LD50) exposure by proteome pathway analysis to gain insight into the complex regulatory mechanisms that lead to impairment of respiratory and cardiovascular control. Guinea pig exposure to sarin resulted in the typical acute behavior/physiology outcomes with death between 15 and 25min. In addition, brain and blood acetylcholinesterase activity was significantly reduced in the presence of sarin to 95%, and 89%, respectively, of control values. Isobaric-tagged (iTRAQ) liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 198 total proteins of which 23% were upregulated, and 18% were downregulated following sarin exposure. Direct gene ontology (GO) analysis revealed a sarin-specific broad-spectrum proteomic profile including glutamate-mediated excitotoxicity, calcium overload, energy depletion responses, and compensatory carbohydrate metabolism, increases in ROS defense, DNA damage and chromatin remodeling, HSP response, targeted protein degradation (ubiquitination) and cell death response. With regards to the sarin-dependent effect on respiration, our study supports the potential interference of sarin with CO2/H(+) sensitive chemoreceptor neurons of the brainstem retrotrapezoid nucleus (RTN) that send excitatory glutamergic projections to the respiratory centers. In conclusion, this study gives insight into the brainstem broad-spectrum proteome following acute sarin exposure and the gained information will assist in the development of novel countermeasures.

  19. Comparison of the sensitive property between soman and its simulant DMMP by hydrogen-bond acidic polymer coated SAW sensor

    NASA Astrophysics Data System (ADS)

    Wang, Yang; Du, Xiaosong; Long, Yin; Jiang, Yadong

    2014-08-01

    Hydrogen-bond acidic (HBA) polymers are widely used for the detection of dimethyl methyl phosphonate (DMMP, a simulant of real nerve agents) based on surface acoustic wave (SAW) sensors. This paper presented an HBA polymer PLF, and subsequently the polymer was dissolved into chloroform and spray-coated on a SAW device to fabricate a gas sensor. Then the sensor was equipped into a SAW test platform to investigate its sensitive property to soman vapor and its simulant DMMP at the concentrations below 20 mg/m3. Results revealed that the sensor showed high sensitivity to the analyte vapors, furthermore, the response of the sensor to soman vapor was relatively smaller and slower than that to DMMP. Tests to some common interference vapors were studied at the concentration of 10 mg/m3, and the results indicated that the sensor showed a good selective property.

  20. Relaxation of soman-induced contracture of airway smooth muscle in vitro. (Reannouncement with new availability information)

    SciTech Connect

    Filbert, M.G.; Moore, D.H.; Adler, M.

    1992-12-31

    A possible role for beta-adrenergic agonists in the management of bronchoconstriction resulting from exposure to anticholinesterase compounds was investigated in vitro in canine tracheal smooth muscle. Norepinephrine, salbutamol and isoproterenol produced partial relaxation of soman-induced contractures. However, the relaxation induced was not sustained; muscle tensions returned to pretreatment levels within minutes despite the continued presence of beta-agonists. Increasing cAMP levels with the non beta-agonist bronchodilators such as thoophylline, a phosphodiesterase inhibitor, or forskolin, a specific stimulator of adenylate cyclase, resulted in more complete and longer lasting relaxation, suggesting that beta-adrenoceptor desensitization may contribute to the failure by beta-agonists to produce sustained relaxation. Nerve agents, Soman, Toxicity, Airway smooth muscle, In vitro, Physiology, Effects.

  1. Comparison of reactivating and therapeutic efficacy of two salts of the oxime HI-6 against tabun, soman and cyclosarin in rats.

    PubMed

    Kassa, Jiri; Jun, Daniel; Kuca, Kamil; Bajgar, Jiri

    2007-11-01

    The reactivating and therapeutic efficacy of two salts of the oxime HI-6 (dichloride and dimethanesulphonate) against chosen nerve agents (tabun, soman and cyclosarin) was compared in rats. The potency of both salts of HI-6 to decrease the acute toxicity of tabun, soman and cyclosarin was similar in nerve agent-poisoned rats. While the potency of HI-6 dichloride and HI-6 dimethanesulphonate to counteract acute toxic effects of tabun is rather low, both salts of HI-6 were able to decrease the acute toxicity of soman two times and acute toxicity of cyclosarin more than three times. The therapeutic efficacy of both salts of the oxime HI-6 corresponds to their reactivating potency. While the reactivating efficacy of HI-6 dichloride as well as HI-6 dimethanesulphonate against tabun was negligible, their potency to reactivate soman-inhibited acetylcholinesterase and cyclosarin-inhibited acetylcholinesterase in peripheral (blood) and central (brain) compartment was relatively high. HI-6 dichloride showed a somewhat higher potency to reactivate tabun-inhibited acetylcholinesterase in brain, and soman-inhibited acetylcholinesterase in blood and brain than HI-6 dimethanesulphonate but the differences were not significant. Thus, the replacement of dichloride anion by dimethanesulphonate anion in the oxime HI-6 does not influence the therapeutic and reactivating efficacy of the oxime HI-6 against nerve agents. In addition, the higher solubility and stability of HI-6 dimethanesulphonate in comparison with HI-6 dichloride makes it possible to increase the dose and thus, the effectiveness of the oxime HI-6 in the antidotal treatment of acute nerve agent poisonings.

  2. Selective Stationary Phase for Solid-Phase Microextraction Analysis of Sarin (GB)

    SciTech Connect

    Harvey, Scott; Nelson, D. A.; Wright, Bob W.; Gates, J. W.

    2002-03-02

    A number of critical field applications require monitoring air samples for trace levels of chemical warfare agents. Solid-phase microextraction (SPME) is a convenient format to conduct these analyses. Measurements could be significantly improved if a SPME phase selective for nerve agents were substituted for nonselective polymers typically used (e.g., polydimethylsiloxane). This paper evaluates a novel stationary phase, previously developed for methylphosphonate sensor applications, for use with SPME sampling. The phenol-based polymer, BSP3, was found to offer far higher selectivity toward sarin (GB) than polydimethylsiloxane due to a pronounced affinity toward the target analyte and a lower affinity toward hydrocarbons.

  3. Selective Stationary Phase for Solid-Phase Microextraction Analysis of Sarin (GB)

    SciTech Connect

    Harvey, Scott D.; Nelson, David A.; Wright, Bob W.; Grate, Jay W.

    2002-04-19

    A number of critical field applications require monitoring air samples for trace levels of chemical warfare agents. Solid-phase microextraction (SPME) is a convenient format to conduct these analyses. Measurements could be significantly improved if a SPME phase selective for nerve agents were substituted for nonselective polymers typically used (e.g.,polydimethylsiloxane). This paper evaluates a novel stationary phase, previously developed for methylphosphonate sensor applications, for use with SPME sampling. The phenol-based polymer, BSP3, was found to offer far higher selectivity toward sarin (GB) than polydimethylsiloxane due to a pronounced affinity toward the target analyte and a lower affinity toward hydrocarbons.

  4. Sarin causes autonomic imbalance and cardiomyopathy: an important issue for military and civilian health.

    PubMed

    Shewale, Swapnil V; Anstadt, Mark P; Horenziak, Michael; Izu, Brent; Morgan, Eric E; Lucot, James B; Morris, Mariana

    2012-07-01

    Sarin, a lethal chemical nerve agent, may be a causative factor in multifactorial syndrome implicated in the Gulf War and Tokyo terrorist attacks. Although a high dose results in seizure and death, low-dose exposure may lead to autonomic imbalance and chronic cardiac pathologies. In this study, echocardiography and electrocardiography were used to examine the late-onset effects of a low-dose sarin on cardiac structure and function in mice. Adrenal corticosterone and tyrosine hydroxylase mRNA levels were measured. Stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis was also tested. Findings demonstrate changes consistent with a dilated cardiomyopathy, including left ventricular dilatation, reduced contractility, and altered electrophysiological and inotropic responses to β-adrenergic stimulation. Results also indicate reduced adrenal tyrosine hydroxylase mRNA, corticosterone and altered stress responsiveness of HPA indicating autonomic imbalance. The role of low-dose sarin/organophosphate exposure needs to be considered in the military and civilian populations that suffer from autonomic imbalance and/or cardiomyopathies of indeterminate origin.

  5. Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam.

    PubMed

    Chapman, Shira; Yaakov, Guy; Egoz, Inbal; Rabinovitz, Ishai; Raveh, Lily; Kadar, Tamar; Gilat, Eran; Grauer, Ettie

    2015-07-01

    Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 μg/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam 1mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning.

  6. In vitro evaluation of bis-pyridinium oximes bearing methoxy alkane linker as reactivators of sarin inhibited human acetylcholinesterase.

    PubMed

    Acharya, Jyotiranjan; Dubey, Devendra Kumar; Raza, Syed Kalbey

    2010-09-01

    A series of bis-pyridinium oximes connected by methoxy alkane linkers were synthesized and their in vitro reactivation efficacy was evaluated against sarin-inhibited human AChE, and data were compared with 2-PAM and obidoxime. Among the synthesized compounds, 1,2-dimethoxy ethylene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (4P-2) and 1,2-dimethoxy ethylene bis-[3,3'-(hydroxyiminomethyl) pyridinium] dichloride (3P-2) were found to be the most potent reactivators of human AChE inhibited by nerve agent sarin. The oximes 4P-2 and 3P-2 exhibited 41% and 36% regeneration of sarin-inhibited AChE, respectively, whereas 2-PAM showed 32% regeneration. The higher reactivation efficacy of the oximes was attributed to their acid dissociation constants (pK(a)). The pK(a) values of all the oximes were determined by UV-vis spectrophotometric method and correlated with their observed reactivation potential. Overall, the study reveals that the oxime 4P-2 may have therapeutic potential in the reactivation of human AChE inhibited by sarin.

  7. Broad-Spectrum Liquid- and Gas-Phase Decontamination of Chemical Warfare Agents by One-Dimensional Heteropolyniobates.

    PubMed

    Guo, Weiwei; Lv, Hongjin; Sullivan, Kevin P; Gordon, Wesley O; Balboa, Alex; Wagner, George W; Musaev, Djamaladdin G; Bacsa, John; Hill, Craig L

    2016-06-20

    A wide range of chemical warfare agents and their simulants are catalytically decontaminated by a new one-dimensional polymeric polyniobate (P-PONb), K12 [Ti2 O2 ][GeNb12 O40 ]⋅19 H2 O (KGeNb) under mild conditions and in the dark. Uniquely, KGeNb facilitates hydrolysis of nerve agents Sarin (GB) and Soman (GD) (and their less reactive simulants, dimethyl methylphosphonate (DMMP)) as well as mustard (HD) in both liquid and gas phases at ambient temperature and in the absence of neutralizing bases or illumination. Three lines of evidence establish that KGeNb removes DMMP, and thus likely GB/GD, by general base catalysis: a) the k(H2 O)/k(D2 O) solvent isotope effect is 1.4; b) the rate law (hydrolysis at the same pH depends on the amount of P-PONb present); and c) hydroxide is far less active against the above simulants at the same pH than the P-PONbs themselves, a critical control experiment.

  8. Coupling Activity-Based Detection, Target Amplification, Colorimetric and Fluorometric Signal Amplification, for Quantitative Chemosensing of Fluoride Generated from Nerve Agents.

    PubMed

    Sun, Xiaolong; Reuther, James F; Phillips, Scott T; Anslyn, Eric V

    2017-03-17

    The G-class nerve agents, which include sarin, soman, and cyclosarin, react readily with nucleophilic reagents to produce fluoride. Thus, a chemosensing protocol has been designed for these agents that pairs the nucleophilic reactivity of oximates for generating fluoride with an autoinductive target amplification reaction to amplify the quantity of fluoride for facile colorimetric and fluorescent optical quantification. The chemosensing protocol was demonstrated by using the nerve agent surrogate diisopropyl fluorophosphate (DFP) and benzaldoxime as the nucleophile. Autoinductive fluoride amplification responds to fluoride released from DFP by amplifying the fluoride concentration and a yellow reporter molecule. The reporter is a conjugated oligomer with a nominal repeating unit that originates from 4-aminobenzaldehyde. Exposure of the amplified fluoride to a fluoride-specific ratiometric fluorescent reporter provides a fluorescent readout, in which three fluorophores are generated per fluoride. Both colorimetric and fluorescent readouts enable quantitative assays with low micromolar limits of detection for fluoride resulting from DFP. More importantly, this work demonstrates the successful merging of multiple complex reactions for achieving selective, sensitive, and quantitative chemosensing.

  9. Efficacy evaluation of physostigmine and anticholinergic adjuncts as a pretreatment for nerve agent intoxication. (Reannouncement with new availability information)

    SciTech Connect

    von Bredow, J.; Corcoran, K.; Maitland, G.; Kaminskis, A.; Adams, N.

    1991-12-31

    Pretreatment of nonhuman primates with physostigmine (Phy) and scopolamine or physostigmine and trihexyphenidyl 25 min before exposure to 2 LD50 soman im resulted in complete survival without convulsions or loss of consciousness. When identically pretreated animals were challenged with 5 LD50s of soman followed by atropine and 2-PAM therapy 1 min later, all animals experienced a loss of consciousness for approximately 10 min followed by functional recovery within an additional 20 min. These findings indicated that a pretreatment regimen composed of Phy and cholinolytic is capable of protecting primates from an absolute lethal dose of soman with rapid recovery from incapacitation. Physostigmine, nerve agent pretreatment, cynomolgus monkeys soman (GD).

  10. What lessons can we learn from the Japanese sarin attacks?

    PubMed

    Vale, Allister

    2005-01-01

    On 27 June 1994 a Japanese terrorist group, Aum Shinrikyo, released sarin in Matsumoto. Some 600 people were exposed: 58 were admitted to six hospitals and all recovered: seven casualties living close to the sarin release died outside hospital. This release followed an earlier attempt by Aum Shinrikyo to use sarin to kill the head of a religious sect perceived as a threat. In December 1994, a former supporter of the group was murdered by Aum Shinrikyo using VX. On 20 March 1995, Aum Shinrikyo launched a coordinated attack using sarin on the Tokyo subway system. Over 5000 "casualties" sought medical attention of whom 984 were moderately poisoned and 54 were severely poisoned; 12 died. Despite some initial difficulties, Japanese emergency units and local hospitals were able to respond reasonably rapidly. Analysis of the events reveals a number of important lessons for authorities as well as physicians to consider when preparing for such incidents.

  11. A comparison of reactivating efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in soman, cyclosarin and tabun-poisoned rats.

    PubMed

    Kassa, Jiri; Jun, Daniel; Karasova, Jana; Bajgar, Jiri; Kuca, Kamil

    2008-09-25

    The potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to reactivate nerve agent-inhibited acetylcholinesterase was evaluated in rats poisoned with soman, tabun or cyclosarin at a lethal dose corresponding to their LD(50) value. In vivo determined percentage of reactivation of soman-inhibited blood and brain acetylcholinesterase in poisoned rats showed that only the oxime HI-6 was able to reactivate soman-inhibited acetylcholinesterase in the peripheral (blood) as well as central (brain) compartment. In vivo determined percentage of reactivation of tabun-inhibited blood and brain acetylcholinesterase in poisoned rats showed that obidoxime is the most efficacious reactivator of tabun-inhibited acetylcholinesterase among studied oximes in the peripheral compartment (blood) while K074 seems to be the most efficacious reactivator of tabun-inhibited acetylcholinesterase among studied oximes in the central compartment (brain). In vivo determined percentage of reactivation of cyclosarin-inhibited blood and brain acetylcholinesterase in poisoned rats showed that HI-6 is the most efficacious reactivator of cyclosarin-inhibited acetylcholinesterase among studied oximes. Due to their reactivating effects, both newly developed K oximes can be considered to be promising oximes for the antidotal treatment of acute tabun poisonings while the oxime HI-6 is still the most promising oxime for the treatment of acute soman and cyclosarin poisonings.

  12. Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs

    SciTech Connect

    Harris, L.W.; Gennings, C.; Carter, W.H.; Anderson, D.R.; Lennox, W.J.

    1994-12-31

    Diazepam (DZ) and scopolamine (SCP) are known to be beneficial when each is used in combination with atropine (AT) + oxime therapy against intoxication by soman, but the efficacy of each might be expected to vary with the dosage of AT. Thus, the therapeutic efficacy of SCP (5 doses; 0 - 0.86 mg/kg) versus DZ (5 doses; 0 - 5 mg/kg), when used in conjunction with AT (3 doses; 0.5 - S mg/kg) + 2-PAM (25 mg/kg) therapy, was tested in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5 or 3.2 LD5Os of soman. Response surface methodology was employed to describe the relationship between lethality and the AT/DZ or AT/SCP dosages. Results show that within the indicated dose ranges used, the efficacy of SCP is not dependent on the presence of AT, whereas AT is needed for DZ to maintain the lowest probability of death. These findings suggest that in guinea pigs SCP could supplement AT or replace DZ as therapy against nerve agent intoxication.

  13. Pseudo LRM waveforms from CryoSat SARin acquisition

    NASA Astrophysics Data System (ADS)

    Scagliola, Michele; Fornari, Marco; Bouffard, Jerome; Parrinello, Tommaso; Féménias, Pierre

    2016-04-01

    CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. The main payload of CryoSat is a Ku-band pulsewidth limited radar altimeter, called SIRAL (Synthetic interferometric radar altimeter). When commanded in SARIn (synthetic aperture radar interferometry) mode, through coherent along-track processing of the returns received from two antennas, the interferometric phase related to the first arrival of the echo is used to retrieve the angle of arrival of the scattering in the across-track direction. When SIRAL operates in SAR or SARin mode, the obtained waveforms have an along-track resolution and a speckle reduction which is increased with respect to the pulse-limited waveforms. Anyway, in order to analyze the continuity of the geophysical retrieved parameters among different acquisition modes, techniques to transform SARin mode data to pseudo-LRM mode data are welcome. The transformation process is known as SAR reduction and it is worth recalling here that only approximate pseudo-LRM waveforms can be obtained in case of closed burst acquisitions, as SIRAL operates. A SAR reduction processing scheme has been developed to obtain pseudo-LRM waveforms from CryoSat SARin acquisition. As a trade-off between the along-track length on Earth surface contributing to one SARin pseudo-LRM waveform and the noisiness of the waveform itself, it has been chosen a SAR reduction approach based on the averaging of all the SARin echoes received each 20Hz, resulting in one pseudo-LRM waveform for each SARin burst given the SARin burst repetition period. SARin pseudo-LRM waveforms have been produced for CryoSat acquisition both on ice and sea surfaces, aiming at verifying the continuity of the retracked surface height over the ellipsoid between genuine LRM products and pseudo-LRM products. Moreover, the retracked height from the SARin pseudo-LRM has been

  14. Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity.

    PubMed

    Amitai, Gabriel; Gez, Rellie; Raveh, Lily; Bar-Ner, Nira; Grauer, Ettie; Chapman, Shira

    2016-11-25

    The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3-10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 × 10(2) vs. 0.2 × 10(2) M(-1)min(-1), respectively, 37 °C). These hybrids inhibited AChE reversibly, IC50 = 16-48 μM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 μmol/kg in rats and 144, 203 and >506 μmol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.

  15. Epidemiological study of sarin poisoning in Matsumoto City, Japan.

    PubMed

    Nakajima, T; Ohta, S; Morita, H; Midorikawa, Y; Mimura, S; Yanagisawa, N

    1998-03-01

    On the night of June 27, 1994, about 12 liters of sarin were released by terrorists in Matsumoto City, Japan. In order to investigate the epidemic, community-based questionnaire surveys were conducted. The subjects were all inhabitants (2052 people) living and staying in an area of 1050 meters from north to south and 850 meters from east to west including the sarin release site. Participants included 1743 people who answered the questionnaire at the first survey; those with symptoms were contacted for follow-up at four months and one year after the episode. The number of sarin victims were 471 persons. Muscarinic signs were common to all victims; nicotinic signs were only seen in severely affected victims. The geographical distribution of sarin victims was closely related to the direction of the wind. Three weeks after the intoxication, 129 victims still had some symptoms such as dysesthesia of the extremities. At that time, many victims had begun to experience asthenopia, which was even more frequent at four months. Although victims who felt sarin-related symptoms had decreased by a year, some still had symptoms such as asthenopia. Sarin released in a suburban area affected approximately 500 inhabitants living nearby; some still had symptoms a year after the intoxication.

  16. Brain neuronal chromatin responses in acute soman intoxicated rats.

    PubMed

    Martin, L J; Doebler, J A; Wall, T J; Shih, T M; Anthony, A

    1986-08-01

    Male Sprague-Dawley rats (200 g) were injected subcutaneously with soman, a potent neuronal acetylcholinesterase (AChE) inhibitor, at doses of 0.5, 0.8 and 1.0 LD50 (1 LD50 = 135 micrograms/kg) before decapitation at 1 and 24 h post-exposure. Correlative data were obtained on the severity of brain AChE inactivation and physicochemical changes in nuclear chromatin of cerebrocortical (layer V) and striatal neurons using Feulgen-DNA (F-DNA) cytophotometry and ocular filar micrometry. Decreased lability of neurons to F-DNA acid hydrolysis (reduced F-DNA yield), nuclear shrinkage and chromatin aggregation (decreased chromophore area) were used as indices of suppression of genomic template activity; conversely, increases in F-DNA yield and chromophore area signify enhanced neuroexcitation. At 1 hr post-soman there was a dose-dependent inactivation of AChE with a moderate increase in chromatin activation, i.e., nuclear hypertrophy and chromatin dispersion. At 24 hr post-soman there was a partial restoration of AChE activity, notably in striatal neurons, with a suppression in chromatin template activity. These data indicate that actions of soman on neuronal functioning are time-dependent. The absence of any dose-related neuronal chromatin changes may signify existence of non-cholinergic mediated events.

  17. Ion mobility spectrometric analysis of vaporous chemical warfare agents by the instrument with corona discharge ionization ammonia dopant ambient temperature operation.

    PubMed

    Satoh, Takafumi; Kishi, Shintaro; Nagashima, Hisayuki; Tachikawa, Masumi; Kanamori-Kataoka, Mieko; Nakagawa, Takao; Kitagawa, Nobuyoshi; Tokita, Kenichi; Yamamoto, Soichiro; Seto, Yasuo

    2015-03-20

    The ion mobility behavior of nineteen chemical warfare agents (7 nerve gases, 5 blister agents, 2 lachrymators, 2 blood agents, 3 choking agents) and related compounds including simulants (8 agents) and organic solvents (39) was comparably investigated by the ion mobility spectrometry instrument utilizing weak electric field linear drift tube with corona discharge ionization, ammonia doping, purified inner air drift flow circulation operated at ambient temperature and pressure. Three alkyl methylphosphonofluoridates, tabun, and four organophosphorus simulants gave the intense characteristic positive monomer-derived ion peaks and small dimer-derived ion peaks, and the later ion peaks were increased with the vapor concentrations. VX, RVX and tabun gave both characteristic positive monomer-derived ions and degradation product ions. Nitrogen mustards gave the intense characteristic positive ion peaks, and in addition distinctive negative ion peak appeared from HN3. Mustard gas, lewisite 1, o-chlorobenzylidenemalononitrile and 2-mercaptoethanol gave the characteristic negative ion peaks. Methylphosphonyl difluoride, 2-chloroacetophenone and 1,4-thioxane gave the characteristic ion peaks both in the positive and negative ion mode. 2-Chloroethylethylsulfide and allylisothiocyanate gave weak ion peaks. The marker ion peaks derived from two blood agents and three choking agents were very close to the reactant ion peak in negative ion mode and the respective reduced ion mobility was fluctuated. The reduced ion mobility of the CWA monomer-derived peaks were positively correlated with molecular masses among structurally similar agents such as G-type nerve gases and organophosphorus simulants; V-type nerve gases and nitrogen mustards. The slope values of the calibration plots of the peak heights of the characteristic marker ions versus the vapor concentrations are related to the detection sensitivity, and within chemical warfare agents examined the slope values for sarin, soman

  18. 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.

  19. 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.

  20. Reactive chromophores for sensitive and selective detection of chemical warfare agents and toxic industrial chemicals

    NASA Astrophysics Data System (ADS)

    Frye-Mason, Greg; Leuschen, Martin; Wald, Lara; Paul, Kateri; Hancock, Lawrence F.

    2005-05-01

    A reactive chromophore developed at MIT exhibits sensitive and selective detection of surrogates for G-class nerve agents. This reporter acts by reacting with the agent to form an intermediate that goes through an internal cyclization reaction. The reaction locks the molecule into a form that provides a strong fluorescent signal. Using a fluorescent sensor platform, Nomadics has demonstrated rapid and sensitive detection of reactive simulants such as diethyl chloro-phosphate (simulant for sarin, soman, and related agents) and diethyl cyanophosphate (simulant for tabun). Since the unreacted chromophore does not fluoresce at the excitation wavelength used for the cyclized reporter, the onset of fluo-rescence can be easily detected. This fluorescence-based detection method provides very high sensitivity and could enable rapid detection at permissible exposure levels. Tests with potential interferents show that the reporter is very selective, with responses from only a few highly toxic, electrophilic chemicals such as phosgene, thionyl chloride, and strong acids such as HF, HCl, and nitric acid. Dimethyl methyl phosphonate (DMMP), a common and inactive simu-lant for other CW detectors, is not reactive enough to generate a signal. The unique selectivity to chemical reactivity means that a highly toxic and hazardous chemical is present when the reporter responds and illustrates that this sensor can provide very low false alarm rates. Current efforts focus on demonstrating the sensitivity and range of agents and toxic industrial chemicals detected with this reporter as well as developing additional fluorescent reporters for a range of chemical reactivity classes. The goal is to produce a hand-held sensor that can sensitively detect a broad range of chemical warfare agent and toxic industrial chemical threats.

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

    PubMed Central

    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.

    2016-01-01

    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

  2. '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.

  3. 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.

  4. Detection and classification characteristics of arrays of carbon black/organic polymer composite chemiresistive vapor detectors for the nerve agent simulants Dimethylmethylphosphonate and Diisopropy

    NASA Astrophysics Data System (ADS)

    Hopkins, Alan R.; Lewis, Nathan S.

    2002-06-01

    Arrays of conducting polymer composite vapor detectors have been evaluated for performance in the presence of the nerve agent simulants dimethylmethylphosphonate (DMMP) and diisopropylmethylphosponate (DIMP). Limits of detection for DMMP on unoptimized carbon black-organic polymer composite vapor detectors in laboratory air were estimated to be 0.047-0.24 mg m-3. These values are lower than the EC50 value for the nerve agents sarin (methylphosphonofluoridic acid, (1-methylethyl) ester) and soman, which have been established as equals 0.8 mg m-3. Arrays of these vapor detectors were easily able to resolve signatures due to exposures to DMMP from those due to DIMP or due to a variety of other test analytes in a laboratory air background. In addition, DMMP at 27 mg m-3 could be detected and differentiated from the signatures of the other test analytes in the presence of backgrounds of potential interferents in the background ambient, including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar and tetrahydrofuran, even when these interferents were present in much higher concentrations than that of the DMMP or DIMP being detected.

  5. Detection and classification characteristics of arrays of carbon black/organic polymer composite chemiresistive vapor detectors for the nerve agent simulants dimethylmethylphosphonate and diisopropylmethylphosponate.

    PubMed

    Hopkins, A R; Lewis, N S

    2001-03-01

    Arrays of conducting polymer composite vapor detectors have been evaluated for performance in the presence of the nerve agent simulants dimethylmethylphosphonate (DMMP) and diisopropylmethylphosponate (DIMP). Limits of detection for DMMP on unoptimized carbon black/ organic polymer composite vapor detectors in laboratory air were estimated to be 0.047-0.24 mg m(-3). These values are lower than the EC50 value (where EC50 is the airborne concentration sufficient to induce severe effects in 50% of those exposed for 30 min) for the nerve agents sarin (methylphosphonofluoridic acid, 1-methylethyl ester) and soman (methylphosphonofluoridic acid, 1,2,2-trimethylpropyl ester), which has been established as approximately 0.8 mg m(-3). Arrays of these vapor detectors were easily able to resolve signatures due to exposures to DMMP from those due to DIMP or due to a variety of other test analytes (including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar, and tetrahydrofuran) in a laboratory air background. In addition, DMMP at 27 mg m(-3) could be detected and differentiated from the signatures of the other test analytes in the presence of backgrounds of potential interferences, including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar, and tetrahydrofuran, even when these interferents were present in much higher concentrations than that of the DMMP or DIMP being detected.

  6. In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives (HNK oximes) against tabun and soman poisoning in Swiss albino mice.

    PubMed

    Kumar, P; Swami, D; Nagar, D P; Singh, K P; Acharya, J; Karade, H N; Yadav, R

    2017-01-01

    The study reports antidotal efficacy of three HNK [ bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives] and pralidoxime (2-PAM), against soman and tabun poisoning in Swiss albino mice. Protection index (PI) was determined (treatment doses: HNK oximes, ×0.20 of their median lethal dose (LD50) and 2-PAM, 30 mg/kg, intramuscularly (im)) together with atropine (10 mg/kg, intraperitoneally). Probit log doses with difference of 0.301 log of LD50 of the nerve agents administered and inhibition of acetylcholinesterase (AChE) activity by 50% (IC50) was calculated at optimized time in brain and serum. Using various doses of tabun and soman (subcutaneously (sc)), in multiples of their IC50, AChE reactivation ability of the oximes was studied. Besides, acute toxicity (0.8× LD50, im, 24 h postexposure) of HNK-102 and 2-PAM was also compared by determining biochemical, hematological variables and making histopathological observations. Protection offered by HNK-102 against tabun poisoning was found to be four times higher compared to 2-PAM. However, nearly equal protection was noted with all the four oximes against soman poisoning. HNK-102 reactivated brain AChE activity by 1.5 times more than 2-PAM at IC50 dose of soman and tabun. Acute toxicity studies of HNK-102 and 2-PAM showed sporadic changes in urea, uric acid, aspartate aminotransferase, and so on compared to control group, however, not supported by histopathological investigations. The present investigation showed superiority of newly synthesized HNK-102 oxime over standard 2-PAM, as a better antidote, against acute poisoning of tabun (4.00 times) and soman (1.04 times), in Swiss albino mice.

  7. The determination of organophosphonate nerve agent metabolites in human urine by hydrophilic interaction liquid chromatography tandem mass spectrometry.

    PubMed

    Mawhinney, Douglas B; Hamelin, Elizabeth I; Fraser, Rheaclare; Silva, Sathya S; Pavlopoulos, Antonis J; Kobelski, Robert J

    2007-06-01

    A sensitive, robust isotope dilution LC/MS/MS method is presented for the quantitative analysis of human urine for the alkyl methylphosphonic acid metabolites of five organophosphorus nerve agents (VX, rVX or VR, GB or Sarin, GD or Soman, and GF or Cyclosarin). The selective sample preparation method employs non-bonded silica solid-phase extraction and is partially automated. While working with a mobile phase composition that enhances the electrospray ionization process, the hydrophilic interaction chromatography method results in a 5-min injection-to-injection cycle time, excellent peak shapes and adequate retention (k'=3.1). These factors lead to limits of detection for these metabolites as low as 30 pg/mL in a 1-mL sample of human urine. The quality control data (15 and 75 ng/mL) demonstrate accurate (-0.5 to +3.4%) and precise (coefficients of variation of 2.1-3.6%) quantitative results over the clinically relevant urine concentration range of 1-200 ng/mL for a validation set of 20 standard and quality control sets prepared by five analysts over 54 days. The selectivity of the method is demonstrated for a 100-individual reference range study, as well as the analysis of relevant biological samples. The combined sample preparation and analysis portions of this method have a throughput of 288 samples per day.

  8. Enhanced Peroxide Resistance of In Vitro Mutagenized Fluorideresistant Klebsiella pneumoniae Ureases for Catalytic Buffering of Agent Decontamination Reactions

    DTIC Science & Technology

    2004-11-17

    1 ENHANCED PEROXIDE RESISTANCE OF IN VITRO MUTAGENIZED FLUORIDE- RESISTANT Klebsiella pneumoniae UREASES FOR CATALYTIC BUFFERING OF...oxidative surety agent decontamination technologies. Ammonia production from urea by urease neutralizes the production of O- alkylphosphonic acids...resulting from the hydrolysis of Nerve agents such as Sarin and VX. Fluoride production from Sarin hydrolysis inhibits native urease at low mM

  9. 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

  10. Fate of chemical warfare agents and toxic industrial chemicals in landfills.

    PubMed

    Bartelt-Hunt, Shannon L; Barlaz, Morton A; Knappe, Detlef R U; Kjeldsen, Peter

    2006-07-01

    One component of preparedness for a chemical attack is planning for the disposal of contaminated debris. To assess the feasibility of contaminated debris disposal in municipal solid waste (MSW) landfills, the fate of selected chemical warfare agents (CWAs) and toxic industrial chemicals (TICs) in MSW landfills was predicted with a mathematical model. Five blister agents [sulfur mustard (HD), nitrogen mustard (HN-2), lewisite (L), ethyldichloroarsine (ED), and phosgene oxime (CX)], eight nerve agents [tabun (GA), sarin (GB), soman (GD), GE, GF, VX, VG, and VM], one riot-control agent [CS], and two TICs [furan and carbon disulfide] were studied. The effects of both infiltration (climate) and contaminant biodegradability on fate predictions were assessed. Model results showed that hydrolysis and gas-phase advection were the principal fate pathways for CWAs and TICs, respectively. Apart from CX and the TICs, none of the investigated compounds was predicted to persist in a landfill for more than 5 years. Climate had little impact on CWA/TIC fate, and biodegradability was only important for compounds with long hydrolysis half-lives. Monte Carlo simulations were performed to assess the influence of uncertainty in model input parameters on CWA/TIC fate predictions. Correlation analyses showed that uncertainty in hydrolysis rate constants was the primary contributor to variance of CWA fate predictions, while uncertainty in the Henry's Law constant and landfill gas-production rate accounted for most of the variance of TIC fate predictions. CWA hydrolysates were more persistent than the parent CWAs, but limited information is available on abiotic or biotic transformation rates for these chemicals.

  11. A systems dynamics approach to the efficacy of oxime therapy for mild exposure to sarin gas.

    PubMed

    Droste, Daniel J; Shelley, Michael L; Gearhart, Jeffery M; Kempisty, David M

    2016-01-01

    The use of nerve agents such as sarin is as much a threat today as any other time in our history. The events in Syria in 2013 are proof of this. "The Obama administration asserted Sunday for the first time that the Syrian government used the nerve gas sarin to kill more than 1,400 people (August 21, 2013) in the world's gravest chemical weapons attack in 25 years." With these recent events clear in our mind, we must focus on the horrific nature of these chemical agents to devise a strategy that will enable first responders to counteract these insidious chemicals. This paper presents research on a physiologically based pharmacokinetic model to determine whether the current treatment protocol prescribed by the Center for Disease Control (CDC) and the US Army is effective in treating victims suffering from acute exposure symptoms. The model was used to determine what treatment should be used for victims suffering from mild exposure symptoms. The results indicate that the current CDC and US Army treatment is effective, but treatment with oxime therapy was not effective in alleviating symptoms of mild exposure. By applying these results, an effective treatment protocol was developed.

  12. Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

    SciTech Connect

    Smith, Carl D. Wright, Linnzi K.M.; Garcia, Gregory E.; Lee, Robyn B.; Lumley, Lucille A.

    2015-09-15

    Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD{sub 50}) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD{sub 50} of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD{sub 50}s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity. - Highlights: • The LD{sub 50} of sarin was determined in female rats throughout the stages of the estrous cycle. • Females in proestrus had a significantly higher LD{sub 50} compared to estrous or ovariectomized females. • No sex differences were observed between male and female rats

  13. Studies on Neuronal Apoptosis Following Soman Exposure in the Rat

    DTIC Science & Technology

    2005-10-01

    kg, i.m.). Brains were removed and three brain regions (thalamus, hippocampus and piriform cortex) dissected at several post-exposure time points to...post-exposure. Highest activation of caspase-3 was observed in the thalamus followed by hippocampus and piriform cortex. Comet assay analysis showed...hippocampus and piriform cortex. In conclusion, an apoptotic cascade is activated following Soman exposure, which along with necrotic cell death may be

  14. Neuronal Death Following Soman Intoxication: Necrosis or Apoptosis?

    DTIC Science & Technology

    2006-05-01

    ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER US Army Medical Research Institute of...MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) US Army Medical Research Institute of Chemical Defense Aberdeen Proving...40 min after onset of seizures, the anticholinergic drugs scopolamine and atropine failed to block soman-induced seizures, but diazepam and MK-801

  15. Biodegradation kinetics of neutralized Sarin by two different consortia

    SciTech Connect

    Zhang, Y.; Autenrieth, R.L.; Bonner, J.S.; Harvey, S.P.; Wild, J.R.; Rainina, E.L.

    1995-12-31

    Sarin (o-isopropyl methylphosphonofluoridate), one of the several highly toxic chemical warfare agents, can be readily neutralized in sodium hydroxide solution forming large quantities of brine solution containing IMPA (o-isopropyl methylphosphonic acid) and sodium fluoride that must be further processed and disposed. Two mixed cultures were successfully acclimated to use IMPA as a phosphorus source. The medium formula was chosen to provide the reactors with adequate alternative carbon sources so that the only limiting factor of the bacterial growth is phosphorus. Kinetic studies of the two cultures both in suspended and encapsulated forms were done with the initial IMPA concentrations ranged from 15 mg/L to 1,280 mg/L. Kinetic parameters were estimated based on IMPA and biomass concentrations measured over time using Monod equation and the least square method. For both cultures IMPA was not inhibitive under the tested conditions. For the free cells, n{sub max} was 131.3 mg/l/day for the APG swamp microorganisms and 120.9 mg/l/day for the soil extracted microorganisms. For the encapsulated cells, n{sub max} was 81.7 mg/l/day for the APG swamp microorganisms and 67.1 mg/l/day for the soil extracted microorganisms. The smaller values of n{sub max} for both types of the encapsulated microorganisms were very likely caused by substrate and nutrient transport limitation. For both cultures and both cell forms, it was observed that the degradation of IMPA formed MPA and phosphate sequentially. This led to the proposal of an IMPA biodegradative pathway involving an organophosphate hydrolase catalyzed reaction forming MPA. This would then be followed by C-P lyase catalyzed reaction transforming MPA to orthophosphate.

  16. Effect of soman on the cholinergic system in mouse brain

    SciTech Connect

    Tripathi, H.L.; Szakal, A.R.; Little, D.M.; Dewey, W.L.

    1986-03-05

    The effects of soman on levels of acetylcholine (ACh) and choline (Ch) and turnover rate of ACh have been studied in whole brain and brain regions (cerebellum, medulla-pons, midbrain, corpus striatum, hippocampus and cortex) of mice. Animals were injected with saline or a dose of soman up to 80..mu..g/kg, i.v. and were sacrificed by focussed microwave irradiation of the head. The tracer, /sup 3/H-Ch was injected (i.v.) 2 min prior to sacrifice and turnover rate of ACh was quantitated by using HPLC with electrochemical detection. A behaviorally effective dose of 80 ..mu..g/kg soman increased the levels of ACh significantly in whole brain (57.5%), corpus striatum (42.8%), hippocampus (24.1%) and cortex (43.1%). The levels of Ch were also increased in cerebellum (80.1%), midbrain (75.7%), corpus striatum (86.0%) and cortex (52.5%). The turnover rate of ACh was decreased in whole brain (53.8%), cerebellum (80.4%), medulla-pons (66.8%), midbrain (57.0%), corpus striatum (62.1%) and cortex (52.6%). The duration of these effects lasted more than 1 hr and the results indicate that the decrease in ACh turnover is not due necessarily to an increase in brain levels of ACh and/or Ch.

  17. The effects of 8-OH-DPAT on neuroinflammation after sarin exposure in mice.

    PubMed

    Garrett, Teresa L; Joshi, Kaushal; Rapp, Christine M; Chapleau, Molly; Cool, David R; Schlager, John J; Lucot, James B

    2013-08-09

    Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered 2h after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology.

  18. Engineering Bacteria to Catabolize the Carbonaceous Component of Sarin: Teaching E. coli to Eat Isopropanol.

    PubMed

    Brown, Margaret E; Mukhopadhyay, Aindrila; Keasling, Jay D

    2016-12-16

    We report an engineered strain of Escherichia coli that catabolizes the carbonaceous component of the extremely toxic chemical warfare agent sarin. Enzymatic decomposition of sarin generates isopropanol waste that, with this engineered strain, is then transformed into acetyl-CoA by enzymatic conversion with a key reaction performed by the acetone carboxylase complex (ACX). We engineered the heterologous expression of the ACX complex from Xanthobacter autotrophicus PY2 to match the naturally occurring subunit stoichiometry and purified the recombinant complex from E. coli for biochemical analysis. Incorporating this ACX complex and enzymes from diverse organisms, we introduced an isopropanol degradation pathway in E. coli, optimized induction conditions, and decoupled enzyme expression to probe pathway bottlenecks. Our engineered E. coli consumed 65% of isopropanol compared to no-cell controls and was able to grow on isopropanol as a sole carbon source. In the process, reconstitution of this large ACX complex (370 kDa) in a system naïve to its structural and mechanistic requirements allowed us to study this otherwise cryptic enzyme in more detail than would have been possible in the less genetically tractable native Xanthobacter system.

  19. Extending injury prevention methodology to chemical terrorism preparedness: the Haddon Matrix and sarin.

    PubMed

    Varney, Shawn; Hirshon, Jon Mark; Dischinger, Patricia; Mackenzie, Colin

    2006-01-01

    The Haddon Matrix offers a classic epidemiological model for studying injury prevention. This methodology places the public health concepts of agent, host, and environment within the three sequential phases of an injury-producing incident-pre-event, event, and postevent. This study uses this methodology to illustrate how it could be applied in systematically preparing for a mass casualty disaster such as an unconventional sarin attack in a major urban setting. Nineteen city, state, federal, and military agencies responded to the Haddon Matrix chemical terrorism preparedness exercise and offered feedback in the data review session. Four injury prevention strategies (education, engineering, enforcement, and economics) were applied to the individual factors and event phases of the Haddon Matrix. The majority of factors identified in all phases were modifiable, primarily through educational interventions focused on individual healthcare providers and first responders. The Haddon Matrix provides a viable means of studying an unconventional problem, allowing for the identification of modifiable factors to decrease the type and severity of injuries following a mass casualty disaster such as a sarin release. This strategy could be successfully incorporated into disaster planning for other weapons attacks that could potentially cause mass casualties.

  20. In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity.

    PubMed

    Calić, Maja; Vrdoljak, Ana Lucić; Radić, Bozica; Jelić, Dubravko; Jun, Daniel; Kuca, Kamil; Kovarik, Zrinka

    2006-02-15

    The increased concern about terrorist use of nerve agents prompted us to search for new more effective oximes against tabun and soman poisoning. We investigated the interactions of five bispyridinium oximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)] with human erythrocyte acetylcholinesterase (AChE; E.C. 3.1.1.7) and their effects on tabun- and soman-poisoned mice. All the oximes reversibly inhibited AChE, and the enzyme-oxime dissociation constants were between 17 and 180 microM. Tabun-inhibited AChE was completely reactivated by TMB-4, K027 and K048, with the overall reactivation rate constants of 306, 376 and 673 min(-1)M(-1), respectively. The reactivation of tabun-inhibited AChE by K033 reached 50% after 24h, while HI-6 failed to reactivate any AChE at all. Soman-inhibited AChE was resistant to reactivation by 1mM oximes. All studied oximes protected AChE from phosphorylation with both soman and tabun. In vivo experiments showed that the studied oximes were relatively toxic to mice; K033 was the most toxic (LD50=33.4 mg/kg), while K027 was the least toxic (LD50=672.8 mg/kg). The best antidotal efficacy was obtained with K048, K027 and TMB-4 for tabun poisoning, and HI-6 for soman poisoning. Moreover, all tested oximes showed no cytotoxic effect on several cell lines in concentrations up to 0.8mM. The potency of the oximes K048 and K027 to protect mice from five-fold LD50 of tabun and their low toxicity make these compounds leading in the therapy of tabun poisoning. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.

  1. Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: hydroxylamine anion is predicted to be a better antidote with DFT calculations.

    PubMed

    Khan, Md Abdul Shafeeuulla; Lo, Rabindranath; Bandyopadhyay, Tusar; Ganguly, Bishwajit

    2011-08-01

    Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP-inhibited AChE due to their α-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that α-effect is not so important for dephosphylation reactions. We report the importance of α-effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin-serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin-serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin-serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin-serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this α-nucleophile can be a good antidote agent for the reactivation process.

  2. Fluorescent polymeric aggregates for selective response to sarin surrogates.

    PubMed

    Rusu, Anca D; Moleavin, Ioana A; Hurduc, Nicolae; Hamel, Matthieu; Rocha, Licinio

    2014-09-07

    By combining the sensitivity of fluorescent units with the response of "smart" polymers to environmental changes, we propose a new approach for chemical detection applications. The system proved to be sensitive to 12 ppb of diethyl chlorophosphate (DCP), a Sarin surrogate, and to discriminate between the interfering molecules.

  3. Response of rats to low levels of sarin.

    PubMed

    Henderson, Rogene F; Barr, Edward B; Blackwell, Walter B; Clark, Connie R; Conn, Carole A; Kalra, Roma; March, Thomas H; Sopori, Mohan L; Tesfaigzi, Yohannes; Ménache, Margaret G; Mash, Deborah C

    2002-10-15

    The purpose of this study was to determine whether exposure to levels of sarin causing no overt clinical signs would cause more subtle, adverse health effects that persisted after the exposure ended. Inhalation exposures of male Fischer 344 rats to 0, 0.2, or 0.4 mg/m(3) of sarin for 1 h/day for 1, 5, or 10 days under normal (25 degrees C) and heat-stressed (32 degrees C) conditions were completed and observations were made at 1 day and 1 month after the exposures. The sarin exposures had no observed effects on body weight, respiration rate, and minute volume during exposure nor in body temperature and activity during the 30-day recovery period. There was no evidence of cellular changes in brain determined by routine histopathology nor of any increase in apoptosis. Brain mRNA for interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was increased in a dose-dependent manner. Autoradiographic studies demonstrated that M1 cholinergic receptor site densities were unchanged at 1 day after repeated exposures with or without heat stress. At 30 days, there was a decrease in M1 receptors in the olfactory tubercle (with and without heat), and, with heat stress, M1 sites also decreased in a dose-dependent manner in the frontal cortex, anterior olfactory nucleus, and hippocampus. M3 receptor sites were not affected by sarin exposure alone. In the presence of heat stress, there was an upregulation in binding site densities in the frontal cortex, olfactory tubercle, anterior nucleus, and striatum immediately after exposure, and these effects persisted at 30 days. Although red blood cell acetylcholinesterase (AChE) was not greatly inhibited by the 1-day exposure, there were 30 and 60% inhibitions after repeated exposures at the low and high doses, respectively. Histochemical staining for AChE demonstrated that sarin exposure alone reduced AChE in the cerebral cortex, striatum, and olfactory bulb. Sarin exposure under heat stress reduced AChE staining in the hippocampus

  4. Sensorimotor deficit and cholinergic changes following coexposure with pyridostigmine bromide and sarin in rats.

    PubMed

    Abou-Donia, Mohamed B; Dechkovskaia, Anjelika M; Goldstein, Larry B; Bullman, Sarah L; Khan, Wasiuddin A

    2002-03-01

    A myriad of neurological symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty in concentration have been reported by Persian Gulf War (PGW) veterans. A large number of these veterans were prophylactically treated with pyridostigmine bromide (PB) and possibly exposed to sarin. In the present study we investigated the effects of PB and sarin, alone and in combination, on sensorimotor performance and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with PB (1.3 mg/kg, 15 daily doses, oral) and sarin (50, 75, 90, and 100 microg/kg, single im dose on day 15), alone and in combination. The animals were evaluated for postural reflexes, limb placing, orienting to vibrissae touch, incline plane performance, beam-walk time, and forepaw grip time 7 and 15 days following treatment with sarin. Treatment with either PB or sarin alone resulted in significant sensorimotor impairments. Coexposure to sarin and PB resulted in significant sensorimotor deficits that worsened over time. By 15 days following sarin treatment, plasma butyrylcholinesterase (BChE) activity returned to normal levels in the animals treated with sarin alone, whereas in the animals exposed to PB or PB plus sarin, there was an increase in the enzyme activity. Cortical acetylcholinesterase (AChE) activity remained inhibited in the animals treated with sarin alone and in combination with PB. Muscarinic acetylcholine receptor (m2 mAChR) ligand binding with [(3)H]AFDX-384 in cortex and brain stem showed significant increases (approximately 120-130% of control) following coexposure to PB and sarin at higher doses. To evaluate the potential of PB for augmentation or inhibition of the toxicity induced by acute sarin exposure, the animals were exposed to either 10 or 100 microg/kg sarin (single im injection) with or without pretreatment with PB, and sacrificed 3 h after treatment with sarin. Pretreatment with PB offered slight protection in the plasma as

  5. Protection against soman or VX poisoning by human butyrylcholinesterase in guinea pigs and cynomolgus monkeys.

    PubMed

    Lenz, David E; Maxwell, Donald M; Koplovitz, Irwin; Clark, Connie R; Capacio, Benjamin R; Cerasoli, Douglas M; Federko, James M; Luo, Chunyuan; Saxena, Ashima; Doctor, Bhupendra P; Olson, Carl

    2005-12-15

    Human butyrylcholinesterase (HuBuChE), purified from outdated human plasma, is being evaluated for efficacy against nerve agents in guinea pigs and cynomolgus monkeys. Previous studies in rodents and nonhuman primates demonstrated that pretreatment of animals with enzymes that can scavenge nerve agents could provide significant protection against behavioral and lethal effects of nerve agent intoxication. In preparation for evaluation of efficacy of HuBuChE prior to initiating an investigational new drug (IND) application, the pharmacokinetics of HuBuChE were evaluated in guinea pigs and in cynomolgus monkeys. HuBuChE was injected intramuscularly (i.m.) at two doses, and blood samples were taken to follow the time-course of HuBuChE in blood for up to 168 h after administration. In guinea pigs, the two doses of HuBuChE, 19.9 and 32.5 mg/kg, produced similar times of maximal blood concentration (T(max) of 26.0 and 26.8 h, respectively) and similar elimination half-times (t(1/2) of 64.6 and 75.5 h, respectively). Enzyme levels were still 10-fold over baseline at 72 h. Based on these data, guinea pigs were administered 150 mg/kg of enzyme i.m. and challenged at T(max). Soman or VX doses were approximately 1.5, 2.0 and 2.0 x LD50 administered subcutaneously (s.c.) in sequence at 90-120 min apart. None of the animals displayed signs of organophosphorus (OP) anticholinesterase intoxication at any of the challenge levels, and all survived for the 14-day duration of the experiment. Similar experiments were carried out with cynomolgus monkeys to determine the pharmacokinetics of HuBuChE and its efficacy against soman. The complete survival of nearly all animals tested to date, coupled with the maximal blood concentration and half-life elimination profile obtained for HuBuChE after i.m. injection, provides strong support for the continued development of HuBuChE as a product to protect against nerve agents.

  6. 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).

  7. Simulant Agent Resistance Test Manikin (SMARTMAN) Testing of Protective Mask Systems

    DTIC Science & Technology

    2013-09-16

    temperature, high humidi- ty, low temperature, low humidity, fungus, salt fog, blowing sand, blowing dust, solar radiation, rain, rough handling, simulated...curve covering the range specified by the project requirements [e.g., concentration range of 0 to 70 mg/m3 for distilled mustard (HD)] into the Airwaves...Cycle Time (min) GB 2.5 × 10-4 200 1 3 GD 2.5 × 10-4 200 1 3 HD 5.0 × 10-3 100 2 5 VX 1.25 × 10-5 500 8 10 aGB – sarin; GD – soman; HD – distilled

  8. Mechanism of soman-induced contractions in canine tracheal smooth muscle. (Reannouncement with new availability information)

    SciTech Connect

    Adler, M.; Moore, D.H.; Filbert, M.G.

    1992-12-31

    The actions of the irreversible organophosphorus cholinesterase (ChE) inhibitor soman were investigated on canine trachea smooth muscle in vitro. Concentrations of soman > or - 1 nM increased the amplitude and decay of contractions elicited by electric field stimulation. The effect on decay showed a marked dependence on stimulation frequency, undergoing a 2.4-fold increase between 3 and 60 Hz. Soman also potentiated tensions due to bath applied acetylcholine (ACh). Little or no potentiation was observed for contractions elicited by carbamylcholine, an agonist that is not hydrolyzed by ChE. Concentration of soman > or - 3 nM led to the appearance of sustained contractures. These contractures developed with a delayed onset and were well correlated with ChE activity. Alkylation of muscarinic receptors by propylbenzilylcholine mustard antagonized the actions of soman on both spontaneous and electrically-evoked muscle contractions. The results are consistent with a mechanism in which the toxic actions of soman are mediated by accumulation of neurally-released ACh secondary to inhibition of ChE activity. An important factor in this accumulation is suggested to be the buffering effect of the muscarinic receptors on the efflux of ACh from the neuroeffector junction. Tracheal smooth muscle, Cholinesterase inhibitors, Muscarinic receptor, Soman, Organophosphate.

  9. Simultaneous initiation of degranulation and inhibition of leukotriene release by soman in human basophils

    SciTech Connect

    Meier, H.L.; Warner, J.; MacGlashan, D.W.

    1995-12-31

    Previous studies noted that the serine esterase inhibitor, soman, could induce histamine release from human basophils. To investigate the mechanisms by which soman causes histamine release (a preformed mediator), we also examined its ability to induce leukotriene release (a newly synthesized mediator) from basophils. We found that no leukotriene release followed activation with soman, while histamine release was usually greater than 70%. In addition, soman and diisopropyl-fluorophosphate were found actively to suppress low level spontaneous leukotriene release as well as ongoing leukotriene release induced by anti-IgE antibody. Soman (0.3 mM) was able to stop leukotriene release as rapidly as the calcium chelator, EDTA. In a series of control experiments, it was noted that soman did not influence the metabolism of LTC4 to LTD4 or LTE4 (for which little metabolism occurred), eliminating the possibility that reduced LTC4 release could have resulted from its enhanced metabolism. Therefore, using one compound (soman), basophils could be simultaneously activated to degranulate while having the pathway leading to leukotriene release actively suppressed. These results provide further evidence that histamine and leukotriene release are independent pathways resulting from the activation of basophils.

  10. Sarin exposure: a simulation case scenario.

    PubMed

    Eason, Martin P

    2013-01-01

    Given the current geopolitical tensions, the risk of a terrorist attack on the United States is constant and increasing. Chemical terrorism, specifically the use of nerve agents, has occurred in other nations. Because of the ease of manufacture, the ability to conceal them, and the lethality of these agents, they pose a potential threat as a weapon of terror. Nerve agent exposure requires prompt recognition, a series of actions to mitigate further exposure to others, and management of the physiological sequelae of exposure. Many civilian healthcare providers are unprepared to manage injuries from nerve exposure. Failure to recognize the signs of nerve agent exposure will increase mortality and morbidity in victims and place healthcare providers at risk. Simulation is an effective methodology to train healthcare personnel in disaster preparedness. This article presents a simulation scenario that reviews the presentation of nerve agent exposure, its management, and a recipe for performing this simulation in a training exercise.

  11. Consequence assessment of indoor dispersion of sarin--a hypothetical scenario.

    PubMed

    Endregard, Monica; Pettersson Reif, B Anders; Vik, Thomas; Busmundrud, Odd

    2010-04-15

    The objective of this study is to provide a hypothetical scenario of indoor dispersion of the highly toxic nerve agent sarin in a large building, which can be used as a starting point for discussion, planning, training and exercises for emergency services and responsible authorities. The indoor dispersion has been simulated using a Computational Fluid Dynamics (CFD) approach. Possible consequences have been calculated based on concentration and dose profiles. Mild intoxication effects appear within minutes, while serious injuries and fatalities occur approximately 20 min after release. Anticipated key emergency response challenges are: (i) the time factor due to rapid onset of symptoms, (ii) the large number of casualties, and (iii) the contaminated hazard scene.

  12. Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.

    PubMed

    Price, Matthew E; Docx, Cerys J; Rice, Helen; Fairhall, Sarah J; Poole, Sarah J C; Bird, Michael; Whiley, Luke; Flint, Daniel P; Green, A Christopher; Timperley, Christopher M; Tattersall, John E H

    2016-02-26

    Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.

  13. A comparison of the neuroprotective efficacy of individual oxime (HI-6) and combinations of oximes (HI-6+trimedoxime, HI-6+K203) in soman-poisoned rats.

    PubMed

    Kassa, Jiri; Karasova, Jana Zdarova; Tesarova, Sandra

    2011-07-01

    The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD₅₀ value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.

  14. Low Dose Sarin Leads To Murine Cardiac Dysfunction

    DTIC Science & Technology

    2010-03-01

    reduced heart rate at smooth muscle level; at exocrine glands , it causes secretions in the lung, nasal, oral, and sweat glands . Among clinical effects...smooth muscles, skeletal muscles, most exocrine glands , the central nervous system (CNS), and the cardiac system (central and ganglionic afferents...sarin need to 8 be critically analyzed at low doses to help provide early diagnosis. Similarly, functional and structural changes in the heart

  15. The Tokyo subway sarin attack--lessons learned.

    PubMed

    Okumura, T; Hisaoka, T; Yamada, A; Naito, T; Isonuma, H; Okumura, S; Miura, K; Sakurada, M; Maekawa, H; Ishimatsu, S; Takasu, N; Suzuki, K

    2005-09-01

    The sarin gas attack in the Tokyo subway system is reviewed from a clinical toxicology perspective. Based on the lessons learned from this attack, the following areas should be addressed on a global scale. First, an adequate supply of protective equipment is required, including level B protective equipment with a pressure demand breathing apparatus. In addition, a system should be established that enables a possible cause to be determined based on symptoms, physical findings, general laboratory tests, and a simple qualitative analysis for poisonous substances. If an antidote is needed, the system should enable it to be administered to the victims as quickly as possible. Preparation for a large-scale chemical attack by terrorists requires the prior establishment of a detailed decontamination plan that utilizes not only mass decontamination facilities but also public facilities in the area. A system should be established for summarizing, evaluating, and disseminating information on poisonous substances. Finally, a large-scale scientific investigation of the Tokyo sarin attack should be conducted to examine its long-term and subclinical effects and the effects of exposure to asymptomatic low levels of sarin.

  16. Nanocrystalline zinc oxide for the decontamination of sarin.

    PubMed

    Mahato, T H; Prasad, G K; Singh, Beer; Acharya, J; Srivastava, A R; Vijayaraghavan, R

    2009-06-15

    Nanocrystalline zinc oxide materials were prepared by sol-gel method and were characterized by X-ray diffraction, scanning electron microscopy, thermogravimetry, nitrogen adsorption and infrared spectroscopy techniques. The data confirmed the formation of zinc oxide materials of zincite phase with an average crystallite size of approximately 55 nm. Obtained material was tested as destructive adsorbent for the decontamination of sarin and the reaction was followed by GC-NPD and GC-MS techniques. The reaction products were characterized by GC-MS and the data explored the role of hydrolysis reaction in the detoxification of sarin. Sarin was hydrolyzed to form surface bound non-toxic phosphonate on the surface of nano-zinc oxide. The data also revealed the values of rate constant and half-life to be 4.12h(-1) and 0.16 h in the initial stages of the reaction and 0.361 h(-1) and 1.9h at the final stages of the reaction for the decontamination reaction on nanocrystalline ZnO.

  17. Selective extraction of organophosphorus nerve agent degradation products by molecularly imprinted solid-phase extraction.

    PubMed

    Le Moullec, Sophie; Bégos, Arlette; Pichon, Valérie; Bellier, Bruno

    2006-03-03

    The analysis of alkyl alkylphosphonic acids, the degradation products of V and G nerve agents as VX, Sarin or Soman, is an important task for the verification of compliance to the Chemical Weapons Convention. The detection of these contaminants at low concentration levels is often difficult in complex matrices due to the amount of interfering substances. Molecularly imprinted solid-phase extraction technique should allow a selective extraction of these compounds from complex samples, and thus make their detection easier. Two molecularly imprinted polymers (MIPs) prepared with methacrylic acid (MAA) as monomer and pinacolyl methylphosphonic acid (PMPA) as template molecule were synthesised and tested. The first polymer, MIP A, was prepared with ethylene glycol dimethacrylate (EGDMA) in dichloromethane. The second polymer, MIP B, was synthesised using trimethylolpropane trimethacrylate (TRIM) in acetonitrile. To evaluate the selectivity provided by these MIPs, the retention of the ethyl methylphosphonic acid (EMPA) target molecule was studied in parallel on a non-imprinted polymer (NIP). While MIP A does not show any difference compared to NIP A, a good selectivity was obtained for MIP B. After the optimisation of the extraction process, 60% of EMPA can be removed from the NIP B without affecting the retention on the MIP B. A recovery of extraction of 93% was then obtained on the MIP B. Its capacity was then measured and corresponds to 97 microg of EMPA per gram of MIP. Finally, the selectivity of MIP B was clearly demonstrated by applying it to the clean-up of a soil extract spiked with EMPA.

  18. Hormone-dependence of sarin lethality in rats: sex differences and stage of the estrous cycle

    PubMed Central

    Smith, Carl D.; Wright, Linnzi K.M.; Garcia, Gregory E.; Lee, Robyn B.; Lumley, Lucille A.

    2015-01-01

    Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females’ sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity. PMID:26079828

  19. Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle.

    PubMed

    Smith, Carl D; Wright, Linnzi K M; Garcia, Gregory E; Lee, Robyn B; Lumley, Lucille A

    2015-09-15

    Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity.

  20. Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes.

    PubMed

    Lazar, Shlomi; Egoz, Inbal; Brandeis, Rachel; Chapman, Shira; Bloch-Shilderman, Eugenia; Grauer, Ettie

    2016-11-01

    Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.

  1. Efficacy comparison of scopolamine and diazepam against soman-induced debilitation in guinea pigs

    SciTech Connect

    Anderson, D.R.; Gennings, C.; Carter, W.H.; Harris, L.W.; Lennox, W.J.

    1994-12-31

    The efficacy of diazepam (DZ) and scopolamine (SCP), in combination with atropine (ATR) + oxime therapy, against soman-induced seizure/convulsive activity and associated brain damage has been demonstrated, but the efficacy of each against the incapacitating effects of soman has not been addressed. Thus, the therapeutic efficacies of SCP (5 doses; 0-0.86 mg/kg) and DZ (5 doses; 0-5 mg/kg), when each was used in conjunction with ATR (3 doses; 0.5-8 mg/kg) + 2-PAM (25 mg/kg) therapy, were compared in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5, or 3.2 LD5Os of soman. Response surface methodology was employed to describe the relationship between soman-induced incapacitation and the ATR/DZ or ATRISCP dosages. Incapacitation was measured by toxicity scores assigned by three graders to test animals at 60 min postsoman. Results show that as the dosage of SCP increased, the mean toxicity scores decreased. Also, within the indicated dose ranges used, the efficacy of SCP was not dependent on the presence of ATR. In contrast, ATR alone was found to be more effective than when combined with DZ at any dose, and indicates that DZ might be temporarily contributing to soman-induced incapacitation. These findings suggest that in guinea pigs, SCP could replace ATR or DZ, or both, as therapy against soman-induced incapacitation.

  2. The benefit of combination of oximes for the neuroprotective efficacy of antidotal treatment of sarin-poisoned rats.

    PubMed

    Kassa, Jiri; Kunesova, Gabriela

    2012-05-01

    The potency of the oxime HI-6 and two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) to reduce sarin-induced acute neurotoxic signs and symptoms was evaluated in this study. Sarin-induced neurotoxicity and the neuroprotective effects of atropine alone or in combination with HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% of LD(50) value) were monitored by a functional observatory battery (FOB) 24 h following sarin administration. The results indicate that both mixtures of oximes combined with atropine were able to survive sarin-poisoned rats 24 h following sarin administration while two non-treated sarin-poisoned rats and one sarin-poisoned rat treated with atropine alone or with atropine in combination with the oxime HI-6 died within 24 h following sarin poisoning. All types of antidotal treatment were able to decrease sarin-induced neurotoxic signs and symptoms but not completely. While atropine alone and atropine in combination with the oxime HI-6 were able to eliminate some sarin-induced neurotoxic signs and symptoms, the neuroprotective efficacy of both combinations of oximes with atropine was slightly higher. Thus, both tested combinations of oximes in combination with atropine bring a small benefit for the neuroprotective efficacy of antidotal treatment of acute sarin poisonings.

  3. Protection against sarin-induced seizures in rats by direct brain microinjection of scopolamine, midazolam or MK-801.

    PubMed

    Skovira, Jacob W; McDonough, John H; Shih, Tsung-Ming

    2010-01-01

    Control of seizure activity is critical to survival and neuroprotection following nerve agent exposure. Extensive research has shown that three classes of drugs, muscarinic antagonists, benzodiazepines, and N-methyl-D: -aspartate antagonists, are capable of moderating these seizures. This study began to map the neural areas in rat brain that respond to these three drug classes resulting in anticonvulsant effects. Drugs of each class (scopolamine, midazolam, MK-801) were evaluated for their ability to prevent sarin-induced seizures when injected into specific brain areas (lateral ventricle, anterior piriform cortex, basolateral amygdala, area tempestas). Animals were pretreated by microinjection with saline or a dose of drug from one of the three classes 30 min prior to receiving 150 microg/kg sarin, subcutaneously, followed by 2.0 mg/kg atropine methylnitrate, intramuscularly. Animals were then returned to their cages, where electroencephalographic activity was monitored for seizures. Anticonvulsant effective doses (ED(50)) were determined using an up-down dosing procedure over successive animals. Scopolamine provided anticonvulsant effects in each area tested, while midazolam was effective in each area except the lateral ventricle. MK-801 was only effective at preventing seizures when injected into the basolateral amygdala or area tempestas. The results show a unique neuroanatomical and pharmacological specificity for control of nerve agent-induced seizures.

  4. Acute microinstillation inhalation exposure to sarin induces changes in respiratory dynamics and functions in guinea pigs.

    PubMed

    Conti, Michele L; Che, Magnus M; Boylan, Megan; Sciuto, Alfred M; Gordon, Richard K; Nambiar, Madhusoodana P

    2009-01-01

    This study investigates the toxic effects of sarin on respiratory dynamics following microinstillation inhalation exposure in guinea pigs. Animals are exposed to sarin for 4 minutes, and respiratory functions are monitored at 4 hours and 24 hours by whole-body barometric plethysmography. Data show significant changes in respiratory dynamics and function following sarin exposure. An increase in respiratory frequency is observed at 4 hours post exposure compared with saline controls. Tidal volume and minute volume are also increased in sarin-exposed animals 4 hours after exposure. Peak inspiratory flow increases, whereas peak expiratory flow increases at 4 hours and is erratic following sarin exposure. Animals exposed to sarin show a significant decrease in expiratory time and inspiratory time. End-inspiratory pause is unchanged whereas end-expiratory pause is slightly decreased 24 hours after sarin exposure. These results indicate that inhalation exposure to sarin alters respiratory dynamics and function at 4 hours, with return to normal levels at 24 hours post exposure.

  5. Soman-induced seizures impair norepinephrine-stimulated phosphoinositide turnover

    SciTech Connect

    Filbert, M.G.; Phann, S.; Forster, J.; Ballough, G.P.; Cann, F.J.

    1993-05-13

    Seizure activity increases turnover of phosphoinositide bisphosphate (PIP2). Turnover of PIP2 is thought to be modulated by neurotransmitter interactions. The effect of soman-induced seizures on neurotransmitter-stimulated PIP 2 turnover was examined in rats. Thirty minutes after induction of seizure activity, rats were euthanized and slices prepared from the hippocampus or cerebral cortex were incubated with myo-(2-3H) inositol for incorporation into phospholipids. Hydrolysis of phosphoinositides was determined by measuring the accumulation of (3H) inositol-l-phosphate (IP1) in the presence of LiCl. Carbachol, norepinephrine (NE) and high K+ increased accumulation of IP1 in slices from control rats. GABA was without effect on IP1 accumulation but potentiated the stimulation of PIP, hydrolysis by NE. NE-stimulated IP1 accumulation in slices from rats undergoing seizures was significantly reduced. GABA potentiation of the NE-stimulated hydrolysis was also reduced.

  6. Protective effects of aerosolized scopolamine against soman-induced acute respiratory toxicity in guinea pigs.

    PubMed

    Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Song, Jian; Oguntayo, Samuel; Morthole, Venee; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2011-12-01

    The protective efficacy of the antimuscarinic agent scopolamine was evaluated against soman (o-pinacolyl methylphosphonofluoridate [GD])-induced respiratory toxicity in guinea pigs. Anesthetized animals were exposed to GD (841 mg/m(3)) by microinstillation inhalation exposure and treated 30 seconds later with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 hours. Treatment with scopolamine significantly increased survival and reduced clinical signs of toxicity and body weight loss in GD-exposed animals. Analysis of bronchoalveolar lavage (BAL) fluid showed normalization of GD-induced increased cell death, total cell count, and protein following scopolamine treatment. The BAL fluid acetylcholinesterase and butyrylcholinesterase levels were also increased by scopolamine treatment. Respiratory dynamics parameters were normalized at 4 and 24 hours post-GD exposure in scopolamine-treated animals. Lung histology showed that scopolamine treatment reduced bronchial epithelial and subepithelial inflammation and multifocal alveolar septal edema. These results suggest that aerosolized scopolamine considerably protects against GD-induced respiratory toxicity.

  7. Evaluation of candidate decontaminants against percutaneous sulfur mustard and thickened soman challenges

    SciTech Connect

    Blank, J.A.; Hobson, D.W.; Menton, R.G.; Olson, C.T.; Korte, D.W.

    1993-05-13

    Studies were conducted to evaluate the efficacy of candidate skin decontaminants relative to a standard control decontaminant, XE-555 resin, against percutaneous sulfur mustard (HD) or thickened soman (TGD) challenge. Male, New Zealand White rabbits were used as the model system with lesion area as the end point for HD exposures and erythrocyte acetylcholinesterase (AChE) inhibition as the endpoint for TGD exposure. Initial studies were performed to establish assay parameters for, and to validate the use of, AChE inhibition as an endpoint for assessing candidate decontaminant efficacy against nerve agent exposures. XE-555 resin was concurrently evaluated with each candidate decontaminant for both assay control and comparative purpose. Decontamination was initiated at 1, 3, or 5 min after HD exposures and 2 min after TGD exposures. U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) compounds 1513, 1514, 1515, 1516, and 1517 were evaluated against HD and against TGD. Results from these studies demonstrated the utility of AChE inhibition for evaluating skin decontaminants. None of the candidate decontaminants evaluated was more effective than the standard control decontaminant against HD or TGD exposures.

  8. Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX.

    PubMed

    Saxena, Ashima; Sun, Wei; Fedorko, James M; Koplovitz, Irwin; Doctor, Bhupendra P

    2011-01-01

    Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2×LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ∼24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5×LD(50) of soman or 8×LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents.

  9. Determination of miosis threshold from whole-body vapor exposure to sarin in African green monkeys.

    PubMed

    Genovese, Raymond F; Benton, Bernard J; Oubre, John L; Fleming, Patrick J; Jakubowski, E Michael; Mioduszewski, Robert J

    2008-02-28

    We determined the threshold concentration of sarin vapor exposure producing miosis in African green monkeys (Chlorocebus aethiops). Monkeys (n=8) were exposed to a single concentration of sarin (0.069-0.701mg/m3) for 10min. Changes in pupil size were measured from photographs taken before and after the exposure. Sarin EC50 values for miosis were determined to be 0.166mg/m3 when miosis was defined as a 50% reduction in pupil area and 0.469mg/m3 when miosis was defined as a 50% reduction in pupil diameter. Monkeys were also evaluated for behavioral changes from sarin exposure using a serial probe recognition test and performance remained essentially unchanged for all monkeys. None of the concentrations of sarin produced specific clinical signs of toxicity other than miosis. Sarin was regenerated from blood sampled following exposure in a concentration-dependent fashion. Consistent with a predominant inhibition of acetylcholinesterase (AChE), more sarin was consistently found in RBC fractions than in plasma fractions. Further, elimination of regenerated sarin from RBC fractions was slower than from plasma fractions. Blood samples following exposure also showed concentration-dependent inhibition of AChE activity and, to a lesser extent, butyrylcholinesterase activity. At the largest exposure concentration, AChE inhibition was substantial, reducing activity to approximately 40% of baseline. The results characterize sarin exposure concentrations that produce miosis in a large primate species in the absence of other overt signs of toxicity. Further, these results extend previous studies indicating that miosis is a valid early indicator for the detection of sarin vapor exposure.

  10. Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: An electrographic, behavioral, and histological study in freely moving rats

    SciTech Connect

    Gilat, E. . E-mail: gilat@iibr.gov.il; Kadar, T.; Levy, A.; Rabinovitz, I.; Cohen, G.; Kapon, Y.; Sahar, R.; Brandeis, R.

    2005-11-15

    Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 {+-} 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 {+-} 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted

  11. Cloning and expression of a gene encoding a bacterial enzyme for decontamination of organophosphorus nerve agents and nucleotide sequence of the enzyme.

    PubMed Central

    Cheng, T C; Harvey, S P; Chen, G L

    1996-01-01

    Organophosphorus acid (OPA) anhydrolase enzymes have been found in a wide variety of prokaryotic and eukaryotic organisms. Interest in these enzymes has been prompted by their ability to catalyze the hydrolysis of toxic organophosphorus cholinesterase-inhibiting compounds, including pesticides and chemical nerve agents. The natural substrates for these enzymes are unknown. The gene (opaA) which encodes an OPA anhydrolase (OPAA-2) was isolated from an Alteromonas sp. strain JD6.5 EcoRI-lambda ZAPII chromosomal library expressed in Escherichia coli and identified by immunodetection with anti-OPAA-2 serum. OPA anhydrolase activity expressed by the immunopositive recombinant clones was demonstrated by using diisopropylfluorophosphate (DFP) as a substrate. A comparison of the recombinant enzyme with native, purified OPAA-2 showed they had the same apparent molecular mass (60 kDa), antigenic properties, and enzyme activity against DFP and the chemical nerve agents sarin, soman, and O-cyclohexyl methylphosphonofluoridate. The gene expressing this activity was found in a 1.74-kb PstI-HindIII fragment of the original 6.1-kb EcoRI DNA insert. The nucleotide sequence of this PstI-HindIII fragment revealed an open reading frame of 1,551 nucleotides, coding for a protein of 517 amino acid residues. Amino acid sequence comparison of OPAA-2 with the protein database showed that OPAA-2 is similar to a 647-amino-acid sequence produced by an open reading frame which appears to be the E. coli pepQ gene. Further comparison of OPAA-2, the E. coli PepQ protein sequence, E. coli aminopeptidase P, and human prolidase showed regions of different degrees of similarity or functionally conserved amino acid substitutions. These findings, along with preliminary data confirming the presence of prolidase activity expressed by OPAA-2, suggest that the OPAA-2 enzyme may, in nature, be used in peptide metabolism. PMID:8633861

  12. Exploring the physicochemical properties of oxime-reactivation therapeutics for cyclosarin, sarin, tabun, and VX inactivated acetylcholinesterase.

    PubMed

    Esposito, Emilio Xavier; Stouch, Terry R; Wymore, Troy; Madura, Jeffry D

    2014-01-21

    The inactivation of acetylcholinesterase (AChE) by organophosphorus agent (OP) compounds is a serious problem regardless of how the individual was exposed. The reactivation of OP-inactivated AChE is dependent on the OP conjugate, and commonly a specific oxime is better at reactivating a specific OP conjugate than several diverse OP conjugates. The presented research explores the physicochemical properties needed for the reactivation of OP-inactivated AChE. Four different OPs, cyclosarin, sarin, tabun, and VX, were analyzed using the same set of oxime reactivators. A trial descriptor pool of semiempirical, traditional, and molecular interaction field descriptors was used to construct an ensemble of QSAR models for each OP-conjugate pair. Based on the molecular information and the cross-validation ability, individual QSAR models were selected to be part of an OP-conjugate consensus model. The OP-conjugate specific models provide important insight into the physicochemical properties required to reactivate the OP conjugates of interest. The reactivation of AChE inactivated with either cyclosarin or tabun requires the oxime therapeutic to possess an overall polar-positive surface area. Oxime therapeutics for the reactivation of sarin-inactivated AChE are conformationally dependent while oxime reverse therapeutics for VX require a compact region with a highly hydrophilic region and two positively charged pyridine rings.

  13. Quantitative analysis of chemical warfare agent degradation products in reaction masses using capillary electrophoresis.

    PubMed

    Nassar, A E; Lucas, S V; Myler, C A; Jones, W R; Campisano, M; Hoffland, L D

    1998-09-01

    Quantitative methods have been developed for the analysis of chemical warfare agent degradation products in reaction masses using capillary electrophoresis (CE). This is the first report of a systematic validation of a CE-based method for the analysis of chemical warfare agent degradation products in agent neutralization matrixes (reaction masses). After neutralization with monoethanolamine/water, the nerve agent GB (isopropyl methylphosphonofluoridate, Sarin) gives isopropyl methylphosphonic acid (IMPA) and O-isopropyl O'-(2-amino)ethyl methylphosphonate (GB-MEA adduct). The nerve agent GD (pinacolyl methylphosphonofluoridate, Soman), [pinacolyl = 2-(3,3-dimethyl)butyl] produces pinacolyl methylphosphonic acid (PMPA) and O-pinacolyl O'-(2-amino)ethyl methylphosphonate (GD-MEA adduct). The samples were prepared by dilution of the reaction masses with deionized water before analysis by CE/indirect UV detection or CE/conductivity detection. Migration time precision was less than 4.0% RSD for IMPA and 5.0 RSD for PMPA on a day-to-day basis. The detection limit for both IMPA and PMPA is 100 micrograms/L; the quantitation limit for both is 500 micrograms/L. For calibration standards, IMPA and PMPA gave a linear response (R2 = 0.9999) over the range 0.5-100 micrograms/mL. The interday precision RSDs were 1.9, 1.0, and 0.7% for IMPA at 7.5, 37.5 and 75.0 micrograms/mL, respectively. Corresponding values for PMPA (again, RSD) were 2.9, 1.1, and 1.0% at 7.5, 37.5 and 87.5 micrograms/mL, respectively, as before. Analysis accuracy was assessed by spiking actual neutralization samples with IMPA or PMPA. For IMPA, the seven spike levels used ranged from 20 to 220% of the IMPA background level, and the incremental change in the found IMPA level ranged from 86 to 99 % of the true spiking increment (R2 = 0.9987 for the linear regression). For PMPA, the five spike levels ranged from 10 to 150% of the matrix background level, and similarly, the accuracy obtained ranged from 95 to 97

  14. Ge4+ doped TiO2 for stoichiometric degradation of warfare agents.

    PubMed

    Stengl, Václav; Grygar, Tomáš Matys; Opluštil, František; Němec, Tomáš

    2012-08-15

    Germanium doped TiO(2) was prepared by homogeneous hydrolysis of aqueous solutions of GeCl(4) and TiOSO(4) with urea. The synthesized samples were characterized by X-ray diffraction, scanning electron microscopy, EDS analysis, specific surface area (BET) and porosity determination (BJH). Ge(4+) doping increases surface area and content of amorphous phase in prepared samples. These oxides were used in an experimental evaluation of their reactivity with chemical warfare agent, sulphur mustard, soman and agent VX. Ge(4+) doping worsens sulphur mustard degradation and improves soman and agent VX degradation. The best degree of removal (degradation), 100% of soman, 99% of agent VX and 95% of sulphur mustard, is achieved with sample with 2 wt.% of germanium.

  15. New method for retrospective detection of exposure to organophosphorus anticholinesterases: application to alleged sarin victims of Japanese terrorists.

    PubMed

    Polhuijs, M; Langenberg, J P; Benschop, H P

    1997-09-01

    With regard to detection of exposure to anticholinesterase, the presently used methods have the disadvantage that they cannot detect either low-level exposures with certainty or the structure of the agent and the extent of poisoning. In principle, organophosphate-inhibited butyrylcholinesterase in human plasma is the most persistent and abundant source for biomonitoring of exposure to organophosphate anticholinesterases. Fluoride ions reactivate the inhibited enzyme readily at pH 4, converting the organophosphate moiety into the corresponding phosphofluoridate. Subsequent quantitation of the latter product provides a reliable, highly sensitive and retrospective method for detection of exposure to, or handling of, organophosphates such as nerve agents and organophosphorus pesticides. We applied the new procedure to serum samples from victims of the Tokyo subway attack by the AUM Shinriyko sect and from an earlier incident at Matsumoto. In serum of 10 of 11 victims from the Tokyo incident and of 2 of the 7 samples from the Matsumoto incident, reactivation with fluoride ions yielded sarin concentrations in the range of 0.2-4.1 ng/ml serum. Evidently, these victims had been exposed to an organophosphate with the structure PriO(CH3)P(O)X, presumably with X = F (sarin). Several applications of the new procedure to establish nerve agent and/or organophosphate (OP) pesticide exposure can be envisaged, e.g., (i) in biomonitoring of exposure for health surveillance of those handling organophosphates, (ii) in cases of alleged exposure to nerve agents and/or OP pesticides in armed conflict situations or terrorist attacks, (iii) in medical treatment of intoxication, and (iv) in forensic cases against suspected terrorists that may have handled anticholinesterases.

  16. Using Nanotechnology to Detect Nerve Agents

    DTIC Science & Technology

    2011-01-01

    Analysis , Industrial Hygiene Branch, “Chemical Warfare Agent Health Risk Assessment Guidance Document,” 61, 2 April 2003, https://afkm.wpafb.af.mil... Bartling et al., “Enzyme-Kinetic Investiga- tion of Different Sarin Analogues Reacting with Hu- man Acetylcholinesterase and Butyrylcholinesterase

  17. 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.

  18. Quantitative Infrared Spectra of Vapor Phase Chemical Agents

    SciTech Connect

    Sharpe, Steven W.; Johnson, Timothy J.; Chu, P. M.; Kleimeyer, J.; Rowland, Brad

    2003-08-01

    Quantitative, moderately high resolution (0.1 cm-1) infrared spectra have been acquired for a number of nitrogen broadened (1 atm N2) vapor phase chemicals including: Sarin (GB), Soman (GD), Tabun (GA), Cyclosarin (GF), VX, Nitrogen Mustard (HN3), Sulfur Mustard (HD), and Lewisite (L). The spectra are acquired using a heated, flow-through White Cell1 of 5.6 meter optical path length. Each reported spectrum represents a statistical fit to Beer’s law, which allows for a rigorous calculation of uncertainty in the absorption coefficients. As part of an ongoing collaboration with the National Institute of Standards and Technology (NIST), cross-laboratory validation is a critical aspect of this work. In order to identify possible errors in the Dugway flow-through system, quantitative spectra of isopropyl alcohol from both NIST and Pacific Northwest National Laboratory (PNNL) are compared to similar data taken at Dugway proving Grounds (DPG).

  19. Quantitative infrared spectra of vapor phase chemical agents

    NASA Astrophysics Data System (ADS)

    Sharpe, Steven W.; Johnson, Timothy J.; Chu, Pamela M.; Kleimeyer, James; Rowland, Brad

    2003-08-01

    Quantitative, high resolution (0.1 cm-1) infrared spectra have been acquired for a number of pressure broadened (101.3 KPa N2), vapor phase chemicals including: Sarin (GB), Soman (GD), Tabun (GA), Cyclosarin (GF), VX, nitrogen mustard (HN3), sulfur mustard (HD) and Lewisite (L). The spectra are acquired using a heated, flow-through White cell of 5.6 m optical path length. Each reported spectrum represents a statistical fit to Beer's law, which allows for a rigorous calculation of uncertainty in the absorption coefficients. As part of an ongoing collaboration with the National Institute of Standards and Technology (NIST), cross-laboratory validation is a critical aspect of this work. In order to identify possible errors in the Dugway flow-through system, quantitative spectra of isopropyl alcohol from both NIST and Pacific Northwest National Laboratory (PNNL) are compared to similar data taken at the Dugway Proving Ground (DPG).

  20. Inhalation of the nerve gas sarin impairs ventilatory responses to hypercapnia and hypoxia in rats.

    PubMed

    Zhuang, Jianguo; Xu, Fadi; Campen, Matthew J; Zhang, Cancan; Pena-Philippides, Juan C; Sopori, Mohan L

    2008-11-01

    Sarin, a highly toxic nerve gas, is believed to cause bronchoconstriction and even death primarily through respiratory failure; however, the mechanism underlying the respiratory failure is not fully understood. The goals of this study were to ascertain whether sarin affects baseline ventilation (VE) and VE chemoreflexes as well as airway resistance and, if so, whether these changes are reversible. Four groups of F344 rats were exposed to vehicle (VEH) or sarin at 2.5, 3.5, and 4.0 mg h m(-3) (SL, SM, and SH, respectively). VE and VE responses to hypercapnia (7% CO2) or hypoxia (10% O2) were measured by plethysmography at 2 h and 1, 2, and 5 days after VEH or sarin exposure. Total pulmonary resistance (RL) also was measured in anesthetized VEH- and SH-exposed animals 2 h after exposure. Our results showed that within 2 h after exposure 11% of the SM- and 52% of the SH- exposed groups died. Although the SM and SH significantly decreased hypercapnic and hypoxic VE to similar levels (64 and 69%), SH induced greater respiratory impairment, characterized by lower baseline VE (30%; P<0.05), and total loss of the respiratory frequency response to hypercapnia and hypoxia. VE impairment recovered within 1-2 days after sarin exposure; interestingly, SH did not significantly affect baseline RL. Moreover, sarin induced body tremors that were unrelated to the changes in the VE responses. Thus, LC50 sarin causes a reversible impairment of VE that is not dependent on the sarin-induced body tremors and not associated with changes in RL.

  1. Inhalation of the nerve gas sarin impairs ventilatory responses to hypercapnia and hypoxia in rats

    SciTech Connect

    Zhuang Jianguo; Xu Fadi Campen, Matthew J.; Zhang Cancan; Pena-Philippides, Juan C.; Sopori, Mohan L.

    2008-11-01

    Sarin, a highly toxic nerve gas, is believed to cause bronchoconstriction and even death primarily through respiratory failure; however, the mechanism underlying the respiratory failure is not fully understood. The goals of this study were to ascertain whether sarin affects baseline ventilation (V{sub E}) and V{sub E} chemoreflexes as well as airway resistance and, if so, whether these changes are reversible. Four groups of F344 rats were exposed to vehicle (VEH) or sarin at 2.5, 3.5, and 4.0 mg h m{sup -3} (SL, SM, and SH, respectively). V{sub E} and V{sub E} responses to hypercapnia (7% CO{sub 2}) or hypoxia (10% O{sub 2}) were measured by plethysmography at 2 h and 1, 2, and 5 days after VEH or sarin exposure. Total pulmonary resistance (R{sub L}) also was measured in anesthetized VEH- and SH-exposed animals 2 h after exposure. Our results showed that within 2 h after exposure 11% of the SM- and 52% of the SH- exposed groups died. Although the SM and SH significantly decreased hypercapnic and hypoxic V{sub E} to similar levels (64 and 69%), SH induced greater respiratory impairment, characterized by lower baseline V{sub E} (30%; P < 0.05), and total loss of the respiratory frequency response to hypercapnia and hypoxia. V{sub E} impairment recovered within 1-2 days after sarin exposure; interestingly, SH did not significantly affect baseline R{sub L}. Moreover, sarin induced body tremors that were unrelated to the changes in the V{sub E} responses. Thus, LC{sub 50} sarin causes a reversible impairment of V{sub E} that is not dependent on the sarin-induced body tremors and not associated with changes in R{sub L}.

  2. Eighteen cases exposed to sarin in Matsumoto, Japan.

    PubMed

    Suzuki, J; Kohno, T; Tsukagosi, M; Furuhata, T; Yamazaki, K

    1997-07-01

    Forty-six patients who were exposed to sarin consulted our hospital because of darkness of vision, and ocular pain, vomiting, dyspnea and headaches on June 27 and 28, 1994. Eighteen patients were admitted and 4 of them were in the critical state. There were 6 features: 1) depression of plasma cholinesterase activity (17 of 18 patients, 94%), 2) hypokalemia (4/18, 22%), 3) depression of triglyceride (12/18, 67%), 4) hypocapnia (5/17, 29%), 5) partial pressure of oxygen (PaO2) <80 mmHg, or requirement of O2 inhalation (15/18, 83%), 6) white blood cells (WBC) >9,000 per mm3 (13/18, 72%). Seventeen patients were discharged from hospital, but one patient is still suffering from akinetic mutism after two years.

  3. A Comprehensive Evaluation of the Efficacy of Leading Oxime Therapies in Guinea Pigs Exposed to Organophosphorus Chemical Warfare Agents or Pesticides

    PubMed Central

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

    2014-01-01

    The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. PMID:25448441

  4. Rapid screening of chemical warfare nerve agent metabolites in urine by atmospheric solids analysis probe-mass spectroscopy (ASAP-MS).

    PubMed

    Zydel, Frank; Smith, J Richard; Pagnotti, Vincent S; Lawrence, Richard J; McEwen, Charles N; Capacio, Benedict R

    2012-01-01

    Exposures to organophosphorus nerve agents (OPNA) remain a threat to both civilian and military populations. Verification of exposures typically involves determinations of urinary metabolites or adducted proteins in blood. Urinary alkyl methylphosphonic acid metabolites resulting from hydrolysis of OPNAs provide a convenient marker for OPNA exposure. In a military setting, urine is a relatively easy sample to obtain, and a rapid turnaround for analyses for the identification of metabolites is critical for field commanders. Timely information on use and identity of OPNAs facilitates decisions regarding employment of personal protective equipment and additional strategies to mitigate additional exposure(s). Herein, we report the development of a rapid mass spectrometric (MS) method to identify OPNA metabolites directly from urine with no sample preparation. Synthetic urine spiked with multiple OPNA metabolites was analyzed using an atmospheric solids analysis probe (ASAP) attached to a high resolution mass spectrometer. The alkyl methylphosphonic acid metabolites resulting from hydrolysis of sarin, cyclosarin, soman, and Russian VX were clearly detectable down to a level of 1.0 ng/ml. The ability to rapidly detect OPNA metabolites in unprepared urine allows for the design of a field-deployable device that could afford field personnel the ability to rapidly screen individuals for specific OPNA exposure. In addition, this provides proof-of-concept evidence that a fieldable ASAP-MS device could afford personnel the ability to rapidly detect OPNAs on skin, equipment, and other porous surfaces. Published 2012. This article is a US Government work and is in the public domain in the USA.

  5. A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides.

    PubMed

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

    2014-12-15

    The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl₂, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.

  6. Lessons learned from the Syrian sarin attack: evaluation of a clinical syndrome through social media.

    PubMed

    Rosman, Yossi; Eisenkraft, Arik; Milk, Nadav; Shiyovich, Arthur; Ophir, Nimrod; Shrot, Shai; Kreiss, Yitshak; Kassirer, Michael

    2014-05-06

    On the night of 21 August 2013, sarin was dispersed in the eastern outskirts of Damascus, killing 1400 civilians and severely affecting thousands more. This article aims to delineate the clinical presentation and management of a mass casualty event caused by a nerve agent as shown in the social media. Authors searched YouTube for videos uploaded of this attack and identified 210 videos. Of these, 67 met inclusion criteria and were evaluated in the final analysis.These videos displayed 130 casualties; 119 (91.5%) of which were defined as moderately injured or worse. The most common clinical signs were dyspnea (53.0%), diaphoresis (48.5%), and loss of consciousness (40.7%). Important findings included a severe shortage of supporting measures and lack of antidotal autoinjectors. Decontamination, documented in 25% of the videos, was done in an inefficient manner. Protective gear was not noticed, except for sporadic use of latex gloves and surgical masks.This is believed to be the first time that social media was used to evaluate clinical data and management protocols to better prepare against future possible events.

  7. 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.

  8. Determination of Parameters for Development of a Physiologically Based Model for the Toxicokinetics of C(+)P(+)-Soman

    DTIC Science & Technology

    1993-06-01

    studies performed in rat, guinea pig, and marmoset , the biochemical and toxicological implications of the chirality of C(±)P(±)-soman have been taken...h in the rat, guinea pig, and marmoset , respectively (2-4). Such levels persist in the guinea pig for approximately 4 h after subcutaneous (s.c...blood flow distribution at 10 min after administration S~/ .. Parameters for modelling of C(±)P(±)-soman toxicokinetics 41 ofC(±)P(±)-soman. Some trends

  9. Disruption of mice sleep stages induced by low doses of organophosphorus compound soman.

    PubMed

    Crouzier, David; Le Crom, Valerie Baille; Four, Elise; Lallement, Guy; Testylier, Guy

    2004-06-01

    We have explored during 7 days, EEG spectral response and sleep pattern of mice after a mild intoxication with soman. Using an automatic staging method, we have quantified the sleep stage of the mice to identify disruptions of the sleep pattern. The 50 microg/kg dose of soman produced several effects during several time windows after intoxication. A first decrease followed by an increase of theta energy, a disturbance of slow wave sleep during 5 days and an increase of the REM sleep during the first and second day after intoxication. During the first 6h, we have observed some effects which were not consistent with a muscarinic activation and might have involved GABA-ergic system. After this early period, the observed effects were in accordance with a muscarinic activation. We observed an increase of energy in the EEG theta band during 3 days after soman injection and an increase of slow wave sleep during the second to the fifth day after soman injection.

  10. Effects of injectable anticholinergic drugs on soman-induced lethality and convulsant/subconvulsant activity

    SciTech Connect

    Harris, L.W.; Anderson, D.R.; Lennox, W.J.; Bowersox, S.L.; Anders, J.C.

    1993-05-13

    FDA approved, injectable preparations of candidate compounds BENZTROPINE (BZT), 1.0 mg/ml; biperiden (BIP), 5.0 mg/ml; dicyclomine (DCL), 10 mg/ml; 1-hyoscyamine (HYO), 0.5 mg/ml; orphenadrine (ORP), 30 mg/ml; scopolamine (SCP), 1.0 mg/ml were tested in parallel with diazepam (DZ, the standard) in male guinea pigs against ongoing soman induced convulsive (CV)/sub-CV activity. Three trained graders concurrently assigned CV/sub-CV scores (12 - convulsions; 0 normal) to each animal. Animals received (im) pyridostigmine (PYR; 26 ug/kg) 30 min before soman (56 ug/kg; 2 LD50), atropine (2 mg/kg) admixed with 2-PAM (25 mg/kg) at one min after soman, and the candidate drug preparation at 5.67 min post soman, a time when CV activity is assured. BIP and SCP demonstrated efficacy over dosage ranges between 10 and 0.3 and 1.0 and 0.13 mg/kg, respectively, while the other preparations were less effective at their respective maximum dosages. At optimal dosages of SCP (0.5 mg/kg) and BIP (10 mg/kg), the CV/sub-CV scores were significantly lower (p < 0.05) than those of DZ.

  11. The Interference of Stress on Physostigmine Pretreatment Against Soman Intoxication in Guinea Pigs

    DTIC Science & Technology

    2002-01-01

    1 THE INTERFERENCE OF STRESS ON PHYSOSTIGMINE PRETREATMENT AGAINST SOMAN INTOXICATION IN GUINEA PIGS Ingrid H.C.H.M. Philippens , Marloes J.A...1985) Fund. Appl. Toxicol. 5: S225-S231. 6 Harris, L.W. et al. (1984) Drug Chem. Toxicol. 7: 605-624. 7 Solana , R.P. et al. (1990) Fundam. Appl

  12. Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

    PubMed Central

    Apland, James P.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Green, Carol E.; Swezey, Robert; Yang, Chun; Qashu, Felicia

    2013-01-01

    Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood–brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound. PMID:23042954

  13. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  14. The organophosphate sarin, at low concentrations, inhibits the evoked release of GABA in rat hippocampal slices.

    PubMed

    Chebabo, S R; Santos, M D; Albuquerque, E X

    1999-12-01

    In the present study, the whole-cell mode of the patch-clamp technique was applied to neurons of the CA1 pyramidal layer of rat hippocampal slices to investigate the effects of the organophosphate (OP) sarin on field stimulation-evoked and on tetrodotoxin (TTX)-insensitive postsynaptic currents (PSCs) mediated by activation of type A gamma-aminobutyric acid (GABA) receptors or AMPA-type glutamate receptors. At 0.3-1 nM, sarin reduced the amplitude of GABA-mediated PSCs and had no effect on the amplitude of glutamatergic PSCs evoked by field stimulation of neurons synaptically connected to the neuron under study. The effect of sarin on evoked GABAergic PSCs was unrelated to cholinesterase inhibition, was partially reversed upon washing of the neurons with sarin-free external solution, and was mediated by a direct interaction of the OP with muscarinic acetylcholine receptors present on presynaptic GABAergic neurons. Sarin had no effect on the amplitude or kinetics of GABA- or glutamate-mediated miniature postsynaptic currents (MPSCs) recorded in the presence of the Na+-channel blocker TTX (300 nM), indicating that the OP does not interact with GABA(A) or glutamate receptors. Further, sarin did not alter the frequency of GABAergic or glutamatergic MPSCs, a finding that led to the conclusion that this OP does not affect the TTX-insensitive release of neurotransmitters. A selective reduction by sarin of the action potential-dependent release of GABA in the hippocampus can account for the occurrence of seizures in intoxicated subjects.

  15. Energetics and Dynamics of the Reactions of O(3P) with Dimethyl Methylphosphonate and Sarin

    NASA Astrophysics Data System (ADS)

    Conforti, Patrick F.; Braunstein, Matthew; Dodd, James A.

    2009-10-01

    Electronic structure and molecular dynamics calculations were performed on the reaction systems O(3P) + sarin and O(3P) + dimethyl methylphosphonate (DMMP), a sarin simulant. Transition state geometries, energies, and heats of reaction for the major reaction pathways were determined at several levels of theory, including AM1, B3LYP/6-311+G(d,p), and CBS-QB3. The major reaction pathways for both systems are similar and include H-atom abstraction, H-atom elimination, and methyl elimination, in rough order from low to high energy. The H-atom abstraction channels have fairly low barriers (˜10 kcal mol-1) and are close to thermoneutral, while the other channels have relatively high energy barriers (>40 kcal mol-1) and a wide range of reaction enthalpies. We have also found a two-step pathway leading to methyl elimination through O-atom attack on the phosphorus atom for DMMP and sarin. For sarin, the two-step methyl elimination pathway is significantly lower in energy than the single-step pathway. We also present results of O(3P) + sarin and O(3P) + DMMP reaction cross sections over a broad range of collision energies (2-10 km s-1 collision velocities) obtained using the direct dynamics method with an AM1 semiempirical potential. These excitation functions are intended as an approximate guide to future hyperthermal measurements, which to our knowledge have not yet examined either of these systems. The reaction barriers, reaction enthalpies, transition state structures, and excitation functions are generally similar for DMMP and sarin, with some moderate differences for methyl elimination energetics, which indicates DMMP will likely be a good substitute for sarin in many O(3P) chemical investigations.

  16. Energetics and dynamics of the reactions of O(3P) with dimethyl methylphosphonate and sarin.

    PubMed

    Conforti, Patrick F; Braunstein, Matthew; Dodd, James A

    2009-12-10

    Electronic structure and molecular dynamics calculations were performed on the reaction systems O((3)P) + sarin and O((3)P) + dimethyl methylphosphonate (DMMP), a sarin simulant. Transition state geometries, energies, and heats of reaction for the major reaction pathways were determined at several levels of theory, including AM1, B3LYP/6-311+G(d,p), and CBS-QB3. The major reaction pathways for both systems are similar and include H-atom abstraction, H-atom elimination, and methyl elimination, in rough order from low to high energy. The H-atom abstraction channels have fairly low barriers (approximately 10 kcal mol(-1)) and are close to thermoneutral, while the other channels have relatively high energy barriers (>40 kcal mol(-1)) and a wide range of reaction enthalpies. We have also found a two-step pathway leading to methyl elimination through O-atom attack on the phosphorus atom for DMMP and sarin. For sarin, the two-step methyl elimination pathway is significantly lower in energy than the single-step pathway. We also present results of O((3)P) + sarin and O((3)P) + DMMP reaction cross sections over a broad range of collision energies (2-10 km s(-1) collision velocities) obtained using the direct dynamics method with an AM1 semiempirical potential. These excitation functions are intended as an approximate guide to future hyperthermal measurements, which to our knowledge have not yet examined either of these systems. The reaction barriers, reaction enthalpies, transition state structures, and excitation functions are generally similar for DMMP and sarin, with some moderate differences for methyl elimination energetics, which indicates DMMP will likely be a good substitute for sarin in many O((3)P) chemical investigations.

  17. Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE).

    PubMed

    Karade, Hitendra N; Valiveti, Aditya Kapil; Acharya, Jyotiranjan; Kaushik, Mahabir Parshad

    2014-05-01

    A series of bis-quaternary pyridinium derivatives 3a-3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE.

  18. Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX.

    PubMed

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

    2016-11-25

    Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.

  19. 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.

  20. Quantitation of fluoride ion released sarin in red blood cell samples by gas chromatography-chemical ionization mass spectrometry using isotope dilution and large-volume injection.

    PubMed

    Jakubowski, E M; McGuire, J M; Evans, R A; Edwards, J L; Hulet, S W; Benton, B J; Forster, J S; Burnett, D C; Muse, W T; Matson, K; Crouse, C L; Mioduszewski, R J; Thomson, S A

    2004-01-01

    A new method for measuring fluoride ion released isopropyl methylphosphonofluoridate (sarin, GB) in the red blood cell fraction was developed that utilizes an autoinjector, a large-volume injector port (LVI), positive ion ammonia chemical ionization detection in the SIM mode, and a deuterated stable isotope internal standard. This method was applied to red blood cell (RBC) and plasma ethyl acetate extracts from spiked human and animal whole blood samples and from whole blood of minipigs, guinea pigs, and rats exposed by whole-body sarin inhalation. Evidence of nerve agent exposure was detected in plasma and red blood cells at low levels of exposure. The linear method range of quantitation was 10-1000 pg on-column with a detection limit of approximately 2-pg on-column. In the course of method development, several conditions were optimized for the LVI, including type of injector insert, injection volume, initial temperature, pressure, and flow rate. RBC fractions had advantages over the plasma with respect to assessing nerve agent exposure using the fluoride ion method especially in samples with low serum butyrylcholinesterase activity.

  1. Review: The occurrence, distribution and mechanism of diisopropyl methylphosphonate (DIMP) formation in the production degradation and demilitarization of sarin

    SciTech Connect

    Luman, F.M.

    1984-05-21

    The presence of (diisopropyl methylphosphonate) with respect to sarin manufacture and degradation is presented in this paper. Much evidence exists to support the presence of DIMP during the manufacturing process of sarin. Similary, DIMP is present in stored solution of GB. Primary literature sources do not support the production of DIMP during the demilitarization process. (Author).

  2. The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

    SciTech Connect

    Schultz, M.K.; Wright, L.K.M.; Stone, M.F.; Schwartz, J.E.; Kelley, N.R.; Moffett, M.C.; Lee, R.B.; Lumley, L.A.

    2012-03-15

    Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA{sub A}) receptors. However, seizure activity itself causes the endocytosis of GABA{sub A} receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD{sub 50}; 132 μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was

  3. Reactions of sulphur mustard and sarin on V 1.02 O 2.98 nanotubes.

    PubMed

    Mahato, T H; Prasad, G K; Singh, Beer; Srivastava, A R; Ganesan, K; Acharya, J; Vijayaraghavan, R

    2009-07-30

    Reactions of sulphur mustard and sarin were studied on the surface of V(1.02)O(2.98) nanotubes by gas chromatography and gas chromatography-mass spectrometry techniques. The V(1.02)O(2.98) nanotube samples were made by using hydrothermal method and characterized by scanning electron microscopy, nitrogen adsorption, X-ray diffractometry and thermogravimetry. Later, they were exposed to sulphur mustard and sarin separately at ambient temperature (30+/-2 degrees C). The data explored the formation of sulphoxide of sulphur mustard, thiodiglycol for sulphur mustard and isopropyl methyl phosphonic acid for sarin on V(1.02)O(2.98) nanotubes illustrating the role of oxidation and hydrolysis reactions in the decontamination.

  4. Synergism Between Anticholinergic and Oxime Treatments Against Sarin-Induced Ocular Insult in Rats.

    PubMed

    Gore, A; Brandeis, R; Egoz, I; Turetz, J; Nili, U; Grauer, E; Bloch-Shilderman, E

    2015-08-01

    Eye exposure to the extremely toxic organophosphorus sarin results in long-term miosis and visual impairment. As current treatment using atropine or homatropine eye drops may lead to considerable visual side effects, alternative combined treatments of intramuscular (im) oximes (16.8 µmol/kg, im) with atropine (0.5 mg/kg, im) or with the short acting antimuscarinic tropicamide (0.5%; w/v) eye drops were thus evaluated. The combined treatments efficacy following topical exposure to sarin (1 µg) was assessed by measuring pupil width and light reflex using an infra-red based digital photographic system. Results showed that the combined treatment of various oximes with atropine or with topical tropicamide eye drops rapidly reversed the sarin-induced miosis and presented a long-term improvement of 67-98% (oxime+tropicamide) or 84-109% (oxime+atropine) in pupil widening as early as 10-min following treatment. This recovery was shown to persist for at least 8-h following exposure. All combined treatments facilitated the ability of the iris to contract following sarin insult as tested by a light reflex response.Our findings emphasize the high efficacy of im oxime treatment combined with either atropine im or tropicamide eye drops in counteracting sarin-induced ocular insult. Therefore, in a mass casualty scenario the systemic combined treatment may be sufficient to ameliorate sarin-induced ocular insult with no need for additional, topical anticholinergic treatment at least in the initial stage of intoxication. For very mild casualties, who are unlikely to receive im treatment, the combined oxime (im) with topical tropicamide treatment may be sufficient in ameliorating the ocular insult.

  5. Purified recombinant organophosphorus acid anhydrase protects mice against soman. (Reannouncement with new availability information)

    SciTech Connect

    Broomfield, C.A.

    1992-12-31

    Since pharmacologic treatments of organophosphorus anticholinesterases (OPs) are nearing their practical limit other types of treatment are being sought. One approach is the prophylactic administration of scavengers that will detoxify OPs before they reach their critical target site. Using mice that were sensitized to OPs by depletion of their serum carboxylesterase with cresylbenzodioxaphosphorin oxide (CBDP), we have shown that animals pretreated intravenously with a purified organophosphorus acid anhydride hydrolase (parathionase) (0.10 mg per g body wt.) are not measurably affected by up to 34.4 microgram soman per kg, a dose more than double that which is lethal to untreated animals. This result indicates that this approach is worthy of exploration and development for protecting military personnel and agricultural workers against OP intoxication. Scavengers, pretreatment, soman, OP intoxication, mice.

  6. Cholinesterase inhibitor soman increases inositol trisphosphate in rat brain. (Reannouncement with new availability information)

    SciTech Connect

    Mobley, P.L.

    1990-12-31

    Studies were conducted to determine the effect of the cholinesterase inhibitor soman on the amount of inositol trisphosphate in the neocortex, striatum, cerebellum, and medulla-pons regions of rat brain in vivo. The studies indicate that treatment with soman increase inositol trisphosphate in the neocortex and striatum, but not in the cerebellum or medulla-pons region. In the neocortex the most pronounced increases were observed in animals with severe poisoning symptoms; however, inositol trisphophate was also found to be elevated in animals with only mild poisoning symptoms. A variety of evidence suggests that the receptor-mediated hydrolysis of phosphatidyl inositol results in the formation of inositol trisphosphate (IP3) and diacylglycerol, both of which function as intracellular signal messengers, and that this mechanism represents a major signal transduction system through which extracellular signals can influence intracellular events.

  7. Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged With Soman

    DTIC Science & Technology

    2004-01-01

    diazepam and biperiden studied in this laboratory in a similar model (Capacio et al., 2001, 2003). This apparent volume of distribution reflects the...for the anticonvulsant biperiden determined under similar conditions (Capacio et al., 2003). In those studies biperiden demonstrated extensive... biperiden in guinea pigs challenged with soman. Drug Chem. Toxicol. 26(1):1-13. Dirnhuber, P., French, M. C., Green, D. M., Leadbeater, L., Stratton, J. A

  8. Efficacy of 2-APB (2-Aminoethyldiphenylborate) in Rescuing Neurons After Soman-Induced Brain Injury

    DTIC Science & Technology

    2005-08-01

    soman intoxication included repetitive chewing , facial and forepaw clonus, motor stereotypy, and wet- dog shakes. Overt motor convulsions were...and secured by dental cement. On the morning of the fifth or sixth day following surgeries, electrode-implanted animals were connected to an ECoG...dimethyl sulphoxide (DMSO) for the dog , pig, rat and rabbit. Toxicology. 1975; 3:143-69. Olney JW, Labruyere J, Price MT. Pathological changes

  9. Evaluating the Anti-Seizure Efficacy of Novel Adenosine Treatment Regimens in a Soman Rat Model

    DTIC Science & Technology

    2015-06-01

    inhibition of neuronal activity and neurotransmitter release (Cunha 2005; Lynge et al. 2000; Svenningsson et al. 1997). Normal metabolic activity...without adenosine treatment. This group received 10 µl multisol (a vehicle containing 48.5% H2O, 40% propylene glycol, 10% ethanol , and 1.5% benzyl... alcohol ) over 3 minutes via ICV injection into the cannulae 1 minute after soman exposure. A baseline treatment group of rats received CPA at a dose

  10. A comparison of the potency of a novel bispyridinium oxime K203 and currently available oximes (obidoxime, HI-6) to counteract the acute neurotoxicity of sarin in rats.

    PubMed

    Kassa, Jiri; Misik, Jan; Karasova, Jana Zdarova

    2012-11-01

    The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.

  11. Anticonvulsant actions of anticholinergic drugs in soman poisoning. (Reannouncement with new availability information)

    SciTech Connect

    Capacio, B.R.; Shih, T.M.

    1991-12-31

    The acute effects of the organophosphorus cholinesterase inhibitor soman include hypersecretions, convulsions, and death. The purpose of this study was to evaluate the anticholinergic compounds, aprophen, atropine sulfate, azaprophen, benactyzine, benztropine, biperiden, scopolamine HBr, and trihexyphenidyl for their efficacy in preventing soman-induced hypersecretions and convulsions. Male rats were injected with the oxime HI-6 (125 mg/kg, i.p.), to increase survival time, along with various intramuscular doses of the anticholinergics 30 min prior to a dose of soman that produced 100% convulsions. Signs of intoxication as well as the time-to-onset of convulsions were observed. The calculated anticonvulsant median effective dose values were 0.18, 0.33, 0.36, 0.55, 2.17, 2.30, 2.45, and 31.09 micro mol per kilogram for scopolamine HBr, biperiden, trihexyphenidy, benactyzine, benztropine, azaprophen, aprophen, and atropine sulfate, respectively. The same rank order by potency for inhibition of hypersecretions among these compounds was observed.

  12. Evaluating of the Anticonvulsant Gabapentin against Nerve Agent-Induced Seizures in a Guinea Pig Model

    DTIC Science & Technology

    2010-07-01

    Neuropharmacological mechanisms of nerve agent-induced seizures and neuropathology. Neuroscience and Biobehavioral Reviews , 1997, 21:559-579...compound soman: pharmacological mechanisms. Neuroscience and Biobehavioral Reviews , 1991, 15:349-362. Shih, T.-M., McDonough, J.H., Koplovitz, I

  13. Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC50 for whole-body (10 and 60 min) exposures.

    PubMed

    Wright, Linnzi K M; Lumley, Lucille A; Lee, Robyn B; Taylor, James T; Miller, Dennis B; Muse, William T; Emm, Edward J; Whalley, Christopher E

    2017-04-01

    Chemical warfare nerve agents (CWNA) inhibit acetylcholinesterase and are among the most lethal chemicals known to man. Children are predicted to be vulnerable to CWNA exposure because of their smaller body masses, higher ventilation rates and immature central nervous systems. While a handful of studies on the effects of CWNA in younger animals have been published, exposure routes relevant to battlefield or terrorist situations (i.e. inhalation for sarin) were not used. Thus, we estimated the 24 h LC50 for whole-body (10 and 60 min) exposure to sarin using a stagewise, adaptive dose design. Specifically, male and female Sprague-Dawley rats were exposed to a range of sarin concentrations (6.2-44.0 or 1.6-12.5 mg/m³) for either 10 or 60 min, respectively, at six different times during their development (postnatal day [PND] 7, 14, 21, 28, 42 and 70). For male and female rats, the lowest LC50 values were observed for PND 14 and the highest LC50 values for PND 28. Sex differences were observed only for PND 42 for the 10 min exposures and PND 21 and 70 for the 60 min exposures. Thus, younger rats (PND 14) were more susceptible than older rats (PND 70) to the lethal effects of whole-body exposure to sarin, while adolescent (PND 28) rats were the least susceptible and sex differences were minimal. These results underscore the importance of controlling for the age of the animal in research on the toxic effects associated with CWNA exposure.

  14. Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.

    PubMed

    Peña-Philippides, Juan Carlos; Razani-Boroujerdi, Seddigheh; Singh, Shashi P; Langley, Raymond J; Mishra, Neerad C; Henderson, Rogene F; Sopori, Mohan L

    2007-05-01

    Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.

  15. In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers.

    PubMed

    Acharya, Jyotiranjan; Dubey, Devendra Kumar; Srivastava, Ashish Kumar; Raza, Syed Kalbey

    2011-02-01

    A series of bis-pyridinium oximes connected by xylene linkers were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by nerve agent sarin and the data were compared with 2-PAM and obidoxime. Among the synthesized compounds, N,N'-p-xylene-bis-[(2,2'-hydroxyiminomethyl)pyridinium] dibromide (3c) was found to be the most potent reactivator for hAChE inhibited by sarin. The oxime 3c exhibited 45% regeneration of inhibited hAChE, in comparison to 34% and 24% regeneration by 2-PAM and obidoxime, respectively, at a concentration of 10(-3) M within 10 min. The higher reactivation efficacies of these oximes were attributed to their acid dissociation constants (pKa). The pKa values of all the oximes were determined spectrophotometrically and correlated with their observed reactivation potential. This method involving the in vitro reactivation of inhibited hAChE may be useful for the screening of new oximes as reactivators.

  16. No Green-On-Blue Against the Reds?: Organizational Strategies Behind Insider Attacks in Afghanistan

    DTIC Science & Technology

    2013-06-01

    guidance provided by Dr. James Kiras. His judgment and experience were critical in converting my original vague idea “to write something about Green...the Soviets killed up to 57 also indicated by the indiscriminate Soviet use of chemical weapons, to include the nerve agents Sarin and Soman.48

  17. Post-exposure treatment with nasal atropine methyl bromide protects against microinstillation inhalation exposure to sarin in guinea pigs

    SciTech Connect

    Che, Magnus M.; Conti, Michele; Boylan, Megan; Sabnekar, Praveena; Rezk, Peter; Sciuto, Alfred M.; Doctor, Bhupendra P.; Nambiar, Madhusoodana P.

    2009-09-15

    We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m{sup 3} sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarin exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.

  18. Post-exposure treatment with nasal atropine methyl bromide protects against microinstillation inhalation exposure to sarin in guinea pigs.

    PubMed

    Che, Magnus M; Conti, Michele; Chanda, Soma; Boylan, Megan; Sabnekar, Praveena; Rezk, Peter; Amari, Ethery; Sciuto, Alfred M; Gordon, Richard K; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2009-09-15

    We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m(3) sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarin exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.

  19. Mechanisms of Organophosphorus (OP) Injury: Sarin-Induced Hippocampal Gene Expression Changes and Pathway Perturbation

    DTIC Science & Technology

    2012-01-01

    nigra neurons from Parkinson disease patients. Ddit4 can be induced by DNA alkylation, ionizing radiation, amyloid beta-peptide and hypoxia. b...related to dopaminergic dysfunction, including Parkinson disease , schizophrenia, and manic depression. Nr4a2 is rapidly and transiently expressed...Neurodegenerative Diseases in Hippocampus Following Sarin Treatment .........32 viii

  20. Insomnia as a sequela of sarin toxicity several years after exposure in Tokyo subway trains.

    PubMed

    Kawada, Tomoyuki; Katsumata, Masao; Suzuki, Hiroko; Li, Qing; Inagaki, Hirofumi; Nakadai, Ari; Shimizu, Takako; Hirata, Kimiko; Hirata, Yukiyo

    2005-06-01

    More than 5,000 passengers on Tokyo subway trains were injured with toxic chemicals including the nerve gas "sarin" on March 20, 1995. The purpose of this study was to identify the effect of sarin exposure on insomnia in a cross-sectional study. A self-administered questionnaire concerning sleep-related items was distributed to victims of sarin exposure in October and November, 2003. Questionnaires were completed by 161 of the 163 participants (98.8%), who were selected from 1,500 subjects. Among them, the authors selected 75 women 30 to 69 years of age. Control participants were collected from inhabitants living in Maebachi City, Gunma Prefecture, Japan. For the younger exposed group (under 50 yr. of age), percentages of poor sleep, difficulty falling asleep, intermittent awakening, early morning awakening, a feeling of light overnight sleep, and insomnia were significantly higher than those for the control group. In contrast, the older exposed group (ages 50 to 69 years) had significantly higher prevalence of poor sleep, a feeling of light overnight sleep, and early morning awakening for the exposed group when compared with the control group. The high prevalence of insomnia and insomnia-related factors for victims especially under 50 years of age suggests a need for research on sleep quality after sarin exposure. Although posttraumatic stress disorder is assumed to be a psychological effect of exposure to a toxic substance, a cause-and-effect relationship has not been established.

  1. Validation of CryoSat-2 SARIn Performance over Arctic Sea Ice

    NASA Astrophysics Data System (ADS)

    Di Bella, A.; Skourup, H.; Bouffard, J.; Parrinello, T.

    2016-08-01

    The main objective of this work is to validate CryoSat-2 (CS2) SARIn performance over sea ice by use of airborne laser altimetry data obtained during the CryoVEx 2012 campaign. A study by [1] has shown that the extra information from the CS2 SARIn mode increases the number of valid sea surface height estimates which are usually discarded in the SAR mode due to snagging of the radar signal. As the number of valid detected leads increases, the uncertainty of the freeboard heights decreases.In this study, the snow freeboard heights estimated using data from the airborne laser scanner are used to validate the sea ice freeboard obtained by processing CS2 SARIn level 1b waveforms. The possible reduction in the random freeboard uncertainty is investigated comparing two scenarios, i.e. a SAR-like and a SARIn acquisition.It is observed that using the extra phase information, CS2 is able to detect leads up to 2370 m off-nadir. A reduction in the the total random freeboard uncertainty of ˜40% is observed by taking advantage of the CS2 interferometric capabilities, which enable to include ˜35% of the wave-forms discarded in the SAR-like scenario.

  2. Behavioral evaluation of rats following low-level inhalation exposure to sarin.

    PubMed

    Genovese, Raymond F; Mioduszewski, Robert J; Benton, Bernard J; Pare, Matthew A; Cooksey, Jessica A

    2009-02-01

    We evaluated the effects, in rats, of single and multiple low-level inhalation exposures to sarin. Rats were trained on a variable-interval, 56 s (VI56) schedule of food reinforcement and then exposed to sarin vapor (1.7-4.0 mg/m(3) x 60 min) or air control. The exposures did not produce clinical signs of toxicity other than miosis. Subsequently, performance on the VI56 and acquisition of a radial-arm maze spatial memory task was evaluated over approximately 11 weeks. Single exposures did not affect performance on the VI56 and had little effect on acquisition of the radial-arm maze task. Multiple exposures (4.0 mg/m(3) x 60 min/day x 3) disrupted performance on the VI56 schedule during the initial post-exposure sessions. The disruption, however, resolved after several days. Multiple exposures also produced a deficit on the radial-arm maze task in that sarin-exposed rats tended to take it longer to complete the maze and to make more errors. The deficit, however, resolved during the first three weeks of acquisition. These results demonstrate that in rats, inhalation exposure to sarin at levels below those causing overt signs of clinical toxicity can produce cognitive and performance deficits. Furthermore, the observed deficits do not appear to be persistent.

  3. Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus. Review of current data and perspectives.

    PubMed

    Dorandeu, Frederic; Barbier, Laure; Dhote, Franck; Testylier, Guy; Carpentier, Pierre

    2013-03-25

    Organophosphorus nerve agents (NA), potent irreversible cholinesterase inhibitors, could induce severe seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Despite the lack of data in the case of NA, clinical evidences suggest that SE survivors could suffer from neurological/cognitive deficits and impairments such as spontaneous recurrent seizures (epilepsy) after a latent period of epileptogenesis. It is beyond doubt that an effective and quick management of the initial seizures and prevention of SRBD are critical to prevent these long-term consequences, explaining why most experimental data are focusing on the 5-40min post-exposure time frame. However, in field conditions, treatment may be delayed and with the exception of NMDA receptor antagonists, currently no drug provides protection (against lethality, seizures, SRBD and neurological consequences) when seizures are left unabated for one hour or more. Ketamine (KET) is the only NMDA antagonist licensed as an injectable drug in different countries and remains an anesthetic of choice in some difficult field conditions. In this short review paper, after a presentation of some of the key points of the pathophysiology of NA-induced SE and a quick survey of the potential therapeutic avenues in the context of delayed treatment of NA-induced SE, we will review the recent data we obtained showing that KET, in combination with atropine sulfate (AS), with or without a benzodiazepine, considerably reduces soman-induced neuroinflammation, provides neuroprotection, histologically and functionally, and also positively modify soman-induced changes in brain metabolism. Finally, we will also mention some results from safety studies including those bringing evidence that, at difference with MK-801, KET does not impair thermoregulation and even seems to reduce AS-induced heat stress. All in all, KET, in combination, appears a good candidate for the out-of-hospital treatment of severe NA-induced SE.

  4. Rapid fluorophosphate nerve agent detection with lanthanides.

    PubMed

    Menzel, E Roland; Menzel, Laird W; Schwierking, Jake R

    2005-08-15

    We explore the detection of vapors of diisopropylfluorophosphate, a model compound for nerve agents such as Sarin, by means of photoluminescence quenching of filter paper impregnated with sensitized complexes of lanthanides, involving thenoyltrifluoroacetone and 1,10-phenanthroline as sensitizing ligands. We find that the presence of the fluorophosphate vapor is detectable in as little as 2s, by simple visual observation under illumination with a hand-held low intensity ultraviolet lamp.

  5. Coastal Sea Level From CRYOSAT-2 SAR and SAR-In Altimetry

    NASA Astrophysics Data System (ADS)

    Andersen, O. B.; Abulaitijiang, A.; Knudsen, P.; Stenseng, L.

    2014-12-01

    Cryosat-2 offers the first ever possibility to perform coastal altimetric studies using bor SAR-altimetry and SAR-In altimetry. With this technological leap forward Cryosat-2 is now able to observe sea level in very small water bodies and also to provide coastal sea level very close to the shore. We perform an investigation into the retrieval of sea surface height around Denmark and Greenland. These regions have been chosen as the coastal regions around Denmark falls within the SAR mask and the coastal regions of Greenland falls in under the SAR-in mask employed on Cryosat-2. SAR-in was mainly used in coastal regions of Greenland because of its huge topographic changes as Cryosat-2 is designed to map the margins of the ice-sheet. The coastal region around Denmark is a test region of the EU FP7 sponsored project LOTUS esablishing SAR altimetry product in preparation for Sentinel-3. With the increased spatial resolution of Cryosat-2 SAR we provide valuable sea level observations within the Straits around Denmark which are crucial to constrain the waterflow in and out of the Baltic Sea. The investigation of SAR-in data in Greenland adds an entire new dimension to coastal altimetry. An amazing result of the investigation is the ability of Cryosat-2 to detect and recover sea level even though the coast (sealevel) is up to 15 km away from the nadir location of the satellite. This ability of capture and use returns from outside the main (-3Db) loop in theory enables Cryosat-2 SAR-in to map sea level height of fjords more frequently than the 369 days repeat.

  6. Low concentrations of pyridostigmine prevent soman-induced inhibition of GABAergic transmission in the central nervous system: involvement of muscarinic receptors.

    PubMed

    Santos, Máriton D; Pereira, Edna F R; Aracava, Yasco; Castro, Newton G; Fawcett, William P; Randall, William R; Albuquerque, Edson X

    2003-01-01

    This study was designed to investigate the effects of the cholinesterase inhibitors soman and pyridostigmine bromide (PB) on synaptic transmission in the CA1 field of rat hippocampal slices. Soman (1-100 nM, 10-15 min) decreased the amplitude of GABAergic postsynaptic currents (IPSCs) evoked by stimulation of Schaffer collaterals and recorded from CA1 pyramidal neurons. It also decreased the amplitude and frequency of spontaneous IPSCs recorded from pyramidal neurons. Whereas the maximal effect of soman on evoked GABAergic transmission was observed at 10 nM, full cholinesterase inhibition was induced by 1 nM soman. After 10-15-min exposure of hippocampal slices to 100 nM PB, GABAergic transmission was facilitated and cholinesterase activity was not significantly affected. At nanomolar concentrations, soman and PB have no direct effect on GABA(A) receptors. The effects of soman and PB on GABAergic transmission were inhibited by the m2 receptor antagonist 11-[[[2-diethylamino-O-methyl]-1-piperidinyl] acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6- one (1 nM) and the m3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (100 nM), respectively, and by the nonselective muscarinic receptor antagonist atropine (1 microM). Thus, changes in GABAergic transmission are likely to result from direct interactions of soman and PB with m2 and m3 receptors, respectively, located on GABAergic fibers/neurons synapsing onto the neurons under study. Although the effects of 1 nM soman and 100 nM PB were diametrically opposed, they only canceled one another when PB was applied to the neurons before soman. Therefore, PB, acting via m3 receptors, can effectively counteract effects arising from the interactions of soman with m2 receptors in the brain.

  7. Why does the G117H mutation considerably improve the activity of human butyrylcholinesterase against sarin? Insights from quantum mechanical/molecular mechanical free energy calculations.

    PubMed

    Yao, Yuan; Liu, Junjun; Zhan, Chang-Guo

    2012-11-06

    Human butyrylcholinesterase (BChE) is recognized as the most promising bioscavenger for organophosphorus (OP) warfare nerve agents. The G117H mutant of human BChE has been identified as a potential catalytic bioscavenger with a remarkably improved activity against OP nerve agents such as sarin, but it still does not satisfy the clinical use. For further design of the higher-activity mutants against OP nerve agents, it is essential to understand how the G117H mutation improves the activity. The reaction mechanisms and the free energy profiles for spontaneous reactivation of wild-type BChE and its G117H mutant phosphorylated by sarin have been explored, in this study, by performing first-principles quantum mechanical/molecular mechanical free energy calculations, and the remarkable role of the G117H mutation on the activity has been elucidated. For both the wild-type and G117H mutant enzymes, H438 acts as a general base to initiate the spontaneous reactivation that consists of two reaction steps: the nucleophilic attack at the phosphorus by a water molecule and decomposition of the pentacoordinated phosphorus intermediate. The calculated overall free energy barriers, i.e., 30.2 and 23.9 kcal/mol for the wild type and G117H mutant, respectively, are in good agreement with available experimental kinetic data. On the basis of the calculated results, the mutated residue (H117 in the G117H mutant) cannot initiate the spontaneous reactivation as a general base. Instead, it skews the oxyanion hole and makes the phosphorus more open to the nucleophilic water molecule, resulting in a remarkable change in the rate-determining step and significantly improved catalytic activity of human BChE.

  8. Anticonvulsant Treatment of Nerve Agent Seizures: Anticholinergics versus Diazepam in Soman-Intoxicated Guinea Pigs

    DTIC Science & Technology

    2000-01-01

    8 June 1999 Abstract A total of eight anticholinergic drugs (aprophen, atropine, azaprophen, benactyzine, biperiden , procyclidine, scopolamine...procyclidine and aprophen terminated seizures most rapidly while scopolamine, trihexyphenidyl, biperiden , and diazepam were significantly slower. When...given 40 min after seizure onset, diazepam was the most potent compound tested, followed by scopolamine, benactyzine and biperiden ; atropine was not

  9. The Neuroprotective Benefits of Central Adenosine Receptor Stimulation in a Soman Nerve Agent Rat Model

    DTIC Science & Technology

    2014-04-01

    µl of multisol (48.5% H2O, 40% propylene glycol, 10% ethanol , and 1.5% benzyl alcohol ) and administered bilaterally at a rate of 5 μl/min. For group...regulates multiple peripheral and central physiologic functions. It is released during normal metabolic activity into the extracellular space where it... metabolism , temperature and brain injury]." Ann Fr Anesth Reanim 28(4): 339-344. Gouder, N., J. M. Fritschy and D. Boison (2003). "Seizure suppression

  10. Evaluation of nine oximes on in vivo reactivation of blood, brain, and tissue cholinesterase activity inhibited by organophosphorus nerve agents at lethal dose.

    PubMed

    Shih, Tsung-Ming; Skovira, Jacob W; O'Donnell, John C; McDonough, John H

    2009-09-01

    The capability of several oximes (HI-6, HLö7, MMB-4, TMB-4, carboxime, ICD 585, ICD 692, ICD 3805, and 2-PAM) to reactivate in vivo AChE inhibited by the nerve agents sarin, cyclosarin, VX, or VR in blood, brain regions, and peripheral tissues in guinea pigs was examined and compared. Animals were injected subcutaneously with 1.0 LD(50) of sarin, cyclosarin, VR, or VX, and treated intramuscularly 5 min later with one of these compounds. Toxic signs and lethality were monitored, and tissue AChE activities were determined at 60 min after nerve agent. The animals exposed to sarin or cyclosarin, alone or with non-oxime treatment, some died within 60 min; however, when treated with an oxime, no animal died. For VR or VX, all animals survived for 60 min after exposure, with or without non-oxime or oxime therapy. These nerve agents caused differential degrees of inhibition: in whole blood sarin = cyclosarin > VR = VX; in brain regions sarin > cyclosarin > VX > VR; and in peripheral tissues sarin > VX > cyclosarin > VR. These oximes exhibited differential potency in reactivating nerve agent-inhibited AChE in various peripheral tissues, but not AChE activity in the brain regions. There was no difference in the AChE reactivating potency between the dichloride and dimethanesulfonate salts of HI-6. AChE inhibited by sarin was the most and cyclosarin the least susceptible to oxime reactivation. Overall, MMB-4 appeared to be, among all oximes tested, the most effective in vivo AChE reactivator against the broadest spectrum of nerve agents.

  11. Quantitative analysis of O-isopropyl methylphosphonic acid in serum samples of Japanese citizens allegedly exposed to sarin: estimation of internal dosage.

    PubMed

    Noort, D; Hulst, A G; Platenburg, D H; Polhuijs, M; Benschop, H P

    1998-10-01

    A convenient and rapid micro-anion exchange liquid chromatography (LC) tandem electrospray mass spectrometry (MS) procedure was developed for quantitative analysis in serum of O-isopropyl methylphosphonic acid (IMPA), the hydrolysis product of the nerve agent sarin. The mass spectrometric procedure involves negative or positive ion electrospray ionization and multiple reaction monitoring (MRM) detection. The method could be successfully applied to the analysis of serum samples from victims of the Tokyo subway attack and of an earlier incident at Matsumoto, Japan. IMPA levels ranging from 2 to 135 ng/ml were found. High levels of IMPA appear to correlate with low levels of residual butyrylcholinesterase activity in the samples and vice versa. Based on our analyses, the internal and exposure doses of the victims were estimated. In several cases, the doses appeared to be substantially higher than the assumed lethal doses in man.

  12. Regeneration of acetylcholinesterase in clonal neuroblastoma-glioma hybrid NG108-15 cells after soman inhibition: Effect of glycyl-l-glutamine. (Reannouncement with new availability information)

    SciTech Connect

    Yourick, J.J.; Eklo, P.A.; McCluskey, M.P.; Ray, R.

    1991-12-31

    Acetylcholinesterase (AChE) in the clonal NG108-15 cell line has been previously characterized. This cell line represents an in vitro system to study AChE regulation and effects of chemical compounds that may alter AChE activity. Recently, glycyl-L-glutamine (GLG) was demonstrated to function as a neurotrophic factor for maintenance of AChE content in cat denervated superior cervical ganglion cells. In the present study, regeneration of AChE activity in cultures of undifferentiated NG108-15 cells after soman inhibition was investigated in the presence and absence of GLG. Cells were treated with soman (5.5 x 10-6 M) for 15 min and then washed to remove excess soman. Culture medium containing either GLG (10-6, 10-5, or 10.4 M) or glycyl-L-glutamic acid (10-6 M) was added to cultures after soman treatment and remained in the medium until cell harvest. Cells were physically detached at various times after soman treatment and specific AChE activity was determined. After soman, AChE activity dramatically decreased to less than 1% of untreated cellular activity at 1 hr. AChe activity gradually increased after 5 hr, while untreated cell AChE activity was regained 20 hr after soman.

  13. Cryosat-2 SAR and SAR-In Altimetry for Coastal Sea Level

    NASA Astrophysics Data System (ADS)

    Baltazar Andersen, Ole; Knudsen, Per; Abulaitijiang, Adil; Stenseng, Lars

    2015-04-01

    Cryosat-2 offers the first ever possibility to perform coastal altimetric studies using SAR-Interferometry as well as SAR altimetry. With this technological leap forward Cryosat-2 is now able to observe sea level in very small water bodies and also to provide coastal sea level very close to the shore. We perform an investigation into the retrieval of sea surface height around Denmark and Greenland. These regions have been chosen as the coastal regions around Denmark falls within the SAR mask and the coastal regions of Greenland falls in under the SAR-in mask employed on Cryosat-2. SAR-in was mainly used in coastal regions of Greenland because of its huge topographic changes as Cryosat-2 is designed to map the margins of the ice-sheet. The coastal region around Denmark is a test region of the EU sponsored project LOTUS in which With the increased spatial resolution of Cryosat-2 SAR we provide valuable sea level observations within the Straits around Denmark which are crucial to constrain the waterflow in and out of the Baltic Sea. The investigation of SAR-in data in Greenland adds an entire new dimension to coastal altimetry. An amazing result of the investigation is the ability of Cryosat-2 to detect and recover sea level even though the coast (sealevel) is up to 15 km away from the nadir location of the satellite. This ability of capture and use returns from outside the main (-3Db) loop in theory enables Cryosat-2 SAR-in to map sea level height of fjords more frequently than the 369 days repeat.

  14. Identification of chemical warfare agents from vapor samples using a field-portable capillary gas chromatography/membrane-interfaced electron ionization quadrupole mass spectrometry instrument with Tri-Bed concentrator.

    PubMed

    Nagashima, Hisayuki; Kondo, Tomohide; Nagoya, Tomoki; Ikeda, Toru; Kurimata, Naoko; Unoke, Shohei; Seto, Yasuo

    2015-08-07

    A field-portable gas chromatograph-mass spectrometer (Hapsite ER system) was evaluated for the detection of chemical warfare agents (CWAs) in the vapor phase. The system consisted of Tri-Bed concentrator gas sampler (trapping time: 3s(-1)min), a nonpolar low thermal-mass capillary gas chromatography column capable of raising temperatures up to 200°C, a hydrophobic membrane-interfaced electron ionization quadrupole mass spectrometer evacuated by a non-evaporative getter pump for data acquisition, and a personal computer for data analysis. Sample vapors containing as little as 22μg sarin (GB), 100μg soman (GD), 210μg tabun (GA), 55μg cyclohexylsarin (GF), 4.8μg sulfur mustard, 390μg nitrogen mustard 1, 140μg of nitrogen mustard 2, 130μg nitrogen mustard 3, 120μg of 2-chloroacetophenone and 990μg of chloropicrin per cubic meter could be confirmed after Tri-Bed micro-concentration (for 1min) and automated AMDIS search within 12min. Using manual deconvolution by background subtraction of neighboring regions on the extracted ion chromatograms, the above-mentioned CWAs could be confirmed at lower concentration levels. The memory effects were also examined and we found that blister agents showed significantly more carry-over than nerve agents. Gasoline vapor was found to interfere with the detection of GB and GD, raising the concentration limits for confirmation in the presence of gasoline by both AMDIS search and manual deconvolution; however, GA and GF were not subject to interference by gasoline. Lewisite 1, and o-chlorobenzylidene malononitrile could also be confirmed by gas chromatography, but it was hard to quantify them. Vapors of phosgene, chlorine, and cyanogen chloride could be confirmed by direct mass spectrometric detection at concentration levels higher than 2, 140, and 10mg/m(3) respectively, by bypassing the micro-concentration trap and gas chromatographic separation.

  15. [Decontamination with clay or alcoholate of pigs percutaneously poisoned with VX and soman].

    PubMed

    Knezević, D L; Tadić, V

    1994-01-01

    The efficacy of clay or alcoholate as decontaminants in pigs percutaneously poisoned with 6 LD50 of O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate (VX) and 3 LD50 of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) nerve gases was tested. It was assessed by the time of onset of the first signs of poisoning and death, as well as by the activity of blood cholinesterase (ChE). No toxic signs or fatalities were observed in decontaminated pigs, regardless of the decontaminant used. In VX poisoning up to 240 min. both decontaminants kept ChE values at normal level. Twenty four hours later, ChE activity in pigs decontaminated with clay was 71%, significantly higher than in pigs decontaminated with alcoholate (49%). In soman poisoning the activity in control group was maintained at almost normal level up to 60 min, followed by rapid fall to 58%. Further readings were impossible due to the death of all animals. No significant difference between decontaminants could be noticed throughout the observation of 24 hr. The values were kept between 80 and 100%, with the trend of rising after 120 min.

  16. Infrared signature of micro-hydration in the organophosphate sarin: An ab initio study

    DOE PAGES

    Alam, Todd M.; Pearce, Charles Joseph

    2015-06-28

    The infrared (IR) spectra of micro-hydrated Sarin•(H2O)n clusters containing between one and four explicit waters have been studied using ab initio density functional theory (DFT) methods. The phosphate group P=O bond vibration region (~1270 to 1290 cm–1) revealed the largest frequency variation with hydration, with a frequency red shift reflecting the direct hydrogen bond formation between the P=O of Sarin and water. Small variations to the P-F stretch (~810 to 815 cm–1) and the C-O-P vibrational modes (~995 to 1004 cm–1) showed that the water interactions with these functional groups were minor, and that the structures of Sarin were notmore » extensively perturbed in the hydrated complexes. Increasing the number of explicit hydration waters produced only small vibrational changes in the lowest free energy complexes. These minor changes were consistent with a single water-phosphate hydrogen bond being the dominant structure, though a second water-phosphate hydrogen bond was observed in some complexes and was identified by an additional red shift of the P=O bond vibration. As a result, the H2O•H2O vibrational modes (~3450 to 3660 cm–1) increased in complexity with higher hydration levels and reflect the extended hydrogen bonding networks formed between the explicit waters in the hydrated Sarin clusters.« less

  17. In Vivo Characterization of Intracellular Signaling Pathways Activated by the Nerve Agent Sarin

    DTIC Science & Technology

    2004-03-01

    Ca+2/calmodulin-dependent protein phosphatase signaling cascade, which dephosphorylates T34- DARPP-32 (Nishi et al., 1999). Activation of the D 1...phosphorylation state of DARPP-32 at Ser-102 (S102) and Ser-137 (S137) (see Figure 1). For example, S 102 on DARPP-32 is phosphorylated by casein kinase...cGMP-dependent protein kinase (PKG) (Girault et al., 1989). DARPP-32 is also phosphorylated on amino acid S137 by casein kinase I (CK1). Increases in

  18. The perirhinal cortex of rats: an intricate area for microinfusion of anticonvulsants against soman-induced seizures.

    PubMed

    Myhrer, Trond; Enger, Siri; Aas, Pål

    2013-01-01

    Microinfusion of anticonvulsants into the perirhinal cortex through 1 guide cannula in each hemisphere only invades a small area of this seizure controlling site in rats exposed to soman. The purpose of the present study was to examine whether infusions made through 2 cannulas in each perirhinal cortex may produce more efficacious anticonvulsant action against soman intoxication than the use of 1 cannula only in rats infused with the ionotropic antagonists procyclidine and caramiphen or the metabotropic glutamate modulators DCG-IV and MPEP. The results showed that the mere presence of indwelling double cannulas caused proconvulsant effect in response to subsequent systemic administration of soman. Both the control and caramiphen groups with double cannulas had significantly shorter latencies to seizure onset than the corresponding groups with single cannula. Procyclidine resulted in anticonvulsant efficacy, even in rats with double cannulas. In rats that received twin infusions of DCG-IV or MPEP, the anticonvulsant impact was very high, inasmuch as a majority of the rats in each group was protected against seizure activity. Drugs possessing powerful anticonvulsant potency can apparently counteract the proconvulsant effect of double cannulas, and some can even gain enhanced anticonvulsant capacity when invading a larger area of the perirhinal cortex. Perirhinal EEG recordings (electrodes in indwelling cannulas) in a separate set of rats not exposed to soman or drugs showed no differences in basal electrical activity (total power 0.5-25Hz or the theta band 4-12Hz) between groups with single or double cannulas. The intrinsic excitability and synaptic connectivity of the perirhinal cortex may be associated with the proconvulsant impact observed in rats with double cannulas when exposed to soman.

  19. Prophylaxis with human serum butyrylcholinesterase protects Göttingen minipigs exposed to a lethal high-dose of sarin vapor.

    PubMed

    Saxena, Ashima; Hastings, Nicholas B; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

    2015-08-05

    Serum-derived human butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a potential prophylactic nerve agent countermeasure. Previously, we reported the prophylactic efficacy of Hu BChE in Göttingen minipigs against a whole-body exposure to 4.1mg/m(3) of sarin (GB) vapor, which produced lethality over 60min. Since the toxicity of nerve agent is concentration-dependent, in the present study, we investigated the toxic effects of an almost 3-fold higher rate of GB vapor exposure and the ability of Hu BChE to protect minipigs against this exposure. Male minipigs were subjected to: (1) air exposure; (2) GB vapor exposure; or (3) pretreatment with 7.5mg/kg of Hu BChE by i.m. injection, 24h prior to whole-body exposure to 11.4mg/m(3) of GB vapor for 10min. Electrocardiogram, electroencephalogram, and pupil size were monitored throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB bound to red blood cells and plasma. A novel finding was that saline-treated animals exposed to GB vapor did not develop any seizures, but manifested a variety of cardiac and whole blood toxic signs and rapidly died due to respiratory failure. Strikingly, pre-treatment with 7.5mg/kg of Hu BChE not only prevented lethality, but also avoided all cardiac toxic signs manifested in the non-treated cohort. Thus, Hu BChE alone can serve as an effective prophylactic countermeasure versus a lethal high-dose exposure to GB vapor.

  20. Individual Passive Chemical Sampler Testing Continued Chemical Agent and TIC Performance Validation

    DTIC Science & Technology

    2002-04-01

    chemical warfare munitions by U.S. demolition units resulted in the release of sarin/cyclosarin nerve agents. The Central Intelligence Agency (CIA) and...DOD estimated in September 1997 that the demolition of Iraqi chemical-filled munitions released plumes of nerve agent gas that extended over U.S...testing that involved nerve and blister agents as well as several of the TICs. The Occupational Safety and Health Administration Technical Center at Salt

  1. Effects of sarin on temperature and activity of rats as a model for gulf war syndrome neuroregulatory functions.

    PubMed

    Conn, Carole A; Dokladny, Karol; Ménache, Margaret G; Barr, Edward B; Kozak, Wieslaw; Kozak, Anna; Wachulec, Maceij; Rudolph, Karin; Kluger, Matthew J; Henderson, Rogene F

    2002-10-15

    Coexposure to subclinical levels of nerve gas and to heat stress may have induced some of the clinical symptoms of the Gulf War Syndrome. We tested the hypothesis that single or repeated subclinical exposure to sarin, particularly under conditions of heat stress, would impair regulation of body temperature and locomotor activity. Male F344 rats were housed at 25 degrees C or under mild heat stress at 32 degrees C and were exposed 1 h/day for 1, 5, or 10 days to 0, 0.2, or 0.4 mg/m(3) of sarin in a nose-only exposure system. Body temperature and activity were monitored continuously by telemetry during exposure and 1 month postexposure. Exposed rats showed no clinical symptoms of toxicity such as tremors, despite evidence of reduced red blood cell cholinesterase activity. Heat stress consistently elevated body temperature in unexposed animals, particularly during the dark period when animals are most active. Inhalation of sarin gas at the two subclinical levels did not affect body temperature acutely in a biologically meaningful manner after the first exposure nor after 5 or 10 repeated exposures, either at thermoneutral ambient temperature or during chronic heat stress. There were no consistent effects of sarin or housing temperature on activity. The data suggest that subclinical levels of sarin have minimal effects on temperature regulation and locomotor activity under these observation conditions.

  2. Development of a Protocol to Evaluate Neuronal Injury and Loss Following Soman-Induced Seizures Using NeuN and Fluoro-Jade C

    DTIC Science & Technology

    2006-07-01

    The extent of neuronal injury was determined by measuring NeuN and FJ-C labeling using imaging analysis. In the piriform cortex of soman-exposed...exposure include the piriform cortex, hippocampus, septum, entorhinal cortex, dentate gyrus, amygdala, and thalamus (Britt et al., 2000; Carpentier et...al., 1991; Lemercier et al., 1983; and McLeod, 1985). Previously, we examined neuronal damage in the piriform cortex of the rat following soman

  3. A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

    SciTech Connect

    Wilhelm, Christina M.; Snider, Thomas H.; Babin, Michael C.; Jett, David A.

    2014-12-15

    The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl{sub 2}, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. - Highlights: • First comprehensive evaluation of leading AChE oxime reactivators • All oximes are compared against current U.S. therapy 2-PAM Cl. • Relative therapeutic oxime efficacies against OP CWNA and pesticides • Contribution to more effective antidotes

  4. Engineering Environmentally-Stable Proteases to Specifically Neutralize Protein Toxins

    DTIC Science & Technology

    2013-10-01

    agents , such as Soman and Sarin . 2. Linkage to binding molecules Conjugating an antibody (or any other binding module) with an initiating protease...to develop the tools and principles necessary to engineer subtilisin proteases which specifically target and deactivate biological warfare agent (BWA...warfare agent (BWA) toxins. We have engineered and evolved subtilisin proteases to specifically target and deactivate BoNT, SEB, ricin, and B

  5. Studies on the role of central catecholaminergic mechanisms in the antidotal effect of the oxime HI 6 in soman poisoned mice.

    PubMed

    Reithmann, C; Arbogast, H; Hallek, M; Auburger, G; Szinicz, L

    1988-08-01

    The effects of atropine and the oxime HI 6 on running performance, brain and plasma cholinesterase activity and brain catecholamines were investigated in mice intoxicated with sublethal doses of soman (100 micrograms/kg s.c.). The running time on a rotating mash wire drum (total running time 60 min) after injection of soman was reduced to 17.2 min. Treatment with atropine (10 mg/kg i.p.) or HI 6 (55 mg/kg i.p.) improved the running performance to 48.2 and 44.8 min, respectively. Cholinesterase activity was decreased in soman poisoned mice to 47.3% in plasma and 43.5% in brain. Therapy with the oxime HI 6 resulted in a reactivation of soman-inhibited peripheral cholinesterase to 76.6%, but failed to reactivate central cholinesterase. Dopamine levels in mice brain were elevated in soman poisoning by 23.2%, whereas noradrenaline levels remained unchanged. The increase in brain dopamine levels was antagonized by atropine as well as by HI 6. The results of this study lead to the speculation that central dopaminergic mechanisms may be involved in soman toxicity as well as in the antidotal action of atropine and the mainly peripherally acting oxime HI 6.

  6. Evaluation of diethyl malonate as a simulant for 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) in shower decontamination of the skin.

    PubMed

    Reifenrath, W G; Mershon, M M; Brinkley, F B; Miura, G A; Broomfield, C A; Cranford, H B

    1984-10-01

    A shower decontamination bench model has been used to assess quantitatively the importance of several variables (water pressure and temperature, surfactant concentration in the decontamination fluid, nozzle type, and shower time) on decontamination of nontoxic chemical warfare-agent simulants diethyl malonate and thickened diethyl malonate from pig skin in vitro. Diethyl malonate was validated as a simulant for 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) by comparison of the skin penetration and decontamination of radiolabeled diethyl malonate to the radiolabeled phosphonofluoridate in shower decontamination trials of pig skin in vitro. Percutaneous penetration of diethyl malonate was significantly greater than that of the phosphonofluoridate during the 15-min period after application. However, both were less than 0.1% of the applied dose. Showering or thickener had no significant effect on the percutaneous penetration of diethyl malonate or the phosphonofluoridate. Most of the phosphonofluoridate removed by showering or scrubbing the skin was inactivated. The quantity of intact 1,2,2-trimethylpropyl methylphosphonofluoridate that penetrated through the skin was below the detection limit of the enzymatic analysis. There was no statistically significant difference between the phosphonofluoridate and diethyl malonate in efficacy of shower decontamination. The presence of thickener did not have a significant effect on decontamination efficacy.

  7. Single dose exposure of sarin and physostigmine differentially regulates expression of choline acetyltransferase and vesicular acetylcholine transporter in rat brain.

    PubMed

    Bhardwaj, Sonika; Musalgaonkar, Nidhi; Waghmare, Chandrakant; Bhattacharya, Bijoy K

    2012-06-25

    Choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are the key components of cholinergic system apart from acetylcholinesterase. Effects of subcutaneous exposures of 0.25 and 0.5 LD(50) sarin and 0.75 mg/kg physostigmine on immunoreactivity levels of these two proteins (ChAT and VAChT) were studied. Immunoreactivity levels of ChAT decreased significantly after 1 and 3 days in cortex and 3 days of 0.25 LD(50) sarin administration in cerebellum. While 0.5 LD(50) sarin exposure caused significant down regulation after 2.5 h to 7 days in cortex and 1 and 3 days in cerebellum with respect to controls. Physostigmine at 0.75 mg/kg dose showed enhanced levels of ChAT after 1 day which decreased significantly after 3 and 7 days both in cortex and cerebellum compared to controls. VAChT level decreased significantly after 1 day in cortex and 3 and 7 days in cerebellum after 0.25 LD(50) sarin administration, while 0.5 LD(50) sarin significantly lowered VAChT immunoreactivity level after 2.5 h and 7 days in cortex and 2.5 h and 1 day in cerebellum. Physostigmine at 0.75 mg/kg dose showed significant enhanced immunoreactivity levels of VAChT after 1, 3, and 7 days in cortex and 3 days in cerebellum. Results show that acetylcholinesterase inhibition by sarin caused reduction in cholinergic neurotransmission at cholinergic proteins expression levels, while physostigmine caused differential expression of key cholinergic proteins. Moreover, cortex, which receives greater cholinergic innervations, is more susceptible to anticholinesterase effect on cholinergic gene expression. These changes can explain delayed neurocognitive changes during anticholinesterases induced chronic neurotoxicity.

  8. Effect of reversible ligands on oxime-induced reactivation of sarin- and cyclosarin-inhibited human acetylcholinesterase.

    PubMed

    Scheffel, Corinna; Thiermann, Horst; Worek, Franz

    2015-02-03

    Poisoning by organophosphorus compounds (OP) used as pesticides and nerve agents is due to irreversible inhibition of the enzyme acetylcholinesterase (AChE). Oximes have been widely recognized for their potency to reactivate the inhibited enzyme. The limited efficacy of currently available oximes against a broad spectrum of OP-compounds initiated novel research efforts to improve oxime-based treatment. Hereby, oxime-induced reactivation of OP-inhibited non-human AChE was reported to be accelerated by different AChE-ligands. To investigate this concept with AChE from human source, the inhibitory potency, binding properties and the potential enhancement of oxime-induced reactivation of OP-inhibited AChE by structurally different AChE-ligands was assessed. Several ligands competed with the oxime for the AChE binding-site impairing reactivation of OP-inhibited AChE whereas a markedly accelerated reactivation of sarin-inhibited enzyme by obidoxime was recorded in the presence of edrophonium, galanthamine and donepezil. Enhancement of oxime-induced reactivation with ligands was presumably subject to prevention of re-inhibition by the reaction product phosphonyloxime (POX). In the end, the results of the present study did not confirm that AChE-ligands directly accelerate the reactivation of OP-inhibited AChE by oximes, but indirectly by prevention of re-inhibition by the reaction product POX. This may be due to different experimental conditions and species differences between human and non-human AChE of previous experiments with non-human AChE.

  9. Fine Ice Sheet margins topography from swath processing of CryoSat SARIn mode data

    NASA Astrophysics Data System (ADS)

    Foresta, Luca; Gourmelen, Noel; Shepherd, Andrew; Escorihuela, Maria Jose; Muir, Alan; Briggs, Kate; Roca, Monica; Baker, Steven; Drinkwater, Mark; Nienow, Pete

    2014-05-01

    Reference and repeat-observations of Glacier and Ice Sheet Margin (GISM) topography are critical to identify changes in ice thickness, provide estimates of mass gain or loss and thus quantify the contribution of the cryosphere to sea level change. The lack of such sustained observations was identified in the Integrated Global Observing Strategy (IGOS) Cryosphere Theme Report as a major shortcoming. Conventional altimetry measurements over GISMs exist, but coverage has been sparse and characterized by coarse ground resolution. Additionally, and more importantly, they proved ineffective in the presence of steep slopes, a typical feature of GISM areas. Since the majority of Antarctic and Greenland ice sheet mass loss is estimated to lie within 100 km from the coast, but only about 10% is surveyed, there is the need for more robust and dense observations of GISMs, in both time and space. The ESA Altimetry mission CryoSat aims at gaining better insight into the evolution of the Cryosphere. CryoSat's revolutionary design features a Synthetic Interferometric Radar Altimeter (SIRAL), with two antennas for interferometry. The corresponding SAR Interferometer (SARIn) mode of operation increases spatial resolution while resolving the angular origin of off-nadir echoes occurring over sloping terrain. The SARIn mode is activated over GISMs and the elevation for the Point Of Closest Approach (POCA) is a standard product of the CryoSat mission. Here we present a new approach for more comprehensively exploiting the SARIn mode of CryoSat and produce an ice elevation product with enhanced spatial resolution compared to standard CryoSat-2 height products. In this so called L2-swath processing approach, the signal beyond the POCA is exploited when signal and surface characteristics are favourable. We will present the rationale, validation exercises and preliminary results from the STSE CryoTop study over selected test regions of the margins of the Greenland and Antarctic Ice Sheets.

  10. An Observation of Antarctic Marginal Subglacial Lake using Cryosat-2 SARin mode

    NASA Astrophysics Data System (ADS)

    Kim, B.; Lee, C. K.; Seo, K. W.

    2015-12-01

    The surface height above active subglacial lake (SGL) varies in accordance with the water storage of lake beneath ice-sheet. Thus, satellite altimeters accurately measuring the ice surface height have discovered numbers of SGLs. In this study, we detect Antarctic SGLs using Cryosat-2 without any auxiliary data. The SARin mode of Cyrosat-2 is designed to retrieve the elevation over steep slope regions, such as margin of ice-sheet or ice-stream. The high-resolution processing of SARin mode yielding the elevation change rate (=Δh/Δt) enables us to verify the specific 2-D boundary of lake and even the small-scale uncategorized lakes. In the Whillans and Mercer Ice Streams (WIS and MIS), drainage or refilling events of 9 SGLs are apparent in Cyrosat-2 era, and one of those is likely an uncategorized lake. In addition, the ice thickening upstream of WIS and MIS, which might be provoked by the deceleration downstream of WIS, alternates between high and low rate. It might be associated with massive drainage event of lake "Conway". In the Kamb Ice Stream (KIS), most of previously known SGLs are not observed except for only one (Kamb trunk1) due to the limited spatial coverage of SARin mode operation. However, two additional lakes (located in 82.304S/147.980W and 82.477S/150.585W, respectively) are discovered at the downstream of Kamb trunk 1 lake. Similar approach is applied at slightly rugged terrain, which is located on the upstream of David Glacier. The drainage event of David 1 SGL is apparent, but the precise location of the lake is significantly (about twenty kilometers) different from previous ICESat measurement. Since ICESat measurements have limited temporal/spatial resolutions, we expect that Cryosat-2 have more optimal performance for measuring Antarctic Marginal SGLs.

  11. Fine Ice Sheet margins topography from swath processing of CryoSat SARIn mode data

    NASA Astrophysics Data System (ADS)

    Gourmelen, N.; Escorihuela, M. J.; Shepherd, A.; Foresta, L.; Muir, A.; Briggs, K.; Hogg, A. E.; Roca, M.; Baker, S.; Drinkwater, M. R.

    2014-12-01

    Reference and repeat-observations of Glacier and Ice Sheet Margin (GISM) topography are critical to identify changes in ice thickness, provide estimates of mass gain or loss and thus quantify the contribution of the cryosphere to sea level change. The lack of such sustained observations was identified in the Integrated Global Observing Strategy (IGOS) Cryosphere Theme Report as a major shortcoming. Conventional altimetry measurements over GISMs exist, but coverage has been sparse and characterized by coarse ground resolution. Additionally, and more importantly, they proved ineffective in the presence of steep slopes, a typical feature of GISM areas. Since the majority of Antarctic and Greenland ice sheet mass loss is estimated to lie within 100 km from the coast, but only about 10% is surveyed, there is the need for more robust and dense observations of GISMs, in both time and space. The ESA Altimetry mission CryoSat aims at gaining better insight into the evolution of the Cryosphere. CryoSat's revolutionary design features a Synthetic Interferometric Radar Altimeter (SIRAL), with two antennas for interferometry. The corresponding SAR Interferometer (SARIn) mode of operation increases spatial resolution while resolving the angular origin of off-nadir echoes occurring over sloping terrain. The SARIn mode is activated over GISMs and the elevation for the Point Of Closest Approach (POCA) is a standard product of the CryoSat mission. Here we present an approach for more comprehensively exploiting the SARIn mode of CryoSat and produce an ice elevation product with enhanced spatial resolution compared to standard CryoSat-2 height products. In this so called L2-swath processing approach, the full CryoSat waveform is exploited under specific conditions of signal and surface characteristics. We will present the rationale, validation exercises and preliminary results from the Eurpean Space Agency's STSE CryoTop study over selected test regions of the margins of the Greenland

  12. Infrared signature of micro-hydration in the organophosphate sarin: An ab initio study

    SciTech Connect

    Alam, Todd M.; Pearce, Charles Joseph

    2015-06-28

    The infrared (IR) spectra of micro-hydrated Sarin•(H2O)n clusters containing between one and four explicit waters have been studied using ab initio density functional theory (DFT) methods. The phosphate group P=O bond vibration region (~1270 to 1290 cm–1) revealed the largest frequency variation with hydration, with a frequency red shift reflecting the direct hydrogen bond formation between the P=O of Sarin and water. Small variations to the P-F stretch (~810 to 815 cm–1) and the C-O-P vibrational modes (~995 to 1004 cm–1) showed that the water interactions with these functional groups were minor, and that the structures of Sarin were not extensively perturbed in the hydrated complexes. Increasing the number of explicit hydration waters produced only small vibrational changes in the lowest free energy complexes. These minor changes were consistent with a single water-phosphate hydrogen bond being the dominant structure, though a second water-phosphate hydrogen bond was observed in some complexes and was identified by an additional red shift of the P=O bond vibration. As a result, the H2O•H2O vibrational modes (~3450 to 3660 cm–1) increased in complexity with higher hydration levels and reflect the extended hydrogen bonding networks formed between the explicit waters in the hydrated Sarin clusters.

  13. Computer Simulation of the Effect of Pretreatment with Reversible Acetylcholinesterase Inhibitors on the Protection Against Soman Poisoning

    DTIC Science & Technology

    1993-12-01

    dan 50 %/ acetyicholinesteraseremming, hetgeen in overeenstemming is met literatuurgegevens. Tevens voorspelt bet model dat het gebruik van een...soman- vergiftiging worden besproken. TNO-rcport PML 213493122 Page CONTENTS M.’ NAGEMENT-LTFFREKSEI. SUMNMARY/SAMENVATTING 3 CONTENTS 4 INTRODUCTION 6 2...genierkte i’-anties/personen ontvangen uitsluitend een management uittreksel, een documentatiepagina en de distributielijst van het rapport. 17* Lid van de

  14. A Physiologically Based Pharmacokinetic (PB/PK) Model for Multiple Exposure Routes of Soman in Multiple Species

    DTIC Science & Technology

    2006-01-01

    levels of soman greater than 0.85 for 95% of the intravenous and sub- challenge in three species (rat, guinea pig, marmoset ). cutaneous datasets and 25...more than a single formula was available for male guinea pigs (500 g), and male marmosets estimating a particular parameter, the model averaged the...used for whole blood. Values for rat and diaphragm was used for the richly perfused compart- marmoset plasma and for liver of the three species were

  15. 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.

  16. Topographical distribution of decrements and recovery in muscarinic receptors from rat brains repeatedly exposed to sublethal doses of soman

    SciTech Connect

    Churchill, L.; Pazdernik, T.L.; Jackson, J.L.; Nelson, S.R.; Samson, F.E.; McDonough, J.H. Jr.

    1984-08-01

    (3H)Quinuclidinyl benzilate binding to rat brain muscarinic receptors decreased after repeated exposure to soman, a potent organophosphorus cholinesterase inhibitor. The topographical distribution of this decrement was analyzed by quantitative receptor autoradiography. After 4 weeks of soman, three times a week, quinuclidinyl benzilate binding decreased to 67 to 80% of control in frontal and parietal cortex, caudate-putamen, lateral septum, hippocampal body, dentate gyrus, superior colliculus, nucleus of the fifth nerve, and central grey. Minor or no decreases were observed in thalamic or hypothalamic nuclei, reticular formation, pontine nuclei, inferior colliculus, nucleus of the seventh nerve, and cerebellum. Scatchard analyses of saturation curves using frontal cortex sections from soman-treated rats revealed a decrease in maximal quinuclidinyl benzilate binding from that in control rats and a return toward control levels by 24 days without any significant change in affinity. These brain areas showing significant decrements in muscarinic receptors recovered with a similar time course. An estimate of the time for 50% recovery for some of the brain areas was 14 days for superior colliculus, 16 days for cortex, and 19 days for hippocampal body. The application of quantitative receptor autoradiography to analyze receptor alterations has been valuable in localizing the telencephalon as a region more susceptible to change in receptor concentration.

  17. Cholinesterases as scavengers for organophosphorus compounds: Protection of primate performance against soman toxicity. (Reannouncement with new availability information)

    SciTech Connect

    Doctor, B.P.; Blick, D.W.; Caranto, G.; Castro, C.A.; Gentry, M.K.

    1993-12-31

    The present treatment for poisoning by organophosphates consists of multiple drugs such as carbamates, antimuscarinics, and reactivators in pre- and post-exposure modalities. Recently an anticonvulsant, diazapam, has been included as a post-exposure drug to reduce convulsions and increase survival. Most regimens are effective in preventing lethality from organophosphate exposure but do not prevent toxic effects and incapacitation observed in animals and likely to occur in humans. Use of enzymes such as cholinesterases as pretreatment drugs for sequestration of highly toxic organophosphate anticholinesterases and alleviation of side effects and performance decrements was successful in animals, including non-human primates. Pretreatment of rhesus monkeys with fetal bovine serum acetyleholinesterase protected them against lethal effects of soman (up to 5 LD50) and prevented signs of OP toxicity. Monkeys pretreated with fetal bovine serum acetylcholinesterase were devoid of behavioral incapacitation after soman exposure, as measured by serial probe recognition or primate equilibrium platform performance tasks. Use of acetylcholinesterase as a single pretreatment drug provided greater protection against both lethal and behavioral effects of potent organophosphates than current multicomponent drug treatments that prevent neither signs of toxicity nor behavioral deficits. Cholinesterases, Pretreatment, Toxicity, Organophosphates, Soman, Scavengers.

  18. Application of Quantitative Proton Nuclear Magnetic Resonance Spectroscopy to Chemical Warfare Agents

    DTIC Science & Technology

    2012-09-01

    sarin, the V-series nerve agent VX and the vesicant agent sulphur mustard (Figure 1).* Figure 1. The chemical structure of the CWAs investigated...diisopropyl methylphosphonic acid (DIMP; 6.6wt%), which is a byproduct formed during synthesis.‡ Finally, the purity of VX (Figure 6) was determined to...Denotes GB resonances. DIMP = O,O-diisopropyl methylphosphonic acid . internal standard internal standard * ** solvent * *** * Figure 6. Example

  19. The Effects of Repeated Sub-Toxic Sarin Exposure on Behavior, EEG and Blood and Brain AChE Activity

    DTIC Science & Technology

    2005-08-01

    patterns in the common marmoset when followed for up to 15 months (one dose, 2.5-3.0 µg/kg sarin, i.m.). Interestingly, as with the current study...cognitive behavior and the electroencephalogram in the common marmoset . J Psychopharmacol. 1999; 13(2): 128-135. (41) Prendergast MA, Terry, AV Jr

  20. 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

  1. Efficacy assessment of a combined anticholinergic and oxime treatment against topical sarin-induced miosis and visual impairment in rats

    PubMed Central

    Gore, A; Bloch-Shilderman, E; Egoz, I; Turetz, J; Brandeis, R

    2014-01-01

    Background and Purpose Eye exposure to the organophosphorus (OP) irreversible cholinesterase inhibitor sarin results in long-term miosis and impaired visual function. We have previously shown that tropicamide is better at ameliorating this insult than topical atropine or cyclopentolate. However, to minimize side effects associated with repeated tropicamide applications and high treatment doses, we evaluated the effects of oximes (ChE re-activators) alone and combined with tropicamide at ameliorating OP-induced ocular impairments. Experimental approach Rats were topically exposed to sarin, followed by topical treatment with various oximes alone or in combination with tropicamide. Pupil width and light reflex were measured by an infrared-based digital photograph system, while visual performance was assessed by employing the cueing version of the Morris water maze (MWM). Key Results Oxime treatment following sarin ocular exposure induced a slow persistent pupil widening with efficacy in the order of HLö-7 > HI-6 > obidoxime = TMB-4 = MMB-4. In the light reflex test, the ability of the iris to contract following oxime treatment was mostly impaired at 1 h and was back to normal at 4 h following sarin exposure. All oxime treatments ameliorated the sarin-induced visual impairment as tested in the visual task (MWM). The combined topical treatment of tropicamide with an oxime induced a rapid improvement in pupil widening, light reflex and visual performance, and enabled a reduction in tropicamide dose. Conclusions and Implications The use of tropicamide combined with an oxime should be considered as the topical treatment of choice against the toxic effects of ocular OP exposure. PMID:24428128

  2. The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior

    PubMed Central

    Prager, Eric M.; Aroniadou-Anderjaska, Vassiliki; Almeida-Suhett, Camila P.; Figueiredo, Taiza H.; Apland, James P.; Rossetti, Franco; Olsen, Cara H.; Braga, Maria F.M.

    2014-01-01

    Organophosphorus nerve agents are powerful neurotoxins that irreversibly inhibit acetylcholinesterase (AChE) activity. One of the consequences of AChE inhibition is the generation of seizures and status epilepticus (SE), which cause brain damage, resulting in long-term neurological and behavioral deficits. Increased anxiety is the most common behavioral abnormality after nerve agent exposure. This is not surprising considering that the amygdala, and the basolateral nucleus of the amygdala (BLA) in particular, plays a central role in anxiety, and this structure suffers severe damage by nerve agent-induced seizures. In the present study, we exposed male rats to lethal doses of the nerve agent soman, and determined the time course of recovery of AChE activity, along with the progression of neuropathological and pathophysiological alterations in the BLA, during a 30-day period after exposure. Measurements were taken at 24 hours, 7 days, 14 days, and 30 days after exposure, and at 14 and 30 days, anxiety-like behavior was also evaluated. We found that more than 90% of AChE is inhibited at the onset of SE, and AChE inhibition remains at this level 24 hours later, in the BLA, as well as in the hippocampus, piriform cortex, and prelimbic cortex, which we analyzed for comparison. AChE activity recovered by day 7 in the BLA and day 14 in the other three regions. Significant neuronal loss and neurodegeneration were present in the BLA at 24 hours and throughout the 30-day period. There was no significant loss of GABAergic interneurons in the BLA at 24 hours post-exposure. However, by day 7, the number of GABAergic interneurons in the BLA was reduced, and at 14 and 30 days after soman, the ratio of GABAergic interneurons to the total number of neurons was lower compared to controls. Anxiety-like behavior in the open-field and the acoustic startle response tests was increased at 14 and 30 days post-exposure. Accompanying pathophysiological alterations in the BLA – studied in

  3. Ice elevation change from Swath Processing of CryoSat SARIn Mode Data

    NASA Astrophysics Data System (ADS)

    Foresta, Luca; Gourmelen, Noel; Shepherd, Andrew; Muir, Alan; Nienow, Pete

    2015-04-01

    Reference and repeat-observations of Glacier and Ice Sheet Margin (GISM) topography are critical to identify changes in ice elevation, provide estimates of mass gain or loss and thus quantify the contribution of the cryosphere to sea level rise (e.g. McMillan et al., 2014). The Synthetic Interferometric Radar Altimeter (SIRAL) onboard the ESA radar altimetry CryoSat (CS) mission has collected ice elevation measurements since 2010. The corresponding SARIn mode of operation, activated over GISM areas, provides high spatial resolution in the along-track direction while resolving the angular origin of echoes (i.e. across-track). The current ESA SARIn processor calculates the elevation of the Point Of Closest Approach (POCA) within each waveform and maps of elevation change in Antarctica and Greenland have been produced using the regular CS height product (McMillan et al., 2014; Helm et al., 2014). Data from the CS-SARIn mode has also been used to produce measurements of ice elevation beyond the POCA, also known as swath elevation (Hawley et al. 2009; Gray et al., 2013; ESA-STSE CryoTop project). Here we use the swath processing approach to generate maps of ice elevation change from selected regions around the margins of the Greenland and Antarctic Ice Sheets. We discuss the impact of the swath processing on the spatial resolution and precision of the resulting ice elevation field and compare our results to current dh/dt estimates. References: ESA STSE CryoTop project - http://www.stse-cryotop.org/ Gray L., Burgess D., Copland L., Cullen R., Galin N., Hawley R. and Helm V. Interferometric swath processing of Cryosat data for glacial ice topography. The Cryosphere, 7(6):1857-1867, December 2013. Hawley R.L., Shepherd A., Cullen R., Helm V. and WIngham D.J. Ice-sheet elevations from across-track processing of airborne interferometric radar altimetry. Geophysical Research Letters, 36(22):L22501, November 2009. Helm V., Humbert A. and Miller H. Elevation and elevation

  4. Pharmacokinetics of intramuscularly administered biperiden in guinea pigs challenged with soman.

    PubMed

    Capacio, B R; Byers, C E; Caro, S T; McDonough, J H

    2003-02-01

    Biperiden is an anticholinergic compound that has demonstrated effectiveness for treating organophosphate-induced seizure/convulsions. The plasma levels of biperiden associated with this efficacy have not yet been defined. In this study, the pharmacokinetics and tissue distribution of biperiden after intramuscular administration of 0.5 mg/kg were conducted while monitoring pharmacodynamic (electroencephalographic) data in soman-exposed guinea pigs. Overall, 59% of the animals had seizures terminated within 30 min of the biperiden administration. The mean time to seizure termination was 15.9 min. The pharmacokinetics of biperiden after i.m. administration to guinea pigs were best described by a one-compartment model with first-order absorption and elimination. The maximal plasma biperiden concentration (34.4 ng/mL) in seizure-terminated animals occurred at 26.3 min. Extensive partitioning into peripheral tissues was noted supporting the relatively large volume of distribution observed. Maximal biperiden concentrations in the cortex and brain stem were found at 30 min and were 2.3 and 1.7 times greater, respectively, than that in plasma. The time for maximal plasma concentration was found to corresponded well with the mean time to seizure termination following drug administration.

  5. Impaired auditory and contextual fear conditioning in soman-exposed rats.

    PubMed

    Moffett, Mark C; Schultz, Mark K; Schwartz, Julia E; Stone, Michael F; Lumley, Lucille A

    2011-03-01

    Exposure to soman (GD) can result in prolonged seizures and subsequent neuropathology in a variety of brain regions including the amygdala and hippocampus. Both regions are believed to play important roles in the development and expression of fear conditioning. The purpose of this experiment was to test these conditioning tasks as a possible behavioral correlate of the observed neuropathology. Male rats were exposed to GD (1.0 or 1.2×LD50) or saline followed with injections of atropine sulfate, the oxime HI-6 and diazepam. Fear conditioning was conducted on post-exposure day (PED) 8 followed by measuring freezing to contextual and auditory conditioned stimuli on PED 9 and 10 respectively. Contextual and auditory fear conditioning was severely impaired in both the 1.0×LD50 and 1.2×LD50 GD groups. Both GD groups spent less time freezing than controls when returned to the context in which conditioning occurred. The 1.0×LD50 and 1.2×LD50 groups had very low levels of freezing following presentation of the auditory conditioned stimulus. Neuronal fiber degeneration was present in the piriform cortex, thalamus, and amygdala in GD-exposed animals regardless of dose. The present study suggests that contextual and auditory fear conditioning is impaired in GD-exposed rats possibly due to neuropathology observed in the hippocampus, amygdala and thalamus.

  6. The benefit of combinations of oximes for the reactivating and therapeutic efficacy of antidotal treatment of sarin poisoning in rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana Zdarova; Sepsova, Vendula; Caisberger, Filip

    2011-07-01

    The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice.

  7. Computational Study of Environmental Effects in the Adsorption of DMMP, Sarin, and VX on gamma-Al2O3: Photolysis and Surface Hydroxylation

    DTIC Science & Technology

    2008-11-01

    methylphosphonate (DMMP) has also been studied computationally.23-31 Of particular interest are the interactions of CWAs with the surfaces of materials. This is an...the environment.32 To date, quantum-chemical work on the interaction of CWAs with materials has focused mainly on the adsorption of Sarin on clays...dissociation of Sarin adsorbed on MgO through the elimination of an HF molecule; whereas, the interaction of Tabun with hydroxylated CaO is weak. The present

  8. CryoSat Level1b SAR/SARin: quality improvements towards BaselineC

    NASA Astrophysics Data System (ADS)

    Scagliola, Michele; Fornari, Marco; Bouzinac, Catherine; Tagliani, Nicolas; Parrinello, Tommaso

    2014-05-01

    CryoSat was launched on the 8th April 2010 and it is the first European ice mission dedicated to monitoring precise changes in the thickness of polar ice sheets and floating sea ice over a 3-year period. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvement in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. Towards the release of the BaselineC of the CryoSat Level1b SAR/SARin products, that is expected during 2014, several improvements have been identified: • a datation bias of about -0.5195 ms will be corrected • a range bias of about -0.6730 m will be corrected • the waveform length in the Level1b product will be doubled with respect to BaselineB • improved processing for 1Hz echoes to have sharper waveforms • surface sample stack weighting to filter out the single look echoes acquired at highest look angle, that results in a sharpening of the 20Hz waveforms This poster details the main improvements that are foreseen to be included in the CryoSat Level1b SAR/SARin products in BaselineC.

  9. Cryosat Level1b SAR/Sarin: Improving the Quality of the Baseline C Products

    NASA Astrophysics Data System (ADS)

    Scagliola, M.; Fornari, M.; Tagliani, N.; Frommknecht, B.; Bouffard, J.; Parrinello, T.

    2014-12-01

    CryoSat was launched on the 8th April 2010 and it is the first European ice mission dedicated to monitoring precise changes in the thickness of polar ice sheets and floating sea ice over a 3-year period. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvement in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. Towards the release of the BaselineC of the CryoSat Level1b SAR/SARin products, that is expected at the end of 2014, several improvements have been identified: a datation bias of about -0.5195 ms will be corrected a range bias of about 0.6730 m will be corrected The range window size will be doubled with respect to BaselineB, so that the in Level1b products the waveforms will be doubled too Improved processing for 1Hz echoes to have sharper waveforms Surface sample stack weighting to filter out the single look echoes acquired at highest look angle, that results in a sharpening of the 20Hz waveforms Additional auxiliary information related to the mispointing angles of the instrument as well as to the stacks of single look echoes will be added This poster details the main quality improvements that are foreseen to be included in the CryoSat Level1b SAR/SARin products in BaselineC.

  10. Kinetic analysis of interactions of different sarin and tabun analogues with human acetylcholinesterase and oximes: is there a structure-activity relationship?

    PubMed

    Aurbek, Nadine; Herkert, Nadja M; Koller, Marianne; Thiermann, Horst; Worek, Franz

    2010-09-06

    The repeated misuse of highly toxic organophosphorus compound (OP) based chemical warfare agents in military conflicts and terrorist attacks poses a continuous threat to the military and civilian sector. The toxic symptomatology of OP poisoning is mainly caused by inhibition of acetylcholinesterase (AChE, E.C. 3.1.1.7) resulting in generalized cholinergic crisis due to accumulation of the neurotransmitter acetylcholine (ACh) in synaptic clefts. Beside atropine as competitive antagonist of ACh at muscarinic ACh receptors oximes as reactivators of OP-inhibited AChE are a mainstay of standard antidotal treatment. However, human AChE inhibited by certain OP is rather resistant to oxime-induced reactivation. The development of more effective oxime-based reactivators may fill the gaps. To get more insight into a potential structure-activity relationship between human AChE, OPs and oximes in vitro studies were conducted to investigate interactions of different tabun and sarin analogues with human AChE and the oximes obidoxime and HI 6 by determination of various kinetic constants. Rate constants for the inhibition of human AChE by OPs, spontaneous dealkylation and reactivation as well as reactivation by obidoxime and HI 6 of OP-inhibited human AChE were determined. The recorded kinetic data did not allow a general statement concerning a structure-activity relationship between human AChE, OP and oximes.

  11. Median lethal dose determination for percutaneous exposure to soman and VX in guinea pigs and the effectiveness of decontamination with M291 SDK or SANDIA foam.

    PubMed

    Clarkson, Edward D; Schulz, Susan M; Railer, Roy F; Smith, Kelly H

    2012-08-03

    Soman (GD) and VX are chemical warfare agents that can be absorbed through the skin. We determined the median lethal dose (MLD) for the cutaneous application of GD and VX in anesthetized haired guinea pigs and then tested the ability of a currently fielded decontamination kit, the M291 Skin Decontamination Kit (SDK), and decontaminating foam made by SANDIA Labs to decontaminate areas that have been exposed to cutaneous applications of GD and VX. The fur of guinea pigs was clipped on the left flank 24h prior to exposure. Animals were anesthetized and 5 min later neat GD or neat VX was applied. The MLD for percutaneous exposure to GD was 11.6 mg/kg, and to VX it was 0.10mg/kg. To test the ability of the M291 SDK, either GD or VX was applied and removed 1 min later with the pads of the M291 SDK clasped in a pair of forceps and wiped across the flank of the animal. The MLDs for GD and VX removed with the M291 SDK pads were 76.9 mg/kg and 0.87 mg/kg, respectively. When neat GD or neat VX was applied and removed 1 min later in the same manner with gauze soaked in SANDIA foam (MDF-100), the MLDs were 412 mg/kg and 10.4 mg/kg respectively. These data demonstrate that GD and VX are significantly less potent when applied cutaneously than previously reported for subcutaneous injections and indicate that improvement is needed on the limited protective ratio provided by the M291 SDK.

  12. A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K727, K733) with the oxime HI-6 and obidoxime in sarin-poisoned rats and mice.

    PubMed

    Kassa, Jiri; Sepsova, Vendula; Matouskova, Lenka; Horova, Anna; Musilek, Kamil

    2015-03-01

    The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.

  13. Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus Nerve Agent Poisoning

    DTIC Science & Technology

    2010-11-01

    MILITARY MEDICINE, 175, 11:878,2010 Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus...Nerve Agent Poisoning Irwin Koplovitz, RhD; Susan Schulz ABSTRACT Scopolamine (SCP) is an anticholinergic drug used clinically for decades to treat...PB is currently EDA approved only for use against soman. Scopolamine (SCP) is a well known anticholinergic drug that has been used clinically for

  14. Microglia as Primary Mediators of Nerve Agent Neuropathy

    DTIC Science & Technology

    2010-01-01

    COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was...hippocampal CA3 regions and especially the dentate gyrus (Fig. 1A and 1B) as well as in the amygdala (Fig. 1C) and piriform cortex (Fig. 1D). By 7 days COX... piriform cortex and amygdala also showed substantial increases in the number of COX-2 immunoreactive cells after soman (Fig 3). These cells were somewhat

  15. The fate of the chemical warfare agent during DNA extraction.

    PubMed

    Wilkinson, Della A; Hulst, Albert G; de Reuver, Leo P J; van Krimpen, Simon H; van Baar, Ben M L

    2007-11-01

    Forensic laboratories do not have the infrastructure to process or store contaminated DNA samples that have been recovered from a crime scene contaminated with chemical or biological warfare agents. Previous research has shown that DNA profiles can be recovered from blood exposed to several chemical warfare agents after the agent has been removed. The fate of four toxic agents, sulfur mustard, sodium 2-fluoroacetate, sarin, and diazinon, in a lysis buffer used in Promega DNA IQ extraction protocol was studied to determine if extraction would render the samples safe. Two independent analytical methods were used per agent, selected from GC-MS, 1H NMR, 19F NMR, (31)P NMR, or LC-ES MS. The methods were validated before use. Determinations were carried out in a semi-quantitative way, by direct comparison to standards. Agent levels in the elution buffer were found to be below the detectable limits for mustard, sarin, sodium 2-fluoroacetate or low (<0.02 mg/mL) for diazinon. Therefore, once extracted these DNA samples could be safely processed in a forensic laboratory.

  16. Fast, sensitive and cost-effective detection of nerve agents in the gas phase using a portable instrument and an electrochemical biosensor.

    PubMed

    Arduini, Fabiana; Amine, Aziz; Moscone, Danila; Ricci, Francesco; Palleschi, Giuseppe

    2007-07-01

    The nerve agents are chemical warfare agents known to be used during terrorist attacks. An inexpensive and portable system to be used by first responders and military personnel is of interest owing to the continuing threat of possible terrorist attacks. Amperometric biosensors based on cholinesterase inhibition show such potentialities. In this work butyrylcholinesterase was immobilized onto screen-printed electrodes modified with Prussian blue and the nerve agent detection was performed by measuring the residual activity of enzyme. The optimized biosensor was tested with sarin and VX standard solutions, showing detection limits of 12 and 14 ppb (10% of inhibition), respectively. The enzymatic inhibition was also obtained by exposing the biosensors to sarin in gas phase. Two different concentrations of sarin gas (0.1 and 0.5 mg m(-3)) at different incubation times (from 30 s up to 10 min) were tested. It is possible to detect sarin at a concentration of 0.1 mg m(-3) with 30-s incubation time, with a degree of inhibition of 34%, which match the legal limits (immediate danger to life and health).

  17. Biosensor System for Continuous Monitoring of Organophosphate Aerosols (Postprint)

    DTIC Science & Technology

    2007-05-01

    detection of a range of organophosphates including paraoxon, demeton-S and malathion . 15. SUBJECT TERMS enzyme immobilization; butyrylcholinesterase...for detection of a range of organophosphates including paraoxon, demeton-S and malathion . 2007 Elsevier B.V. All rights reserved. ydrol c s i e c r s...OPH ydrolyzes a range of OPs including pesticides (e.g. parathion nd malathion ) and chemical warfare agents (e.g. soman, sarin nd VX) (Dumas et al

  18. Biosensor for Continuous Monitoring of Organophosphate Aerosols (Preprint)

    DTIC Science & Technology

    2006-12-01

    of a range of organophosphates inclnding paraoxon, demeton-S and malathion . The detection limits ofthe Ev1ERs for specific organophosphates are...pesticides such as parathion and malathion and chemical warfare agents such as soman, sarin and VX (Dumas et al., 1989; Di Sioudi et cl.. 1Q99...continuously at 412 run for malathion and demeton-S and 400 11m for paraoxon. Ellman’s reagent within the mobile phase reacts with free thiols generated

  19. Comparative Strategic Cultures Curriculum Project: Assessing Strategic Culture as a Methodological Approach to Understanding WMD Decision-Making by States and Non-State Actors

    DTIC Science & Technology

    2006-10-31

    cyanide , phosgene). Second generation agents, discovered in the World War II era, act against the nervous system (e.g., sarin, soman, tabun...is chemicals, ranging from “low end” applications such as cyanide (e.g., to contaminate food or water) and toxic industrial chemicals to traditional...secular authority through today. However, the ulama did on occasion “stand up” to the secular authority as in 1891-2 the “ tobacco revolt.” For a

  20. Atropine and Other Anticholinergic Drugs

    DTIC Science & Technology

    2007-01-01

    compromise near- who first analyzed the pharmacology and toxicol- vision in the case of accidental use. Military re- ogy of tabun obtained from captured...Lipp JA and Dola TJ (1978). Effect of atropine upon 290-293. the cerebrovascular system during soman-induced NakajimaT.Ohta S. Morita H etal. (1997...sarin: Clinical manifes- Wills JH (1963). Pharmacological antagonists of the tations and treatment of accidental poisoning by anticholinesterase agents

  1. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    PubMed

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  2. Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: dose-response relationships.

    PubMed

    Abdel-Rahman, A; Shetty, A K; Abou-Donia, M B

    2002-01-01

    We hypothesize that a single exposure to an LD(50) dose of sarin induces widespread early neuropathological changes in the adult brain. In this study, we evaluated the early changes in the adult brain after a single exposure to different doses of sarin. Adult male rats were exposed to sarin by a single intramuscular injection at doses of 1, 0.5, 0.1 and 0.01 x LD(50). Twenty-four hours after the treatment, both sarin-treated and vehicle-treated (controls) animals were analyzed for: (i) plasma butyrylcholinesterase (BChE) activity; (ii) brain acetylcholinesterase (AChE) activity, (iii) m2 muscarinic acetylcholine receptor (m2 mAChR) ligand binding; (iv) blood brain barrier (BBB) permeability using [H(3)]hexamethonium iodide uptake assay and immunostaining for endothelial barrier antigen (EBA); and (v) histopathological changes in the brain using H&E staining, and microtubule-associated protein (MAP-2) and glial fibrillary acidic protein immunostaining. In animals treated with 1 x LD(50) sarin, the significant changes include a decreased plasma BChE, a decreased AChE in the cerebrum, brainstem, midbrain and the cerebellum, a decreased m2 mAChR ligand binding in the cerebrum, an increased BBB permeability in the cerebrum, brainstem, midbrain and the cerebellum associated with a decreased EBA expression, a diffuse neuronal cell death and a decreased MAP-2 expression in the cerebral cortex and the hippocampus, and degeneration of Purkinje neurons in the cerebellum. Animals treated with 0.5 x LD(50) sarin however exhibited only a few alterations, which include decreased plasma BChE, an increased BBB permeability in the midbrain and the brain stem but without a decrease in EBA expression, and degeneration of Purkinje neurons in the cerebellum. In contrast, animals treated with 0.1 and 0.01 x LD(50) did not exhibit any of the above changes. However, m2 mAChR ligand binding in the brainstem was increased after exposure to all doses of the sarin.Collectively, the above

  3. Immediate post-dosing paralysis following severe soman and VX toxicosis in guinea pigs.

    PubMed

    Bide, R W; Schofield, L; Risk, D J

    2005-01-01

    There have been numerous studies of the central nervous system (CNS) involvement in organophosphate (OP) poisoning showing status epilepticus and/or 'electrographic seizures'. Brain damage has been demonstrated as 'neuronal necrosis' primarily in the cortex, thalamus and hippocampus. To the authors' knowledge there have been no reports of partial/total paralysis following close upon OP exposure although delayed paralysis has been reported. This report summarizes the immediate, OP induced paralytic events recorded in guinea pigs during development of the Canadian reactive skin decontaminant lotion (RSDL). As part of the development work, supra-lethal cutaneous doses of OP were applied to large numbers of guinea pigs followed by decontamination with the RSDL or predecessor lotions and solvents. Soman (pinacolyl methylphosphonofluoridate; GD) challenges were applied to 1277 animals and S-(2-diisopropyl-aminoethyl) methylphosphorothiolate (VX) challenges to 108. The classic sequence of clinical signs--ptyalism, tremors, fasciculations, convulsions, apnea and flaccid paralysis before death--was seen in the 658 animals that died and in many of the survivors. Eighty-four of 688 survivors of GD and 4 of 39 survivors of VX showed random paralysis of various distal regions following recovery from an insult which produced convulsions and/or flaccid paralysis. Because the experiments were designed to assess the decontamination procedures, there were no apparent relationships between the amounts of OP applied and the sequellae recorded. The observations of paralysis were also incidental to the prime focus of the experiments. Because of this, only ten animals paralysed following GD exposure were examined for histological effects. The pathologist diagnosed 'encephalomalacia' and 'focal necrotic lesions' in the cerebral cortex and 'focal necrotic lesions' in one spinal cord. Of the 84 guinea pigs paralysed after GD challenge, one was not decontaminated and the decontaminants used

  4. A concise colorimetric and fluorimetric probe for sarin related threats designed via the "covalent-assembly" approach.

    PubMed

    Lei, Zuhai; Yang, Youjun

    2014-05-07

    A turn-on signal from zero background allows sensitive detection of a weak signal and is highly desired. The "covalent-assembly" probe design principle is powerful in this regard. Herein, we report an embodiment of this principle (NA570) for detection of Sarin related threats, based on a phenylogous Vilsmeier-Haack reaction. NA570 bears a concise molecular construct, exhibits a colorimetric and a fluorimetric signal, and has potential for real applications.

  5. Seasonal sea surface and sea ice signal in the fjords of Eastern Greenland from CryoSat-2 SARin altimetry

    NASA Astrophysics Data System (ADS)

    Abulaitijiang, Adili; Baltazar Andersen, Ole; Stenseng, Lars

    2014-05-01

    Cryosat-2 offers the first ever possibility to perform coastal altimetric studies using SAR-Interferometry. This enabled qualified measurements of sea surface height (SST) in the fjords in Greenland. Scoresbysund fjord on the east coast of Greenland is the largest fjord in the world which is also covered by CryoSat-2 SAR-In mask making it a good test region. Also, the tide gauge operated by DTU Space is sitting in Scoresbysund bay, which provides solid ground-based sea level variation records throughout the year. We perform an investigation into sea surface height variation since the start of the Cryosat-2 mission using SAR-In L1B data processed with baseline B processing. We have employed a new develop method for projecting all SAR-In observations in the Fjord onto a centerline up the Fjord. Hereby we can make solid estimates of the annual and (semi-) annual signal in sea level/sea ice freeboard within the Fjord. These seasonal height variations enable us to derive sea ice freeboard changes in the fjord from satellite altimetry. Derived sea level and sea-ice freeboard can be validated by comparison with the tide gauge observations for sea level and output from the Microwave Radiometer derived observations of sea ice freeboard developed at the Danish Meteorological Institute.

  6. Cryosat-2 SAR-In altimetry for coastal sea level recovery -Results from the fjords of eastern Greenland

    NASA Astrophysics Data System (ADS)

    Baltazar Andersen, Ole; Abulaitijing, Adili; Lars, Stenseng

    2014-05-01

    Cryosat-2 offers the first ever possibility to perform coastal altimetric studies using SAR-Interferometry. As part of the cryospheric mask on Cryosat, this was designed to map the margins of the ice-sheet using SAR interferometry when the slopes are high. Scoresbysund on the east coast of Greenland is a large fjord system at 70N, that falls in under the SAR-in mask employed on Greenland and this region has been mapped using SAR interferometry with Cryosat-2. Here we have evaluted the ability and use of SAR-in altimetry for coastal sea level recovery but deriving empirical retrackers to process 20 hz Cryosat-2 waveforms from 2010-2014. An amazing result of the investigation is the ability of Cryosat-2 to recover sea level even though the coast (sea level) is up to 15 km away from the nadir location of the satellite. This ability of capture and use returns form outside the main loop in theory enables Cryosat-2 SAR-in to map sea level height of fjords much more frequently than the 369 days repeat.

  7. CRUCIAL: Cryosat-2 Success over Inland Water and Land: SAR and SARin Full Bit Rate Altimetric Heights and Validation

    NASA Astrophysics Data System (ADS)

    Moore, Philip; Birkinshaw, Stephen; Restano, Marco; Ambrozio, Americo; Benveniste, Jerome

    2016-04-01

    CRUCIAL is an ESA/STSE funded project investigating innovative land and inland water applications from Cryosat-2 with a forward-look component to the future Sentinel-3 and Jason-CS/Sentinel-6 missions. The high along-track sampling and resolution of Cryosat-2 altimeter in SAR and SARin modes offer the opportunity to recover high frequency signals over inland waters. This paper will present the theoretical approach to analysis of the FBR L1A Doppler beams to form a product using ground cell gridding, beam steering and beam stacking from which inland water heights are derivable from the retracked Cryosat-2 altimetric waveforms. Details of the processing strategy will include a comparison of waveforms and heights from the burst echoes (~80 m along-track) and from multi-look waveforms (~320 m along-track). SAR and SARin FBR data are available for the Amazon, Brahmaputra and Mekong. The Mekong and Amazon FBR SAR data has been processed for 2011-2015 and results will be compared against stage data from the nearest gauge. Similarly, heights from Tonle Sap will be compared against Jason-2 data from the United States Department of Agriculture web site. A strategy to select the number of multi-looks over rivers will also be presented. Results of FBR SARin processing will be presented including comparison of heights from the two antennae and the extraction of slope of the ground surface.

  8. Identical kinetics of human erythrocyte and muscle acetylcholinesterase with respect to carbamate pre-treatment, residual activity upon soman challenge and spontaneous reactivation after withdrawal of the inhibitors.

    PubMed

    Herkert, Nadja M; Eckert, Saskia; Eyer, Peter; Bumm, Rudolf; Weber, Georg; Thiermann, Horst; Worek, Franz

    2008-04-18

    The efficacy of oxime treatment in soman poisoning is limited due to rapid aging of inhibited acetylcholinesterase (AChE). Pre-treatment with carbamates was shown to improve antidotal treatment substantially. Recently, by using a dynamically working in vitro model with real-time determination of membrane-bound AChE activity, we were able to demonstrate that pre-inhibition of human erythrocyte AChE with pyridostigmine or physostigmine resulted in a markedly higher residual AChE activity after inhibition by soman or paraoxon than in the absence of reversible inhibitors. The purpose of the present study was to compare the effect of carbamate pre-treatment and soman challenge with human erythrocyte and muscle homogenate AChE. Both enzyme sources were immobilized on particle filters which were perfused with acetylthiocholine, Ellman's reagent and phosphate buffer. AChE activity was continuously analyzed in a flow-through detector. Pre-inhibition of AChE with pyridostigmine or physostigmine resulted in a concentration-dependent increase in carbamylation, residual activity after soman inhibition and fraction of decarbamylation AChE after discontinuation of the inhibitors without differences between human erythrocyte and muscle AChE. This data support the view that human erythrocyte AChE is an adequate surrogate marker for synaptic AChE in OP poisoning.

  9. ETS2 regulating neurodegenerative signaling pathway of human neuronal (SH-SY5Y) cells exposed to single and repeated low-dose sarin (GB).

    PubMed

    Pachiappan, Arjunan; Thwin, Maung Maung; Weng Keong, Loke; Lee, Fook Kay; Manikandan, Jayapal; Sivakumar, Viswanathan; Gopalakrishnakone, Ponnampalam

    2009-06-01

    The mechanistic understanding of low-level sarin-induced neurotoxicity after single or repeated doses has yet to be explored at a cellular level. Using the microarray (Affymetrix-GeneChips) transcription profiling approach, the present study examined gene expression in human SH-SY5Y cells exposed to single (3 and 24 h) or repeated (2 x 24 h) doses of sarin (5 microg/mL) to delineate the possible mechanism. Two hundred twenty-four genes whose expression was significantly (P < 0.01) altered by at least 3-fold were selected by GeneSpringGX analysis. The comparative gene expression data confirmed the transcriptional changes to be related to dose and exposure time of sarin. The effect of a single noncytotoxic sarin dose on gene transcription was variable, whereas repeated doses over 48 h persistently down-regulated genes linked to neurodegenerative mechanisms. Thirty persistently altered genes were validated using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Similar qRT-PCR profiles obtained in sarin-treated SH-SY5Y and HCN-1A cells confirmed the cell-independent alterations in expression levels. Genes (ETS2, APOE, PSEN1, DDC, and CD9) implicated mainly in the regulation of sarin-induced neuropathogenesis were further confirmed by Western blot and double-immunofluorescence assays. The regulome pathway suggests a new feasible mechanism by which sarin increases ETS2 expression and takes control over other genes involved in the neurodegenerative pathway. The overall data delineate an in vitro experimental model suitable for studying the neuropathology of cells and may provide novel insights into therapeutic interventions.

  10. The decay of chemical weapons agents under environmental conditions

    SciTech Connect

    McGuire, R.R.; Haas, J.S.; Eagle, R.J.

    1993-04-09

    The rate and mechanism of decay of chemical agents in the environment was studied via live agent field trials at the chemical and Biological Defence Establishment, Porton Down, UK. The plan was to deposit the agents GD (Soman), VX, and H (sulfur mustard) on separate l-m{sup 2} plots on three successive days; i.e., Tuesday through Thursday. The depositions were to be made so as to give an areal concentration of 10 g/m{sup 2}. Four felt pads of approximately 25 cm{sup 2} each were placed at the corners of each of the test plots. These were subsequently extracted and analyzed by CBDE to determine the actual agent concentration. Samples for LLNL (two different types of soil, disks of silicone rubber gasket material, and short cylinders of concrete were to be contaminated and analyzed. Results are described.

  11. Accuracy analysis of CryoSat-2 SARIn mode data over Antarctica

    NASA Astrophysics Data System (ADS)

    Wang, Fang; Bamber, Jonathan; Cheng, Xiao

    2015-04-01

    In 2010, CryoSat-2 was launched, carrying a unique satellite radar altimetry (SRA) instrument called SAR/Interferometric Radar Altimeter (SIRAL), with the aim of measuring and monitoring sea ice, ice sheets and mountain glaciers. The novel SAR Interferometric mode (SARInM) of CryoSat-2 is designed to improve the accuracy, resolution and geolocation of height measurements over the steeper margins of ice sheets and ice caps. Over these areas, it employs the synthetic aperture radar (SAR) capability to reduce the size of the footprint to effectively 450m along track and ~1km across track implemented from an airborne prototype originally termed a delay-Doppler altimeter. Additionally, CryoSat-2 used the phase difference between its two antennas to estimate surface slope in the across-track direction and identify the point of closed approach directly. The phase difference is 2pi for a surface slope of approximately 1deg. If the slope is above this threshold, the tracked surface in the returned waveform may be not the point of closed approach causing an error in slope correction. For this reason, the analysis was limited to slopes of 1deg or less in this study. We used extensive coverage of Antarctica provided by the ICESat laser altimeter mission between 2003 and 2009 to assess the accuracy of SARInM data. We corrected for changes in elevations due to the interval between the acquisition of the ICESat and CryoSat-2 data (from July 2010 and December 2013). Two methods were used: (1) the ICESat point was compared with a DEM derived from CryoSat-2 data (Point-to-DEM; PtoDEM), and (2) the ICESat point was compared with a CryoSat-2 point directly (Point-to-Point; PtoP). For PtoDEM, CryoSat-2 elevations were interpolated onto a regular 1km polar stereographic grid with a standard parallel of 71°S, using ordinary kriging. For PtoP, the maximum distance between a CryoSat-2 point location and ICESat point location was set to 35m. For the areas with slopes less than 0.2deg, the

  12. Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

    NASA Astrophysics Data System (ADS)

    Yang, Jun; Fan, Lixue; Wang, Feijian; Luo, Yuan; Sui, Xin; Li, Wanhua; Zhang, Xiaohong; Wang, Yongan

    2016-05-01

    The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and

  13. Quantification of sarin and cyclosarin metabolites isopropyl methylphosphonic acid and cyclohexyl methylphosphonic acid in minipig plasma using isotope-dilution and liquid chromatography- time-of-flight mass spectrometry.

    PubMed

    Evans, R A; Jakubowski, E M; Muse, W T; Matson, K; Hulet, S W; Mioduszewski, R J; Thomson, S A; Totura, A L; Renner, J A; Crouse, C L

    2008-01-01

    An analysis method for determining isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA), the metabolic hydrolysis products of toxic organophosphorus nerve agents isopropyl methylphosphonofluoridate (sarin, GB) and cyclohexyl methylphosphonofluoridate (cyclosarin, GF), respectively, has been developed and validated using high-performance liquid chromatography-mass spectrometry with negative ion electrospray ionization with time-of-flight detection (LC-ESI-MS-TOF). The linear range of quantitation was 5 to 125 ng/mL in plasma with a method detection limit of 2 ng/mL for each compound. This method was developed to determine the amount of metabolic hydrolysis that was formed during and after nerve agent exposure in minipigs to account for a major pathway of GB and GF elimination that had not been previously characterized in the bloodstream, particularly during low-level whole-body inhalation experiments. Metabolic hydrolysis accounted for 70% to 90% of the recoverable agent in the bloodstream during exposure, when compared to both unbound and cholinesterase bound agent recovered by fluoride ion reactivation analysis for the same samples. The estimated half-life of IMPA and CMPA in plasma was determined to be 44 and 61 min, respectively. The method utilizes the mass selectivity of LC-ESI-MS-TOF using a bench-top instrument to achieve a detection limit that is consistent with reported LC-MS-MS methods analyzing blood samples.

  14. Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology

    SciTech Connect

    Testylier, Guy . E-mail: guytestylier@crssa.net; Lahrech, Hana; Montigon, Olivier; Foquin, Annie; Delacour, Claire; Bernabe, Denis; Segebarth, Christoph; Dorandeu, Frederic; Carpentier, Pierre

    2007-04-15

    Purpose: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. Methods: Three hours and 24 h after the intoxication with soman (172 {mu}g/kg), the mice were anesthetized with an isoflurane/N{sub 2}O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. Results: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication and was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. Conclusions: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into Brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures.

  15. The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures

    DTIC Science & Technology

    2015-01-30

    convulsions. Electroencephalography and clinical neurophysiology 32:557-60 170 163. Lipp JA. 1973. Effect of benzodiazepine derivatives on soman...232. Racine RJ. 1972. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalography and clinical

  16. Alumina-supported oxime for the degradation of sarin and diethylchlorophosphate.

    PubMed

    Verma, Aniza K; Srivastava, Avanish K; Singh, Beer; Shah, Dilip; Shrivastava, Smriti; Shinde, Chandra Kant P

    2013-02-01

    1-(4-Chlorophenyl))-N-hydroxymethanimine and cyclohexyl-N-hydroxymethanimine were synthesized and a well-established oxime, i.e., 2-[(hydroxyimino)methyl]-1-methylpyridinium chloride was purchased. Thereafter; all were loaded over Al(2)O(3) using incipient wetness technique. The prepared systems were characterized using surface area analyzer, scanning electron microscope, energy dispersive X-ray spectrophotometer, Fourier transform infrared spectrophotometer and thermogravimetric analyzer. Kinetics of the degradation of sarin (GB) and simulant, i.e. diethylchlorophosphate (DEClP) was studied over synthesized oxime impregnated Al(2)O(3) and results were compared with well reported oxime impregnated Al(2)O(3). Kinetics of reaction was found to be following the pseudo first order reaction kinetics. The order of reactivity of the prepared systems was found to be cyclohexyl-N-hydroxymethanimine/Al(2)O(3)>1-(4-chlorophenyl)-N-hydroxymethanimine/Al(2)O(3)>2-[(hydroxyimino)methyl]-1-methylpyridinium chloride/Al(2)O(3)>Al(2)O(3). From the reaction kinetics it was observed that the reaction with DEClP was faster than with GB. Cyclohexyl-N-hydroxymethanimine/Al(2)O(3) was found to be the most reactive system with half-life of 0.94 and 15 h for DEClP and GB respectively.

  17. Symptoms of Gulf War veterans possibly exposed to organophosphate chemical warfare agents at Khamisiyah, Iraq.

    PubMed

    McCauley, L A; Rischitelli, G; Lambert, W E; Lasarev, M; Sticker, D L; Spencer, P S

    2001-01-01

    During the 1991 Gulf War, some Allied troops were potentially exposed to sarin/cyclosarin as the result of the destruction of Iraqi munitions at Khamisiyah. To evaluate the prevalence of past and current symptoms known to be associated with exposure to these chemical warfare agents, the authors conducted a computer-assisted telephone survey of 2,918 U.S. Gulf War veterans. Veterans who had participated in or witnessed the demolition in 1991 were more likely to report historical or extant symptoms than were veterans from other military units. These results should be viewed cautiously because they are based on symptoms recalled nine years after the event without precise characterization of exposure. Nonetheless, the findings suggest that symptoms consistent with low-level sarin exposure may have initially occurred, and health effects may have persisted in the veterans who were nearest to the demolition activity. Further research is warranted.

  18. Increased expression of immune modulator proteins and decreased expression of apolipoprotein A-1 and haptoglobin in blood plasma of sarin exposed rats.

    PubMed

    Chaubey, Kalyani; Rao, M Kameshwar; Alam, S Imteyaz; Waghmare, Chandrakant; Bhattacharya, Bijoy K

    2016-02-25

    Sarin is a highly toxic organophosphonate and neural enzyme acetylcholinesterase (AChE) inhibitor. Inhibition of AChE causes large accumulation of acetylcholine at synaptic cleft leading to hyper activation of nicotinic and muscarinic acetylcholine receptors, causing excessive secretions, muscle fasciculation, nausea, vomiting, respiratory distress and neurological effects. There are cases in which long term psychomotor function deficiency, reduced learning and memory functions have been observed several years after exposure of sarin among survivors. This phenomenon is called Organophosphorus ester Induced Chronic Neurotoxicity (OPICN) and cannot be explained by AChE inhibition alone. Plasma proteomics at earlier stages was carried out to study changes reflected at blood level that can help predict possible neurological insults at an early time point to take proper therapeutic interventions against OPICN. In the present study, a 0.5 LD50 dose of sarin was administered to Wistar rats and possible changes in blood plasma proteomic profile were investigated after one and seven days of sarin exposure. Proteins were separated on 2-dimensional gel electrophoresis and identified by MALDI-TOF/MS. Expression profile of major proteins was validated by Western blot. Result showed that after exposure of sarin inhibition of AChE persisted after one week of exposure. There were 14 plasma proteins that showed significant changes in expression (>1.5-fold). It included proteins related to immune function, neurodegenerative condition and chaperone function. Interestingly sarin exposure caused decreased expression of plasma Apolipoprotein A-1 and Haptoglobin on day seven, which are the putative early molecular markers for cognitive impairment and neurodegenerative changes.

  19. Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans

    PubMed Central

    Chao, Linda L.; Rothlind, Johannes C.; Cardenas, Valerie A.; Meyerhoff, Dieter J.; Weiner, Michael W.

    2010-01-01

    Background Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Methods Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002–2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. Results GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p≤0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. Conclusions These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. PMID:20580739

  20. Pretreatment with human serum butyrylcholinesterase alone prevents cardiac abnormalities, seizures, and death in Göttingen minipigs exposed to sarin vapor.

    PubMed

    Saxena, Ashima; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Hastings, Nicholas B; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

    2011-12-15

    Human serum butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a prophylactic countermeasure against organophosphorus nerve agents. This study was designed to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to a lethal dose of sarin (GB) vapor. Male Göttingen minipigs were subjected to: air exposure, GB vapor exposure, or pretreatment with Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection 24 h prior to exposure to 4.1 mg/m(3) of GB vapor for 60 min. Electrocardiograms (ECG), electroencephalograms (EEG), and pupil size were recorded throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB present. Untreated animals exposed to GB vapor exhibited cardiac abnormalities and generalized seizures, ultimately succumbing to respiratory failure. Pretreatment with 3.0 or 6.5 mg/kg of Hu BChE delayed blood gas and acid-base disturbances and the onset of cardiac and neural toxic signs, but failed to increase survivability. Pretreatment with 7.5 mg/kg of Hu BChE, however, completely prevented toxic signs, with blood chemistry and ECG and EEG parameters indistinguishable from control during and after GB exposure. GB bound in plasma was 200-fold higher than plasma from pigs that did not receive Hu BChE, suggesting that Hu BChE scavenged GB in blood and prevented it from reaching other tissues. Thus, prophylaxis with Hu BChE alone not only increased survivability, but also prevented cardiac abnormalities and neural toxicity in minipigs exposed to a lethal dose of GB vapor.

  1. Single whole-body exposure to sarin vapor in rats: long-term neuronal and behavioral deficits.

    PubMed

    Grauer, Ettie; Chapman, Shira; Rabinovitz, Ishai; Raveh, Lily; Weissman, Ben-Avi; Kadar, Tamar; Allon, Nahum

    2008-03-01

    Freely moving rats were exposed to sarin vapor (34.2+/-0.8 microg/l) for 10 min. Mortality at 24 h was 35% and toxic sings in the surviving rats ranged from sever (prolonged convulsions) through moderate to almost no overt signs. Some of the surviving rats developed delayed, intermittent convulsions. All rats were evaluated for long-term functional deficits in comparison to air-exposed control rats. Histological analysis revealed typical cell loss at 1 week post inhalation exposure. Neuronal inflammation was demonstrated by a 20-fold increase in prostaglandin (PGE(2)) levels 24 h following exposure that markedly decreased 6 days later. An additional, delayed increase in PGE(2) was detected at 1 month and continued to increase for up to 6 months post exposure. Glial activation following neural damage was demonstrated by an elevated level of peripheral benzodiazepine receptors (PBR) seen in the brain 4 and 6 months after exposure. At the same time muscarinic receptors were unaffected. Six weeks, four and six months post exposure behavioral evaluations were performed. In the open field, sarin-exposed rats showed a significant increase in overall activity with no habituation over days. In a working memory paradigm in the water maze, these same rats showed impaired working and reference memory processes with no recovery. Our data suggest long lasting impairment of brain functions in surviving rats following a single sarin exposure. Animals that seem to fully recover from the exposure, and even animals that initially show no toxicity signs, developed some adverse neural changes with time.

  2. Single whole-body exposure to sarin vapor in rats: Long-term neuronal and behavioral deficits

    SciTech Connect

    Grauer, Ettie Chapman, Shira; Rabinovitz, Ishai; Raveh, Lily; Weissman, Ben-Avi; Kadar, Tamar; Allon, Nahum

    2008-03-01

    Freely moving rats were exposed to sarin vapor (34.2 {+-} 0.8 {mu}g/l) for 10 min. Mortality at 24 h was 35% and toxic sings in the surviving rats ranged from sever (prolonged convulsions) through moderate to almost no overt signs. Some of the surviving rats developed delayed, intermittent convulsions. All rats were evaluated for long-term functional deficits in comparison to air-exposed control rats. Histological analysis revealed typical cell loss at 1 week post inhalation exposure. Neuronal inflammation was demonstrated by a 20-fold increase in prostaglandin (PGE{sub 2}) levels 24 h following exposure that markedly decreased 6 days later. An additional, delayed increase in PGE{sub 2} was detected at 1 month and continued to increase for up to 6 months post exposure. Glial activation following neural damage was demonstrated by an elevated level of peripheral benzodiazepine receptors (PBR) seen in the brain 4 and 6 months after exposure. At the same time muscarinic receptors were unaffected. Six weeks, four and six months post exposure behavioral evaluations were performed. In the open field, sarin-exposed rats showed a significant increase in overall activity with no habituation over days. In a working memory paradigm in the water maze, these same rats showed impaired working and reference memory processes with no recovery. Our data suggest long lasting impairment of brain functions in surviving rats following a single sarin exposure. Animals that seem to fully recover from the exposure, and even animals that initially show no toxicity signs, developed some adverse neural changes with time.

  3. 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.

  4. Decontamination of chemical agents in Freon-113. Final report, February 1984-August 1988

    SciTech Connect

    Johnson, W.C.; Collins, K.R.; Ward, J.R.; Richmond, J.A.

    1993-06-01

    Freon solubilizes hydrophobic chemical warfare agents, such as soman, without damaging sensitive electronic equipment, such as night-vision goggles or communication equipment. Freon is used in this manner in the Nonaqueous Equipment Decontamination System (NAEDS) under development at CRDEC. The contaminated Freon is returned to a still, after which it is distilled through an aqueous layer containing bleach to decontaminate the residual agent. This report describes the results of experiments to measure how effectively agent is destroyed in the NAEDS. These results show that residual agent is still left in the redistilled Freon, and there is little difference whether the active decontaminant is removed from the aqueous layer. A mixture was prepared consisting of a 1:1:1 mixture of ethanol, 8 m sodium hydroxide, and Freon. It was demonstrated that the use of this mixture in the NAEDS would destroy all agent and that the redistilled Freon was free of soman. Freon-113, Bleach, Decontamination, Distillation, Non-Aqueous equipment decontamination system, Ethanol blend.

  5. The Role of DARPP-32, an Intracellular Signaling Molecule, in the Actions of the Nerve Agent Sarin

    DTIC Science & Technology

    2005-08-01

    calmodulin-dependent protein phosphatase signaling cascade, which dephosphorylates phospho-T34-DARPP-32 (Nishi et al., 1999). DARPP-32 is also...32 at Ser-102 (S102) and Ser-137 (S137). For example, S102 on DARPP-32 is phosphorylated by casein kinase II (CK2). In previously published...al., 1989). DARPP-32 is also phosphorylated on amino acid S137 by casein kinase I (CK1). Increases in phosphorylation at this site decrease the rate

  6. CryoSat Level1b SAR/SARin BaselineC: Product Format and Algorithm Improvements

    NASA Astrophysics Data System (ADS)

    Scagliola, Michele; Fornari, Marco; Di Giacinto, Andrea; Bouffard, Jerome; Féménias, Pierre; Parrinello, Tommaso

    2015-04-01

    CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvements in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. The current IPF, Baseline B, was released in operation in February 2012. A reprocessing campaign followed, in order to reprocess the data since July 2010. After more than 2 years of development, the release in operations of Baseline C is expected in the first half of 2015. BaselineC Level1b products will be distributed in an updated format, including for example the attitude information (roll, pitch and yaw) and, for SAR/SARIN, the waveform length doubled with respect to Baseline B. Moreveor, various algorithm improvements have been identified: • a datation bias of about -0.5195 ms will be corrected (SAR/SARIn) • a range bias of about 0.6730 m will be corrected (SAR/SARIn) • a roll bias of 0.1062 deg and a pitch bias of 0.0520 deg • Surface sample stack weighting to filter out the single look echoes acquired at highest look angle, that results in a sharpening of the 20Hz waveforms With the operational release of BaselineC, the second CryoSat reprocessing campaign will be initiated, taking benefit of the upgrade implemented in the IPF1 processing chain but also at IPF2 level. The reprocessing campaign will cover the full Cryosat mission starting on 16th July 2010

  7. Docking and molecular dynamics studies of peripheral site ligand-oximes as reactivators of sarin-inhibited human acetylcholinesterase.

    PubMed

    de Almeida, Joyce S F D; Cuya Guizado, Teobaldo R; Guimarães, Ana P; Ramalho, Teodorico C; Gonçalves, Arlan S; de Koning, Martijn C; França, Tanos C C

    2016-12-01

    In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.

  8. Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats.

    PubMed

    Mioduszewski, R; Manthei, J; Way, R; Burnett, D; Gaviola, B; Muse, W; Thomson, S; Sommerville, D; Crosier, R

    2002-04-01

    Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.

  9. A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

    SciTech Connect

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.; and others

    2015-04-15

    Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after

  10. A comparison of the ability of a new bispyridinium oxime--1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods.

    PubMed

    Kuca, K; Kassa, J

    2003-12-01

    The efficacy of a new bispyridinium oxime 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide, called K048, and currently used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. The new oxime K048 was found to be a more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than pralidoxime (in the case of VX, tabun and cyclosarin), obidoxime (cyclosarin and tabun) and HI-6 (tabun) but it did not reach the efficacy of currently used oximes for the reactivation of acetylcholinesterase inhibited by sarin. Thus, the oxime K048 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, it could be useful for the treatment of a nerve agent-exposed population if information about detection of the type of nerve agent is not available.

  11. Estimate of Forest Height in the Brazilian Amazon Using Radar Altimeter Data of SARIN Mode Onboard Cryosat-2

    NASA Astrophysics Data System (ADS)

    Yang, Le; Liu, Qinhuo

    2014-11-01

    This paper addresses the potential and limitations of radar altimetry inversion techniques for quantitative forest parameter estimation in tropical forests using Cryosat2 SIRAL waveform data of the synthetic aperture/interferometric (SARin) mode for very dense and tall forest canopies in Brazil, Amazon. The 20Hz waveform data of SARin mode of Cycle 5 subcycle 3 (August 20th, 2012) and subcycles 4 (September 18th, 2012) were analyzed and used to retrieve canopy height under Cryosat2 ground track. Waveform analysis shows that the power waveform exhibits interesting features in detecting forest vertical structures in different area. With the help of coherence waveform, the canopy height is derived by determining the key points of forest top and ground returns. Because of lack of field tree height measurement in 2012 at Amazon, we validated the results using the global forest height product based on ICEsat1 GLAS data in 2005 and the field measurements at Tapajos National Forest, Brazil in 1999. Results indicated that the mean value of the canopy height from Cryosat2/SIRAL is between that of the Lidar data and field measurements. The height estimated using Cryosat2/ SIRAL data is much closer to the Lorey's height than the mean and maximum height. Radar altimeter has shown promise to map structure in high density regions of the tropics.

  12. Estimate of Forest Height in the Brazilian Amazon Using Radar Altimeter Data of SARIN Mode Onboard Cryosat-2

    NASA Astrophysics Data System (ADS)

    Yang, Le; Liu, Qinhuo

    2014-11-01

    This paper addresses the potential and limitations of radar altimetry inversion techniques for quantitative forest parameter estimation in tropical forests using Cryosat2 SIRAL waveform data of the synthetic aperture/interferometric (SARin) mode for very dense and tall forest canopies in Brazil, Amazon. The 20Hz waveform data of SARin mode of Cycle 5 subcycle 3 (August 20th, 2012) and subcycles 4 (September 18th, 2012) were analyzed and used to retrieve canopy height under Cryosat2 ground track. Waveform analysis shows that the power waveform exhibits interesting features in detecting forest vertical structures in different area. With the help of coherence waveform, the canopy height is derived by determining the key points of forest top and ground returns. Because of lack of field tree height measurement in 2012 at Amazon, we validated the results using the global forest height product based on ICEsat1 GLAS data in 2005 and the field measurements at Tapajos National Forest, Brazil in 1999. Results indicated that the mean value of the canopy height from Cryosat2/SIRAL is between that of the Lidar data and field measurements. The height estimated using Cryosat2/ SIRAL data is much closer to the Lorey’s height than the mean and maximum height. Radar altimeter has shown promise to map structure in high density regions of the tropics.

  13. Our recent experiences with sarin poisoning cases in Japan and pesticide users with references to some selected chemicals.

    PubMed

    Yokoyama, Kazuhito

    2007-03-01

    Attention has been paid to neurobehavioral effects of occupational and environmental exposures to chemicals such as pesticides, heavy metals and organic solvents. The area of research that includes neurobehavioral methods and effects in occupational and environmental health has been called "Occupational and Environmental Neurology and Behavioral Medicine." The methods, by which early changes in neurological, cognitive and behavioral function can be assessed, include neurobehavioral test battery, neurophysiological methods, questionnaires and structured interview, biochemical markers and imaging techniques. The author presents his observations of neurobehavioral and neurophysiological effects in Tokyo subway sarin poisoning cases as well as in pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness (GTS). In sarin cases, a variety effects were observed 6-8 months after exposure, suggesting delayed neurological effects. Studies on pesticide users revealed that organophosphorus and dithiocarbamate affected peripheral nerve conduction and postural balance; subjective symptoms related to GTS were also observed, indicating the effects of nicotine absorbed from wet tobacco leaves. In addition, non-neurological effects of pesticides and other chemicals are presented, in relation to genetic polymorphism and oxidative stress.

  14. Zirconium doped nano-dispersed oxides of Fe, Al and Zn for destruction of warfare agents

    SciTech Connect

    Stengl, Vaclav; Houskova, Vendula; Bakardjieva, Snejana; Murafa, Nataliya; Marikova, Monika; Oplustil, Frantisek; Nemec, Tomas

    2010-11-15

    Zirconium doped nano dispersive oxides of Fe, Al and Zn were prepared by a homogeneous hydrolysis of the respective sulfate salts with urea in aqueous solutions. Synthesized metal oxide hydroxides were characterized using Brunauer-Emmett-Teller (BET) surface area and Barrett-Joiner-Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), scanning electron microscopy (SEM) and energy-dispersive X-ray microanalysis (EDX). These oxides were taken for an experimental evaluation of their reactivity with sulfur mustard (HD or bis(2-chloroethyl)sulfide), soman (GD or (3,3'-Dimethylbutan-2-yl)-methylphosphonofluoridate) and VX agent (S-[2-(diisopropylamino)ethyl]-O-ethyl-methylphosphonothionate). The presence of Zr{sup 4+} dopant can increase both the surface area and the surface hydroxylation of the resulting doped oxides, decreases their crystallites' sizes thereby it may contribute in enabling the substrate adsorption at the oxide surface thus it can accelerate the rate of degradation of warfare agents. Addition of Zr{sup 4+} converts the product of the reaction of ferric sulphate with urea from ferrihydrite to goethite. We found out that doped oxo-hydroxides Zr-FeO(OH) - being prepared by a homogeneous hydrolysis of ferric and zirconium oxo-sulfates mixture in aqueous solutions - exhibit a comparatively higher degradation activity towards chemical warfare agents (CWAs). Degradation of soman or VX agent on Zr-doped FeO(OH) containing ca. 8.3 wt.% of zirconium proceeded to completion within 30 min.

  15. High-sensitivity, high-selectivity detection of chemical warfare agents

    NASA Astrophysics Data System (ADS)

    Pushkarsky, Michael B.; Webber, Michael E.; Macdonald, Tyson; Patel, C. Kumar N.

    2006-01-01

    We report high-sensitivity detection of chemical warfare agents (nerve gases) with very low probability of false positives (PFP). We demonstrate a detection threshold of 1.2ppb (7.7μg/m3 equivalent of Sarin) with a PFP of <1:106 in the presence of many interfering gases present in an urban environment through the detection of diisopropyl methylphosphonate, an accepted relatively harmless surrogate for the nerve agents. For the current measurement time of ˜60s, a PFP of 1:106 corresponds to one false alarm approximately every 23months. The demonstrated performance satisfies most current homeland and military security requirements.

  16. Nanodispersive mixed oxides for destruction of warfare agents prepared by homogeneous hydrolysis with urea

    NASA Astrophysics Data System (ADS)

    Daněk, Ondřej; Štengl, Václav; Bakardjieva, Snejana; Murafa, Nataliya; Kalendová, Andrea; Opluštil, Frantisek

    2007-05-01

    Nanocrystalline mixed oxides of Ti, Zn, Al and Fe were prepared by a homogeneous hydrolysis of sulphates with urea at temperature of 100 °C in an aqueous solution. The prepared samples were characterized by BET and BJH measurements, an X-ray powder diffraction and scanning electron microscopy. These oxides were taken for an experimental evaluation of their reactivity with yperite (2,2‧-dichloroethyl sulphide), soman (3,3-dimethyl-2-butyl methylphosphonofluoridate) and matter VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothionate). An excellent activity in decomposition of chemical warfare agents was observed in these materials (conversion degree higher then 96%/h).

  17. Robust Lake Level Extraction in Mountainous Areas By Retracking Cryosat Sarin Mode Waveforms.

    NASA Astrophysics Data System (ADS)

    Kleinherenbrink, M.; Ditmar, P.; Lindenbergh, R.

    2014-12-01

    Since the beginning of the 1990s, lake levels can be monitored using satellite altimetry.This is notably an advantage for lakes located in remote areas, where no gauges are present.Two disadvantages of traditional satellite altimetry however are the limited number of ground tracks and the pulse limited footprint size.In 2010 Cryosat was launched with onboard a SAR Interferometric Radar ALtimeter (SIRAL), which has a dense ground track spacing of 7-8 km and a along-track resolution of approximately 300 m in the SAR Interferometric (SARIn) mode.This potentially enables Cryosat to sample more lakes and obtain more reliable lake levels in near-shore regions.Still, the accuracy and robustness of standard level 2 data is limited due to pollution of the waveform in near-shore regions.We propose therefore to actively extract the water surface by a novel retracking algorithm based on cross-correlation of observed level 1b waveforms with a generic simulated waveform.As a result, we obtain multiple elevations per waveform.As the water level is contributing to each consecutive waveform over the lake, it can efficiently be extracted using a majority voting scheme.By comparing the lake levels to those obtained with Jason-2 over Lake Nasser an RMS of differences of 0.30 m is found.After this validation step, we applied the procedure to lakes in Tian Shan and Tibet.In these areas 125 lakes are measured at least four times in two years, of which 30 are even sampled ten times in two years and 16 more than twenty times.For the ones sampled more than twenty times an additional slope in the water surface could be estimated, which can be an effect of prevailing winds or errors in the geoid model.Ultimately, we found a negative water balance in the natural lakes in Tian Shan and a positive balance in Tibet between February 2012 and February 2014.These results clearly demonstrate the potential of Cryosat, as previous radar altimetry missions were only able to sample about 70 lakes over

  18. Deterioration in brain and heart functions following a single sub-lethal (0.8 LCt{sub 50}) inhalation exposure of rats to sarin vapor:

    SciTech Connect

    Allon, N. Chapman, S.; Egoz, I.; Rabinovitz, I.; Kapon, J.; Weissman, B.A.; Yacov, G.; Bloch-Shilderman, E.; Grauer, E.

    2011-05-15

    The main injuries among victims of the terrorist act in the Tokyo subway resulted from sub-lethal inhalation and whole body exposure to sarin vapor. In order to study the long term effects of such exposure and to simulate these conditions, freely moving rats were exposed to sarin vapor (27.2 {+-} 1.7 {mu}g/l) for 10 min. About 50% of the rats showed no overt symptoms and the rest had mild to moderate clinical symptoms that subsided within 4 h following exposure. A reduction of weight was noted during the first 3 days with full recovery on the 4th day. Rat's heart was challenged with epinephrine 1 and 6 months post exposure. A significant reduction in the threshold for epinephrine-induced arrhythmia (EPIA) was noted in rats exposed to sarin. A time dependent increase in the kD and Bmax values of muscarinic auto receptors (M2) was recorded in the rat's cortex and striatum. No changes were recorded in the rats' brain trans locator protein (TSPO) levels, concomitant with no observed changes in the animals' performance in A Morris water maze test. A significant increase in open field activity was noted 6 months following exposure to sarin vapor as well as a significant decrease in prostaglandin E{sub 2} (PGE{sub 2}) production in the brain. It is speculated that down regulation of the M2 auto receptor function, caused hyper reactivity of the cholinergic system which leads to the changes described above. The continuous reduction in M2 auto-receptor system through an unknown mechanism may be the cause for long lasting decline in sarin-exposed casualties' health.

  19. Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin & physostigmine.

    PubMed

    Bansal, Iti; Waghmare, C K; Anand, T; Gupta, A K; Bhattacharya, B K

    2009-07-01

    A time-course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short-term effects were studied with an acute single subcutaneous dose (s.c.) of 80 microg kg(-1) (0.5 x LD(50)) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 h. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 h, which came back to near control values by 24 h in both cases. For long-term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg(-1) day(-1)) intramuscularly (i.m.), sarin (15 microg kg(-1) day(-1)) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg(-1) day(-1)) followed by sarin (s.c.) (15 microg kg(-1) day(-1)) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short-term as well as chronic long-term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression.

  20. 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.

  1. Aminopeptidase p mediated detoxification of organophosphonate analogues of sarin: mechanistic and stereochemical study at the phosphorus atom of the substrate.

    PubMed

    Huang, Li-Fang; Su, Benson; Jao, Shu-Chuan; Liu, Kwang-Ting; Li, Wen-Shan

    2006-03-01

    The activity of the aminopeptidase P from Escherichia coli in hydrolyzing a series of organophosphonate sarin analogues (1-6) was evaluated. The enzymatic rates of hydrolysis for methylphosphonate 1 with a methoxy group attached to the phosphorus center were 7- to 15-fold higher than those for the corresponding analogues 2-6. Double mutant R153W/R370L was able to hydrolyze the S(p) enantiomer of racemic 1 at a considerable rate. This mutant allowed the preparation of the R(p) isomer of the sarin analogue 1. All the mutants, R370L, R153A, W88L, R153L/R370L, and R153W/R370L, preferred the formation of (S(p))-8 to that of the corresponding (R(p))-8 enantiomer and displayed a better enantiomeric excess of products, by 1.4- to 2-fold as compared to the wild-type enzyme. Enzymatic hydrolysis of O,O-diisopropyl-p-nitrophenyl phosphate (9) in H(2) (18)O led to the formation of the (18)O-labeled O,O-diisopropyl phosphate product and confirmed that the catalytic reaction starts with cleavage of the P--O bond. From chemical and kinetic studies, the utilization of an optically pure S(p) enantiomer of O-methyl-p-nitrophenyl methylphosphonothioate (S(p))-MNMPT, 7) has demonstrated that the enzymatic reaction proceeds through a displacement mechanism and generates a chiral product in situ with an inversion of stereochemical configuration at the phosphorus atom. The results also lead to the conclusion that alteration of the active site through site-directed mutagenesis can result in a preference for (S(p))-MNMPT (7) rather than the R(p) isomer.

  2. Stack Characterization in CryoSat Level1b SAR/SARin Baseline C

    NASA Astrophysics Data System (ADS)

    Scagliola, Michele; Fornari, Marco; Di Giacinto, Andrea; Bouffard, Jerome; Féménias, Pierre; Parrinello, Tommaso

    2015-04-01

    CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. CryoSat is the first altimetry mission operating in SAR mode and it carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. The current CryoSat IPF (Instrument Processing Facility), Baseline B, was released in operation in February 2012. After more than 2 years of development, the release in operations of the Baseline C is expected in the first half of 2015. It is worth recalling here that the CryoSat SAR/SARin IPF1 generates 20Hz waveforms in correspondence of an approximately equally spaced set of ground locations on the Earth surface, i.e. surface samples, and that a surface sample gathers a collection of single-look echoes coming from the processed bursts during the time of visibility. Thus, for a given surface sample, the stack can be defined as the collection of all the single-look echoes pointing to the current surface sample, after applying all the necessary range corrections. The L1B product contains the power average of all the single-look echoes in the stack: the multi-looked L1B waveform. This reduces the data volume, while removing some information contained in the single looks, useful for characterizing the surface and modelling the L1B waveform. To recover such information, a set of parameters has been added to the L1B product: the stack characterization or beam behaviour parameters. The stack characterization, already included in previous Baselines, has been reviewed and expanded in Baseline C. This poster describes all the stack characterization parameters, detailing what they represent and how they have been computed. In details, such parameters can be summarized in: - Stack

  3. Synthesis and in vitro kinetic evaluation of N-thiazolylacetamido monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE).

    PubMed

    Valiveti, Aditya Kapil; Bhalerao, Uma M; Acharya, Jyotiranjan; Karade, Hitendra N; Acharya, Badri Narayan; Raviraju, G; Halve, Anand K; Kaushik, Mahabir Parshad

    2015-08-01

    Presently available medications for treatment of organiphosphorus poisoning are not sufficiently effective due to various pharmacological and toxicological reasons. In this regard, herein we report the synthesis of a series of N-thiazolylacetamide monoquaternary pyridinium oximes and its analogs (1a-1b to 6a-6b) with diversely substituted thiazole ring and evaluation of their in vitro reactivation efficacies against nerve agent (sarin, O-ethylsarin and VX) inhibited human erythrocyte acetylcholinesterase (hAChE). Reactivation kinetics was performed to determine dissociation constant (KD), reactivity rate constant (kr) and the second order rate constant (kr2) for all the compounds and compared their efficacies with commercial antidotes viz. 2-PAM and obidoxime. All the newly synthesized oximes were evaluated for their physicochemical parameters (pKa) and correlated with their respective reactivation efficacies to assess the capability of the oxime reactivator. Three of these novel compounds showed promising reactivation efficacies toward OP inhibited hAChE. Molecular docking studies were performed in order to correlate the reactivation efficacies with their interactions in the active site of the AChE.

  4. Resolving pathways of interaction of mipafox and a sarin-analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches

    PubMed Central

    Mangas, I; Taylor, P; Vilanova, E; Estévez, J; Franca, T; Radić, Z

    2016-01-01

    The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide mass fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF-TOF. The ACP was detected with a diethyl phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl phosphonylated and a methyl phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diidopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand

  5. Resolving pathways of interaction of mipafox and a sarin analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches.

    PubMed

    Mangas, I; Taylor, P; Vilanova, E; Estévez, J; França, T C C; Komives, E; Radić, Z

    2016-03-01

    The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here, our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF/TOF. The ACP was detected with a diethyl-phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl-phosphonylated and a methyl-phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diisopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However, with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand calculated

  6. Evaluation of the direct actions of HI-6 in reversing soman-induced tetanic fade

    SciTech Connect

    Adler, M.; Maxwell, D.M.; Sweeney, R.E.; Deshpande, S.S.

    1995-12-31

    The most widely accepted mechanism for the acute toxicity of organophosphorus anticholinesterase agents is irreversible inhibition of acetyicholinesterase (AChE), an enzyme present at all known cholinergic synapses (Taylor, 1990). Inhibition of AChE results in accumulation of acetyicholine (ACh), which then leads to aberrant cholinergic transmission (Katz and Miledi, 1973). The precise nature of the abnormality varies with the synapse, and can include depolorization, desensitization, repetitive firing or sustained activation (Hobbiger, 1976; Adler et al., 1992).

  7. Emergency management of chemical weapons injuries.

    PubMed

    Anderson, Peter D

    2012-02-01

    The potential for chemical weapons to be used in terrorism is a real possibility. Classes of chemical weapons include nerve agents, vesicants (blister agents), choking agents, incapacitating agents, riot control agents, blood agents, and toxic industrial chemicals. The nerve agents work by blocking the actions of acetylcholinesterase leading to a cholinergic syndrome. Nerve agents include sarin, tabun, VX, cyclosarin, and soman. The vesicants include sulfur mustard and lewisite. The vesicants produce blisters and also damage the upper airways. Choking agents include phosgene and chlorine gas. Choking agents cause pulmonary edema. Incapacitating agents include fentanyl and its derivatives and adamsite. Riot control agents include Mace and pepper spray. Blood agents include cyanide. The mechanism of toxicity for cyanide is blocking oxidative phosphorylation. Toxic industrial chemicals include agents such as formaldehyde, hydrofluoric acid, and ammonia.

  8. Development of a surface acoustic wave gas sensor for organophosphorus nerve agents employing lanthanide compounds as the chemical interface.

    PubMed

    Nieuwenhuizen, M S; Harteveld, J L

    1994-03-01

    The results of a study dealing with surface acoustic wave gas sensors for organophosphorus compounds such as nerve agents are described. Several lanthanum coordination compounds were applied as the chemical interface. The various sensors prepared were challenged with both the nerve agent sarin and the simulant dimethyl methylphosphonate. Many aspects were studied, such as sensitivity, selectivity, reversibility and response rate as well as the effect of temperature and structural features. Detection limits down to 0.1 ppm were found. Response rates require further improvement. Degradation phenomena were observed which in some cases yielded irreversible responses. The selectivity for organophosphorus compounds was found to be promising.

  9. Preliminary screening of alternative technologies to incineration for treatment of chemical-agent-contaminated soil, Rocky Mountain Arsenal

    SciTech Connect

    Shem, L.M.; Rosenblatt, D.H.; Smits, M.P.; Wilkey, P.L.; Ballou, S.W.

    1995-12-01

    In support of the U.S. Army`s efforts to determine the best technologies for remediation of soils, water, and structures contaminated with pesticides and chemical agents, Argonne National Laboratory has reviewed technologies for treating soils contaminated with mustard, lewisite, sarin, o-ethyl s-(2- (diisopropylamino)ethyl)methyl-phosphonothioate (VX), and their breakdown products. This report focuses on assessing alternatives to incineration for dealing with these contaminants. For each technology, a brief description is provided, its suitability and constraints on its use are identified, and its overall applicability for treating the agents of concern is summarized. Technologies that merit further investigation are identified.

  10. 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.

  11. Evaluation of a Recombinant Escherichia coli Strain that Uses the Sarin Simulant Isopropylmethylphosphonic Acid (IMPA) as a Sole Carbon and Phosphate Source

    DTIC Science & Technology

    2016-04-01

    phase before beginning exponential growth (Figure 4). However, similar results were observed by de la Pena et al. (6) when they used a similar...strains produced by LBNL yielded little growth on the sarin simulant isopropylmethylphosphonic acid (IMPA). However, ECBC-transformed strains, using...plasmids, had successful growth when transformed into a different E. coli background, which correlated with IMPA degradation. Ultimately, the

  12. The Fate of Chemical Warfare Agents in the Environment

    SciTech Connect

    Talmage, Sylvia Smith; Munro, Nancy B; Watson, Annetta Paule; King, J.; Hauschild, Veronique

    2007-01-01

    Chemical Warfare Agents, Second Edition has been totally revised since the successful first edition and expanded to about three times the length, with many new chapters and much more in-depth consideration of all the topics. The chapters have been written by distinguished international experts in various aspects of chemical warfare agents and edited by an experienced team to produce a clear review of the field. The book now contains a wealth of material on the mechanisms of action of the major chemical warfare agents, including the nerve agent cyclosarin, formally considered to be of secondary importance, as well as ricin and abrin. Chemical Warfare Agents, Second Edition discusses the physico-chemical properties of chemical warfare agents, their dispersion and fate in the environment, their toxicology and management of their effects on humans, decontamination and protective equipment. New chapters cover the experience gained after the use of sarin to attack travelers on the Tokyo subway and how to deal with the outcome of the deployment of riot control agents such as CS gas. This book provides a comprehensive review of chemical warfare agents, assessing all available evidence regarding the medical, technical and legal aspects of their use. It is an invaluable reference work for physicians, public health planners, regulators and any other professionals involved in this field.

  13. CW simulant detection by NDIR

    NASA Astrophysics Data System (ADS)

    Daly, Jim; McNeal, Mark; Gully, Bill; Swanson, Frank

    2005-11-01

    A compact, low-cost, multi-wavelength NDIR sensor was designed to measure G-type CW agents at ppm-levels. This 4-color sensor can distinguish between the different agents (sarin, soman, tabun) and is more sensitive than a single wavelength sensor. The design of the sensor and test results with simulants R-12 (dichlorodifluoromethane) and sulfur hexafluoride is presented. These test results support a lower detection limit of 3 ppmv for a 1 sec integration time. Modifications of the sensor design which will enable us to achieve <1 ppmv sensitivity are discussed.

  14. Serum cholesterol, uric acid and cholinesterase in victims of the Tokyo subway sarin poisoning: a relation with post-traumatic stress disorder.

    PubMed

    Tochigi, Mamoru; Umekage, Tadashi; Otani, Toshiyuki; Kato, Tadafumi; Iwanami, Akira; Asukai, Nozomu; Sasaki, Tsukasa; Kato, Nobumasa

    2002-11-01

    Cholesterol and uric acid, which might correlate with steroidogenesis and monoamine functions, may change under emotionally stressful conditions and in mental disturbances. Among anxiety disorders, an increase of serum cholesterol has been observed in panic disorder. However, the issue has not been adequately investigated in other anxiety disorders, including post-traumatic stress disorder (PTSD). The present study investigated serum cholesterols, uric acid and cholinesterase in victims of the Tokyo subway sarin poisoning, 1995, in a series of 5-year follow-ups. Cholinesterase was studied, in relevance with serum lipid changes and symptoms of PTSD, and also in light of a biological effect of sarin. Out of 34 victims, eight developed PTSD and two were currently diagnosed with PTSD using the Clinician-Administered PTSD Scale (CAPS). No significant relationship was observed between PTSD and serum cholesterols or uric acid. Several factors including co-occurrence of other mental disturbances with PTSD, in addition to the limited sample size, might have affected the result. In contrast, serum cholinesterase level was significantly reduced in the victims with the development of PTSD, compared with the matched controls (P<0.02, t-test). This might partly reflect a long-term remnant effect of sarin intoxication, although an effect of the psychological experience could not be totally excluded.

  15. CRUCIAL: Cryosat-2 Success over Inland Water and Land: Analyses and Validation of SAR and SARin Full Bit Rate Altimetric Heights

    NASA Astrophysics Data System (ADS)

    Moore, Philip; Benveniste, Jérôme; Birkinshaw, Stephen; Ambrózio, Américo; Restano, Marco

    2016-07-01

    CRUCIAL is an ESA/STSE funded project investigating innovative land and inland water applications from Cryosat-2 with a forward-look component to the future Sentinel-3 and Jason-CS/Sentinel-6 missions. The high along-track sampling of Cryosat-2 in its SAR and SARin modes offer the opportunity to recover high frequency signals over inland waters. A theoretical approach has been developed to process the FBR L1A Doppler beams to form a product using ground cell gridding, beam steering and beam stacking from which inland water heights are derivable from the retracked Cryosat-2 altimetric waveforms. Results of the processing strategy will include a comparison of waveforms and heights from the burst echoes (˜80 m along-track) and from multi-look waveforms (˜320 m along-track). SAR and SARin FBR data are available for the Amazon, Brahmaputra and Mekong for 2011-2015. FBR SAR results will be compared against stage data from the nearest gauge where applicable with heights from Tonle Sap compared against Jason-2 data from the United States Department of Agriculture. A strategy to select the number of multi-looks over rivers will also be presented. Results of FBR SARin processing for the Amazon and Brahmaputra will be presented including comparison of heights from the two antennae, extraction of slope of the ground surface and validation against ground data where appropriate.

  16. 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.

  17. Estimates of forest height in the Amazon basin using radar altimeter data of SARIN mode onboard Cryosat-2

    NASA Astrophysics Data System (ADS)

    Yang, L.; Sun, G.; Liu, Q.

    2013-12-01

    Forest height is an important parameter for global carbon cycle studies. New technologies are required since the end of the operation ofGeoscience Laser Altimeter System (GLAS) onboard The Ice, Cloud, and land Elevation Satellite (IceSat) in 2009. CryoSat-2 is a European Space Agencyenvironmental research satellite which was launched in April 2010.The SIRAL (SAR Interferometer Radar Altimeter) on board CryoSat-2 provides three operational modes for different observational requirements. Before the launch of Icesat2 around July 2016, CryoSat data represents a unique source of information on regional-to-global scale forest canopy height.We propose to use radar altimetry waveforms from the synthetic aperture/interferometric (SARin) mode to estimate canopy height in the Amazon basin. To understand the relation between canopy structure and the SIRAL waveform in Ku band, a 3D model was developed and implemented based on a Lidar model by introducingthe scattering items from crown, trunk and ground surface at Ku band. The vertical distribution of tree crown volume within a SIRAL footprint was calculated from its 3-D stand model by summing the volumes of all tree crown cells at the same height from the ground. The preliminary comparisons between simulated and measured SIRAL waveforms show that the model captures the major characteristics of the SIRAL signature. Cryosat waveform data of SARin mode and from June, 2011 to June, 2012 (cycle 04) is used to retrieve canopy height at Amazon basin under Cryosat groundtrack. The canopy height is derived by extracting the key points of vegetation and ground returns after noise estimation. Because of lack of field tree height measurement in 2012 at Amazon, we validated the results using the field measurements at four areas (the km 67 camp, the km 77 camp, Ruropolis, the Taoajos river) of Tapajos National Forest, Brazil in November 1999, and compared the results with the canopy height estimation from previous studies using Laser

  18. [Toxicological effects of weapons of mass destruction and noxious agents in modern warfare and terrorism].

    PubMed

    Vucemilović, Ante

    2010-06-01

    Weapons of mass destruction (WMD) best portray the twisted use of technological achievements against the human species. Despite arm control efforts, WMD threat continues to exist and even proliferate. This in turn calls for improvement in defensive measures against this threat. The modern soldier is exposed to a number of chemical, biological, and radiological agents in military and peace operations, while civilians are mainly exposed to terrorist attacks. Regardless of origin or mode of action, WMDs and other noxious agents aim for the same - to make an organism dysfunctional. Because their effects are often delayed, these agents are hard to spot on time and treat. This review presents a biomedical aspect of agents used in warfare and terrorism, including polonium-210, depleted uranium, salmonella, anthrax, genetically modified bacteria, cobweb-like polymer fibre, sarin, and mustard gas.

  19. 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.

  20. Chemical warfare agent and high explosive identification by spectroscopy of neutron-induced gamma rays

    SciTech Connect

    Caffrey, A.J.; Cole, J.D.; Gehrke, R.J.; Greenwood, R.C. )

    1992-10-01

    This paper reports on a non-destructive assay method to identify chemical warfare (CW) agents and high explosive (HE) munitions which was tested with actual chemical agents and explosives at the Tooele Army Depot, Tooele, Utah, from 22 April 1991 through 3 May 1991. The assay method exploits the gamma radiation produced by neutron interactions inside a container or munition to identify the elemental composition of its contents. The characteristic gamma-ray signatures of the chemical elements chlorine, phosphorus, and sulfur were observed form the CW agent containers and munitions, in sufficient detail to enable us to reliably discern agents GB (sarin), HD (mustard gas), and VX from one another, and from HE-filled munitions. By detecting of the presence of nitrogen, the key indictor of explosive compounds, and the absence of elements Cl, P, and S, HE shells were also clearly identified.

  1. Monitoring of lake level changes on the Tibetan Plateau and Tian Shan by retracking Cryosat SARIn waveforms

    NASA Astrophysics Data System (ADS)

    Kleinherenbrink, M.; Lindenbergh, R. C.; Ditmar, P. G.

    2015-02-01

    In this study we present, for the first time, the application of Cryosat SARIn mode data to monitor lakes in mountainous areas and to find their water balance. By applying a novel retracker, tailored for lake level observations, we find at least four useable passes for 125 lakes on the Tibetan Plateau and Tian Shan areas over the period February 2012 to January 2014. From these 125 lakes, 30 are passed at least ten times, for which we compute trends and periodic variations, and 16 lakes more then twenty times, for which we additionally apply a water slope correction. This slope correction accounts for geoid inaccuracies or wind effects. We compared the results over two lakes, Langa Co and Bosten, with Jason-2 measurements. Over Langa Co we find an RMS difference of 0.55 m, while for Lake Bosten this is only 0.26 m. For Lake Bosten, the estimated trends, annual and semi-annual variations from the Cryosat and Jason-2 datasets are compared as well. The estimated amplitudes are comparable, while derived phases differ by a few days. Using the trends of all lakes passed at least ten times, a water volume balance of natural lakes is estimated. A loss of 1.51 ± 0.11 km3 y-1 is observed in the lakes in the Tian Shan area. In Tibet, a positive mass balance is estimated of 1.76 ± 0.24 km3 y-1.

  2. QSAR models for the reactivation of sarin inhibited acetylcholinesterase by quaternary pyridinium oximes based on Monte Carlo method.

    PubMed

    Veselinović, Aleksandar M; Veselinović, Jovana B; Toropov, Andrey A; Toropova, Alla P; Nikolić, Goran M

    2014-01-01

    Monte Carlo method has been used as a computational tool for building QSAR models for the reactivation of sarin inhibited acetylcholinesterase (AChE) by quaternary pyridinium oximes. Simplified molecular input line entry system (SMILES) together with hydrogen-suppressed graph (HSG) was used to represent molecular structure. Total number of considered oximes was 46 and activity was defined as logarithm of the AChE reactivation percentage by oximes with concentration of 0.001 M. One-variable models have been calculated with CORAL software for one data split into training, calibration and test set. Computational experiments indicated that this approach can satisfactorily predict the desired endpoint. Best QSAR model had the following statistical parameters: for training set r2=0.7096, s=0.177, MAE=0.148; calibration set: r2=0.6759, s=0.330, MAE=0.271 and test set: r2=0.8620, s=0.182, MAE=0.150. Structural indicators (SMILES based molecular fragments) for the increase and the decrease of the stated activity are defined. Using defined structural alerts computer aided design of new oxime derivatives with desired activity is presented.

  3. Sampling and monitoring operations for mustard (HD) and sarin (GB) at Rocky Mountain Arsenal

    SciTech Connect

    Not Available

    1990-01-01

    This report is a summarization of Phase II activities at RMA which Included: Sampling operations for the presence of HD and GB in the south plants and north plants areas; Protection of workers and the environment during the sample preparation and sampling periods. A total of 203 samples were analyzed (182 GB and 21 HD). 6 HD and 43 GB sample points were verified as 'X' or above the TWA. The report is divided into the following sections: Summary of sampling results; Building descriptions; Chemical agent information; Sampling plan; Summary of sampling operations; Monitoring plan. (Author).

  4. In Vivo Reactivation by Oximes of Inhibited Blood, Brain and Peripheral Tissue Cholinesterase Activity Following Exposure to Nerve Agents in Guinea Pigs

    DTIC Science & Technology

    2010-01-01

    nerve agent intoxication ( salivation , rhinorrhea, tremors,muscle asciculations, convulsions) at 60min following the 1.0× LD50 dose f GB, GF, VR or VX...reactivation of GF-, soman-, or VR-inhibited enzyme byHI-6 andHLö7. However, these in vitro experiments [24,25] were conducted with a pH of 8.0 at 25 ◦C...data. Even the study of Worek et al. [23] that was performed at a pH of 7.4 at 37 ◦C, whose in vitro kinetic data obtained from guinea pig RBC ghosts

  5. Analysis for chemical agent breakdown products: Avoiding IMPA false positives

    SciTech Connect

    Ives, K.M.; Markowitz, V.

    1996-12-31

    Cleanup of DOD sites where chemical warfare agents have been used or stored presents a number of unique problems. Isopropylmethylphosphonic Acid (IMPA), a degradation product of Sarin (GB), is one important contaminant to be monitored at many such sites. IMPA has historically been determined by Army Environmental Center (AEC) method UT02, an ion chromatography method. This method is prone to serious interference problems which can lead an inexperienced analyst to report false positive results. A study of interferences present in groundwater samples taken from a US military installation was undertaken. The interference problems were identified, and techniques were developed which minimize the problem in most samples. These techniques have been used by the authors in several large studies at DOD sites, and have virtually eliminated false positive problems.

  6. Characterization of organophosphorus hydrolases and the genetic manipulation of the phosphotriesterase from pseudomonas diminuta

    SciTech Connect

    Dave, K.I.; Miller, C.E.; Wild, J.R.

    1993-12-31

    There are a variety of enzymes which are specifically capable of hydrolyzing organophosphorus esters with different phosphoryl bonds from the typical phosphotriester bonds of common insecticidal neurotoxins (e.g. paraoxon or coumaphos) to the phosphonate-fluoride bonds of chemical warfare agents (e.g. soman or sarin). These enzymes comprise a diverse set of enzymes whose basic architecture and substrate specificities vary dramatically, yet they appear to be ubiquitous throughout nature. The most thoroughly studied of these enzymes is the organophosphate hydrolase (opd gene product) of Pseudomonas diminuta and Ftavobacterium sp. ATCC 27551, and the heterologous expression, post-translational modification, and genetic engineering studies undertaken with this enzyme are described.

  7. Characterization of organophosphorus hydrolases and the genetic manipulation of the phosphotriesterase from Pseudomonas diminuta.

    PubMed

    Dave, K I; Miller, C E; Wild, J R

    1993-06-01

    There are a variety of enzymes which are specifically capable of hydrolyzing organophosphorus esters with different phosphoryl bonds from the typical phosphotriester bonds of common insecticidal neurotoxins (e.g. paraoxon or coumaphos) to the phosphonate-fluoride bonds of chemical warfare agents (e.g. soman or sarin). These enzymes comprise a diverse set of enzymes whose basic architecture and substrate specificities vary dramatically, yet they appear to be ubiquitous throughout nature. The most thoroughly studied of these enzymes is the organophosphate hydrolase (opd gene product) of Pseudomonas diminuta and Flavobacterium sp. ATCC 27551, and the heterologous expression, post-translational modification, and genetic engineering studies undertaken with this enzyme are described.

  8. Development of a thermal evaporation cell for gas-phase infrared absorption spectroscopy of compounds with low volatility.

    PubMed

    Ingram, John M; Fountain, Augustus W

    2007-11-01

    To facilitate in-depth hazard prediction models, we must understand the spectral properties of expulsion plumes from conventional weapon attacks. Precise data on the spectral absorption of three chemical weapon agent simulants, in the infrared regime, are required to properly determine the mass of simulant in expulsion plumes from field demonstrations and small scale tests. Data for triethyl phosphate (a Soman simulant), triethyl phosphite (a Sarin simulant), and tributyl phosphate (a VX simulant) are presented. A thermal evaporation cell was designed and built that incorporated features that are not commercially available.

  9. 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.

  10. Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.

    PubMed

    Ekström, Fredrik; Hörnberg, Andreas; Artursson, Elisabet; Hammarström, Lars-Gunnar; Schneider, Gunter; Pang, Yuan-Ping

    2009-06-18

    Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.

  11. Comparison of sarin and cyclosarin toxicity by subcutaneous, intravenous and inhalation exposure in Gottingen minipigs.

    PubMed

    Hulet, Stanley W; Sommerville, Douglas R; Miller, Dennis B; Scotto, Jacqueline A; Muse, William T; Burnett, David C

    2014-02-01

    Sexually mature male and female Gottingen minipigs were exposed to various concentrations of GB and GF vapor via whole-body inhalation exposures or to liquid GB or GF via intravenous or subcutaneous injections. Vapor inhalation exposures were for 10, 60 or 180 min. Maximum likelihood estimation was used to calculate the median effect levels for severe effects (ECT50 and ED50) and lethality (LCT50 and LD50). Ordinal regression was used to model the concentration × time profile of the agent toxicity. Contrary to that predicted by Haber's rule, LCT50 values increased as the duration of the exposures increased for both nerve agents. The toxic load exponents (n) were calculated to be 1.38 and 1.28 for GB and GF vapor exposures, respectively. LCT50 values for 10-, 60- and 180-min exposures to vapor GB in male minipigs were 73, 106 and 182 mg min/m(3), respectively. LCT50 values for 10-, 60 - and 180-min exposures to vapor GB in female minipigs were 87, 127 and 174 mg min/m(3), respectively. LCT50 values for 10-, 60- and 180-min exposures to vapor GF in male minipigs were 218, 287 and 403 mg min/m(3), respectively. LCT50 values for 10-, 60- and 180-min exposures in female minipigs were 183, 282 and 365 mg min/m(3), respectively. For GB vapor exposures, there was a tenuous gender difference which did not exist for vapor GF exposures. Surprisingly, GF was 2-3 times less potent than GB via the inhalation route of exposure regardless of exposure duration. Additionally GF was found to be less potent than GB by intravenous and subcutaneous routes.

  12. Monitoring recent lake level variations on the Tibetan Plateau using CryoSat-2 SARIn mode data

    NASA Astrophysics Data System (ADS)

    Jiang, Liguang; Nielsen, Karina; Andersen, Ole B.; Bauer-Gottwein, Peter

    2017-01-01

    Lakes on the Tibetan Plateau (TP) are of great interest due to their value as water resources but also as an important indicator of climate change. However, in situ data in this region are extremely scarce and only a few lakes have gauge measurements. Satellite altimetry has been used successfully to monitor lake levels. In this study, Cryosat-2 SARIn mode data over the period 2010-2015 are used to investigate recent lake level variations. The estimated water levels of the 70 largest lakes (> 100 km2) on the TP show that 48 lakes reveal a rising trend (avg. 0.28 ± 0.06 m/yr) while the other 22 show a slightly decreasing trend (avg. -0.10 ± 0.04 m/yr). To compare with the change rates during 2003-2009, ICESat data which cover 42 of the 70 lakes are also used. When combining the data, the results show that during the period of 2003-2015, 28 lakes maintained a rising trend and the change rates are comparable. Lakes in the northern part of the TP experienced pronounced rising (avg. 0.37 ± 0.10 m/yr), while lakes in southern part were steady or decreasing even in glaciated basins with high precipitation. Factor analysis indicates that driving factors for lake change are variable due to high spatial heterogeneity. However, autumn/winter temperature plays an important role in lake level change. These results demonstrate that lakes on the TP are still rapidly changing under climate change, especially in northern part of the TP, but the driving factors are variable and more research is needed to understand the mechanisms behind observed changes.

  13. Differences between male and female rhesus monkey erythrocyte acetylcholinesterase and plasma cholinesterase activity before and after exposure to sarin

    SciTech Connect

    Woodard, C.L.; Calamaio, C.A.; Kaminskis, A.; Anderson, D.R.; Harris, L.W.

    1993-05-13

    The female rhesus monkey has a menstrual cycle like the human. Additionally, several differences in enzyme levels between males and females and in the female during the menstrual cycle are present. Therefore we quantitated plasma cholinesterase (ChE/BuChE) and erythrocyte (RBC) acetylcholinesterase (AChE) activity before and after exposure to sarin (GB)(1 5 ug/kg, iv; a 0.75 LD50), in male and female rhesus (Macaca mulatta) monkeys. Twenty-eight-day preexposure baseline plasma ChE and RBC AChE values for six male and six female rhesus monkeys were compared for intra-animal, within sex and between sex differences. After these baseline values were obtained, the organophosphorus (OP) compound/Isopropyl methylphosphono-fluoridate (GB) was administered to atropinized monkeys to determine if there was a significant in vivo difference between the sexes in their response to this intoxication in regard to the rate of BuChE /AChE inhibition, pyridine-2-aldoxime methyl chloride (2-PAM) reactivation of the phosphonylated BuChE and the rate of aging of the phosphonylated:BuChE/AChE. In the pre-exposure portion of the protocol; the intra-animal and intra-group BuChE/AChE variations were found to be minimal; but there were significant differences between the male and female monkeys in both plasma BuChE and RBC AChE levels; although probably clinically insignificant in respect to an OP intoxication. No significant cyclic fluctuations were seen during the 28-day study in either sex.

  14. The chemical agent experience at Rocky Mountain Arsenal

    SciTech Connect

    Mohrman, G.

    1995-06-01

    Rocky Mountain Arsenal (RMA) was constructed and commissioned in 1942 for the production of sulfur mustard and other chemical munitions for possible use in World War II. RMA also became a production site for Lewisite and Sarin, including synthesis and munition filling. Other chemical agents such as Phosgene were routinely handled, filled into munitions and demilitarized. During the 1970`s and the early 1980`s, RMA served as a primary demilitarization facility for the destruction of chemical agents. Throughout its chemical weapons history, RMA generated waste materials from production, neutralization, decontamination and testing. These operations led to the possibility of chemical agent contamination in soils, process equipment and structures that have required special attention as part of the overall Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) environmental cleanup operations being conducted by the Program Manager Rocky Mountain Arsenal (PMRMA). Adjusting normal sampling operations associated with CERCLA-type activities for the special Army regulations covering chemical agents has been a difficult task. This presentation will describe the evolution of chemical agent related efforts and operations as they pertain to RMA environmental cleanup activities, to include field sampling requirements, analytical methods, commercial laboratory use and the role of the on-site PMRMA laboratory.

  15. Feasibility assessment of piezoelectric crystals as chemical warfare agent sensors. Final report, 1 August 1983-31 August 1985

    SciTech Connect

    Balog, P.P.; Stanford, T.B.; Nordstrom, R.J.; Burgener, R.C.

    1986-04-01

    The feasibility of a vibrating piezoelectric crystal as a CW agent detector was assessed by applying CW agent-sensitive coatings to the crystal and testing the detector with 0.3 mg/cum of GB (Sarin). Eight different coating materials were selected, based on previous data with G-agent simulants. No responses were observed to 0.3 mg/cum. GB, but three costings (XAD-4/Cu(2=)-diamine, polyethylenemaleate, and succinyl choline chloride) gave responses of -59 Hz, -22 Hz, and =11 Hz, respectively, to 10 mg/cm.of DIMP (diisopropyl methylphosphonate). Circuit optimization and the use of an operating frequency higher than 9 MHz is recommended to enhance sensitivity. Far-term recommendations are to apply the same coatings to a high-frequency (e.g., 300 MHz) surface acoustic-wave device and test again with CW agents.

  16. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... Orange Parkinson’s Awareness Month Were you exposed to herbicides during service and have Parkinson’s disease? You may ...

  17. Neurobiology of Soman

    DTIC Science & Technology

    1991-06-30

    provide an Important new therapeutic approech. Previous studies (Aronstam ot at, 1986 ; Buccafusco and Aronstam, 1986 ; Buccafusco et a, 1988) have shown...Ceccateill, ot aL, 1989; Greenberg t a4, 1986 ; Herrera and Robertson, 1990; Hunt ot al, 1987; Morgan and Curran, 1986 ; Morgan et aL, 1987; Sagar et aL, 1988...Konnerth, 1983; Madison and Ntcoll, 1982, 1986 ; Nicoll, 1988; Segal, 1981). 1 13 .I // ift as suggested by the c-fos results, LC neurons are driven

  18. Synthesis and in-vitro reactivation screening of imidazolium aldoximes as reactivators of sarin and VX-inhibited human acetylcholinesterase (hAChE).

    PubMed

    Sharma, Rahul; Gupta, Bhanushree; Sahu, Arvind Kumar; Acharya, Jyotiranjan; Satnami, Manmohan L; Ghosh, Kallol K

    2016-11-25

    Post-treatment of organophosphate (OP) poisoning involves the application of oxime reactivator as an antidote. Structurally different oximes are widely studied to examine their kinetic and mechanistic behavior against OP-inhibited cholinesterase enzyme. A series of structurally related 1,3-disubstituted-2-[(hydroxyiminomethyl)alkyl]imidazolium halides (5a-5e, 9a-9c) were synthesized and further evaluated for their in-vitro reactivation ability to reactivate sarin- and VX-inhibited human acetylcholinesterase (hAChE). The observed results were compared with the reactivation efficacy of standard reactivators; 2-PAM, obidoxime and HI-6. Amongst the synthesized oximes, 5a, 9a and 9b were found to be most potent reactivators against sarin-inhibited hAChE while in case of VX only 9a exhibited comparable reactivity with 2-PAM. Incorporation of pyridinium ring to the imidazole ring resulted in substantial increase in the reactivation strength of prepared reactivator. Physicochemical properties of synthesized reactivators have also been evaluated.

  19. Design and synthesis of immunoconjugates and development of competition inhibition enzyme-linked immunosorbent assay (CIEIA) for the detection of O-isopropyl methylphosphonofluoridate (sarin): an organophosphorous toxicant.

    PubMed

    Sathe, Manisha; Merwyn, S; Ghorpade, R; Agarwal, G S; Rao, M K; Rai, G P; Kaushik, M P

    2011-09-15

    Three haptens of the organophosphorus (OP) toxicant 'sarin' having different spacer arm were designed and synthesized. Haptens were conjugated with BSA (bovine serum albumin) and ovalbumin (OVA) for raising antibody and coating antigen. High antibody titer with higher specificity was obtained from 4-(4-(isopropoxy(methyl)phosphoryloxy)phenylamino)-4-oxobutanoic acid (hapten B) having reasonable long spacer arm. For the standard curve, an IC(50) (inhibitory concentration) of free antigen was found to be 0.415 μg mL(-1) on the basis of indirect competitive ELISA. The study revealed that heterology in competition inhibition enzyme immunoassay (CIEIA) produced remarkable improvement in the sensitivity and specificity of the assay. Under the optimized conditions, the quantitative working range was found to be 0.19-1.56 μg mL(-1) with a limit of detection (LOD) of 0.05 μg mL(-1). The antibodies showed negligible cross reactivity (CR) with other OP toxicants and pesticides, which makes the assay suitable for the selective detection of sarin.

  20. Brain Damage from Soman-Induced Seizures Is Greatly Exacerbated by Dimethyl sulfoxide (DMSO): Modest Neuroprotection by 2-Aminoethyl diphenylborinate (2- APB), a Transient Receptor Potential Channel Inhibitor and Inositol 1,4,5-triphosphate Receptor Antagonist

    DTIC Science & Technology

    2008-03-04

    dental cement. On the morning of the fifth or sixth day following surgeries, electrode-implanted animals were connected to an ECoG recording...epilepticus for several hours. Proconvulsive behavioral signs of soman intoxication included repetitive chewing , facial and forepaw clonus, motor...stereotypy, and wet- dog shakes. Overt motor convulsions were characterized by rhythmic clonic jerks of head and forepaws, rearing, salivation and Straub