Acute toxic effects of nerve agent VX on respiratory dynamics and functions following microinsillation inhalation exposure in guinea pigs.

PubMed

Rezk, Peter E; Graham, Jacob R; Moran, Theodore S; Gordon, Richard K; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2007-03-01

Exposure to a chemical warfare nerve agent (CWNA) leads to severe respiratory distress, respiratory failure, or death if not treated. We investigated the toxic effects of nerve agent VX on the respiratory dynamics of guinea pigs following exposure to 90.4 mug/m3 of VX or saline by microinstillation inhalation technology for 10 min. Respiratory parameters were monitored by whole-body barometric plethysmography at 4, 24, and 48 h, 7 d, 18 d, and 4 wk after VX exposure. VX-exposed animals showed a significant decrease in the respiratory frequency (RF) at 24 and 48 h of recovery (p value .0329 and .0142, respectively) compared to the saline control. The tidal volume (TV) slightly increased in VX exposed animals at 24 and significantly at 48 h (p = .02) postexposure. Minute ventilation (MV) increased slightly at 4 h but was reduced at 24 h and remained unchanged at 48 h. Animals exposed to VX also showed an increase in expiratory (Te) and relaxation time (RT) at 24 and 48 h and a small reduction in inspiratory time (Ti) at 24 h. A significant increase in end expiratory pause (EEP) was observed at 48 h after VX exposure (p = .049). The pseudo lung resistance (Penh) was significantly increased at 4 h after VX exposure and remained slightly high even at 48 h. Time-course studies reveal that most of the altered respiratory dynamics returned to normal at 7 d after VX exposure except for EEP, which was high at 7 d and returned to normal at 18 d postexposure. After 1 mo, all the monitored respiratory parameters were within normal ranges. Bronchoalveolar lavage (BAL) 1 mo after exposure showed virtually no difference in protein levels, cholinesterase levels, cell number, and cell death in the exposed and control animals. These results indicate that sublethal concentrations of VX induce changes in respiratory dynamics and functions that over time return to normal levels.

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

PubMed

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

2011-09-15

The present study was initiated to develop a sensitive and highly selective method for the simultaneous quantification of the nerve agent VX (O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate) and its toxic metabolite (EA-2192) in blood and plasma samples in vivo and in vitro. For the quantitative detection of VX and EA-2192 the resolution was realized on a HYPERCARB HPLC phase. A specific procedure was developed to isolate both toxic analytes from blood and plasma samples. The limit of detection was 0.1 pg/ml and the absolute recovery of the overall sample preparation procedure was 74% for VX and 69% for EA-2192. After intravenous and percutaneous administration of a supralethal doses of VX in anaesthetised swine both VX and EA-2192 could be quantified over 540 min following exposure. This study is the first to verify the in vivo formation of the toxic metabolite EA-2192 after poisoning with the nerve agent VX. Further toxicokinetic and therapeutic studies are required in order to determine the impact of EA-2192 on the treatment of acute VX poisoning. Copyright © 2011 Elsevier B.V. All rights reserved.

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

PubMed Central

Munro, N

1994-01-01

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

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

Simultaneous Time-concentration Analysis of Soman and VX Adducts to Butyrylcholinesterase and Albumin by LC-MS-MS.

PubMed

Lee, Jin Young; Kim, Changhwan; Lee, Yong Han

2018-06-01

A sensitive method for the purification and determination of two protein adducts, organophosphorus (OP)-BChE and OP-albumin adducts, in a single sample using a simultaneous sample preparation method was developed and validated using liquid chromatography-tandem mass spectrometry. First, we isolated O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) and O-pinacolyl methylphosphonofluoridate (soman, GD)-BChE adducts using an immunomagnetic separation (IMS) method and the HiTrap™ Blue affinity column was subsequently used to isolate and purify VX and GD-albumin adducts from the plasma of rhesus monkeys exposed to nerve agents. Additionally, we examined the time-concentration profiles of two biomarkers, VX and GD-nonapeptides and VX and GD-tyrosines, derived from OP-BChE and OP-albumin adducts up to 8 weeks after exposure. Based on the results, we determined that VX and GD-tyrosine is more suitable than VX and GD-nonapeptide as a biomarker owing to its longevity. This integrated approach is expected to be applicable for the quantification of other OP-BChE and OP-albumin adducts in human plasma, thus serving as a potential generic assay for exposure to nerve agents.

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 timesmore » 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.« less

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

PubMed

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

2015-04-08

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

Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6.

PubMed

Wille, Timo; von der Wellen, Jens; Thiermann, Horst; Worek, Franz

2017-03-01

Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to obidoxime. With freshly prepared plasma, obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.

Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition.

PubMed

Fawcett, William P; Aracava, Yasco; Adler, Michael; Pereira, Edna F R; Albuquerque, Edson X

2009-02-01

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

Acute lung injury following inhalation exposure to nerve agent VX in guinea pigs.

PubMed

Wright, Benjamin S; Rezk, Peter E; Graham, Jacob R; Steele, Keith E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

2006-05-01

A microinstillation technique of inhalation exposure was utilized to assess lung injury following chemical warfare nerve agent VX [methylphosphonothioic acid S-(2-[bis(1-methylethyl)amino]ethyl) O-ethyl ester] exposure in guinea pigs. Animals were anesthetized using Telazol-meditomidine, gently intubated, and VX was aerosolized using a microcatheter placed 2 cm above the bifurcation of the trachea. Different doses (50.4 microg/m3, 70.4 micro g/m(m3), 90.4 microg/m(m3)) of VX were administered at 40 pulses/min for 5 min. Dosing of VX was calculated by the volume of aerosol produced per 200 pulses and diluting the agent accordingly. Although the survival rate of animals exposed to different doses of VX was similar to the controls, nearly a 20% weight reduction was observed in exposed animals. After 24 h of recovery, the animals were euthanized and bronchoalveolar lavage (BAL) was performed with oxygen free saline. BAL was centrifuged and separated into BAL fluid (BALF) and BAL cells (BALC) and analyzed for indication of lung injury. The edema by dry/wet weight ratio of the accessory lobe increased 11% in VX-treated animals. BAL cell number was increased in VX-treated animals compared to controls, independent of dosage. Trypan blue viability assay indicated an increase in BAL cell death in 70.4 microg/m(m3) and 90.4 microg/m(m3) VX-exposed animals. Differential cell counting of BALC indicated a decrease in macrophage/monocytes in VX-exposed animals. The total amount of BAL protein increased gradually with the exposed dose of VX and was highest in animals exposed to 90.4 microg/m(m3), indicating that this dose of VX caused lung injury that persisted at 24 h. In addition, histopathology results also suggest that inhalation exposure to VX induces acute lung injury.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

2004-03-09

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

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

PubMed

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

2012-11-20

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

Combining SBR systems for chemical and biological treatment: the destruction of the nerve agent VX.

PubMed

Irvine, R L; Haraburda, S S; Galbis-Reig, C

2004-01-01

The US Army is pilot testing the neutralization of VX nerve agent stockpiled at Newport, Indiana using caustic hydrolysis in a Sequencing Batch Reactor (SBR). The resulting hydrolysate was tested at the bench-scale for treatment with activated sludge biodegradation in two distinct studies, one in the SBR and another, in the PACT process. The feed to both biological systems was pretreated to enhance the biodegradability of the hydrolysis products. Both biodegradation studies demonstrated that the hydrolysate could easily meet the Chemical Weapons Convention treaty and US environmental regulations following pretreatment.

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

PubMed

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

2006-05-01

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

Metal organic frameworks (MOFs) for degradation of nerve agent simulant parathion

USDA-ARS?s Scientific Manuscript database

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

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

USDA-ARS?s Scientific Manuscript database

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1994-01-01

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

Evaluation of Veriox as a Skin Decontamination Product after Dermal Exposure to the Nerve Agent VX

DTIC Science & Technology

2016-09-01

in hair -clipped, unanesthetized guinea pigs. Efficacy was established by generating VX dose-lethality curves for each DC product based on 24 survival...This study compared the effectiveness of Veriox® to RSDL when each was used as a DC product 2 min after dermal exposure to VX in hair -clipped...by the dermal LD90 of VX in untreated animals. A LD90 value of 188 μg/kg generated in hair -clipped, unanesthetized guinea pigs (Clarkson, personal

Bioscavenger is effective as a delayed therapeutic intervention following percutaneous VX poisoning in the guinea-pig.

PubMed

Mann, T M; Price, M E; Whitmore, C L; Perrott, R L; Laws, T R; McColm, R R; Emery, E R; Tattersall, J E H; Green, A C; Rice, H

2017-11-26

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD 50 ). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2h after the appearance of signs of poisoning survived to the end of the study at 48h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n=6+6) that received only MedCM, without the addition of BChE, died within 10h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4h after percutaneous dosing with 0.4×LD 50 ; VX was still detectable at 36h and had declined to levels below the lower limit of quantification (10pg/mL) by 48h in 7 of 8 animals, with the remaining animal having a concentration of 12pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed. Copyright © 2017. Published by Elsevier B.V.

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

PubMed Central

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

2015-01-01

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM–VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved. PMID:27547080

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hovanec, J.W.; Albizo, J.M.; Henderson, V.D.

1994-06-01

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

Detoxification of Chemical Warfare Agents Using a Zr6 -Based Metal-Organic Framework/Polymer Mixture.

PubMed

Moon, Su-Young; Proussaloglou, Emmanuel; Peterson, Gregory W; DeCoste, Jared B; Hall, Morgan G; Howarth, Ashlee J; Hupp, Joseph T; Farha, Omar K

2016-10-10

Owing to their high surface area, periodic distribution of metal sites, and water stability, zirconium-based metal-organic frameworks (Zr 6 -MOFs) have shown promising activity for the hydrolysis of nerve agents GD and VX, as well as the simulant, dimethyl 4-nitrophenylphosphate (DMNP), in buffered solutions. A hurdle to using MOFs for this application is the current need for a buffer solution. Here the destruction of the simulant DMNP, as well as the chemical warfare agents (GD and VX) through hydrolysis using a MOF catalyst mixed with a non-volatile, water-insoluble, heterogeneous buffer is reported. The hydrolysis of the simulant and nerve agents in the presence of the heterogeneous buffer was fast and effective. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

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

2014-01-01

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

Screening of nerve agent degradation products by MALDI-TOFMS.

PubMed

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

2006-07-01

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

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.

Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: a mini review.

PubMed

Lenz, David E; Yeung, David; Smith, J Richard; Sweeney, Richard E; Lumley, Lucille A; Cerasoli, Douglas M

2007-04-20

Currently fielded treatments for nerve agent intoxication promote survival, but do not afford complete protection against either nerve agent-induced motor and cognitive deficits or neuronal pathology. The use of human plasma-derived butyrylcholinesterase (HuBuChE) to neutralize the toxic effects of nerve agents in vivo has been shown to both aid survival and protect against decreased cognitive function after nerve agent exposure. Recently, a commercially produced recombinant form of human butyrylcholinesterase (r-HuBuChE; PharmAthene Inc.) expressed in the milk of transgenic goats has become available. This material is biochemically similar to plasma-derived HuBuChE in in vitro assays. The pharmacokinetic characteristics of a polyethylene glycol coated (pegylated) form of r-HuBuChE were determined in guinea pigs; the enzyme was rapidly bioavailable with a half-life (t(1/2)) and pharmacokinetic profile that resembled that of plasma-derived huBuChE. Guinea pigs were injected with 140mg/kg (i.m.) of pegylated r-HuBuChE 18h prior to exposure (sc) to 5.5xLD(50) VX or soman. VX and soman were administered in a series of three injections of 1.5xLD(50), 2.0xLD(50), and 2.0xLD(50), respectively, with injections separated by 2h. Pretreatment with pegylated r-HuBuChE provided 100% survival against multiple lethal doses of VX and soman. Guinea pigs displayed no signs of nerve agent toxicity following exposure. Assessments of motor activity, coordination, and acquisition of spatial memory were performed for 2 weeks following nerve agent exposure. There were no measurable decreases in motor or cognitive function during this period. In contrast, animals receiving 1.5xLD(50) challenges of soman or VX and treated with standard atropine, 2-PAM, and diazepam therapy showed 50 and 100% survival, respectively, but exhibited marked decrements in motor function and, in the case of GD, impaired spatial memory acquisition. The advances in this field have resulted in the decision to select both the plasma-derived and the recombinant form of BuChE for advanced development and transition to clinical trials. Efforts have now been expanded to identify a catalytic protein capable of not only binding, but also rapidly hydrolyzing the standard threat nerve agents. Recent work has focused on paraoxonase-1 (PON1), a naturally occurring human serum enzyme with the capacity to catalyze the hydrolysis of nerve agents, albeit too slowly to afford dramatic protection. Using rational design, several amino acids involved in substrate binding have been identified and site-directed mutations have revealed that residue H115 plays an important role in binding. In addition, the stereospecificity of PON1 for the catalytic hydrolysis of soman has been examined. The enzyme exhibits a slight stereospecificity for the C+P+ isomer of soman, which is due more to preferential binding than to selective hydrolysis of this isomer. The results suggest that it may be possible to engineer a mutant form of PON1 with enhanced activity and stereospecificity for the most toxic nerve agent isoforms.

Natural Detoxification Capacity to Inactivate Nerve Agents Sarin and VX in the Rat Blood.

PubMed

Bajgar, Jiří; Cabal, Jiří; Kassa, Jiří; Pavlík, Michal

2015-01-01

The method of continual determination of the rat blood cholinesterase activity was developed to study the changes of the blood cholinesterases following different intervetions. The aim of this study is registration of cholinesterase activity in the rat blood and its changes to demonstrate detoxification capacity of rats to inactivate sarin or VX in vivo. The groups of female rats were premedicated (ketamine and xylazine) and cannulated to a. femoralis. Continual blood sampling (0.02 ml/min) and monitoring of the circulating blood cholinesterase activity were performed. Normal activity was monitored 1-2 min and then the nerve agent was administered i.m. (2×LD50). Using different time intervals of the leg compression and relaxation following the agent injection, cholinesterase activity was monitored and according to the inhibition obtained, detoxification capacity was assessed. Administration of sarin to the leg, then 1 and 5 min compression and 20 min later relaxation showed that further inhibition in the blood was not observed. On the other hand, VX was able to inhibit blood cholinesterases after this intervention. The results demonstrated that sarin can be naturally detoxified on the contrary to VX. Described method can be used as model for other studies dealing with changes of cholinesterases in the blood following different factors.

Phosphoproteomic analysis reveals compensatory effects in the piriform cortex of VX nerve agent exposed rats.

PubMed

Nirujogi, Raja Sekhar; Wright, James D; Manda, Srikanth S; Zhong, Jun; Na, Chan Hyun; Meyerhoff, James; Benton, Bernard; Jabbour, Rabih; Willis, Kristen; Kim, Min-Sik; Pandey, Akhilesh; Sekowski, Jennifer W

2015-01-01

To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.v.) dose with the most notable changes occurring at the 1 h postexposure time point. Five major functional classes of proteins exhibited changes in their phosphorylation status: (i) ion channels/transporters, including ATPases, (ii) kinases/phosphatases, (iii) GTPases, (iv) structural proteins, and (v) transcriptional regulatory proteins. This study is the first quantitative phosphoproteomic analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain and aid in the elucidation of novel molecular targets that would be important for development of improved countermeasures. All MS data have been deposited in the ProteomeXchange with identifier PXD001184 (http://proteomecentral.proteomexchange.org/dataset/PXD001184). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Butyrylcholinesterase in guinea pig lung lavage: a novel biomarker to assess lung injury following inhalation exposure to nerve agent VX.

PubMed

Graham, Jacob R; Wright, Benjamin S; Rezk, Peter E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

2006-06-01

Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 microg/m3 VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 microg/m3 and 90.4 mg/m3 VX, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.

Identification of V-type nerve agents in vapor samples using a field-portable capillary gas chromatography/membrane-interfaced electron ionization quadrupole mass spectrometry instrument with Tri-Bed concentrator and fluoridating conversion tube.

PubMed

Ohrui, Y; Nagoya, T; Kurimata, N; Sodeyama, M; Seto, Y

2017-07-01

A field-portable gas chromatography-mass spectrometry (GC-MS) system (Hapsite ER) was evaluated for the detection of nonvolatile V-type nerve agents (VX and Russian VX (RVX)) in the vapor phase. The Hapsite ER system consists of a Tri-Bed concentrator gas sampler, a nonpolar low thermal-mass capillary GC column and a hydrophobic membrane-interfaced electron ionization quadrupole mass spectrometer evacuated by a non-evaporative getter pump. The GC-MS system was attached to a VX-G fluoridating conversion tube containing silver nitrate and potassium fluoride. Sample vapors of VX and RVX were converted into O-ethyl methylphosphonofluoridate (EtGB) and O-isobutyl methylphosphonofluoridate (iBuGB), respectively. These fluoridated derivatives were detected within 10 min. No compounds were detected when the VX and RVX samples were analyzed without the conversion tube. A vapor sample of tabun (GA) was analyzed, in which GA and O-ethyl N,N-dimethylphosphoramidofluoridate were detected. The molar recovery percentages of EtGB and iBuGB from VX and RVX vapors varied from 0.3 to 17%, which was attributed to variations in the vaporization efficiency of the glass vapor container. The conversion efficiencies of the VX-G conversion tube for VX and RVX to their phosphonate derivatives were estimated to be 40%. VX and RVX vapors were detected at concentrations as low as 0.3 mg m -3 . Gasoline vapor was found to interfere with the analyses of VX and RVX. In the presence of 160 mg m -3 gasoline, the detection limits of VX and RVX vapor were increased to 20 mg m -3 . Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Polarimetry and infrared spectroscopy in the detection of low-volatility chemical threats

NASA Astrophysics Data System (ADS)

Petryk, Michael W. P.; Marenco, Armando J.

2011-05-01

The polarization modulation infrared reflection absorption spectroscopy (PMIRRAS) spectra of the nerve agents GB (O-isopropyl methylphosphonofluoridate) and GF (cyclohexyl methylphoshonofluoridate) were recorded for the first time. A comparison of these spectra with the nerve agent VX (ethyl S-2-diisopropylaminoethyl methylphosphonothiolate) and the spectra of some trialkyl phosphates indicates that it is easy to distinguish between chemical warfare agents and simulants on militarily-relevant surfaces using PMIRRAS.

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

PubMed

Josse, Denis; Wartelle, Julien; Cruz, Catherine

2015-05-05

In this work, our goals were to establish whether hair decontamination by showering one hour post-exposure to the highly toxic organophosphate nerve agent VX was effective, whether it required the addition of a detergent to water and, if it could be improved by using the adsorbent Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering. Hair exposure to VX and decontamination was performed by using an in vitro model. Hair showering led to 72% reduction of contamination. Addition of detergent to water slightly increased the decontamination effectiveness. Hair treatment with FE or RSDL improved the decontamination rate. Combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. Hair wiping after showering was shown to contribute to hair decontamination. Altogether, our results highlighted the importance of considering hair decontamination as an important part of body surface decontamination protocols. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Computational characterization of how the VX nerve agent binds human serum paraoxonase 1.

PubMed

Fairchild, Steven Z; Peterson, Matthew W; Hamza, Adel; Zhan, Chang-Guo; Cerasoli, Douglas M; Chang, Wenling E

2011-01-01

Human serum paraoxonase 1 (HuPON1) is an enzyme that can hydrolyze various chemical warfare nerve agents including VX. A previous study has suggested that increasing HuPON1's VX hydrolysis activity one to two orders of magnitude would make the enzyme an effective countermeasure for in vivo use against VX. This study helps facilitate further engineering of HuPON1 for enhanced VX-hydrolase activity by computationally characterizing HuPON1's tertiary structure and how HuPON1 binds VX. HuPON1's structure is first predicted through two homology modeling procedures. Docking is then performed using four separate methods, and the stability of each bound conformation is analyzed through molecular dynamics and solvated interaction energy calculations. The results show that VX's lone oxygen atom has a strong preference for forming a direct electrostatic interaction with HuPON1's active site calcium ion. Various HuPON1 residues are also detected that are in close proximity to VX and are therefore potential targets for future mutagenesis studies. These include E53, H115, N168, F222, N224, L240, D269, I291, F292, and V346. Additionally, D183 was found to have a predicted pKa near physiological pH. Given D183's location in HuPON1's active site, this residue could potentially act as a proton donor or accepter during hydrolysis. The results from the binding simulations also indicate that steered molecular dynamics can potentially be used to obtain accurate binding predictions even when starting with a closed conformation of a protein's binding or active site.

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

NASA Astrophysics Data System (ADS)

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

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

Characterization of chemical agent transport in paints.

PubMed

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

2013-09-15

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

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

PubMed

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

2012-11-01

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

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.

Reactivation of Brain Acetylcholinesterase by Monoisonitrosoacetone Increases the Therapeutic Efficacy Against Nerve Agents in Guinea Pigs

DTIC Science & Technology

2010-01-01

hese findings support previous reports that protection of ChE nzyme activity in the brain as well as in peripheral tissues with entrally acting... activity . Animals were injected s.c. with either saline (0.5ml/kg) or a 1.0× LD50 dose of GB (42.0g/kg), GF (57.0g/kg), or VX (8.0g/kg). The severity...of toxic signs of each animal was scored at 13min after nerve agent. Fifteen minutes after nerve agent injection, when the inhibition of ChE activity

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

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.

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

PubMed

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

2013-03-05

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

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

VX fate on common matrices: evaporation versus degradation.

PubMed

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

2012-04-03

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

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

PubMed

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

2011-07-04

The organophosphate (OP) nerve agent VX is a weaponized chemical warfare agent that has also been used by terrorists against civilians. This contact poison produces characteristic signs of OP poisoning, including miosis, salivation, mastication, dysrhythmias and respiratory distress prior to death. Although successful treatment of OP poisoning can be obtained through decontamination and/or oxime reactivation of agent-inhibited cholinesterase, medical countermeasures that increase the therapeutic window for these measures would be of benefit. An anaesthetized swine model was utilized to examine the effects of lethal VX exposure to the skin, followed by cooling the exposure site prior to decontamination or treatment. The cooling was simply accomplished by using crushed ice in grip-seal plastic bags applied to the exposure sites. Cooling of skin exposed to lethal doses of VX significantly increased the window of opportunity for successful decontamination using the Reactive Skin Decontaminant Lotion(®) (RSDL(®)) or treatment with the oxime antidotes HI-6 and 2PAM. Analyses of blood VX levels showed that cooling acted to slow or prevent the entry of VX into the bloodstream from the skin. If the exposure site is known, the simple and non-invasive application of cooling provides a safe means with which to dramatically increase the therapeutic window in which decontamination and/or antidote treatment against VX are life-saving. Copyright © 2011. Published by Elsevier Ireland Ltd.

An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice.

PubMed

Calas, André-Guilhem; Dias, José; Rousseau, Catherine; Arboléas, Mélanie; Touvrey-Loiodice, Mélanie; Mercey, Guillaume; Jean, Ludovic; Renard, Pierre-Yves; Nachon, Florian

2017-04-01

Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2-pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 μmol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes.

DTIC Science & Technology

1999-10-01

nerve gas intoxication, as well as of insecticide poisoning. Such structures can yield direct information concerning the functional groups and steric...Glyll7His mutant (48). Recent solution of the 3D structures of conjugates of the nerve agents , sarin, soman, DFP and VX with 7cAChE (49, 50) has revealed... pesticides and chemical warfare agents is a topic of considerable environmental and toxicological importance. Hence, a substantial research effort is being

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

PubMed

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

2015-05-01

A product of the arms race during the Cold War, the Russian VX, or VR, is an organophosphorus compound that is a structural isomer of the western VX compound (or A4), with which it shares a very high toxicity. It is much less studied and known than VX because the knowledge of its existence is relatively recent. A very low volatility and high resistance in the environment make it a persistent agent. Poisoning occurs mainly following penetration through skin and mucosa but vapour inhalation is a credible risk in some circumstances. The clinical presentation may be differed by several hours and despite the absence of signs and symptoms, the casualty should not be considered as contamination or intoxication-free. This agent has a long residence time in blood, a characteristics that clearly differentiates it from other compounds such as sarin. The protocols for antidote administration may thus have to be changed accordingly. The fact that VR poisoned individuals will less respond to the current oxime therapy used in France, the 2-PAM and that VR represents a higher threat than VX, being probably possessed by some proliferating states, justify the interest for this toxic product. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Proceedings of the U.S. Army Chemical Research, Development and Engineering Center Scientific Conference on Chemical Defense Research Held in Aberdeen Proving Ground, Maryland on 14-17 November 1989

DTIC Science & Technology

1990-08-01

to react in a similar electrochemical manner to the agent 2,21- dichlorodiethylsulfide (Mustard gas or HD). As a simulant for the nerve agents ...attack which may permit effective discrimination of pesticides from nerve agents in a chemical agent detector. Table 1 shows the results of film badge...amount of CASARM agent ( GA , GB, HD or VX) was placed into a 5 mm O.D. Pyrex NMR tube and 1.0 ml of the decontaminating solution was added. The tube was

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1996-10-01

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

Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin.

PubMed

Kranawetvogl, Andreas; Küppers, Jim; Gütschow, Michael; Worek, Franz; Thiermann, Horst; Elsinghorst, Paul W; John, Harald

2017-08-01

Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long-term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high-resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2-(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met-Pro-Cys-DPAET, MPC-DPAET and Asp-Ile-Cys-DPAET, DIC-DPAET). MPC-DPAET was shown to undergo partial in-source decay during electrospray ionization for MS detection thereby losing the N-terminal Met residue. This results in the more stable Pro-Cys-DPAET (PC-DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC-DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Vesicants and nerve agents in chemical warfare. Decontamination and treatment strategies for a changed world.

PubMed

Devereaux, Asha; Amundson, Dennis E; Parrish, J S; Lazarus, Angeline A

2002-10-01

Vesicants and nerve agents have been used in chemical warfare for ages. They remain a threat in today's altered political climate because they are relatively simple to produce, transport, and deploy. Vesicants, such as mustard and lewisite, can affect the skin, eyes, respiratory system, and gastrointestinal system. They leave affected persons at risk for long-term effects. Nerve agents, such as tabun, sarin, soman, and VX, hyperstimulate the muscarinic and nicotinic receptors of the nervous system. Physicians need to familiarize themselves with the clinical findings of such exposures and the decontamination and treatment strategies necessary to minimize injuries and deaths.

Heme-Containing Metal-Organic Frameworks for the Oxidative Degradation of Chemical Warfare Agents

DTIC Science & Technology

2016-04-14

stability of the oxo without sacrificing its inherent reactivity, we have synthesized a new framework featuring fluorinated groups in the ortho...especially suitable for the degradation of electrophilic phosphorous center, leading to the cleavage of P-S or P-O bond present in VX nerve agents

Tertiary Oximes on Brain Acetylcholinesterase and Central Excitatory Effects of Nerve Agents

DTIC Science & Technology

2012-01-01

5 test doses of the oxime. Animals were euthanized 45 min after oxime treatment when blood and target tissues were collected. AChE activity was...the ability of MINA and DHAP to block or terminate nerve agent-induced electroencephalographic (EEG) seizure activity was evaluated. Animals...instrumented to record brain EEG activity were challenged with a seizure-inducing dose (2.0 x LD50) of GB, GF, or VX, and oxime was administered one min

The efficacy of HI-6 DMS in a sustained infusion against percutaneous VX poisoning in the guinea-pig.

PubMed

Whitmore, C; Cook, A R; Mann, T; Price, M E; Emery, E; Roughley, N; Flint, D; Stubbs, S; Armstrong, S J; Rice, H; Tattersall, J E H

2018-09-01

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal. Copyright © 2017 Crown Copyright. Published by Elsevier B.V. All rights reserved.

Comparison of skin decontamination efficacy of commercial decontamination products following exposure to VX on human skin.

PubMed

Thors, L; Koch, M; Wigenstam, E; Koch, B; Hägglund, L; Bucht, A

2017-08-01

The decontamination efficacy of four commercially available skin decontamination products following exposure to the nerve agent VX was evaluated in vitro utilizing a diffusion cell and dermatomed human skin. The products included were Reactive Skin Decontamination Lotion (RSDL), the Swedish decontamination powder 104 (PS104), the absorbent Fuller's Earth and the aqueous solution alldecontMED. In addition, various decontamination procedures were assessed to further investigate important mechanisms involved in the specific products, e.g. decontamination removal from skin, physical removal by sponge swabbing and activation of degradation mechanisms. The efficacy of each decontamination product was evaluated 5 or 30 min after dermal application of VX (neat or diluted to 20% in water). The RSDL-lotion was superior in reducing the penetration of VX through human skin, both when exposed as neat agent and when diluted to 20% in water. Swabbing with the RSDL-sponge during 2 min revealed decreased efficacy compared to applying the RSDL-lotion directly on the skin for 30 min. Decontamination with Fuller's Earth and alldecontMED significantly reduced the penetration of neat concentration of VX through human skin. PS104-powder was insufficient for decontamination of VX at both time-points, independently of the skin contact time of PS104. The PS104-slurry (a mixture of PS104-powder and water), slightly improved the decontamination efficacy. Comparing the time-points for initiated decontamination revealed less penetrated VX for RSDL and Fuller's Earth when decontamination was initiated after 5 min compared to 30 min post-exposure, while alldecontMED displayed similar efficacy at both time-points. Decontamination by washing with water only resulted in a significant reduction of penetrated VX when washing was performed 5 min after exposure, but not when decontamination was delayed to 30 min post-exposure of neat VX. In conclusion, early initiated decontamination with the RSDL-lotion, containing both absorption and degrading properties, allowed to act on skin for 30 min was superior in preventing VX from penetrating human skin. Adding water during decontamination resulted in increased penetration of neat VX, however, water in the decontaminant removal process did not influence the decontamination efficacy. From our study on commercially available decontaminants, it is recommended that future product developments should include both strong absorbents and efficient nerve agent degrading components. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-11-16

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

Detection of nerve gases using surface-enhanced Raman scattering substrates with high droplet adhesion

NASA Astrophysics Data System (ADS)

Hakonen, Aron; Rindzevicius, Tomas; Schmidt, Michael Stenbæk; Andersson, Per Ola; Juhlin, Lars; Svedendahl, Mikael; Boisen, Anja; Käll, Mikael

2016-01-01

Threats from chemical warfare agents, commonly known as nerve gases, constitute a serious security issue of increasing global concern because of surging terrorist activity worldwide. However, nerve gases are difficult to detect using current analytical tools and outside dedicated laboratories. Here we demonstrate that surface-enhanced Raman scattering (SERS) can be used for sensitive detection of femtomol quantities of two nerve gases, VX and Tabun, using a handheld Raman device and SERS substrates consisting of flexible gold-covered Si nanopillars. The substrate surface exhibits high droplet adhesion and nanopillar clustering due to elasto-capillary forces, resulting in enrichment of target molecules in plasmonic hot-spots with high Raman enhancement. The results may pave the way for strategic life-saving SERS detection of chemical warfare agents in the field.Threats from chemical warfare agents, commonly known as nerve gases, constitute a serious security issue of increasing global concern because of surging terrorist activity worldwide. However, nerve gases are difficult to detect using current analytical tools and outside dedicated laboratories. Here we demonstrate that surface-enhanced Raman scattering (SERS) can be used for sensitive detection of femtomol quantities of two nerve gases, VX and Tabun, using a handheld Raman device and SERS substrates consisting of flexible gold-covered Si nanopillars. The substrate surface exhibits high droplet adhesion and nanopillar clustering due to elasto-capillary forces, resulting in enrichment of target molecules in plasmonic hot-spots with high Raman enhancement. The results may pave the way for strategic life-saving SERS detection of chemical warfare agents in the field. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06524k

Environmental Fate of Organophosphorus Compounds Related to Chemical Weapons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davisson, M L; Love, A H; Vance, A

2005-02-08

Man-made organophosphorus compounds have been widely distributed throughout our environment as pesticides since their development during and after WWII. Many important studies have documented their relative persistence and toxicity. Development and use of some organophosphorus compounds as nerve agents gave rise to a separate but parallel effort to understand environmental persistence. In this latter case, the experiments have focused mainly on evaporation rates and first-order reaction kinetics. However, because organophosphorus compounds are easily polarized, the ionic content of a surrounding media directly factors into these reaction rates, but limited work in this regard has been done under environmentally relevant conditions.more » Furthermore, limited experiments investigating persistence of these agents on soil has resulted in widely varying degradation rates. Not surprisingly, no studies have investigated affinities of organophosphorus nerve agents to mineral or organic matter typically found in soil. As a result, we initiated laboratory experiments on dilute concentrations of nerve agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) to quantify persistence in simulated environmental aqueous conditions. A quantitative analytical method was developed for VX and its degradation products using High Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (HPLC-ESI-MS). VX hydrolysis rate is known to have a pH-dependency, however, the type of buffer and the relative proportion of different nucleophiles in solution significantly affect the overall rate and mechanism of degradation. For example, dissolved carbonate, a weak nucleophile dominating natural water, yielded pseudo-first order rate constants of {approx} 8 x 10{sup -3}/hr at pH 5 and 2 x 10{sup -2}/hr at pH 11. This small pH-dependent variation departs significantly from widely accepted rates at this pH range (4 x 10{sup -4}/hr to 8 x 10{sup -2}/hr) that were based on chloride and hydroxyl (strong nucleophile) dominated experimental solutions. Because of its overwhelming abundance in solution relative to hydroxyl ion, bicarbonate likely effectively competes in nucleophilic attack on phosphorus. The addition of natural dissolved organic matter at 100 mg/L in pH 7 bicarbonate buffered solution slowed VX hydrolysis rates {approx}2 times relative to controls, suggesting hydrophobic interaction. Adsorption experiments derived isotherms from batch aqueous experiments on montmorillonite clay, iron-oxyhydroxide goethite, and on amorphous silica. VX had moderate affinity for montmorillonite and amorphous silica, and very low affinity toward goethite. The addition of dissolved organic matter into solution enhanced VX adsorption to goethite, consistent with its high affinity for hydrophobic organic matter (log K{sub oc} = 2.52). Diisopropylaminoethylthiol (DESH), a hydrolysis product of VX showed equivalent adsorption to montmorillonite, and poor affinity to goethite and silica. However, hydrolysis products O-Ethylmethylphosphonic acid (EMPA) and methylphosphonic acid (MPA) strongly adsorbed on goethite, but not on montmorillonite or silica, suggesting a ligand-exchange mechanism. VX degraded rapidly when completely dried onto goethite followed by rehydration, consistent with an irreversible chemical adsorption mechanism.« less

Structural characterization of chemical warfare agent degradation products in decontamination solutions with proton band-selective (1)H-(31)P NMR spectroscopy.

PubMed

Koskela, Harri; Hakala, Ullastiina; Vanninen, Paula

2010-06-15

Decontamination solutions, which are usually composed of strong alkaline chemicals, are used for efficient detoxification of chemical warfare agents (CWAs). The analysis of CWA degradation products directly in decontamination solutions is challenging due to the nature of the matrix. Furthermore, occasionally an unforeseen degradation pathway can result in degradation products which could be eluded to in standard analyses. Here, we present the results of the application of proton band-selective (1)H-(31)P NMR spectroscopy, i.e., band-selective 1D (1)H-(31)P heteronuclear single quantum coherence (HSQC) and band-selective 2D (1)H-(31)P HSQC-total correlation spectroscopy (TOCSY), for ester side chain characterization of organophosphorus nerve agent degradation products in decontamination solutions. The viability of the approach is demonstrated with a test mixture of typical degradation products of nerve agents sarin, soman, and VX. The proton band-selective (1)H-(31)P NMR spectroscopy is also applied in characterization of unusual degradation products of VX in GDS 2000 solution.

Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats.

PubMed

Bloch-Shilderman, E; Rabinovitz, I; Egoz, I; Yacov, G; Allon, N; Nili, U

2018-02-01

VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225-45 µg/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 µg/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 µg/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 µg/kg/day.

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

PubMed

Gon Ryu, Sam; Wan Lee, Hae

2015-01-01

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

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

PubMed

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

2012-04-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishay Columbus; Daniel Waysbort; Liora Shmueli

2006-06-15

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

Poly High Internal Phase Emulsion for the Immobilization of Chemical Warfare Agents.

PubMed

Wright, Alexander J; Main, Marcus J; Cooper, Nicholas J; Blight, Barry A; Holder, Simon J

2017-09-20

We report a facile method for the absorption (characterized by the weight/weight swelling degree, Q) of a variety of chemical warfare agents (CWAs); including sulfur mustard (HD) (Q = 40) and V-series (VM, VX, i-Bu-VX, n-Bu-VX) of nerve agents (Q ≥ 45) and a simulant, methyl benzoate (Q = 55), through the use of a poly(styrene-co-vinyl benzyl chloride-co-divinylbenzene) lightly cross-linked poly high internal phase emulsion (polyHIPE). By varying the vinyl benzyl chloride (VBC) content and the volume of the internal phase of the precursor emulsion it is demonstrated that absorption is facilitated both by the swelling of the polymer and the uptake of liquid in the pores. In particular the sample prepared from a 95% internal emulsion water content showed rapid swelling (<5 min to total absorption) and the ability to swell both from a monolithic state and from a compressed state, making these systems ideal practical candidates for the rapid immobilization of CWAs.

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

PubMed

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

2013-02-01

The chemical warfare agents such as VX represent a threat for both military and civilians, which involves an immediate need of effective decontamination systems. Since human scalp is usually unprotected compared to other body regions covered with clothes, it could be a preferential site of exposure in case of terrorist acts. The purpose of this study was to determine if skin decontamination could be efficient when performed more than 1h after exposure. In addition, the impact of hairs in skin contamination was investigated. By using in vitro skin models, we demonstrated that about 75% of the applied quantity of VX was recovered on the skin surface 2h after skin exposition, which means that it is worth decontaminating even if contamination occurred 2h before. The stratum corneum reservoir for VX was quickly established and persistent. In addition, the presence of hairs modified the percutaneous penetration of the nerve agent by binding of VX to hairs. Hair shaft has thus to be taken into account in the decontamination process. Reactive Skin Decontamination Lotion (RSDL) and Fuller's Earth (FE) were active in the skin decontamination 45min post-exposure, but RSDL was more efficient in reducing the amount of VX either in the skin or in the hair. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

2010-01-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maxwell, Donald M.; Koplovitz, Irwin; Worek, Franz

2008-09-01

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

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

PubMed

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

2014-08-01

In the event of alleged use of organophosphorus nerve agents, all kinds of environmental samples can be received for analysis. These might include decontaminated and charred matter collected from the site of a suspected chemical attack. In other scenarios, such matter might be sampled to confirm the site of a chemical weapon test or clandestine laboratory decontaminated and burned to prevent discovery. To provide an analytical capability for these contingencies, we present a preliminary investigation of the effect of accelerant-based fire and liquid decontamination on soil contaminated with the nerve agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX). The objectives were (a) to determine if VX or its degradation products were detectable in soil after an accelerant-based fire promoted by aviation fuel, including following decontamination with Decontamination Solution 2 (DS2) or aqueous sodium hypochlorite, (b) to develop analytical methods to support forensic analysis of accelerant-soaked, decontaminated and charred soil and (c) to inform the design of future experiments of this type to improve analytical fidelity. Our results show for the first time that modern analytical techniques can be used to identify residual VX and its degradation products in contaminated soil after an accelerant-based fire and after chemical decontamination and then fire. Comparison of the gas chromatography-mass spectrometry (GC-MS) profiles of VX and its impurities/degradation products from contaminated burnt soil, and burnt soil spiked with VX, indicated that the fire resulted in the production of diethyl methylphosphonate and O,S-diethyl methylphosphonothiolate (by an unknown mechanism). Other products identified were indicative of chemical decontamination, and some of these provided evidence of the decontaminant used, for example, ethyl 2-methoxyethyl methylphosphonate and bis(2-methoxyethyl) methylphosphonate following decontamination with DS2. Sample preparation procedures and analytical methods suitable for investigating accelerant and decontaminant-soaked soil samples are presented. VX and its degradation products and/or impurities were detected under all the conditions studied, demonstrating that accelerant-based fire and liquid-based decontamination and then fire are unlikely to prevent the retrieval of evidence of chemical warfare agent (CWA) testing. This is the first published study of the effects of an accelerant-based fire on a CWA in environmental samples. The results will inform defence and security-based organisations worldwide and support the verification activities of the Organisation for the Prohibition of Chemical Weapons (OPCW), winner of the 2013 Nobel Peace Prize for its extensive efforts to eliminate chemical weapons.

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. Published by Elsevier Ireland Ltd.

Post-exposure treatment of VX poisoned guinea pigs with the engineered phosphotriesterase mutant C23: a proof-of-concept study.

PubMed

Worek, Franz; Seeger, Thomas; Reiter, Georg; Goldsmith, Moshe; Ashani, Yacov; Leader, Haim; Sussman, Joel L; Aggarwal, Nidhi; Thiermann, Horst; Tawfik, Dan S

2014-11-18

The highly toxic organophosphorus (OP) nerve agent VX is characterized by a remarkable biological persistence which limits the effectiveness of standard treatment with atropine and oximes. Existing OP hydrolyzing enzymes show low activity against VX and hydrolyze preferentially the less toxic P(+)-VX enantiomer. Recently, a phosphotriesterase (PTE) mutant, C23, was engineered towards the hydrolysis of the toxic P(-) isomers of VX and other V-type agents with relatively high in vitro catalytic efficiency (kcat/KM=5×10(6)M(-1)min(-1)). To investigate the suitability of the PTE mutant C23 as a catalytic scavenger, an in vivo guinea pig model was established to determine the efficacy of post-exposure treatment with C23 alone against VX intoxication. Injection of C23 (5mgkg(-1) i.v.) 5min after s.c. challenge with VX (∼2LD50) prevented systemic toxicity. A lower C23 dose (2mgkg(-1)) reduced systemic toxicity and prevented mortality. Delayed treatment (i.e., 15min post VX) with 5mgkg(-1) C23 resulted in survival of all animals and only in moderate systemic toxicity. Although C23 did not prevent inhibition of erythrocyte acetylcholinesterase (AChE) activity, it partially preserved brain AChE activity. C23 therapy resulted in a rapid decrease of racemic VX blood concentration which was mainly due to the rate of degradation of the toxic P(-)-VX enantiomer that correlates with the C23 blood levels and its kcat/KM value. Although performed under anesthesia, this proof-of-concept study demonstrated for the first time the ability of a catalytic bioscavenger to prevent systemic VX toxicity when given alone as a single post-exposure treatment, and enables an initial assessment of a time window for this approach. In conclusion, the PTE mutant C23 may be considered as a promising starting point for the development of highly effective catalytic bioscavengers for post-exposure treatment of V-agents intoxication. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

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

2016-09-06

The recent attacks with the nerve agent sarin in Syria reveal the necessity of effective countermeasures against highly toxic organophosphorus compounds. Multiple studies provide evidence that a rapid onset of antidotal therapy might be life-saving but current standard antidotal protocols comprising reactivators and competitive muscarinic antagonists show a limited efficacy for several nerve agents. We here set out to test the newly developed phosphotriesterase (PTE) mutant C23AL by intravenous (i.v.), intramuscular (i.m.; model for autoinjector) and intraosseous (i.o.; model for intraosseous insertion device) application in an in vivo guinea pig model after VX challenge (∼2LD50). C23AL showed a Cmax of 0.63μmolL(-1) after i.o. and i.v. administration of 2mgkg(-1) providing a stable plasma profile up to 180min experimental duration with 0.41 and 0.37μmolL(-1) respectively. The i.m. application of C23AL did not result in detectable plasma levels. All animals challenged with VX and subsequent i.o. or i.v. C23AL therapy survived although an in part substantial inhibition of erythrocyte, brain and diaphragm AChE was detected. Theoretical calculation of the time required to hydrolyze in vivo 96.75% of the toxic VX enantiomer is consistent with previous studies wherein similar activity of plasma containing catalytic scavengers of OPs resulted in non-lethal protection although accompanied with a variable severity of cholinergic symptoms. The relatively low C23AL plasma level observed immediately after its i.v. or i.o load, point at a possible volume of distribution greater than the guinea pig plasma content, and thus underlines the necessity of in vivo experiments in antidote research. In conclusion the i.o. application of PTE is efficient and resulted in comparable plasma levels to the i.v. application at a given time. Thus, i.o. vascular access systems could improve the post-exposure PTE therapy of nerve agent poisoning. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

VX hydrolysis by human serum paraoxonase 1: a comparison of experimental and computational results.

PubMed

Peterson, Matthew W; Fairchild, Steven Z; Otto, Tamara C; Mohtashemi, Mojdeh; Cerasoli, Douglas M; Chang, Wenling E

2011-01-01

Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VX(ts)) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VX(ts) complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bloch-Shilderman, Eugenia; Rabinovitz, Ishai; Egoz, Inbal

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

Phosphotriesterase variants with high methylphosphonatase activity and strong negative trade-off against phosphotriesters.

PubMed

Briseño-Roa, Luis; Timperley, Christopher M; Griffiths, Andrew D; Fersht, Alan R

2011-01-01

The most lethal organophosphorus nerve agents (NA), like sarin, soman, agent-VX and Russian-VX, share a methylphosphonate moiety. Pseudomonas diminuta phosphotriesterase (PTE) catalyses the hydrolysis of methylphosphonate NA analogues with a catalytic efficiency orders of magnitude lower than that towards the pesticide paraoxon. With a view to obtaining PTE variants that more readily accept methylphosphonate NA, ~75,000 PTE variants of the substrate-binding residues Gly-60, Ile-106, Leu-303 and Ser-308 were screened with fluorogenic analogues of the NA Russian-VX and cyclosarin. Seven new PTE variants were isolated, purified and their k(cat)/K(M) determined against five phosphotriesters and five methylphosphonate analogues of sarin, cyclosarin, soman, agent-VX and Russian-VX. The novel PTE variants exhibited as much as a 10-fold increase in activity towards the methylphosphonate compounds--many reaching a k(cat)/K(M) of 10⁶ M⁻¹ s⁻¹--and as much as a 29,000-fold decrease in their phosphotriesterase activity. The mutations found in two of the variants, SS0.5 (G60V/I106L/S308G) and SS4.5 (G60V/I106A/S308G), were modelled into a high-resolution structure of PTE-wild type and docked with analogues of cyclosarin and Russian-VX using Autodock 4.2. The kinetic data and docking simulations suggest that the increase in activity towards the methylphosphonates and the loss of function against the phosphotriesters were due to an alteration of the shape and hydrophobicity of the binding pocket that hinders the productive binding of non-chiral racemic phosphotriesters, yet allows the binding of the highly asymmetric methylphosphonates.

Variants of Phosphotriesterase for the Enhanced Detoxification of the Chemical Warfare Agent VR.

PubMed

Bigley, Andrew N; Mabanglo, Mark F; Harvey, Steven P; Raushel, Frank M

2015-09-08

The V-type organophosphorus nerve agents are among the most hazardous compounds known. Previous efforts to evolve the bacterial enzyme phosphotriesterase (PTE) for the hydrolytic decontamination of VX resulted in the identification of the variant L7ep-3a, which has a kcat value more than 2 orders of magnitude higher than that of wild-type PTE for the hydrolysis of VX. Because of the relatively small size of the O-ethyl, methylphosphonate center in VX, stereoselectivity is not a major concern. However, the Russian V-agent, VR, contains a larger O-isobutyl, methylphosphonate center, making stereoselectivity a significant issue since the SP-enantiomer is expected to be significantly more toxic than the RP-enantiomer. The three-dimensional structure of the L7ep-3a variant was determined to a resolution of 2.01 Å (PDB id: 4ZST ). The active site of the L7ep-3a mutant has revealed a network of hydrogen bonding interactions between Asp-301, Tyr-257, Gln-254, and the hydroxide that bridges the two metal ions. A series of new analogues that mimic VX and VR has helped to identify critical structural features for the development of new enzyme variants that are further enhanced for the catalytic detoxification of VR and VX. The best of these mutants has been shown to have a reversed stereochemical preference for the hydrolysis of VR-chiral center analogues. This mutant hydrolyzes the two enantiomers of VR 160- and 600-fold faster than wild-type PTE hydrolyzes the SP-enantiomer of VR.

Experimental Therapeutics Against the Toxic and Lethal Effects Resulting from Acute Exposure to Nerve Agents Without Carbamate Pretreatment in Guinea Pigs

DTIC Science & Technology

2010-09-01

or VX. Guinea pigs chronically instrumented for concurrent recordings of EEG, cardiorespiratory activities , diaphragm and skeletal muscle EMG were... activities , or any debilitating effects. The animals were asymptomatic within 30 min following therapy and survived the agent challenge 24 hr later. In...For a thorough efficacy evaluation, the animals were chronically instrumented to permit concurrent recordings of central nervous system activity

The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study.

PubMed

Cuya, Teobaldo; Gonçalves, Arlan da Silva; da Silva, Jorge Alberto Valle; Ramalho, Teodorico C; Kuca, Kamil; C C França, Tanos

2017-10-27

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.

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

PubMed

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

2013-03-25

Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4× LD50 VX in IPA. The results showed that RSDL decontamination at 15 min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90 min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

VX Hydrolysis by Human Serum Paraoxonase 1: A Comparison of Experimental and Computational Results

PubMed Central

Peterson, Matthew W.; Fairchild, Steven Z.; Otto, Tamara C.; Mohtashemi, Mojdeh; Cerasoli, Douglas M.; Chang, Wenling E.

2011-01-01

Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VXts) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VXts complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VXts coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX. PMID:21655255

Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

DTIC Science & Technology

2008-03-01

throughout history where nerve agents have been used on human populations, such as the subway bombing in Tokyo and Matsumoto, Japan. Data can be...kidney, fat, diaphragm, arterial blood, venous blood, bronchial passages, and the skin. The remaining tissues will be lumped together as either slowly...were then further developed as a weapon, whose primary effect is on the central nervous system. These agents are tabun, sarin, soman, and VX. They

Proceedings of the Army Numerical Analysis Conference (11th) Held at Frankford Arsenal, Philadelphia, Pa., on 13-14 February 1974

DTIC Science & Technology

1974-12-01

incineration of chemical agent mustard and pesticides are presented. 1. EDGEWOOD ARSENAL INCINERATION PROGRAM The name of the program which we...only 5 elements to a compound read. -This was fine for mustard, but had to be altered when we wished to simulate the incineration of a nerve agent VX...input data to this program. A process flow sheet of the scrubber system is shown in Figure 1. The incinerator burns Mustard Agent . The off gas from

Acetylcholinesterases of Rhipicephalus (Boophilus) microplus – Multiple gene expression presents an opportune model system for elucidation of multiple functions of AChEs.

USDA-ARS?s Scientific Manuscript database

Acetylcholinesterase (AChE) is a key neural enzyme of both vertebrates and invertebrates, and is the biochemical target of organophosphate and carbamate pesticides for invertebrates, as well as vertebrate nerve agents, e.g., soman, tabun, VX, and others. AChE inhibitors are also key drugs among thos...

History and perspectives of bioanalytical methods for chemical warfare agent detection.

PubMed

Black, Robin M

2010-05-15

This paper provides a short historical overview of the development of bioanalytical methods for chemical warfare (CW) agents and their biological markers of exposure, with a more detailed overview of methods for organophosphorus nerve agents. Bioanalytical methods for unchanged CW agents are used primarily for toxicokinetic/toxicodynamic studies. An important aspect of nerve agent toxicokinetics is the different biological activity and detoxification pathways for enantiomers. CW agents have a relatively short lifetime in the human body, and are hydrolysed, metabolised, or adducted to nucleophilic sites on macromolecules such as proteins and DNA. These provide biological markers of exposure. In the past two decades, metabolites, protein adducts of nerve agents, vesicants and phosgene, and DNA adducts of sulfur and nitrogen mustards, have been identified and characterized. Sensitive analytical methods have been developed for their detection, based mainly on mass spectrometry combined with gas or liquid chromatography. Biological markers for sarin, VX and sulfur mustard have been validated in cases of accidental and deliberate human exposures. The concern for terrorist use of CW agents has stimulated the development of higher throughput analytical methods in support of homeland security. Copyright (c) 2010. Published by Elsevier B.V.

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).

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun†,‡

PubMed Central

Fleming, Christopher D.; Edwards, Carol C.; Kirby, Stephen D.; Maxwell, Donald M.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

2008-01-01

The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 Å resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 104-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure. PMID:17407327

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 recovered, whereas <1% of VX and Russian VX were recovered in the same concentration range. The results indicate that CWA vapors, with the exception of VX and Russian VX, can be measured by an on-site collection procedure using the Tenax(®) TA resin tubes, followed by a subsequent TD-GC/MS analysis. Copyright © 2015 Elsevier B.V. All rights reserved.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.

PubMed

Albuquerque, Edson X; Pereira, Edna F R; Aracava, Yasco; Fawcett, William P; Oliveira, Maristela; Randall, William R; Hamilton, Tracey A; Kan, Robert K; Romano, James A; Adler, Michael

2006-08-29

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

PubMed Central

Albuquerque, Edson X.; Pereira, Edna F. R.; Aracava, Yasco; Fawcett, William P.; Oliveira, Maristela; Randall, William R.; Hamilton, Tracey A.; Kan, Robert K.; Romano, James A.; Adler, Michael

2006-01-01

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer’s disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning. PMID:16914529

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

PubMed

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

2014-10-01

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

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

PubMed

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

2006-01-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Y.C.; Szafraniec, L.L.; Beaudry, W.T.

1993-07-01

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

Post-exposure therapy with human butyrylcholinesterase following percutaneous VX challenge in guinea pigs.

PubMed

Mumford, Helen; E Price, Matthew; Lenz, David E; Cerasoli, Douglas M

2011-04-01

Human butyrylcholinesterase (huBuChE) has potential utility as a post-exposure therapy following percutaneous nerve agent poisoning as there is a slower absorption of agent by this route and hence a later onset of poisoning. METHODS. We used surgically implanted radiotelemetry devices to monitor heart rate, EEG, body temperature and locomotor activity in guinea pigs challenged with VX via the percutaneous route. RESULTS. Treatment with huBuChE (24.2 mg/kg, i.m.) at 30 or 120 min following percutaneous VX (~2.5 × LD(50)) protected 9 out of 10 animals from lethality. When i.m. huBuChE administration was delayed until the onset of observable signs of systemic cholinergic poisoning, only one out of six animals survived to 7 days. Survival increased to 50% when the same dose of huBuChE was given intravenously at the onset of signs of poisoning. This dose represents approximately 1/10th the stoichiometric equivalent of the dose of VX administered (0.74 mg/kg). Intramuscular administration of huBuChE (24.2 mg/kg) alone did not produce any changes in heart rate, brain electrical activity, temperature or locomotion compared to saline control. Survival following VX and huBuChE treatment was associated with minimal incapacitation and observable signs of poisoning, and the mitigation or prevention of detrimental physiological changes (e.g. seizure, bradycardia and hypothermia) observed in VX + saline-treated animals. At 7 days, cholinesterase activity in the erythrocytes and most brain areas of guinea pigs that received huBuChE at either 18 h prior to or 30 min following VX was not significantly different from that of naïve, weight-matched control animals. CONCLUSION. Percutaneous VX poisoning was successfully treated using post-exposure therapy with huBuChE bioscavenger. The opportunity for post-exposure treatment may have particular relevance in civilian settings, and this is a promising indication for the use of huBuChE.

Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents*

PubMed Central

Wandhammer, Marielle; Carletti, Eugénie; Van der Schans, Marcel; Gillon, Emilie; Nicolet, Yvain; Masson, Patrick; Goeldner, Maurice; Noort, Daan; Nachon, Florian

2011-01-01

Nerve agents are chiral organophosphate compounds (OPs) that exert their acute toxicity by phosphorylating the catalytic serine of acetylcholinesterase (AChE). The inhibited cholinesterases can be reactivated using oximes, but a spontaneous time-dependent process called aging alters the adduct, leading to resistance toward oxime reactivation. Human butyrylcholinesterase (BChE) functions as a bioscavenger, protecting the cholinergic system against OPs. The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhibited in solution or in cristallo with racemic V-agents (VX, Russian VX, and Chinese VX) systematically show the formation of the PS adduct. In this configuration, no catalysis of aging seems possible as confirmed by the three-dimensional structures of the three conjugates incubated over a period exceeding a week. Crystals of BChE soaked in optically pure VXR-(+) and VXS-(−) solutions lead to the formation of the PS and PR adduct, respectively. These structural data support an in-line phosphonylation mechanism. Additionally, they show that BChE reacts with VXR-(+) in the presence of racemic mixture of V-agents, at odds with earlier kinetic results showing a moderate higher inhibition rate for VXS-(−). These combined results suggest that the simultaneous presence of both enantiomers alters the enzyme stereoselectivity. In summary, the three-dimensional data show that BChE reacts preferentially with PR enantiomer of V-agents and does not age, in complete contrast to AChE, which is selectively inhibited by the PS enantiomer and ages. PMID:21454498

Acute pulmonary toxicity following inhalation exposure to aerosolized VX in anesthetized rats.

PubMed

Peng, Xinqi; Perkins, Michael W; Simons, Jannitt; Witriol, Alicia M; Rodriguez, Ashley M; Benjamin, Brittany M; Devorak, Jennifer; Sciuto, Alfred M

2014-06-01

This study evaluated acute toxicity and pulmonary injury in rats at 3, 6 and 24 h after an inhalation exposure to aerosolized O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX). Anesthetized male Sprague-Dawley rats (250-300 g) were incubated with a glass endotracheal tube and exposed to saline or VX (171, 343 and 514 mg×min/m³ or 0.2, 0.5 and 0.8 LCt₅₀, respectively) for 10 min. VX was delivered by a small animal ventilator at a volume of 2.5 ml × 70 breaths/minute. All VX-exposed animals experienced a significant loss in percentage body weight at 3, 6, and 24 h post-exposure. In comparison to controls, animals exposed to 514 mg×min/m³ of VX had significant increases in bronchoalveolar lavage (BAL) protein concentrations at 6 and 24 h post-exposure. Blood acetylcholinesterase (AChE) activity was inhibited dose dependently at each of the times points for all VX-exposed groups. AChE activity in lung homogenates was significantly inhibited in all VX-exposed groups at each time point. All VX-exposed animals assessed at 20 min and 3, 6 and 24 h post-exposure showed increases in lung resistance, which was prominent at 20 min and 3 h post-exposure. Histopathologic evaluation of lung tissue of the 514 mg×min/m³ VX-exposed animals at 3, 6 and 24 h indicated morphological changes, including perivascular inflammation, alveolar exudate and histiocytosis, alveolar septal inflammation and edema, alveolar epithelial necrosis, and bronchiolar inflammatory infiltrates, in comparison to controls. These results suggest that aerosolization of the highly toxic, persistent chemical warfare nerve agent VX results in acute pulmonary toxicity and lung injury in rats.

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. © 2016 New York Academy of Sciences.

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

PubMed Central

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

2016-01-01

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 invented novel substituted phenoxyalkyl pyridinium oximes (U.S. Patent 9,227,937 B2) 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, these novel oximes also showed an attenuation of seizure-like behavior compared to rats treated with 2-PAM, giving additional evidence of the ability of these oximes to penetrate the blood–brain barrier. Further, some of these oximes provided 24-hour 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 concept of these life-saving oximes penetrating the brain. PMID:27153507

Preliminary assessment of the health and environmental impacts of continuing to store M55 rockets at Lexington-Blue Grass Depot Activity, Anniston Army Depot, Umatilla Depot Activity, Pine Bluff Arsenal, and Tooele Army Depot

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyette, J.A.; Breck, J.E.; Coleman, P.R.

1986-03-01

The purpose is to provide an assessment of the potential health and environmental impacts of continuing to store M55 rockets filled with nerve agent GB or VX at their current storage locations at Anniston Army Depot in Alabama, Lexington-Blue Grass Depot Activity in Kentucky, Pine Bluff Arsenal in Arkansas, Tooele Army Depot in Utah, and Umatilla Depot Activity in Oregon. The assessment considers the possible impacts of (1) normal storage (with no release to the environment) and (2) two postulated accidents on the air quality, ground and surface water, aquatic ecology, terrestrial ecology, human health, and cultural and socioeconomic resourcesmore » in and around the various storage depots. The analysis considers three basic scenarios during storage: (1) normal operations; (2) a minor spill of agent (the contents of one rocket released to the biosphere); and (3) a maximum credible event or MCE. The MCE is an igloo fire resulting in the aerosolization of a small (in the case of GB) or an extremely small (in the case of VX) percentage of the igloo's nerve agent contents to the biosphere. The extremely low probabilities of such accidents, which are reported elsewhere, are noted. Our assessments of the impacts of a minor spill and of an MCE consider two sets of meteorological conditions: conservative most likely and worst-case. In addition, we assume that an agent plume would travel toward the area of highest population density. 21 figs., 47 tabs.« less

Toward antibody-catalyzed hydrolysis of organophosphorus poisons

PubMed Central

Vayron, Philippe; Renard, Pierre-Yves; Taran, Frédéric; Créminon, Christophe; Frobert, Yveline; Grassi, Jacques; Mioskowski, Charles

2000-01-01

We report here our preliminary results on the use of catalytic antibodies as an approach to neutralizing organophosphorus chemical weapons. A first-generation hapten, methyl-α-hydroxyphosphinate Ha, was designed to mimic the approach of an incoming water molecule for the hydrolysis of exceedingly toxic methylphosphonothioate VX (1a). A moderate protective activity was first observed on polyclonal antibodies raised against Ha. The results were further confirmed by using a mAb PAR 15 raised against phenyl-α-hydroxyphosphinate Hb, which catalyzes the hydrolysis of PhX (1b), a less toxic phenylphosphonothioate analog of VX with a rate constant of 0.36 M−1⋅min−1 at pH 7.4 and 25°C, which corresponds to a catalytic proficiency of 14,400 M−1 toward the rate constant for the uncatalyzed hydrolysis of 1b. This is a demonstration on the organophosphorus poisons themselves that mAbs can catalytically hydrolyze nerve agents, and a significant step toward the production of therapeutically active abzymes to treat poisoning by warfare agents. PMID:10860971

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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

L.W.Harris, D.L. Stitcher , Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats, Drug Chem. Toxicol. 6 (1983) 235–240. [9] P.M. Lundy, T.-M...rat, monkey and human, Arch. Toxicol. 68 (1994) 648–655. 2 gical In [ [ 14 T.-M. Shih et al. / Chemico-Biolo27] L.W. Harris, W.C. Heyl, D.L. Stitcher

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Groenewold, Gary Steven; Appelhans, Anthony David; Gresham, Garold Linn

2002-09-01

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

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

PubMed

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

2002-11-15

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

The percutaneous toxicokinetics of VX in a damaged skin porcine model and the evaluation of WoundStat™ as a topical decontaminant.

PubMed

Lydon, Helen; Hall, Charlotte; Matar, Hazem; Dalton, Christopher; Chipman, J Kevin; Graham, John S; Chilcott, Robert P

2018-03-01

This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for the decontamination of superficial, nerve agent-contaminated wounds. Anaesthetized animals were randomly assigned to either control (n = 7), no decontamination (n = 12) or WoundStat™ (n = 12) treatment groups. Pigs were exposed to a 5× LD 50 dose of neat, radiolabelled S-[2-(diisopropylamino)ethyl]-O-ethyl methyl-phosphonothioate (VX; or equivalent volume of sterile saline for the control group) via an area of superficially damaged skin on the ear. WoundStat™ was applied at 30 seconds post-exposure to assigned animals. The VX contaminant (or saline) and decontaminant remained in place for the duration of the study (up to 6 hours). Physiological parameters and signs of intoxication were recorded during the exposure period. Skin and organ samples were taken post mortem for 14 C-VX distribution analyses. Blood samples were taken periodically for toxicokinetic and whole-blood acetylcholinesterase (AChE) activity analyses. VX exposure was accompanied by a rapid decrease in AChE activity in all animals, regardless of decontamination. However, decontamination significantly improved survival rate and time and reduced the severity of signs of intoxication. In addition, the distribution of 14 C-VX in key internal organs and post mortem blood samples was significantly lower in the WoundStat™ treatment group. This study demonstrates that WoundStat™ may be a suitable medical countermeasure for increasing both survival rate and time following VX exposure. The results also suggest that AChE activity is not a useful prognostic indicator. Copyright © 2017 John Wiley & Sons, Ltd.

Dual-Function Metal-Organic Framework as a Versatile Catalyst for Detoxifying Chemical Warfare Agent Simulants.

PubMed

Liu, Yangyang; Moon, Su-Young; Hupp, Joseph T; Farha, Omar K

2015-12-22

The nanocrystals of a porphyrin-based zirconium(IV) metal-organic framework (MOF) are used as a dual-function catalyst for the simultaneous detoxification of two chemical warfare agent simulants at room temperature. Simulants of nerve agent (such as GD, VX) and mustard gas, dimethyl 4-nitrophenyl phosphate and 2-chloroethyl ethyl sulfide, have been hydrolyzed and oxidized, respectively, to nontoxic products via a pair of pathways catalyzed by the same MOF. Phosphotriesterase-like activity of the Zr6-containing node combined with photoactivity of the porphyrin linker gives rise to a versatile MOF catalyst. In addition, bringing the MOF crystals down to the nanoregime leads to acceleration of the catalysis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Worek, Franz, E-mail: franzworek@bundeswehr.org; Wille, Timo; Aurbek, Nadine

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary highmore » MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning.« less

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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

Richardson, Douglas D; Caruso, Joseph A

2007-06-01

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

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. Published by Elsevier Inc.

Development of a sensitive, generic and easy to use organophosphate skin disclosure kit.

PubMed

Worek, Franz; Wosar, Andreas; Baumann, Madlen; Thiermann, Horst; Wille, Timo

2017-10-05

Various organophosphorus compounds (OP), primarily the nerve agent VX and other V-agents, are highly toxic to humans after skin exposure. Percutaneous exposure by such OP results in a delayed onset of toxic signs which enables the initiation of specific countermeasures if contamination is detected rapidly. Presently available mobile detection systems can hardly detect skin exposure by low volatile OP. In order to fill this gap an OP skin disclosure kit was developed which should fulfill different requirements, i.e. a high sensitivity, coverage of human toxic OP, easy handling, rapid results, small dimension and weight. The kit includes a cotton swab to sample skin, human AChE as target and chemicals for a color reaction based on the Ellman assay which is recorded by visual inspection. OP is dissolved from the sampler in a test tube filled with phosphate buffer (0.1M, pH 7.4) and incubated with lyophilized human AChE for 1min. The reaction with acetylthiocholine and 5,5'-dithio-bis-2-nitrobenzoic acid (1min) results in a rich yellow color in the absence of OP and in contrast, in transparent or pale yellow buffer in the presence of OP. At the recommended conditions, the limit of detection is 100ng VX and Russian VX and 50ng Chinese VX on plain surface and 200ng VX on rat skin. With activated pesticides, paraoxon and malaoxon, a concentration of ∼10μg can be detected on plain surface. The ready-to-use kit has a weight of 16g and a size of 10×12×1cm. In the end, this kit has the potential to fill a major gap and to enable timely detection of OP skin exposure and initiation of life-saving countermeasures. Copyright © 2017 Elsevier B.V. All rights reserved.

A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katalinić, Maja; Maček Hrvat, Nikolina

A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.8) as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE. Their efficiency in the reactivation of paraoxon-,more » VX-, and tabun-inhibited human BChE, as well as human AChE was tested and compared with the efficiencies of HI-6 and obidoxime, used in medical practice today. A comprehensive analysis was performed for the most promising oximes defining kinetic parameters of reactivation as well as interactions with uninhibited BChE. Furthermore, experimental data were compared with computational studies (docking, QSAR analysis) as a starting point in future oxime structure refinement. Considering the strict criteria set for in vivo applications, we determined the cytotoxicity of lead oximes on two cell lines. Among the tested oxime library, one imidazolium compound was selected for preliminary in vivo antidotal study in mice. The obtained protection in VX poisoning outlines its potential in development oxime-assisted OP-bioscavenging with BChE. - Highlights: • 36 new imidazolium and benzimidazolium oximes were designed and synthesized. • In vitro reactivation kinetics of phosphylated butyrylcholinesterase was studded. • The modes of actions were elucidated by QSAR and docking simulations. • Protection in VX poisoning was 6.3 × LD{sub 50} in in vivo antidotal study in mice. • Imidazolium oxime-assisted catalysis is feasible for OP-bioscavenging with BChE.« less

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

PubMed

Willison, Stuart A

2015-01-20

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

Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach.

PubMed

Worek, Franz; Wille, Timo; Aurbek, Nadine; Eyer, Peter; Thiermann, Horst

2010-12-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary high MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning. Copyright © 2010 Elsevier Inc. All rights reserved.

Persistence and Effective Half-Life of Chemical Warfare Agent VX on Grass Foliage

DTIC Science & Technology

2017-08-01

obtain results applicable to VX- contaminated battlefields. The Effective Half-Life of VX on grass foliage was determined as the net effect of factors...Soldiers on VX- contaminated battlefields. 15. SUBJECT TERMS Chemical warfare agent (CWA) Agent–plant Echinochloa crus-galli Foliage Effective Half...The use of either trade or manufacturers ’ names in this report does not constitute an official endorsement of any commercial products. This report may

Expression of Membrane-Bound Human AminopeptidaseP as a Soluble Enzyme and an Investigation into Its Efficacy Towards Offering Protection Against the Toxicity of Chemical Warfare Nerve Agents

DTIC Science & Technology

2016-09-01

survival rate of guinea pigs from GF toxicity [31]. The overall catalytic efficiency of II-G1 reported by Worek against GF was 8.4 × 107 M-1 min-1 and...al., Protection against soman or VX poisoning by human butyrylcholinesterase in guinea pigs and cynomolgus monkeys. Chem Biol Interact, 2005. 157...97-102. 30. Valiyaveettil, M., et al., Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

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 evaluation of both the agent and thiodiglycol. Images Figure 1 Figure 3 Figure 5 PMID:10585900

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

PubMed

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

2011-09-25

The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD₅₀ for VR topically applied on the ear was 100 μg/kg. Treatment of VR exposed animals (5 × LD₅₀) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Preliminary assessment of the health and environmental impacts of transporting M55 rockets from Lexington-Blue Grass Depot activity, Anniston Army depot, and Umatilla depot activity to alternative disposal facilities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carnes, S.A.; Breck, J.E.; Copenhaver, E.D.

1986-03-01

This assessment discusses the potential health and environmental impacts of transporting M55 rockets filled with nerve agent GB or VX from various existing Army storage depots to alternative Army depots for disposal. The origin depots include Anniston Army Depot in Alabama, Lexington-Blue Grass Depot Activity in Kentucky, and Umatilla Depot Activity in Oregon. The destination depots include Pine Bluff Arsenal in Arkansas, Tooele Army Depot in Utah, and the facility on Johnston Island in the central Pacific Ocean. This assessment considers the possible impacts of normal transport operations and of two postulated accident scenarios on the air quality, ground andmore » surface water, aquatic ecology, terrestrial ecology, human health, and cultural and socioeconomic resources of the various transport corridors involved. The impacts of these scenarios are assessed for truck, train, and air transport for each orgin-destination pair. The analysis considers three basic scenario during transport: (1) normal operations with no atmospheric release of nerve agent; (2) a minor agent spill (the contents of one rocket being released to the biosphere); and (3) a worst-case accident involving the release of a large, specified quantity of nerve agent to the biosphere. The extremely low probabilities of such accidents, which are reported elsewhere, are noted.« less

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. Published by Elsevier Inc.

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.

Decontamination of adsorbed chemical warfare agents on activated carbon using hydrogen peroxide solutions.

PubMed

Osovsky, Ruth; Kaplan, Doron; Nir, Ido; Rotter, Hadar; Elisha, Shmuel; Columbus, Ishay

2014-09-16

Mild treatment with hydrogen peroxide solutions (3-30%) efficiently decomposes adsorbed chemical warfare agents (CWAs) on microporous activated carbons used in protective garments and air filters. Better than 95% decomposition of adsorbed sulfur mustard (HD), sarin, and VX was achieved at ambient temperatures within 1-24 h, depending on the H2O2 concentration. HD was oxidized to the nontoxic HD-sulfoxide. The nerve agents were perhydrolyzed to the respective nontoxic methylphosphonic acids. The relative rapidity of the oxidation and perhydrolysis under these conditions is attributed to the microenvironment of the micropores. Apparently, the reactions are favored due to basic sites on the carbon surface. Our findings suggest a potential environmentally friendly route for decontamination of adsorbed CWAs, using H2O2 without the need of cosolvents or activators.

A Structural Biology and Protein Engineering Approach to the Engineering Highly Proficient Catalytic Bioscavengers for In Vivo Detoxification of a Broad Spectrum of Nerve Agents

DTIC Science & Technology

2016-06-30

enzyme. 2 6. The N-terminus of subunit B of PTE-A53 was shown by X-ray crystallography to protrude into the active site of subunit A in a symmetry... crystallography unit. 8. The tagless C23-A203L variant was over-expressed and purified , and was tested for protection against VX intoxication by Prof. Franz...2.3 A, was collected ’in house’, at the WIS X-ray Crystallography Facility. The data collected are summarized in Table 10. Figure 15: The crystals

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 molar amount underlining the usefulness for quantitative adduct determination. In conclusion, the current analytical design exhibits potential as a verification tool for high-dose exposure.

Iron oxide functionalized graphene nano-composite for dispersive solid phase extraction of chemical warfare agents from aqueous samples.

PubMed

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

2015-05-15

Present study deals with the preparation and evaluation of graphene based magnetic nano-composite for dispersive solid phase extraction of Chemical Weapons Convention (CWC) relevant chemicals from aqueous samples. Nano-composite, Fe3O4@SiO2-G was synthesized by covalently bonding silica coated Fe3O4 onto the graphene sheets. Nerve agents (NA), Sulfur mustard (SM) and their non-toxic environmental markers were the target analytes. Extraction parameters like amount of sorbent, extraction time and desorption conditions were optimized. Dispersion of 20 milligram of sorbent in 200mL of water sample for 20min. followed by methanol/chloroform extraction produced average to good recoveries (27-94%) of targeted analytes. Recoveries of real agents exhibited great dependency upon sample pH and ionic strength. Sarin produced maximum recovery under mild acidic conditions (56% at pH 5) while VX demanded alkaline media (83% at pH 9). Salts presence in the aqueous samples was found to be advantageous, raising the recoveries to as high as 94% for SM. Excellent limits of detection (LOD) for sulphur mustard and VX (0.11ngmL(-1) and 0.19ngmL(-1) respectively) proved the utility of the developed method for the off-site analysis of CWC relevant chemicals. Copyright © 2015 Elsevier B.V. All rights reserved.

Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse. (I) Development of a model for screening studies in skin decontamination and protection.

PubMed

Dorandeu, F; Taysse, L; Boudry, I; Foquin, A; Hérodin, F; Mathieu, J; Daulon, S; Cruz, C; Lallement, G

2011-06-01

Exposure to lethal chemical warfare agents (CWAs) is no longer only a military issue due to the terrorist threat. Among the CWAs of concern are the organophosphorus nerve agent O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX) and the vesicant sulfur mustard (SM). Although efficient means of decontamination are available, most of them lose their efficacy when decontamination is delayed after exposure of the bare skin. Alternatively, CWA skin penetration can be prevented by topical skin protectants. Active research in skin protection and decontamination is thus paramount. In vivo screening of decontaminants or skin protectants is usually time consuming and may be expensive depending on the animal species used. We were thus looking for a suitable, scientifically sound and cost-effective model, which is easy to handle. The euthymic hairless mouse Crl: SKH-1 (hr/hr) BR is widely used in some skin studies and has previously been described to be suitable for some experiments involving SM or SM analogs. To evaluate the response of this species, we studied the consequences of exposing male anaesthetized SKH-1 mice to either liquid VX or to SM, the latter being used in liquid form or as saturated vapours. Long-term effects of SM burn were also evaluated. The model was then used in the companion paper (Taysse et al.(1)).

Limitations and challenges in treatment of acute chemical warfare agent poisoning.

PubMed

Thiermann, Horst; Worek, Franz; Kehe, Kai

2013-12-05

Recent news from Syria on a possible use of chemical warfare agents made the headlines. Furthermore, the motivation of terrorists to cause maximal harm shifts these agents into the public focus. For incidents with mass casualties appropriate medical countermeasures must be available. At present, the most important threats arise from nerve agents and sulfur mustard. At first, self-protection and protection of medical units from contamination is of utmost importance. Volatile nerve agent exposure, e.g. sarin, results in fast development of cholinergic crisis. Immediate clinical diagnosis can be confirmed on-site by assessment of acetylcholinesterase activity. Treatment with autoinjectors that are filled with 2mg atropine and an oxime (at present obidoxime, pralidoxime, TMB-4 or HI-6) are not effective against all nerve agents. A more aggressive atropinisation has to be considered and more effective oximes (if possible with a broad spectrum or a combination of different oximes) as well as alternative strategies to cope with high acetylcholine levels at synaptic sites should be developed. A further gap exists for the treatment of patients with sustained cholinergic crisis that has to be expected after exposure to persistent nerve agents, e.g. VX. The requirement for long-lasting artificial ventilation can be reduced with an oxime therapy that is optimized by using the cholinesterase status for guidance or by measures (e.g. scavengers) that are able to reduce the poison load substantially in the patients. For sulfur mustard poisoning no specific antidote is available until now. Symptomatic measures as used for treatment of burns are recommended together with surgical or laser debridement. Thus, huge amounts of resources are expected to be consumed as wound healing is impaired. Possible depots of sulfur mustard in tissues may aggravate the situation. More basic knowledge is necessary to improve substantially therapeutic options. The use of stem cells may provide a new and promising option. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Biocatalytic nerve agent detoxification in fire fighting foams.

PubMed

LeJeune, K E; Russell, A J

1999-03-20

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

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

PubMed

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

2014-05-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hovanec, J.W.; Szafraniec, L.L.; Albizo, J.M.

1993-04-01

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

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.

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents

PubMed Central

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-01

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design—wearable APP (WAPP)—that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents. PMID:28098192

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents

NASA Astrophysics Data System (ADS)

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-01

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design—wearable APP (WAPP)—that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents.

Wearable Atmospheric Pressure Plasma Fabrics Produced by Knitting Flexible Wire Electrodes for the Decontamination of Chemical Warfare Agents.

PubMed

Jung, Heesoo; Seo, Jin Ah; Choi, Seungki

2017-01-18

One of the key reasons for the limited use of atmospheric pressure plasma (APP) is its inability to treat non-flat, three-dimensional (3D) surface structures, such as electronic devices and the human body, because of the rigid electrode structure required. In this study, a new APP system design-wearable APP (WAPP)-that utilizes a knitting technique to assemble flexible co-axial wire electrodes into a large-area plasma fabric is presented. The WAPP device operates in ambient air with a fully enclosed power electrode and grounded outer electrode. The plasma fabric is flexible and lightweight, and it can be scaled up for larger areas, making it attractive for wearable APP applications. Here, we report the various plasma properties of the WAPP device and successful test results showing the decontamination of toxic chemical warfare agents, namely, mustard (HD), soman (GD), and nerve (VX) agents.

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.

Efficacy studies of Reactive Skin Decontamination Lotion, M291 Skin Decontamination Kit, 0.5% bleach, 1% soapy water, and Skin Exposure Reduction Paste Against Chemical Warfare Agents, part 1: guinea pigs challenged with VX.

PubMed

Braue, Ernest H; Smith, Kelly H; Doxzon, Bryce F; Lumpkin, Horace L; Clarkson, Edward D

2011-03-01

This report, first in a series of five, directly compares the efficacy of 4 decontamination products and Skin Exposure Reduction Paste Against Chemical Warfare Agents (SERPACWA) in the haired guinea pig model following exposure to VX. In all experiments, guinea pigs were close-clipped and given anesthesia. In the decontamination experiments, the animals were challenged with VX and decontaminated after a 2-minute delay for the standard procedure or at longer times for the delayed-decontamination experiments. Skin Exposure Reduction Paste Against Chemical Warfare Agents was applied as a thin coating (0.1 mm thick), allowed to dry for 15 minutes, and challenged with VX. After a 2-hour challenge, any remaining VX was blotted off the animal, but no additional decontamination was done. Positive control animals were challenged with VX in the same manner as the treated animals, except that they received no treatment. In addition, the positive control animals were always challenged with 5% VX in isopropyl alcohol (IPA) solution, whereas the treatment animals received either neat (undiluted) VX or 5% VX in IPA solution. All animals were observed during the first 4 hours and again at 24 hours after exposure for signs of toxicity and death. The protective ratio (PR, defined as the median lethal dose [LD(50)] of the treatment group divided by the LD(50) of the untreated positive control animals) was calculated from the probit dose-response curves established for each treatment group and nontreated control animals. Significance in this report was defined as p < .05. In the standard 2-minute neat VX decontamination experiments, the calculated PRs for Reactive Skin Decontamination Lotion (RSDL), 0.5% bleach, 1% soapy water, and the M291 Skin Decontamination Kit (SDK) were 66, 17, 16, and 1.1, respectively. Reactive Skin Decontamination Lotion was by far the most effective decontamination product tested and was significantly better than any of the other products. Bleach and soapy water provided equivalent and good (PR > 5) protection. They were both significantly better than the M291 SDK. The M291 SDK did not provide significant protection compared with positive controls. In the neat VX delayed-decontamination experiments, the calculated LT(50) (the delayed-decontamination time at which 50% of the animals died in the test population following a 5-LD(50) challenge) values for RSDL, 0.5% bleach, and 1% soapy water were 31, 48, and 26 minutes, respectively. The results showed that SERPACWA provided significant, but modest (PR < 5), protection against neat VX, with a PR of 2.1. Several conclusions can be drawn from this study: 1) RSDL provided superior protection against VX compared with the other products tested; 2) 0.5% bleach and 1% soapy water were less effective than RSDL, but still provided good protection against VX; 3) the M291 SDK was the least effective decontamination product and did not provide significant protection against VX; 4) the agent was observed to streak when using the M291 SDK, and efficacy may improve if the agent is first blotted, followed by wiping with a new or clean part of the M291 SDK pad; 5) RSDL, 0.5% bleach, and 1% soapy water provided significant protection against a 5-LD(50) challenge of VX, even when decontamination was delayed for up to about 30 minutes; and 6) SERPACWA provided significant, but modest, protection against VX.

Human scalp permeability to the chemical warfare agent VX.

PubMed

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

2011-12-01

The use of chemical warfare agents such as VX in terrorism act might lead to contamination of the civilian population. Human scalp decontamination may require appropriate products and procedures. Due to ethical reasons, skin decontamination studies usually involve in vitro skin models, but human scalp skin samples are uncommon and expensive. The purpose of this study was to characterize the in vitro permeability to VX of human scalp, and to compare it with (a) human abdominal skin, and (b) pig skin from two different anatomic sites: ear and skull roof, in order to design a relevant model. Based on the VX skin permeation kinetics and distribution, we demonstrated that (a) human scalp was significantly more permeable to VX than abdominal skin and (b) pig-ear skin was the most relevant model to predict the in vitro human scalp permeability. Our results indicated that the follicular pathway significantly contributed to the skin absorption of VX through human scalp. In addition, the hair follicles and the stratum corneum significantly contributed to the formation of a skin reservoir for VX. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mechanisms of Aging of Phosphylated Serine Hydrolases

DTIC Science & Technology

2009-08-25

These findings can be compared to previous molecular dynamics research on AChE undertaken by Hurley et al. (2005) that reported a net- RMSD of...1.2 Å associated with in silico inhibition (but not aging) of AChE by the nerve agent VX. This RMSD is comparable to our result of 1.4 Å for simulated ...4 4.2. Mass spectrometry…………………………………………………………………. 5 4.3. Computational molecular modeling……………………………………………….. 7 5

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hovanec, J.W.; Albizo, J.M.; Henderson, V.D.

1994-08-01

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

Sample Preparation Report of the Fourth OPCW Confidence Building Exercise on Biomedical Sample Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Udey, R. N.; Corzett, T. H.; Alcaraz, A.

Following the successful completion of the 3rd biomedical confidence building exercise (February 2013 – March 2013), which included the analysis of plasma and urine samples spiked at low ppb levels as part of the exercise scenario, another confidence building exercise was targeted to be conducted in 2014. In this 4th exercise, it was desired to focus specifically on the analysis of plasma samples. The scenario was designed as an investigation of an alleged use of chemical weapons where plasma samples were collected, as plasma has been reported to contain CWA adducts which remain present in the human body for severalmore » weeks (Solano et al. 2008). In the 3rd exercise most participants used the fluoride regeneration method to analyze for the presence of nerve agents in plasma samples. For the 4th biomedical exercise it was decided to evaluate the analysis of human plasma samples for the presence/absence of the VX adducts and aged adducts to blood proteins (e.g., VX-butyrylcholinesterase (BuChE) and aged BuChE adducts using a pepsin digest technique to yield nonapeptides; or equivalent). As the aging of VX-BuChE adducts is relatively slow (t1/2 = 77 hr at 37 °C [Aurbek et al. 2009]), soman (GD), which ages much more quickly (t1/2 = 9 min at 37 °C [Masson et al. 2010]), was used to simulate an aged VX sample. Additional objectives of this exercise included having laboratories assess novel OP-adducted plasma sample preparation techniques and analytical instrumentation methodologies, as well as refining/designating the reporting formats for these new techniques.« less

Adaptation of the Conditions of US EPA Method 538 for the ...

EPA Pesticide Factsheets

Report The objective of this study was to evaluate U.S. EPA’s Method 538 for the assessment of drinking water exposure to the nerve agent degradation product, EA2192, the most toxic degradation product of nerve agent VX. As a result of the similarities in sample preparation and analysis that Method 538 uses for nonvolatile chemicals, this method is applicable to the nonvolatile Chemical Warfare Agent (CWA) degradation product, EA2192, in drinking water. The method may be applicable to other nonvolatile CWAs and their respective degradation products as well, but the method will need extensive testing to verify compatibility. Gaps associated with the need for analysis methods capable of analyzing such analytes were addressed by adapting the EPA 538 method for this CWA degradation product. Many laboratories have the experience and capability to run the already rigorous method for nonvolatile compounds in drinking water. Increasing the number of laboratories capable of carrying out these methods serves to significantly increase the surge laboratory capacity to address sample throughput during a large exposure event. The approach desired for this study was to start with a proven high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method for nonvolatile chemicals in drinking water and assess the inclusion of a similar nonvolatile chemical, EA2192.

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.

Development of Novel Decontamination Techniques for Chemical Agents (GB, VX, HD) Contaminated Facilities. Phase II. Laboratory Evaluation of Novel Agent Decontamination Concepts

DTIC Science & Technology

1985-06-21

mild steel, unpainted mild steel, and porous (i.e., concrete and unglazed porcelain ) test coupons contaminated with agent to a hot-gas composition near...unpainted *’ mild steel, painted stainless steel, concrete, and unglazed porcelain * coupons contaminated with HD, GB, or VX. The detectable limit for the Sub...similar decontamination efficiency was observable in the concrete and unglazed porcelain tests for an initial dose level of 1.8 mg agent/g of material

Natural Attenuation of Persistent Chemical Warfare Agent VX ...

EPA Pesticide Factsheets

Report Natural attenuation of persistent CWAs such as VX was investigated and occurs, given sufficient time (days to weeks). Natural attenuation was found to be faster at warmer temperatures (i.e., 35 °C and 25 °C) than cooler temperatures (i.e., 10 °C). Attenuation of VX was material dependent with a general trend of faster to slower attenuation in the order ceramic tile - galvanized metal - silanized glass - painted drywall. Trace amounts of VX may still be present weeks to months after a contamination event.

Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study.

PubMed

Khan, Md Abdul Shafeeuulla; Ganguly, Bishwajit

2012-05-01

Oximate anions are used as potential reactivating agents for OP-inhibited AChE because of they possess enhanced nucleophilic reactivity due to the α-effect. We have demonstrated the process of reactivating the VX-AChE adduct with formoximate and hydroxylamine anions by applying the DFT approach at the B3LYP/6-311 G(d,p) level of theory. The calculated results suggest that the hydroxylamine anion is more efficient than the formoximate anion at reactivating VX-inhibited AChE. The reaction of formoximate anion and the VX-AChE adduct is a three-step process, while the reaction of hydroxylamine anion with the VX-AChE adduct seems to be a two-step process. The rate-determining step in the process is the initial attack on the VX of the VX-AChE adduct by the nucleophile. The subsequent steps are exergonic in nature. The potential energy surface (PES) for the reaction of the VX-AChE adduct with hydroxylamine anion reveals that the reactivation process is facilitated by the lower free energy of activation (by a factor of 1.7 kcal mol(-1)) than that of the formoximate anion at the B3LYP/6-311 G(d,p) level of theory. The higher free energy of activation for the reverse reactivation reaction between hydroxylamine anion and the VX-serine adduct further suggests that the hydroxylamine anion is a very good antidote agent for the reactivation process. The activation barriers calculated in solvent using the polarizable continuum model (PCM) for the reactivation of the VX-AChE adduct with hydroxylamine anion were also found to be low. The calculated results suggest that V-series compounds can be more toxic than G-series compounds, which is in accord with earlier experimental observations.

Fluorescent Chemosensors for Toxic Organophosphorus Pesticides: A Review

PubMed Central

Obare, Sherine O.; De, Chandrima; Guo, Wen; Haywood, Tajay L.; Samuels, Tova A.; Adams, Clara P.; Masika, Noah O.; Murray, Desmond H.; Anderson, Ginger A.; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction. PMID:22163587

Fluorescent chemosensors for toxic organophosphorus pesticides: a review.

PubMed

Obare, Sherine O; De, Chandrima; Guo, Wen; Haywood, Tajay L; Samuels, Tova A; Adams, Clara P; Masika, Noah O; Murray, Desmond H; Anderson, Ginger A; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction.

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, tabun and nitrogen mustards were higher. Some CWA simulants and organic solvents gave the ion peaks eluting at the similar positions of the CWAs, resulting in false positive alarms. Copyright © 2015 Elsevier B.V. All rights reserved.

Reevaluation of 1999 Health-Based Environmental Screening Levels (HBESLs) for Chemical Warfare Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watson, Annetta Paule; Dolislager, Fredrick G

2007-05-01

This report evaluates whether new information and updated scientific models require that changes be made to previously published health-based environmental soil screening levels (HBESLs) and associated environmental fate/breakdown information for chemical warfare agents (USACHPPM 1999). Specifically, the present evaluation describes and compares changes that have been made since 1999 to U.S. Environmental Protection Agency (EPA) risk assessment models, EPA exposure assumptions, as well as to specific chemical warfare agent parameters (e.g., toxicity values). Comparison was made between screening value estimates recalculated with current assumptions and earlier health-based environmental screening levels presented in 1999. The chemical warfare agents evaluated include themore » G-series and VX nerve agents and the vesicants sulfur mustard (agent HD) and Lewisite (agent L). In addition, key degradation products of these agents were also evaluated. Study findings indicate that the combined effect of updates and/or changes to EPA risk models, EPA default exposure parameters, and certain chemical warfare agent toxicity criteria does not result in significant alteration to the USACHPPM (1999) health-based environmental screening level estimates for the G-series and VX nerve agents or the vesicant agents HD and L. Given that EPA's final position on separate Tier 1 screening levels for indoor and outdoor worker screening assessments has not yet been released as of May 2007, the study authors find that the 1999 screening level estimates (see Table ES.1) are still appropriate and protective for screening residential as well as nonresidential sites. As such, risk management decisions made on the basis of USACHPPM (1999) recommendations do not require reconsideration. While the 1999 HBESL values are appropriate for continued use as general screening criteria, the updated '2007' estimates (presented below) that follow the new EPA protocols currently under development are also protective. When EPA finalizes and documents a position on the matter of indoor and outdoor worker screening assessments, site-specific risk assessments should make use of modified models and criteria. Screening values such as those presented in this report may be used to assess soil or other porous media to determine whether chemical warfare agent contamination is present as part of initial site investigations (whether due to intentional or accidental releases) and to determine whether weather/decontamination has adequately mitigated the presence of agent residual to below levels of concern. However, despite the availability of scientifically supported health-based criteria, there are significant resources needs that should be considered during sample planning. In particular, few analytical laboratories are likely to be able to meet these screening levels. Analyses will take time and usually have limited confidence at these concentrations. Therefore, and particularly for the more volatile agents, soil/destructive samples of porous media should be limited and instead enhanced with headspace monitoring and presence-absence wipe sampling.« less

Simultaneous quantification of soman and VX adducts to butyrylcholinesterase, their aged methylphosphonic acid adduct and butyrylcholinesterase in plasma using an off-column procainamide-gel separation method combined with UHPLC-MS/MS.

PubMed

Liu, Chang-Cai; Huang, Gui-Lan; Xi, Hai-Ling; Liu, Shi-Lei; Liu, Jing-Quan; Yu, Hui-Lan; Zhou, Shi-Kun; Liang, Long-Hui; Yuan, Ling

2016-11-15

This work describes a novel and sensitive non-isotope dilution method for simultaneous quantification of organophosphorus nerve agents (OPNAs) soman (GD) and VX adducts to butyrylcholinesterase (BChE), their aged methylphosphonic acid (MeP) adduct and unadducted BChE in plasma exposed to OPNA. OPNA-BChE adducts were isolated with an off-column procainamide-gel separation (PGS) from plasma, and then digested with pepsin into specific adducted FGES * AGAAS nonapeptide (NP) biomarkers. The resulting NPs were detected by UHPLC-MS/MS MRM. The off-column PGS method can capture over 90% of BChE, MeP-BChE, VX-BChE and GD-BChE from their respective plasma materials. One newly designed and easily synthesized phosphorylated BChE nonapeptide with one Gly-to-Ala mutation was successfully reported to serve as internal standard instead of traditional isotopically labeled BChE nonapeptide. The linear range of calibration curves were from 1.00-200ngmL -1 for VX-NP, 2.00-200ngmL -1 for GD-NP and MeP-NP (R 2 ≥0.995), and 3.00-200ngmL -1 for BChE NP (R 2 ≥0.990). The inter-day precision had relative standard deviation (%RSD) of <8.89%, and the accuracy ranged between 88.9-120%. The limit of detection was calculated to be 0.411, 0.750, 0.800 and 1.43ngmL -1 for VX-NP, GD-NP, MeP-NP and BChE NP, respectively. OPNA-exposed quality control plasma samples were characterized as part of method validation. Investigation of plasma samples unexposed to OPNA revealed no baseline values or interferences. Using the off-column PGS method combined with UHPLC-MS/MS, VX-NP and GD-NP adducts can be unambiguously detected with high confidence in 0.10ngmL -1 and 0.50ngmL -1 of exposed human plasma respectively, only requiring 0.1mL of plasma sample and taking about four hours without special sample preparation equipment. These improvements make it a simple, sensitive and robust PGS-UHPLC-MS/MS method, and this method will become an attractive alternative to immunomagnetic separation (IMS) method and a useful diagnostic tool for retrospective detection of OPNA exposure with high confidence. Furthermore, using the developed method, the adducted BChE levels from VX and GD-exposed (0.10-100ngmL -1 ) plasma samples were completely characterized, and the fact that VX being more active and specific to BChE than GD was re-confirmed. Copyright © 2016 Elsevier B.V. All rights reserved.

On-matrix Derivatization for Dynamic Headspace Sampling of Nonvolatile Surface Residues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harvey, Scott D.; Wahl, Jon H.

2012-09-01

The goal of this study is to extend sampling by the field and laboratory emission cell (FLEC) purge-and-trap technique to applications that target nonvolatile residues. On-matrix derivatization of residues to render analytes stable and more volatile is explored to achieve this goal. Results show that on-matrix derivatizations of nerve agent hydrolysis products (monoalkyl methylphosphonic acids and methylphosphonic acid [MPA]) with diazomethane were successful on glass and painted wallboard (at the 10-µg level). It also was successful on the more difficult concrete (at the 500-µg level) and carpet (at the 20-µg level) substrates that cannot be successfully sampled using swipe techniques.more » Analysis of additional chemical warfare (CW)-associated residues can be approached by on-matrix derivatization with trifluoroacetic anhydride (TFAA). For example, amines (used as stabilizers or present as decomposition products of the nerve agent VX) or thiodiglycol (hydrolysis product of sulfur mustard) could be sampled as their TFAA derivatives from glass, painted wallboard, and concrete (at the 40-µg level), as well as carpet (at the 80-µg level) surfaces. Although the amine and thiodiglycol are semi-volatile and could be sampled directly, derivatization improves the recovery and chromatographic behavior of these analytes.« less

On-matrix derivatization for dynamic headspace sampling of nonvolatile surface residues.

PubMed

Harvey, Scott D; Wahl, Jon H

2012-09-21

The goal of this study is to extend sampling by the field and laboratory emission cell (FLEC) dynamic headspace technique to applications that target nonvolatile residues. On-matrix derivatization of residues to render analytes stable and more volatile is explored to achieve this goal. Results show that on-matrix derivatizations of nerve agent hydrolysis products (monoalkyl methylphosphonic acids and methylphosphonic acid [MPA]) with diazomethane were successful on glass and painted wallboard (at the 10-μg level). It also was successful on the more difficult concrete (at the 500-μg level) and carpet (at the 20-μg level), substrates that cannot be successfully sampled using swipe techniques. Analysis of additional chemical warfare (CW)-associated residues can be approached by on-matrix derivatization with trifluoroacetic anhydride (TFAA). For example, amines (used as stabilizers or present as decomposition products of the nerve agent VX) or thiodiglycol (hydrolysis product of sulfur mustard) could be sampled as their TFAA derivatives from glass, painted wallboard, and concrete (at the 40-μg level), as well as carpet (at the 80-μg level) surfaces. Although the amine and thiodiglycol are semi-volatile and could be sampled directly, derivatization improves the recovery and chromatographic behavior of these analytes. Copyright © 2012 Elsevier B.V. All rights reserved.

Computer-generated predictions of the structure and of the IR and Raman spectra of VX. Final report, May-August 1992

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hameka, H.F.; Jensen, J.O.

1993-05-01

This report presents the computed optimized geometry and vibrational IR and Raman frequencies of the V-agent VX. The computations are performed with the Gaussian 90 Program Package using 6-31G* basis sets. We assign the vibrational frequencies and correct each frequency by multiplying it with a previously derived 6-31G* correction factor. The result is a computer-generated prediction of the IR and Raman spectra of VX. This study was intended as a blind test of the utility of IR spectral prediction. Therefore, we intentionally did not look at experimental data on the IR and Raman spectra of VX.... IR Spectra, VX, Ramanmore » spectra, Computer predictions.« less

Pickering emulsions for skin decontamination.

PubMed

Salerno, Alicia; Bolzinger, Marie-Alexandrine; Rolland, Pauline; Chevalier, Yves; Josse, Denis; Briançon, Stéphanie

2016-08-01

This study aimed at developing innovative systems for skin decontamination. Pickering emulsions, i.e. solid-stabilized emulsions, containing silica (S-PE) or Fuller's earth (FE-PE) were formulated. Their efficiency for skin decontamination was evaluated, in vitro, 45min after an exposure to VX, one of the most highly toxic chemical warfare agents. Pickering emulsions were compared to FE (FE-W) and silica (S-W) aqueous suspensions. PE containing an oil with a similar hydrophobicity to VX should promote its extraction. All the formulations reduced significantly the amount of VX quantified on and into the skin compared to the control. Wiping the skin surface with a pad already allowed removing more than half of VX. FE-W was the less efficient (85% of VX removed). The other formulations (FE-PE, S-PE and S-W) resulted in more than 90% of the quantity of VX removed. The charge of particles was the most influential factor. The low pH of formulations containing silica favored electrostatic interactions of VX with particles explaining the better elimination from the skin surface. Formulations containing FE had basic pH, and weak interactions with VX did not improve the skin decontamination. However, these low interactions between VX and FE promote the transfer of VX into the oil droplets in the FE-PE. Copyright © 2016 Elsevier B.V. All rights reserved.

Atmospheric-pressure plasma decontamination/sterilization chamber

DOEpatents

Herrmann, Hans W.; Selwyn, Gary S.

2001-01-01

An atmospheric-pressure plasma decontamination/sterilization chamber is described. The apparatus is useful for decontaminating sensitive equipment and materials, such as electronics, optics and national treasures, which have been contaminated with chemical and/or biological warfare agents, such as anthrax, mustard blistering agent, VX nerve gas, and the like. There is currently no acceptable procedure for decontaminating such equipment. The apparatus may also be used for sterilization in the medical and food industries. Items to be decontaminated or sterilized are supported inside the chamber. Reactive gases containing atomic and metastable oxygen species are generated by an atmospheric-pressure plasma discharge in a He/O.sub.2 mixture and directed into the region of these items resulting in chemical reaction between the reactive species and organic substances. This reaction typically kills and/or neutralizes the contamination without damaging most equipment and materials. The plasma gases are recirculated through a closed-loop system to minimize the loss of helium and the possibility of escape of aerosolized harmful substances.

Rain-Induced Wash-Off of Chemical Warfare Agent (VX) from Foliar Surfaces of Living Plants Maintained in a Surety Hood

DTIC Science & Technology

2016-09-01

than those at 0.017 h. Grass contaminated with 3 µL VX droplets was exposed to multiple (10×) 100 µL light rain events, followed by multiple (10...No-Go” decisions that can affect soldiers on agent- contaminated battlefields. 15. SUBJECT TERMS Wash-off coefficient Echinochloa crus...trade or manufacturers ’ names in this report does not constitute an official endorsement of any commercial products. This report may not be cited

Modulation of kinase-inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX-680 and with TPX2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Baoguang; Smallwood, Angela; Yang, Jingsong

2008-10-24

VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 {angstrom} resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a {pi}-{pi} interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggestmore » that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.« less

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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Absorbent Analysis of Anniston Chemical Agent Disposal Facility Munition Demilitarization Building (MDB) Banks 1 and 2 Filter Samples Following Completion of The GB Agent and VX Rocket Campaigns

DTIC Science & Technology

2013-01-01

adsorbed on wet carbon (13 wt% water ). Left to right: initial and t = 6, 13, and 16 days ..............................3 2. 31 P MAS NMR spectra...obtained for 10 wt% VX adsorbed on wet carbon (13 wt% water ) Left to right: initial and t = 24 days ...............................................4...of feed air. Each Class A Type II filter contained approximately 48.2 lb of granular, activated, coconut shell-based carbon. A given filter bank

Degradation Kinetics of VX

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gary S. Groenewold

2010-12-01

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

Decontamination of VX, GD, and HD on a surface using modified vaporized hydrogen peroxide.

PubMed

Wagner, George W; Sorrick, David C; Procell, Lawrence R; Brickhouse, Mark D; Mcvey, Iain F; Schwartz, Lewis I

2007-01-30

Vaporized hydrogen peroxide (VHP) has proven efficacy for biological decontamination and is a common gaseous sterilant widely used by industry. Regarding chemical warfare agent decontamination, VHP is also effective against HD and VX, but not GD. Simple addition of ammonia gas to VHP affords reactivity toward GD, while maintaining efficacy for HD (and bioagents) and further enhancing efficacy for VX. Thus, modified VHP is a broad-spectrum CB decontaminant suitable for fumigant-type decontamination scenarios, i.e., building, aircraft, and vehicle interiors and sensitive equipment. Finally, as an interesting aside to the current study, commercial ammonia-containing cleaners are also shown to be effective surface decontaminants for GD, but not for VX or HD.

Preservation Study for Ultra-Dilute VX Standards | Science ...

EPA Pesticide Factsheets

Report Lawrence Livermore National Laboratory (LLNL) supplies ultra-dilute (10 µg/mL) chemical warfare agent (CWA) standards to the Environmental Response Laboratory Network (ERLN) laboratories to allow the use of authentic standards to assist in analyses required for a remediation event involving CWAs. For this reason, it is important to collect data regarding the shelf-lives of these standards. The instability has the potential to impact quality control in regional ERLN laboratories, resulting in data that are difficult to interpret. Thus, this study investigated the use of chemical stabilizers to increase the shelf-life of VX standards. VX standards with long shelf-lives are desirable, as long shelf-life would significantly reduce the costs associated with synthesizing and resupplying the ERLN laboratories with VX.

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

PubMed

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

2014-08-01

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

High Throughput Determination of VX in Drinking Water by ...

EPA Pesticide Factsheets

Methods Report This document provides the standard operating procedure for determination of the chemical warfare agent VX (O-Ethyl S-2-Diisopropylamino-Ethyl Methylphosphonothioate) in drinking water by isotope dilution liquid chromatography tandem mass spectrometer (LC/MS/MS). This method was adapted from one that was initially developed by the Centers for Disease Control and Prevention, in the National Center for Environmental Health for the determination and quantitation of VX in aqueous matrices. This method is designed to support site-specific cleanup goals of environmental remediation activities following a homeland security incident involving this analyte.

Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging.

PubMed

Nachon, Florian; Asojo, Oluwatoyin A; Borgstahl, Gloria E O; Masson, Patrick; Lockridge, Oksana

2005-02-01

Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.

Biological monitoring of exposure to nerve agents.

PubMed Central

Bajgar, J

1992-01-01

Changes in acetylcholinesterase activity in blood and some organs of rats after intoxication with sarin, soman, VX, and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV), in doses of roughly 2 x LD50 given intramuscularly, were obtained from published data and by experiment. The time course of inhibition of acetylcholinesterase in blood, regions of brain, and diaphragm and the occurrence of signs and symptoms of poisoning (none, salivation, disturbed ventilation and fasciculations, convulsions, or death) were summarised and compared. When blood enzyme activities were 70-100% normal, no obvious signs were seen; at 60-70%, salivation occurred; at less than 30-55%, disturbed ventilation and fasciculations were seen, and at 15-30%, convulsions occurred. Less than 10% was fatal. In experiments with narcotised dogs, the blood acetylcholinesterase activity and the ability to reactivate it with trimedoxime were determined after intoxication by intramuscular administration of the four compounds. It is concluded that acetylcholinesterase activity in the blood corresponds to that in the target organs and can be considered as an appropriate parameter for biological monitoring of exposure to nerve gases. Moreover, determination of reactivation of blood acetylcholinesterase gives more information than simple determination of enzyme activity. PMID:1390271

An Inverse Analysis Approach to the Characterization of Chemical Transport in Paints

PubMed Central

Willis, Matthew P.; Stevenson, Shawn M.; Pearl, Thomas P.; Mantooth, Brent A.

2014-01-01

The ability to directly characterize chemical transport and interactions that occur within a material (i.e., subsurface dynamics) is a vital component in understanding contaminant mass transport and the ability to decontaminate materials. If a material is contaminated, over time, the transport of highly toxic chemicals (such as chemical warfare agent species) out of the material can result in vapor exposure or transfer to the skin, which can result in percutaneous exposure to personnel who interact with the material. Due to the high toxicity of chemical warfare agents, the release of trace chemical quantities is of significant concern. Mapping subsurface concentration distribution and transport characteristics of absorbed agents enables exposure hazards to be assessed in untested conditions. Furthermore, these tools can be used to characterize subsurface reaction dynamics to ultimately design improved decontaminants or decontamination procedures. To achieve this goal, an inverse analysis mass transport modeling approach was developed that utilizes time-resolved mass spectroscopy measurements of vapor emission from contaminated paint coatings as the input parameter for calculation of subsurface concentration profiles. Details are provided on sample preparation, including contaminant and material handling, the application of mass spectrometry for the measurement of emitted contaminant vapor, and the implementation of inverse analysis using a physics-based diffusion model to determine transport properties of live chemical warfare agents including distilled mustard (HD) and the nerve agent VX. PMID:25226346

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. Published by Elsevier Ireland Ltd.

Destruction of VX by aqueous-phase oxidation using peroxydisulfate (direct chemical oxidation)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cooper, J.F.; Krueger, R.; Farmer, J.C.

1995-10-11

Chemical warfare agents may be completely destroyed (converted to H{sub 2}O, CO{sub 2}, salts) by oxidation at 90--100 C using acidified ammonium peroxydisulfate, with recycle of NH{sub 4}SO{sub 4} byproduct. The process requires no toxic or expended catalysts and produces no secondary wastes other than the precipitated inorganic content of the agents. To determine oxidative capability of peroxydisulfate at low reductant contents, we measured rate data for oxidation of 20 diverse compounds with diverse functional groups; 4 of these have bonds similar to those found in VX, HD, and GB. On an equivalence basis, integral first-order rate constants for 100more » C oxidation are 0.012{plus_minus}0.005 min{sup {minus}1} for di-isopropyl-methyl-phosphonate, methyl phosphonic acid, triethylamine, and 2,2{prime}-thiodiethanol at low initial concentrations of 50 ppM(as carbon) and pH 1.5. To provide scale-up equations for a bulk chemical agent destruction process, we measured time-dependent oxidation of bulk model chemicals at high concentrations (0.5 N) and developed and tested a quantitative model. A practical process for bulk VX destruction would begin with chemical detoxification by existing techniques (eg, hydrolysis or mild oxidation using oxone), followed by mineralization of the largely detoxified products by peroxydisulfate. Secondary wastes would be avoided by use of commercial electrolysis equipment to regenerate the oxidant. Reagent requirements, mass balance and scaleup parameters are given for VX destruction, using peroxydisulfate alone, or supplemented with hydrogen peroxide. For the use of 2.5 N peroxydisulfate as the oxidant, a 1 m{sup 3} digester will process about 200 kg (as C) per day. The process may be extended to total destruction of HD and hydrolysis products of G agents.« less

Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study.

PubMed

Marciano, Daniele; Columbus, Ishay; Elias, Shlomi; Goldvaser, Michael; Shoshanim, Ofir; Ashkenazi, Nissan; Zafrani, Yossi

2012-11-16

Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate. Noteworthy and of practical importance is the fact that the toxic side product desethyl-VX, which is formed in substantial quantities during the slow degradation of VX in unbuffered water, is completely avoided in the presence of fluoride. A computational study on a VX-model, O,S-diethyl methylphosphonothioate (1), clarifies the distinctive tendency of aqueous fluoride ions to react with such organophosphorus compounds. The facility of the degradation process even in dilute fluoride solutions is due to the increased reactivity of fluoride, which is caused by the significant low activation barrier for the P-F bond formation. In addition, the unique nucleophilicity of fluoride versus hydroxide toward VX, in contrast to their relative basicity, is discussed. Although the reaction outcomes were similar, much slower reaction rates were observed experimentally for the VX-model (1) in comparison to VX.

Galantamine is a Novel Post-Exposure Therapeutic Against Lethal VX Challenge

DTIC Science & Technology

2009-01-01

administered as a post- exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality...The standard U.S. military therapy for intoxication by anticholinesterase agents consists of administering ATR to antagonize excessive muscarinic...2003). A ball-and-stick repre- sentation of GAL is shown in Fig. 1 docking to the active site of two different acetylcholinesterase forms. GAL

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

PubMed Central

Byrn, Randal A.; Jones, Steven M.; Bennett, Hamilton B.; Bral, Chris; Clark, Michael P.; Jacobs, Marc D.; Kwong, Ann D.; Ledeboer, Mark W.; Leeman, Joshua R.; McNeil, Colleen F.; Murcko, Mark A.; Nezami, Azin; Perola, Emanuele; Rijnbrand, Rene; Saxena, Kumkum; Tsai, Alice W.; Zhou, Yi

2014-01-01

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m7GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. PMID:25547360

Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.

PubMed

Byrn, Randal A; Jones, Steven M; Bennett, Hamilton B; Bral, Chris; Clark, Michael P; Jacobs, Marc D; Kwong, Ann D; Ledeboer, Mark W; Leeman, Joshua R; McNeil, Colleen F; Murcko, Mark A; Nezami, Azin; Perola, Emanuele; Rijnbrand, Rene; Saxena, Kumkum; Tsai, Alice W; Zhou, Yi; Charifson, Paul S

2015-03-01

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Multifunctional Ultra-High Vacuum Apparatus for Studies of the Interactions of Chemical Warfare Agents on Complex Surfaces

DTIC Science & Technology

2014-01-02

colleagues employed solid state NMR to study the decomposition of CWAs on MgO,36 AgY and NaY zeolites ,37 CaO,38 and Al2O3.39 More recently, the...37G. W. Wagner and P. W. Bartram, “Reactions of VX, HD, and their simu- lants with NaY and AgY zeolites . Desulfurization of VX on AgY,” Lang- muir 15

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

PubMed

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

2011-06-01

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

Reactivation of organophosphate-inhibited human acetylcholinesterase by isonitrosoacetone (MINA): a kinetic analysis.

PubMed

Worek, Franz; Thiermann, Horst

2011-11-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP) with atropine and an acetylcholinesterase (AChE) reactivator (oxime) is of limited effectiveness in case of different nerve agents and pesticides. One challenge is the reactivation of OP-inhibited brain AChE which shows inadequate success with charged pyridinium oximes. Recent studies with high doses of the tertiary oxime isonitrosoacetone (MINA) indicated a beneficial effect on central and peripheral AChE and on survival in nerve agent poisoned guinea pigs. Now, an in vitro study was performed to determine the reactivation kinetics of MINA with tabun-, sarin-, cyclosarin-, VX- and paraoxon-inhibited human AChE. MINA showed an exceptionally low affinity to inhibited AChE but, with the exception of tabun-inhibited AChE, a moderate to high reactivity. In comparison to the pyridinium oximes obidoxime, 2-PAM and HI-6 the affinity and reactivity of MINA was in most cases lower and in relation to the most effective reactivators, the second order reactivation constant of MINA was 500 to 3400-fold lower. Hence, high in vivo MINA concentrations would be necessary to achieve at least partial reactivation. This assumption corresponds to in vivo data showing a dose-dependent effect on reactivation and survival in animals. In view, of the toxic potential of MINA in animals human studies would be necessary to determine the tolerability and pharmacokinetics of MINA in order to enable a proper assessment of the value of this oxime as an antidote in OP poisoning. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Oxotremorine-induced hypothermia as a method for evaluating long-term neuronal changes following poisoning by cholinesterase inhibitors in rats.

PubMed

Grauer, E; Levy, A

2007-12-05

Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naïve rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD(50) of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.

Balancing the stability and the catalytic specificities of OP hydrolases with enhanced V-agent activities.

PubMed

Reeves, T E; Wales, M E; Grimsley, J K; Li, P; Cerasoli, D M; Wild, J R

2008-06-01

Rational site-directed mutagenesis and biophysical analyses have been used to explore the thermodynamic stability and catalytic capabilities of organophosphorus hydrolase (OPH) and its genetically modified variants. There are clear trade-offs in the stability of modifications that enhance catalytic activities. For example, the H254R/H257L variant has higher turnover numbers for the chemical warfare agents VX (144 versus 14 s(-1) for the native enzyme (wild type) and VR (Russian VX, 465 versus 12 s(-1) for wild type). These increases are accompanied by a loss in stability in which the total Gibb's free energy for unfolding is 19.6 kcal/mol, which is 5.7 kcal/mol less than that of the wild-type enzyme. X-ray crystallographic studies support biophysical data that suggest amino acid residues near the active site contribute to the chemical and thermal stability through hydrophobic and cation-pi interactions. The cation-pi interactions appear to contribute an additional 7 kcal/mol to the overall global stability of the enzyme. Using rational design, it has been possible to make amino acid changes in this region that restored the stability, yet maintained effective V-agent activities, with turnover numbers of 68 and 36 s(-1) for VX and VR, respectively. This study describes the first rationally designed, stability/activity balance for an OPH enzyme with a legitimate V-agent activity, and its crystal structure.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartmann, H.; Environmental Assessment

2002-06-01

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

Development of Novel Decontamination Techniques for Chemical Agents (GB, VX, HD) Contaminated Facilities. Phase I. Identification and Evaluation of Novel Decontamination Concepts. Volume 1

DTIC Science & Technology

1983-02-01

ACTIVITY . . . . . . 4 3.0 PHASE I RESULTS . . . . . . . . . . . . . . . . . . . . . . 5 3.1 RESOURCE REVIEW . . . . . . . . . . . . . 5 ŗ.1.1 Surveys...commonly known as mustard, is a vesicant while VX and GB are organophosphorus compounds which act as anticholinesterases . HD Cl-( CH)-S-(CH- );cI 0...order to satisfy the task objective, work during this phase . consisted of three principal interrelated activities . The goal of the first activity was

Fate and Transport of Chemical Warfare Agents VX and HD ...

EPA Pesticide Factsheets

Report The intent of this investigation was to study the fate and transport of CWA applied to painted/sealed materials including the potential partitioning of CWA into permeable paints/sealants and subsequently into underlying porous materials. Based on the results obtained from this investigation, VX and sulfur mustard (HD) have the ability to permeate into paints and sealants, including in some cases the underlying porous materials. It is likely that other permeable materials besides paints and sealants may also show similar behavior.

VX Toxicity in the Gottingen Minipig

DTIC Science & Technology

2016-02-01

mouse, and guinea pig ) to determine estimates for differences in lethality based on route of administration. The slope of the dose-response curve was...alter agent toxicity in other species, such as rats (Benke and Murphy, 1975; Karanth and Pope, 2000; Shih et al., 1990) and guinea pigs (Myers and...LD50 is between 8 µg/kg and 16.25 µg/kg (Maxwell, 1992; Shih and McDonough, 1999). In the guinea pig (Dunkin-Hartley) the IM LD50 of VX has been

Cholinesterases, a target of pharmacology and toxicology.

PubMed

Pohanka, Miroslav

2011-09-01

Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

Decontamination of Chemical/Biological Warfare (CBW) Agents Using an Atmospheric Pressure Plasma Jet (APPJ)

NASA Astrophysics Data System (ADS)

Herrmann, Hans W.

1998-11-01

The atmospheric pressure plasma jet (APPJ) is a non-thermal, high pressure, uniform glow discharge that produces a high velocity effluent stream of highly reactive chemical species. The discharge operates on a feedstock gas (e.g. He/O_2/H_2O) which flows between an outer, grounded, cylindrical electrode and an inner, coaxial electrode powered at 13.56 MHz RF. While passing through the plasma, the feedgas becomes excited, dissociated or ionized by electron impact. Once the gas exits the discharge volume, ions and electrons are rapidly lost by recombination, but the fast-flowing effluent still contains metastables (e.g. O2*, He*) and radicals (e.g. O, OH). These reactive species have been shown to be effective neutralizers of surrogates for anthrax spores, mustard blister agent and VX nerve gas. Unlike conventional, wet decontamination methods, the plasma effluent does not cause corrosion of most surfaces and does not damage wiring, electronics, nor most plastics. This makes it highly suitable for decontamination of high value sensitive equipment such as is found in vehicle interiors (i.e. tanks, planes...) for which there is currently no good decontamination technique. Furthermore, the reactive species rapidly degrade into harmless products leaving no lingering residue or harmful byproducts. Physics of the APPJ will be discussed and results of surface decontamination experiments using simulant and actual CBW agents will be presented.

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

PubMed Central

Boucher, Diane M.; Eustace, Brenda; Gu, Yong; Hare, Brian; Johnson, Mac A.; Milton, Sean; Murphy, Cheryl E.; Takemoto, Darin; Tolman, Crystal; Wood, Mark; Charlton, Peter; Charrier, Jean-Damien; Furey, Brinley; Golec, Julian; Reaper, Philip M.; Pollard, John R.

2014-01-01

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients. PMID:25010037

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.

PubMed

Hall, Amy B; Newsome, Dave; Wang, Yuxin; Boucher, Diane M; Eustace, Brenda; Gu, Yong; Hare, Brian; Johnson, Mac A; Milton, Sean; Murphy, Cheryl E; Takemoto, Darin; Tolman, Crystal; Wood, Mark; Charlton, Peter; Charrier, Jean-Damien; Furey, Brinley; Golec, Julian; Reaper, Philip M; Pollard, John R

2014-07-30

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

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.

Porphyrin-containing polyaspartamide gadolinium complexes as potential magnetic resonance imaging contrast agents.

PubMed

Yan, Guo-Ping; Li, Zhen; Xu, Wei; Zhou, Cheng-Kai; Yang, Lian; Zhang, Qiao; Li, Liang; Liu, Fan; Han, Lin; Ge, Yuan-Xing; Guo, Jun-Fang

2011-04-04

Porphyrin-containing polyaspartamide ligands (APTSPP-PHEA-DTPA) were synthesized by the incorporation of diethylenetriaminepentaacetic acid (DTPA) and 5-(4'-aminophenyl)-10,15,20-tris(4'-sulfonatophenyl) porphyrin, trisodium salt (APTSPP) into poly-α,β-[N-(2-hydroxyethyl)-l-aspartamide] (PHEA). These ligands were further reacted with gadolinium chloride to produce macromolecule-gadolinium complexes (APTSPP-PHEA-DTPA-Gd). Experimental data of (1)H NMR, IR, UV and elemental analysis evidenced the formation of the polyaspartamide ligands and gadolinium complexes. In vitro and in vivo property tests indicated that APTSPP-PHEA-DTPA-Gd possessed noticeably higher relaxation effectiveness, less toxicity to HeLa cells, and significantly higher enhanced signal intensities (SI) of the VX2 carcinoma in rabbits with lower injection dose requirement than that of Gd-DTPA. Moreover, APTSPP-PHEA-DTPA-Gd was found to greatly enhance the contrast of MR images of the VX2 carcinoma, providing prolonged intravascular duration, and distinguished the VX2 carcinoma and normal tissues in rabbits according to MR image signal enhancements. These porphyrin-containing polyaspartamide gadolinium complexes can be used as the candidates of contrast agents for targeted MRI to tumors. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

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

In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime.

PubMed

Nakab, Lauren; Bardot, Isabelle; Bardot, Sébastien; Simar, Sophie; Marzin, Daniel; Nesslany, Fabrice

2014-03-01

Organophosphate compounds, which induce organophosphate poisoning, were originally used as pesticides. But this type of product has also been used as warfare nerve agent like sarin, soman, Russian VX, or tabun. HI-6-dimethanesulfonate is a salt of the oxime HI-6 used in the treatment of nerve-agent poisoning. It is known to be the best re-activator component of inactivated acetyl cholinesterase. HI-6-dimethanesulfonate has shown a higher level of solubility with similar potency to reactivate acetyl cholinesterase and a similar pharmacokinetics profile compared with HI-6 dichloride. HI-6 dimethanesulfonate was tested for its mutagenic and genotoxic potential by use of the standard ICH S2R (1) battery for the evaluation of pharmaceuticals. HI-6-dimethanesulfonate was mutagenic in the Ames test only in the presence of metabolic activation. In the mutation assay at the Tk locus in L5178Y mouse-lymphoma cells, HI-6-dimethanesulfonate showed mutagenic activity both with and without metabolic activation, with a significant increase in small colonies. The effects were in favour of a clastogenic activity. It was concluded that the compound was mutagenic and possibly clastogenic in vitro. In contrast, the in vivo micronucleus test in rat bone-marrow did not demonstrate any genotoxic activity and the Comet assay performed in rat liver did not show any statistically or biologically significant increases in DNA strand-breaks. The results of both in vivo studies performed on two different organs with two endpoints are sufficient to conclude the absence of a genotoxic hazard in vivo and to consider that there is no genotoxic concern in humans for HI-6-dimethanesulfonate. Copyright © 2014 Elsevier B.V. All rights reserved.

All-Weather Hydrogen Peroxide-Based Decontamination of CBRN Contaminants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagner, George W.; Procell, Lawrence R.; Sorrick, David C.

2010-03-11

A hydrogen peroxide-based decontaminant, Decon Green, is efficacious for the decontamination of chemical agents VX (S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothioate), GD (Soman, pinacolyl methylphosphonofluoridate), and HD (mustard, bis(2-chloroethyl) sulfide); the biological agent anthrax (Bacillus anthracis); and radiological isotopes Cs-137 and Co-60; thus demonstrating the ability of this decontamination approach to ameliorate the aftermath of all three types of weapons of mass destruction (WMD). Reaction mechanisms afforded for the chemical agents are discussed as are rationales for the enhanced removal efficacy of recalcitrant 60Co on certain surfaces. Decontaminants of this nature can be deployed, and are effective, at very low temperatures (-32 °C),more » as shown for studies done with VX and HD simulants, without the need for external heat sources. Finally, the efficacy of a lower-logistics, dry decontaminant powder concentrate (utilizing the solid active-oxygen compounds peracetyl borate and Peroxydone) which can be reconstituted with water in the field prior to use, is presented.« less

Atmospheric Pressure Plasma Jet for Chem/Bio Warfare Decontamination

NASA Astrophysics Data System (ADS)

Herrmann, Hans W.; Henins, Ivars; Park, Jaeyoung; Selwyn, Gary S.

1999-11-01

Atmospheric Pressure Plasma Jet (APPJ) technology may provide a much needed method of CBW decontamination which, unlike traditional decon methods, is dry and nondestructive to sensitive equipment and materials. The APPJ discharge uses a high-flow feedgas consisting primarily of an inert carrier gas, such as He, and a small amount of a reactive additive, such as O2, which flows between capacitively-coupled electrodes powered at 13.56 MHz. The plasma generates highly reactive metastable and atomic species of oxygen which are then directed onto a contaminated surface. The reactive effluent of the APPJ has been shown to effectively neutralize VX nerve agent as well as simulants for anthrax and mustard blister agent. Research efforts are now being directed towards reducing He consumption and increasing the allowable stand-off distance. Recent results demonstrate that by replacing the O2 reactive additive with CO2, ozone formation is greatly reduced. This has the result of extending the lifetime of atomic oxygen by an order of magnitude or more. A recirculating APP Decon Chamber which combines heat, vacuum, forced convection and reactivity is currently being developed for enhanced decontamination of sensitive equipment. Several techniques are also being evaluated for use in an APP Decon Jet for decontamination of items which cannot be placed inside a chamber.

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

PubMed

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

2016-05-01

Comparison of solvent-wetted gauze with body paint, a peelable surface sampling media, for the sampling of the chemical warfare agents VX and sulfur mustard from nine surfaces was performed. The nine surfaces sampled are those typical of interior public venues and include smooth, rough, porous, and non-porous surfaces. Overall, solvent-wetted gauze (wipes) performed better for the recovery of VX from non-porous surfaces while body paint (BP) performed better for the porous surfaces. The average percent VX recoveries using wipes and BP, respectively, are: finished wood flooring, 86.2%, 71.4%; escalator handrail, 47.3%, 26.7%; stainless steel, 80.5%, 56.1%; glazed ceramic tile, 81.8%, 44.9%; ceiling tile, 1.77%, 13.1%; painted drywall 7.83%, 21.1%; smooth cement, 0.64%, 10.3%; upholstery fabric, 24.6%, 23.1%; unfinished wood flooring, 9.37%, 13.1%. Solvent-wetted gauze performed better for the recovery of sulfur mustard from three of the relatively non-porous surfaces while body paint performed better for the more porous surfaces. The average percent sulfur mustard recoveries using wipes and BP, respectively, are: finished wood flooring, 30.2%, 2.97%; escalator handrail, 4.40%, 4.09%; stainless steel, 21.2%, 3.30%; glazed ceramic tile, 49.7%, 16.7%; ceiling tile, 0.33%, 11.1%; painted drywall 2.05%, 10.6%; smooth cement, 1.20%, 35.2%; upholstery fabric, 7.63%, 6.03%; unfinished wood flooring, 0.90%, 1.74%. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Novel fluorescence nanobubbles for contrast-enhanced ultrasound imaging in rabbit VX2 hepatocellular carcinoma model

NASA Astrophysics Data System (ADS)

Yu, Houqiang; Wang, Wei; He, Xiaoling; Zhou, Qibing; Ding, Mingyue

2017-03-01

Ultrasound contrast agents (UCAs) such as SonoVue or Optison have been used widely in clinic for contrast-enhanced vascular imaging. However, microbubbles UCAs display limitations in tumor-targeted imaging due to the large sizes, nanoscaled UCAs has consequently attracted increasing attentions. In this work, we synthesized nanobubbles (NBs) by ultrasonic cavitation method, then a fluorescent marker of Alexa Fluor 680 was conjugated to the shell in order to observe the localization of NBs in tumor tissue. Measurement of fundamental characteristics showed that the NBs had homogeneous distribution of mean diameter of 267.9 +/- 19.2 nm and polydispersity index of 0.410 +/- 0.056. To assess in vivo tumor-selectivity of NBs, we established the rabbits VX2 hepatocellular carcinoma model though surgical implantation method. After the rabbits were intravenous administered of NBs, contrast-enhanced sonograms was observed in the surrounding of VX2 tumor, which showed there are rich capillaries in the tumor periphery. We additionally investigated the toxic of the NBs by hematoxylin-eosin staining. The results indicated that the NBs is a biocompatible non-toxic lipid system. Furthermore, the VX2 tumors and major organs were analyzed using ex vivo fluorescence imaging to confirm the targeted selectivity of NBs, and the results verified that the NBs were capable of targeting VX2 tumor. Confocal laser scanning microscopy examination showed that the NBs can traverse the VX2 tumor capillaries and target to the hepatocellular carcinoma tumor cells. All these results suggested that the newly prepared NBs have a potential application in molecular imaging and tumor-targeting therapy.

Department of Defense Chemical, Biological, Defense Program, Annual Report to Congress, March 2005

DTIC Science & Technology

2005-03-01

nerve agents ( GA , GB, GD, and GF), V type nerve agents , and H (mustard) type blister agents . M8 paper can identify agents through...The M21 RSCAAL is an automatic scanning, passive infrared sensor that detects nerve ( GA , GB, and GD) and blister (H and L) agent vapor clouds...Chief of Staff for Programs GA – tabun, a nerve agent GAO – General Accounting Office GB – sarin, a nerve agent GD – soman, a nerve

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

PubMed Central

Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Cao, Dong; Neuberger, Tim; Turnbull, Amanda; Singh, Ashvani; Joubran, John; Hazlewood, Anna; Zhou, Jinglan; McCartney, Jason; Arumugam, Vijayalaksmi; Decker, Caroline; Yang, Jennifer; Young, Chris; Olson, Eric R.; Wine, Jeffery J.; Frizzell, Raymond A.; Ashlock, Melissa; Negulescu, Paul

2009-01-01

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl− secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by ≈10-fold, to ≈50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na+ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway. PMID:19846789

United States Army Biomedical Research and Development Laboratory Annual Progress Report FY90

DTIC Science & Technology

1991-01-01

pesticide . Parallel and follow-on studies will include hydrolysis products of nerve agents , vesicants, and agents of...Division FO Fog oil FORSCOM U.S. Army Forces Command FY Fiscal year 249 GA The nerve agent tabun GB The nerve agent soman GD The nerve agent sarin GLP... Nerve Agents , Industrial Hygiene Sampling, Microbiology, Combustion Products, Liquid Gun Propellant, Organic Chemistry, Inorganic

Natural Attenuation of the Persistent Chemical Warfare Agent ...

EPA Pesticide Factsheets

Report This project studied the influence of temperature on the natural attenuation of VX from five types of porous/permeable materials: unsealed concrete, plywood, rubber escalator handrail, high density polyethylene (HDPE) plastic, and acoustic ceiling tile.

Therapeutic efficacy of ferrofluid bound anticancer agent

NASA Astrophysics Data System (ADS)

Alexiou, Ch.; Arnold, W.; Hulin, P.; Klein, R.; Schmidt, A.; Bergemannand, Ch.; Parak, F. G.

2001-09-01

Ferrofluids coated with starch polymers can be used as biocompatible carriers in a new field of locoregional tumor therapy called "magnetic drug targeting". Bound to medical drugs, such magnetic nanoparticles can be enriched in a desired body compartment using an external magnetic field. In the present study, we confirm the concentration of ferrofluids in VX2 squamous cell carcinoma tissue of the rabbit using histological investigations and MR imaging. The therapeutic efficacy of "magnetic drug targeting" was studied using the rabbit VX2 squamous cell carcinoma model. Mitoxantrone coupled ferrofluids were injected intraarterially into the artery supplying the tumor (femoral artery). The magnetic field (1.7 Tesla) was focused to the tumor placed at the medial portion of the hind limb of New Zealand White rabbits. Complete tumor remissions could be seen without any negative side effects by using only 20% of the normal systemic dosage of the chemotherapeutic agent mitoxantrone. Figs 3, Refs 14.

Multicomponent Diffusion of Penetrant Mixtures in Rubbery Polymers: A Molecular Dynamics Study

NASA Astrophysics Data System (ADS)

Bringuier, Stefan; Varady, Mark; Knox, Craig; Cabalo, Jerry; Pearl, Thomas; Mantooth, Brent

The importance of understanding transport of chemical species across liquid-solid boundaries is of particular interest in the decontamination of harmful chemicals absorbed within polymeric materials. To characterize processes associated with liquid-phase extraction of absorbed species from polymers, it is necessary to determine an appropriate physical description of species transport in multicomponent systems. The Maxwell-Stefan (M-S) formulation is a rigorous description of mass transport in multicomponent solutions, in which, mutual diffusivities determine the degree of relative motion between interacting molecules in response to a chemical potential gradient. The work presented focuses on the determination of M-S diffusivities from molecular dynamics (MD) simulations of nerve agent O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate (VX), water, and methanol mixtures within a poly(dimethylsiloxane) matrix. We investigate the composition dependence of M-S diffusivities and compare the results to values predicted using empirical relations for binary and ternary mixtures. Finally, we highlight the pertinent differences in molecular mechanisms associated with species transport and employ non-equilibrium MD to probe transport across the mixture-polymer interface.

Development of the 2007 Chemical Decontaminant Source Document

DTIC Science & Technology

2009-03-01

Chemical Agent Simulant Specific DEM diethyl malonate MeS methyl salicylate PEG200 Polyethylene glycol 200 TEP triethyl phosphate Group 6...simulants • H-agent simulants o Methyl salicylate (MeS) o Chloroethyl phenyl sulfide (CEPS) o Chloroethyl ethyl sulfide (CEES) • VX simulants... Methyl bromide Ethyl phosphonothioic dichloride Sulfur dioxide Methyl chloroformate Ethyl phosphonic dichloride Sulfuric acid Methyl chlorosilane

Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR

DTIC Science & Technology

2005-12-31

recognize and predict prospective toxicity among covalent -binding AChE inhibitors of potential application to nerve agent prophylaxis and...is below since many authors do not follow the 200 word limit 14. SUBJECT TERMS nerve agents , acetylcholinesterase, prophylaxis, QSAR, virtual...Report: Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR Report Title ABSTRACT Organophosphorus (OP) nerve agents are among the

Separation of thiol and cyanide hydrolysis products of chemical warfare agents by capillary electrophoresis.

PubMed

Copper, Christine L; Collins, Greg E

2004-03-01

The fluorescence derivatizing agent, o-phthalaldehyde (OPA), has been applied to the separation and detection of cyanide and several structurally similar thiols by capillary electrophoresis (CE)-laser induced fluorescence (LIF). Of particular interest to this investigation was the separation of 2-dimethylaminoethanethiol, 2-diethylaminoethanethiol, and cyanide, each of which are hydrolysis products or hydrolysis product simulants of the chemical warfare (CW) agents O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX), O-isobutyl S-2-diethylaminoethyl methylphosphonothiolate (R-VX), and tabun (GA). Other structurally similar thiols simultaneously resolved by this method include 1-pentanethiol and 2-mercaptoethanol. Instrumental parameters were probed and optimum values for capillary length (50 cm) and inner diameter (75 microm), injection time (30 s) and field strength (15 kV) were determined. Sample stacking methods enabled detection limits of 9.3 microg/L for cyanide, 1.8 microg/L for 2-diethylaminoethanethiol, 35 microg/L for 2-dimethylaminoethanethiol, 15 microg/L for 2-mercaptoethanol, and 89 microg/L for 1-pentanethiol. The linearity of the method was verified over an order of magnitude and the reproducibility was found to be 3.0%.

Proximal detection of chemical warfare agents using PMIRRAS

NASA Astrophysics Data System (ADS)

Petryk, Michael W. P.; Marenco, Armando J.

2010-04-01

Non-contact chemical warfare agent detection has been demonstrated on military painted surfaces using polarization modulation infrared reflection-absorption spectroscopy (PMIRRAS). Notably, VX has been detected on chemical agent resistance coating (CARC) paint at a distance of approximately 10 cm. PMIRRAS does not rely on the presence of chemical vapors and is not affected by many common battlefield interferants such as aerosolized dust, water and diesel vapors, etc., making it highly suitable for use in operational environments.

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

DTIC Science & Technology

2016-05-09

Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure Amanda S. Appel,† John H. McDonough,‡ Joseph D...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

Establish an Agent-Simulant Technology Relationship (ASTR)

DTIC Science & Technology

2017-04-14

for quantitative measures that characterize simulant performance in testing , such as the ability to be removed from surfaces. Component-level ASTRs...Overall Test and Agent-Simulant Technology Relationship (ASTR) process. 1.2 Background. a. Historically, many tests did not develop quantitative ...methodology report14. Report provides a VX-TPP ASTR for post -decon contact hazard and off- gassing. In the Stryker production verification test (PVT

Metal organic frameworks for the catalytic detoxification of chemical warfare nerve agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hupp, Joseph T.; Farha, Omar K.; Katz, Michael J.

A method of using a metal organic framework (MOF) comprising a metal ion and an at least bidendate organic ligand to catalytically detoxify chemical warfare nerve agents including exposing the metal-organic-framework (MOF) to the chemical warfare nerve agent and catalytically decomposing the nerve agent with the MOF.

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. Copyright © 2011 Elsevier B.V. All rights reserved.

Symposium on Toxic Substance Control: Decontamination, April 22 - 24, 1980, Columbus, Ohio.

DTIC Science & Technology

1981-06-01

standard decontaminants is used. TABLE 1. Standard Chemical Decontaminants Decontaminant Agents Used On STB Blister and nerve agents DS-2 All chemical... agents M258 Kit Sodium Hydroxide, Ethanol, G-Series nerve agents Phenol, Water Chloramine B, ZnCI2, Blister ana V-Series Ethanol, Water nerve agents A...is a point source alarm that actively samples ambient air and reacts to low concentrations of nerve agents . The M-8 alarm detector also detects several

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hemmert, Andrew C.; Otto, Tamara C.; Wierdl, Monika

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 withmore » 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.« less

Reactions of VX, HD, and their simulants with NaY and AgY zeolites. Desulfurization of VX on AgY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagner, G.W.; Bartram, P.W.

1999-11-09

The room-temperature reactions of the chemical warfare agents VX (O-ethyl S-2-(diisopropylamino)-ethyl methylphosphonothioate), HD (2,2{prime}-dichloroethyl sulfide, or mustard), and their common simulants, O,S-diethyl phenylphosphonothioate (DEPPT) and 2-chloroethyl phenyl sulfide (CEPS), with NaY and silver-exchanged (AgY) zeolites have been studied using solid-state magic angle spinning NMR. VX hydrolyzes via exclusive cleavage of the P{single{underscore}bond}S bond on both NaY and AgY to yield ethyl methylphosphonate (EMPA). The reaction is significantly faster on AgY than on NaY, suggesting catalysis by silver. On AgY, an intermediate silver salt of EMPA is apparently formed which is slowly converted to ethyl 2-(diisopropylamino)ethyl methylphosphonate (QB, the desulfurized analoguemore » of VX) in about a 78% yield. DEPPT similarly hydrolyzes via P{single{underscore}bond}S cleavage on AgY to yield an apparent silver salt of ethyl phenylphosphonate, which does not undergo further reaction to the desulfurized analogue. No reaction is observed for DEPPT on NaY. HD on AgY forms both vinyl sulfide and the cyclic ether 1,4-thioxane. HD reacts faster on NaY to exclusively form the CH-TG sulfonium ion (HOCH{sub 2}CH{sub 2}SCH{sub 2}CH{sub 2}S{sup +}[CH{sub 2}CH{sub 2}OH]{sub 2}). CEPS also reacts faster on NaY, forming 2-hydroxyethyl phenyl sulfide. On AgY, CEPS does not give the vinyl product, but does yield the ether product PhSCH{sub 2}CH{sub 2}OCH{sub 2}CH{sub 2}SPh. A mechanism is proposed for the silver-catalyzed hydrolysis of VX, the desulfurization of the cleaved thiol, and the formation of QB.« less

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

PubMed

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

2010-05-15

The purpose of this study was to check the applicability of different analytical methods for the identification of unknown nerve agents in human body fluids. Plasma and urine samples were spiked with nerve agents (plasma) or with their metabolites (urine) or were left blank. Seven random samples (35% of all samples) were selected for the verification test. Plasma was worked up for unchanged nerve agents and for regenerated nerve agents after fluoride-induced reactivation of nerve agent-inhibited butyrylcholinesterase. Both extracts were analysed by GC-MS. Metabolites were extracted from plasma and urine, respectively, and were analysed by LC-MS. The urinary metabolites and two blank samples could be identified without further measurements, plasma metabolites and blanks were identified in six of seven samples. The analysis of unchanged nerve agent provided five agents/blanks and the sixth agent after further investigation. The determination of the regenerated agents also provided only five clear findings during the first screening because of a rather noisy baseline. Therefore, the sample preparation was extended by a size exclusion step performed before addition of fluoride which visibly reduced baseline noise and thus improved identification of the two missing agents. The test clearly showed that verification should be performed by analysing more than one biomarker to ensure identification of the agent(s). Copyright (c) 2010 Elsevier B.V. All rights reserved.

Development of Novel Decontamination Techniques for Chemical Agents (GB, VX, HD) Contaminated Facilities. Phase 1. Identification and Evaluation of Novel Decontamination Concepts. Volume 2

DTIC Science & Technology

1983-02-01

Phosphoric, citric or other acids may be used as coupling agent/solvents in the cleaning tank. Decontamination solutions may also be used. Ultrasonics may be...111-54 "THERMAL DECOMPOSITION USING CO2 LASER . . . . . . . . . . . . . . 111-63 >’HYDROBLASTING. III-70 (-7, ACID ETCH/ NUTRALIZATION...111-192 NITRIC ACID . . .*. . . . .\\. . . . . . . . . . . . . . . TII-197 AMMONIA • • . . . • . . . . • . . . . . .... . ...... . 111-202 DANC .1

Rho Inhibitor VX-210 in Acute Traumatic Subaxial Cervical Spinal Cord Injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial.

PubMed

Fehlings, Michael G; Kim, Kee D; Aarabi, Bizhan; Rizzo, Marco; Bond, Lisa M; McKerracher, Lisa; Vaccaro, Alexander R; Okonkwo, David O

2018-05-01

Traumatic spinal cord injury (SCI) is associated with a lifetime of disability stemming from loss of motor, sensory, and autonomic functions; these losses, along with increased comorbid sequelae, negatively impact health outcomes and quality of life. Early decompression surgery post-SCI can enhance patient outcomes, but does not directly facilitate neural repair and regeneration. Currently, there are no U.S. Food and Drug Administration-approved pharmacological therapies to augment motor function and functional recovery in individuals with traumatic SCI. After an SCI, the enzyme, Rho, is activated by growth-inhibitory factors and regulates events that culminate in collapse of the neuronal growth cone, failure of axonal regeneration, and, ultimately, failure of motor and functional recovery. Inhibition of Rho activation is a potential treatment for injuries such as traumatic SCI. VX-210, an investigational agent, inhibits Rho. When administered extradurally after decompression (corpectomy or laminectomy) and stabilization surgery in a phase 1/2a study, VX-210 was well tolerated. Here, we describe the design of the SPRING trial, a multicenter, phase 2b/3, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of VX-210 (NCT02669849). A subset of patients with acute traumatic cervical SCI is currently being enrolled in the United States and Canada. Medical, neurological, and functional changes are evaluated at 6 weeks and at 3, 6, and 12 months after VX-210 administration. Efficacy will be assessed by the primary outcome measure, change in upper extremity motor score at 6 months post-treatment, and by secondary outcomes that include question-based and task-based evaluations of functional recovery.

Zirconium doped nano-dispersed oxides of Fe, Al and Zn for destruction of warfare agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stengl, Vaclav, E-mail: stengl@uach.cz; Houskova, Vendula; Bakardjieva, Snejana

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 resultingmore » 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.« less

N-Chloramide Modified Nomex(Registered) as a Regenerable Self-Decontaminating Material for Protection Against Chemical Warfare Agents (Postprint)

DTIC Science & Technology

2009-02-26

weaponizable bacteria, mustard, and VX, as well as possessing antimicrobial properties against nuisance organisms that cause conditions such as athlete’s foot...were assayed for content of active oxidizing agent, and tested for efficacy against 2-chloroethyl ethyl sulfide and Demeton-S, simulants for mustard and...attached to Nomex intended for use as self-decontaminating regenerable military textiles. The materials were assayed for content of active oxidizing

Cranial nerve contrast using nerve-specific fluorophores improved by paired-agent imaging with indocyanine green as a control agent

NASA Astrophysics Data System (ADS)

Torres, Veronica C.; Vuong, Victoria D.; Wilson, Todd; Wewel, Joshua; Byrne, Richard W.; Tichauer, Kenneth M.

2017-09-01

Nerve preservation during surgery is critical because damage can result in significant morbidity. This remains a challenge especially for skull base surgeries where cranial nerves (CNs) are involved because visualization and access are particularly poor in that location. We present a paired-agent imaging method to enhance identification of CNs using nerve-specific fluorophores. Two myelin-targeting imaging agents were evaluated, Oxazine 4 and Rhodamine 800, and coadministered with a control agent, indocyanine green, either intravenously or topically in rats. Fluorescence imaging was performed on excised brains ex vivo, and nerve contrast was evaluated via paired-agent ratiometric data analysis. Although contrast was improved among all experimental groups using paired-agent imaging compared to conventional, solely targeted imaging, Oxazine 4 applied directly exhibited the greatest enhancement, with a minimum 3 times improvement in CNs delineation. This work highlights the importance of accounting for nonspecific signal of targeted agents, and demonstrates that paired-agent imaging is one method capable of doing so. Although staining, rinsing, and imaging protocols need to be optimized, these findings serve as a demonstration for the potential use of paired-agent imaging to improve contrast of CNs, and consequently, surgical outcome.

Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides.

PubMed

Musilek, Kamil; Dolezal, Martin; Gunn-Moore, Frank; Kuca, Kamil

2011-07-01

Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and heterogeneous group of organophosphorus compounds. Their biological activity of inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) ranks them as life endangering agents. The necessary treatment after OPP exposure involves the use of parasympatolytics (e.g. atropine), oxime reactivators (e.g. obidoxime), and anticonvulsive drugs (e.g. diazepam). Therefore, the reactivators of AChE are essential compounds in the treatment of OPP intoxications. Commercial AChE reactivators (e.g. pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) were originally developed for other members of the organophosphate family, such as nerve agents (e.g. sarin, soman, tabun, VX). Pralidoxime, HI-6, and methoxime were found to be weak reactivators of OPP-inhibited AChE. Obidoxime and trimedoxime showed satisfactory reactivation against various OPPs with minor toxicity issues. During the last two decades, the treatment of OPP exposure has become more widely discussed because of growing agricultural production, industrialization, and harmful social issues (e.g. suicides). In this review is the summarized design, evaluation, and structure-activity relationship studies of recently produced AChE reactivators. Since pralidoxime, over 300 oximes have been produced or tested against OPP poisoning, and several novel compounds show very promising abilities as comparable (or higher) to commercial oximes. Some of these are highlighted for their further testing of OPP exposure and, additionally, the main structure-activity relationship of AChE reactivators against OPP is discussed. © 2009 Wiley Periodicals, Inc.

A Structural Biology and Protein Engineering Approach to the Development of Antidotes against the Inhibition of Human Acetylcholinesterase by OP-based Nerve Agents

DTIC Science & Technology

2014-03-01

for Biotechnology, Gurgaon, India (Sep, 2013) by Joel L. Sussman, title: “Molecular Basis of How Nerve Agents through anti- Alzheimer Drugs Function...Molecular Basis of How Nerve Agents through anti- Alzheimer Drugs Function: 3D Structure of Acetylcholinesterase • Florida International University...FIU), Miami, FL (Dec 2013) - Invited Lecture by Joel L. Sussman, title: “Molecular Basis of anti- Alzheimer Drugs & Nerve Agents: 3D Structure of

31P-edited diffusion-ordered 1H NMR spectroscopy for the spectral isolation and identification of organophosphorus compounds related to chemical weapons agents and their degradation products.

PubMed

Mayer, Brian P; Valdez, Carlos A; Hok, Saphon; Chinn, Sarah C; Hart, Bradley R

2012-12-04

Organophosphorus compounds represent a large class of molecules that include pesticides, flame-retardants, biologically relevant molecules, and chemical weapons agents (CWAs). The detection and identification of organophosphorus molecules, particularly in the cases of pesticides and CWAs, are paramount to the verification of international treaties by various organizations. To that end, novel analytical methodologies that can provide additional support to traditional analyses are important for unambiguous identification of these compounds. We have developed an NMR method that selectively edits for organophosphorus compounds via (31)P-(1)H heteronuclear single quantum correlation (HSQC) and provides an additional chromatographic-like separation based on self-diffusivities of the individual species via (1)H diffusion-ordered spectroscopy (DOSY): (1)H-(31)P HSQC-DOSY. The technique is first validated using the CWA VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate) by traditional two-dimensional DOSY spectra. We then extend this technique to a complex mixture of VX degradation products and identify all the main phosphorus-containing byproducts generated after exposure to a zinc-cyclen organometallic homogeneous catalyst.

Measurements of Raman scattering in the middle ultraviolet band from persistent chemical warfare agents

NASA Astrophysics Data System (ADS)

Kullander, Fredrik; Landström, Lars; Lundén, Hampus; Mohammed, Abdesalam; Olofsson, Göran; Wästerby, Pär.

2014-05-01

The very low Raman scattering cross section and the fluorescence background limit the measuring range of Raman based instruments operating in the visible or infrared band. We are exploring if laser excitation in the middle ultraviolet (UV) band between 200 and 300 nm is useful and advantageous for detection of persistent chemical warfare agents (CWA) on various kinds of surfaces. The UV Raman scattering from tabun, mustard gas, VX and relevant simulants in the form of liquid surface contaminations has been measured using a laboratory experimental setup with a short standoff distance around 1 meter. Droplets having a volume of 1 μl were irradiated with a tunable pulsed laser swept within the middle UV band. A general trend is that the signal strength moves through an optimum when the laser excitation wavelength is swept between 240 and 300 nm. The signal from tabun reaches a maximum around 265 nm, the signal from mustard gas around 275 nm. The Raman signal from VX is comparably weak. Raman imaging by the use of a narrow bandpass UV filter is also demonstrated.

A Review of the Literature on the Applications of CW Agents with Recommendations of Further Research on Thickened GD

DTIC Science & Technology

1975-12-01

be effective not only in GD but also in VX, although as much as 30% is needed to form a gel. Wills cites the polymethacrylates : the methyl and ethyl...percutaneous toxicity of additives. Horton et al showed that a 50/50 mixture of GB with hexafluoroglutaric acid , phosgene oxime, or xylene is signifi- cantly...amounts of certain products of the decomposition of the agent, viz pinacolyl hydrogen methylphosphonate and methylphosphonic acid , as much as 40 weeks

Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation

DTIC Science & Technology

2005-05-01

nerve agents , soman is the great- terrorist acts. At the same time, OP pesticides , such as est challenge since both the rapid aging of the soman- paraoxon...also from enzyme very slowly (requiring hours, days, or weeks used as nerve warfare agents . Similar to pesticides , nerve for complete dissociation...TERMS acetylcholinesterase, nerve agent antidotes and propylaxis, organophosphate scavenging , oxime reactivation fluorescence spectroscopy, exposure

Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells

PubMed Central

Stanton, Bruce A.; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

2015-01-01

Background P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770. Methods and Results F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR. Conclusion The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials. PMID:26018799

Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells.

PubMed

Stanton, Bruce A; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

2015-01-01

P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770. F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR. The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials.

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

PubMed

Dunn, Emily N; Ferrara-Bowens, Teresa M; Chachich, Mark E; Honnold, Cary L; Rothwell, Cristin C; Hoard-Fruchey, Heidi M; Lesyna, Catherine A; Johnson, Erik A; Cerasoli, Douglas M; McDonough, John H; Cadieux, C Linn

2018-06-07

Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

Neuroprotective Effects of Galantamine on Nerve Agent-Induced Neuroglial and Biochemical Changes.

PubMed

Golime, RamaRao; Palit, Meehir; Acharya, J; Dubey, D K

2018-05-01

Neuroprotection from nerve agent such as soman-induced neural damage is a major challenge for existing drugs. Nerve agent exposure can cause many neural effects in survivors arising mainly due to acetylcholinesterase (AChE) inhibition or death within minutes. Unraveling the mechanisms underlying the nerve agent-induced multiple neurological effects is useful to develop better and safe drugs. The present study aimed to understand the molecular response during soman exposure and to evaluate the neuroprotective efficacy of galantamine on nerve agent-induced neurotoxic changes. mRNA expression studies using quantitative real-time PCR revealed significant changes in S-100β, Gfap, c-fos, and Bdnf in the hippocampus and piriform cortex after soman (90 μg/kg, s.c) exposure. Immunoblot analysis showed acute soman exposure significantly increased the protein levels of neuroglial markers (S100-β and GFAP); c-Fos and protein oxidation in discrete rat brain areas indicate their role in nerve agent-induced neurotoxicity. Induction of BDNF levels during soman exposure may indicate the recovery mechanisms activation. AChE was inhibited in the blood and brain up to 82% after soman exposure. Antidotal treatment with galantamine alone (3 mg/kg) and galantamine plus atropine (10 mg/kg) has protected animals from nerve agent-induced intoxication, death, and soman-inhibited AChE up to 45% in the blood and brain. Animal received galantamine displayed increased levels of neuroprotective genes (nAChRα-7, Bcl-2, and Bdnf) in the brain suggest the neuroprotective value of galantamine. Neuroglial changes, c-Fos, and protein oxidation levels significantly reduced after galantamine and galantamine plus atropine treatment indicate their potential antidotal value in nerve agent treatment.

Modified model of VX2 tumor overexpressing vascular endothelial growth factor.

PubMed

Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre

2012-06-01

To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (ρ = .883, P = .012). The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 tomore » 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.« less

ARO in Review 2010

DTIC Science & Technology

2010-01-01

develop a fundamental understanding of the key recognition elements in various nerve agents , pesticides , and simulants. Using this knowledge, these groups...SCIENCES DIVISION 29 ARO IN REVIEW 2010 1. Low-power Nerve Agent Detector. Three Phase I CBD-SBIR contracts were awarded to Identizyme Defense...Technologies, Inc., Luna Innovations, Inc., and Lynntech, Inc. to develop a nerve agent detection system that requires little to no operating power

Improved identification of cranial nerves using paired-agent imaging: topical staining protocol optimization through experimentation and simulation

NASA Astrophysics Data System (ADS)

Torres, Veronica C.; Wilson, Todd; Staneviciute, Austeja; Byrne, Richard W.; Tichauer, Kenneth M.

2018-03-01

Skull base tumors are particularly difficult to visualize and access for surgeons because of the crowded environment and close proximity of vital structures, such as cranial nerves. As a result, accidental nerve damage is a significant concern and the likelihood of tumor recurrence is increased because of more conservative resections that attempt to avoid injuring these structures. In this study, a paired-agent imaging method with direct administration of fluorophores is applied to enhance cranial nerve identification. Here, a control imaging agent (ICG) accounts for non-specific uptake of the nerve-targeting agent (Oxazine 4), and ratiometric data analysis is employed to approximate binding potential (BP, a surrogate of targeted biomolecule concentration). For clinical relevance, animal experiments and simulations were conducted to identify parameters for an optimized stain and rinse protocol using the developed paired-agent method. Numerical methods were used to model the diffusive and kinetic behavior of the imaging agents in tissue, and simulation results revealed that there are various combinations of stain time and rinse number that provide improved contrast of cranial nerves, as suggested by optimal measures of BP and contrast-to-noise ratio.

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

PubMed

Matson, Liana M; McCarren, Hilary S; Cadieux, C Linn; Cerasoli, Douglas M; McDonough, John H

2018-01-15

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies. Here, we discuss the available literature on strain and selected line differences in cholinesterase activity levels and response to nerve agent-induced toxicity and seizures. We also discuss the available cholinesterase and toxicity literature across different non-human primate species. The available data suggest that robust genetic differences exist in cholinesterase activity, nerve agent-induced toxicity, and chemical-induced seizures. Available cholinesterase data suggest that acetylcholinesterase activity differs across strains, but are limited by the paucity of carboxylesterase data in strains and selected lines. Toxicity and seizures, two outcomes of nerve agent exposure, have not been fully evaluated for genetic differences, and thus further studies are required to understand baseline strain and selected line differences. Published by Elsevier B.V.

Studies on residue-free decontaminants for chemical warfare agents.

PubMed

Wagner, George W

2015-03-17

Residue-free decontaminants based on hydrogen peroxide, which decomposes to water and oxygen in the environment, are examined as decontaminants for chemical warfare agents (CWA). For the apparent special case of CWA on concrete, H2O2 alone, without any additives, effectively decontaminates S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothioate (VX), pinacolyl methylphosphorofluoridate (GD), and bis(2-choroethyl) sulfide (HD) in a process thought to involve H2O2 activation by surface-bound carbonates/bicarbonates (known H2O2 activators for CWA decontamination). A plethora of products are formed during the H2O2 decontamination of HD on concrete, and these are characterized by comparison to synthesized authentic compounds. As a potential residue-free decontaminant for surfaces other than concrete (or those lacking adsorbed carbonate/bicarbonate) H2O2 activation for CWA decontamination is feasible using residue-free NH3 and CO2 as demonstrated by reaction studies for VX, GD, and HD in homogeneous solution. Although H2O2/NH3/CO2 ("HPAC") decontaminants are active for CWA decontamination in solution, they require testing on actual surfaces of interest to assess their true efficacy for surface decontamination.

Development and Structural Modifications of Cholinesterase Reactivators against Chemical Warfare Agents in Last Decade: A Review.

PubMed

Sharma, Rahul; Gupta, Bhanushree; Singh, Namrata; Acharya, J R; Musilek, Kamil; Kuca, Kamil; Ghosh, Kallol Kumar

2015-01-01

Organophosphate (OP) pesticides and nerve agents are responsible for suicidal and accidental poisonings. The acute toxicity of nerve agents leads to progressive inhibition of the enzyme acetylcholinesterase (AChE) by phosphylation of serine residue at the active site of gorge. The recent massive destruction of Syrian civilians by nerve gas sarin, has again renewed the research attention of global science fraternity towards nerve agents, their mode of action and most prominently their therapeutic treatment. This review is principally focused on nerve agent intoxication. The common approach to deal with OP-intoxication is, application of antimuscarinic drug (atropine), anticonvulsant drug (diazepam) and clinically used oximes (pralidoxime, trimedoxime, obidoxime and asoxime). However, the existing therapeutic approach is arguable and has several failings to cure all kinds of nerve agent poisonings. Considering this issue, numerous oximes have been synthesized and screened through various in-vitro and in-vivo studies in last decade to overcome the downsides. At present, only a few oximes (bis pyridinum-oximes) exhibit sound efficacy against selective OPs. In spite of extensive efforts, till date no oxime is available as a universal antidote against all the classes of OPs. This review is centered on the recent developments and structural modification of AChE reactivators against nerve agent toxicity. In particular, a deeper look has been taken into chemical modifications of the reactivators by incorporation of different structural moieties targeted towards the increased reactivation affinity and improved blood brain barrier (BBB) penetration.

Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor).

PubMed

Matthes, Elizabeth; Goepp, Julie; Carlile, Graeme W; Luo, Yishan; Dejgaard, Kurt; Billet, Arnaud; Robert, Renaud; Thomas, David Y; Hanrahan, John W

2016-02-01

The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination. Functional expression of CFTR was assayed as the forskolin-stimulated short-circuit current (Isc ) across airway epithelial monolayers expressing F508del CFTR. The potentiated Isc response during forskolin stimulation was increased sixfold after pretreatment with VX-809 alone and reached ~11% that measured across non-CF monolayers. VX-770 (100 nM) and genistein (50 μM) caused similar levels of potentiation, which were not additive and were abolished by the CFTR inhibitor CFTRinh -172. The unbound fraction of VX-770 in plasma was 0.13 ± 0.04%, which together with previous measurements in patients given 250 mg p.o. twice daily, suggests a peak free plasma concentration of 1.5-8.5 nM. Chronic exposure to high VX-770 concentrations (>1 μM) inhibited functional correction by VX-809 but not in the presence of physiological protein levels (20-40 mg·mL(-1) ). Chronic exposure to a low concentration of VX-770 (100 nM) together with VX-809 (1 μM) also did not reduce the forskolin-stimulated Isc , relative to cells chronically exposed to VX-809 alone, provided it was assayed acutely using the same, clinically relevant concentration of potentiator. Chronic exposure to clinically relevant concentrations of VX-770 did not reduce F508del CFTR function. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by inhibition by VX-770. © 2015 The British Pharmacological Society.

Conference on Receptor-Based Biosensors (3rd) Held in Aberdeen Proving Ground, Maryland, September 1987

DTIC Science & Technology

1988-07-01

agents throughout the world had mode the threat to U.S. forces an urgent reality, perhaps more so now than ever. The use of blister and nerve agents ...today we have no capability to detect biological organism, toxins, or anything other then the traditional nerve , blood, and blister type agents . For...anticholinesterase. This kind of result was duplicated by Dr. Valdes at his lab at Edgewood. All the nerve agents that we looked at produced this result

Molecular modeling and residue interaction network studies on the mechanism of binding and resistance of the HCV NS5B polymerase mutants to VX-222 and ANA598.

PubMed

Xue, Weiwei; Jiao, Pingzu; Liu, Huanxiang; Yao, Xiaojun

2014-04-01

Hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase (RdRp) with essential functions in viral genome replication and represents a promising therapeutic target to develop direct-acting antivirals (DAAs). Multiple nonnucleoside inhibitors (NNIs) binding sites have been identified within the polymerase. VX-222 and ANA598 are two NNIs targeting thumb II site and palm I site of HCV NS5B polymerase, respectively. These two molecules have been shown to be very effective in phase II clinical trials. However, the emergence of resistant HCV replicon variants (L419M, M423T, I482L mutants to VX-222 and M414T, M414L, G554D mutants to ANA598) has significantly decreased their efficacy. To elucidate the molecular mechanism about how these mutations influenced the drug binding mode and decreased drug efficacy, we studied the binding modes of VX-222 and ANA598 to wild-type and mutant polymerase by molecular modeling approach. Molecular dynamics (MD) simulations results combined with binding free energy calculations indicated that the mutations significantly altered the binding free energy and the interaction for the drugs to polymerase. The further per-residue binding free energy decomposition analysis revealed that the mutations decreased the interactions with several key residues, such as L419, M423, L474, S476, I482, L497, for VX-222 and L384, N411, M414, Y415, Q446, S556, G557 for ANA598. These were the major origins for the resistance to these two drugs. In addition, by analyzing the residue interaction network (RIN) of the complexes between the drugs with wild-type and the mutant polymerase, we found that the mutation residues in the networks involved in the drug resistance possessed a relatively lower size of topology centralities. The shift of betweenness and closeness values of binding site residues in the mutant polymerase is relevant to the mechanism of drug resistance of VX-222 and ANA598. These results can provide an atomic-level understanding about the mechanisms of drug resistance conferred by the studied mutations and will be helpful to design more potent inhibitors which could effectively overcome drug resistance of antivirus agents. Copyright © 2014 Elsevier B.V. All rights reserved.

The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE.

PubMed

Chao, Chih-Kai; Balasubramanian, Narayanaganesh; Gerdes, John M; Thompson, Charles M

2018-06-16

In this study, the mechanisms of HuAChE and HuBChE inhibition by Me-P(O) (OPNP) (OR) [PNP = p-nitrophenyl; R = CH 2 CH 3 , CH 2 CH 2 F, OCH(CH 3 ) 2 , OCH(CH 3 ) (CH 2 F)] representing surrogates and fluoro-surrogates of VX and sarin were studied by in vitro kinetics and mass spectrometry. The in vitro measures showed that the VX- and fluoro-VX surrogates were relatively strong inhibitors of HuAChE and HuBChE (k i  ∼ 10 5 -10 6  M -1 min -1 ) and underwent spontaneous and 2-PAM-mediated reactivation within 30 min. The sarin surrogates were weaker inhibitors of HuAChE and HuBChE (k i  ∼ 10 4 -10 5  M -1 min -1 ), and in general did not undergo spontaneous reactivation, although HuAChE adducts were partially reactivatable at 18 h using 2-PAM. The mechanism of HuAChE and HuBChE inhibition by the surrogates was determined by Q-TOF and MALDI-TOF mass spectral analyses. The surrogate-adducted proteins were trypsin digested and the active site-containing peptide bearing the OP-modified serine identified by Q-TOF as triply- and quadruply-charged ions representing the respective increase in mass of the attached OP moiety. Correspondingly, monoisotopic ions of the tryptic peptides representing the mass increase of the OP-adducted peptide was identified by MALDI-TOF. The mass spectrometry analyses validated the identity of the OP moiety attached to HuAChE or HuBChE as MeP(O) (OR)-O-serine peptides (loss of the PNP leaving group) via mechanisms consistent with those found with chemical warfare agents. MALDI-TOF MS analyses of the VX-modified peptides versus time showed a steady reduction in adduct versus parent peptide (reactivation), whereas the sarin-surrogate-modified peptides remained largely intact over the course of the experiment (24 h). Overall, the presence of a fluorine atom on the surrogate modestly altered the rate constants of inhibition and reactivation, however, the mechanism of inhibition (ejection of PNP group) did not change. Copyright © 2018. Published by Elsevier B.V.

The effects of hemostatic agents on peripheral nerve function: an experimental study.

PubMed

Alkan, Alper; Inal, Samet; Yildirim, Mehmet; Baş, Burcu; Ağar, Erdal

2007-04-01

In the practice of oral and maxillofacial surgery, hemostatic agents are sometimes placed in close proximity to peripheral nerves. In the present study, we evaluated immediate and delayed effects of 4 hemostatic agents (oxidized regenerated cellulose, 5% colloid silver-added gelatine sponge, bovine collagen, bone wax) on peripheral nerve function. A total of 25 rat sciatic nerves were prepared, and the amplitudes were recorded with a physiological data acquisition system. Animals were randomly assigned to 5 groups: control, oxidized regenerated cellulose, gelatine sponge, bone wax, and bovine collagen. The first hour records are defined as immediate effects of these hemostatic agents on nerve function. The animals were then allowed to recover for 4 weeks. At the end of this period, the same surgical and recording procedures were performed. These final records are defined as delayed effects of hemostatic agents on nerve function. According to nerve conduction velocity (NCV) and compound action potential (CAP) values of the experimental groups, early and delayed effects of each hemostatic agent were statistically compared with Bonferroni corrected test (P < .05). Statistically, NCV was significantly reduced, and the CAP was significantly increased 1 hour after surgery (P < .05) in the group of oxidized regenerated cellulose. However, there were no significant differences after 4 weeks compared with the first records. In the gelatine sponge group, CAP was significantly increased 4 weeks after the application. In the bovine collagen and bone wax groups, NCV and CAP values (1 hour and 4 weeks after the application) were not statistically significant compared with initial control records. The present study shows that bovine collagen is the most suitable hemostatic agent applicable for peripheral nerves.

Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels.

PubMed

Kopeikin, Z; Yuksek, Z; Yang, H-Y; Bompadre, S G

2014-09-01

The most common cystic fibrosis-associated mutation, the deletion of phenylalanine 508 (F508del), results in channels with poor membrane expression and impaired function. VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking. The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments. VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported. The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

The main thylakoid membrane lipid monogalactosyldiacylglycerol (MGDG) promotes the de-epoxidation of violaxanthin associated with the light-harvesting complex of photosystem II (LHCII).

PubMed

Schaller, Susann; Latowski, Dariusz; Jemioła-Rzemińska, Małgorzata; Wilhelm, Christian; Strzałka, Kazimierz; Goss, Reimund

2010-03-01

In higher plants, the major part of the xanthophyll cycle pigment violaxanthin (Vx) is non-covalently bound to the main light-harvesting complex of PSII (LHCII). Under saturating light conditions Vx has to be released from its binding site into the surrounding lipid phase, where it is converted to zeaxanthin (Zx) by the enzyme Vx de-epoxidase (VDE). In the present study we investigated the influence of thylakoid lipids on the de-epoxidation of Vx, which was still associated with the LHCII. We isolated LHCII with different concentrations of native, endogenous lipids and Vx by sucrose gradient centrifugation or successive cation precipitation. Analysis of the different LHCII preparations showed that the concentration of LHCII-associated Vx was correlated with the concentration of the main thylakoid lipid monogalactosyldiacylglycerol (MGDG) associated with the complexes. Decreases in the MGDG content of the LHCII led to a diminished Vx concentration, indicating that a part of the total Vx pool was located in an MGDG phase surrounding the LHCII, whereas another part was bound to the LHCII apoproteins. We further studied the convertibility of LHCII-associated Vx in in-vitro enzyme assays by addition of isolated VDE. We observed an efficient and almost complete Vx conversion in the LHCII fractions containing high amounts of endogenous MGDG. LHCII preparations with low concentrations of MGDG exhibited a strongly reduced Vx de-epoxidation, which could be increased by addition of exogenous, pure MGDG. The de-epoxidation of LHCII-associated Vx was saturated at a much lower concentration of native, endogenous MGDG compared with the concentration of isolated, exogenous MGDG, which is needed for optimal VDE activity in in-vitro assays employing pure isolated Vx. Copyright 2009 Elsevier B.V. All rights reserved.

Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller's earth in domestic swine.

PubMed

Taysse, L; Daulon, S; Delamanche, S; Bellier, B; Breton, P

2007-02-01

Research in skin decontamination and therapy of chemical warfare agents has been a difficult problem due to the simultaneous requirement of rapid action and non-aggressive behaviour. The aim of this study was to compare the performance of two decontaminating systems: the Canadian Reactive Skin Decontaminant Lotion (RSDL) and the Fuller's Earth (FE). The experiment was conducted with domestic swine, as a good model for extrapolation to human skin. RSDL and FE were tested against sulphur mustard (SM), a powerful vesicant, and VX, a potent and persistent cholinesterase inhibitor. When used 5 min after contamination, the results clearly showed that both systems were active against SM (10.1 mg/cm(2)) and VX (0.06 mg/cm(2)). The potency of the RSDL/sponge was statistically better than FE against skin injury induced by SM, observed 3 days post-exposure. RSDL was rather more efficient than FE in reducing the formation of perinuclear vacuoles and inflammation processes in the epidermis and dermis. Against a severe inhibition (67%) of plasmatic cholinesterases induced by VX poisoning, the potencies of the RSDL/sponge and FE were similar. Both systems completely prevented cholinesterase inhibition, which indirectly indicates a prevention of toxic absorption through the skin.

Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770

PubMed Central

Gentzsch, Martina; Ren, Hong Y.; Houck, Scott A.; Quinney, Nancy L.; Cholon, Deborah M.; Sopha, Pattarawut; Chaudhry, Imron G.; Das, Jhuma; Dokholyan, Nikolay V.; Randell, Scott H.

2016-01-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. PMID:27402691

Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.

PubMed

Gentzsch, Martina; Ren, Hong Y; Houck, Scott A; Quinney, Nancy L; Cholon, Deborah M; Sopha, Pattarawut; Chaudhry, Imron G; Das, Jhuma; Dokholyan, Nikolay V; Randell, Scott H; Cyr, Douglas M

2016-09-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. Copyright © 2016 the American Physiological Society.

Recent Advances in the Development of Chromophore-Based Chemosensors for Nerve Agents and Phosgene.

PubMed

Chen, Liyan; Wu, Di; Yoon, Juyoung

2018-01-26

The extreme toxicity and ready accessibility of nerve agents and phosgene has caused an increase in the demand to develop effective systems for the detection of these substances. Among the traditional platforms utilized for this purpose, chemosensors including surface acoustic wave (SAW) sensors, enzymes, carbon nanotubes, nanoparticles, and chromophore based sensors have attracted increasing attention. In this review, we describe in a comprehensive manner recent progress that has been made on the development of chromophore-based chemosensors for detecting nerve agents (mimic) and phosgene. This review comprises two sections focusing on studies of the development of chemosensors for nerve agents (mimic) and phosgene. In each of the sections, the discussion follows a format which concentrates on different reaction sites/mechanisms involved in the sensing processes. Finally, chemosensors uncovered in these efforts are compared with those based on other sensing methods and challenges facing the design of more effective chemosensors for the detection of nerve agents (mimic) and phosgene are discussed.

Preliminary screening of alternative technologies to incineration for treatment of chemical-agent-contaminated soil, Rocky Mountain Arsenal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shem, L.M.; Rosenblatt, D.H.; Smits, M.P.

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.

Increasing nerve agent treatment efficacy by P-glycoprotein inhibition.

PubMed

Joosen, Marloes J A; Vester, Stefanie M; Hamelink, Jouk; Klaassen, Steven D; van den Berg, Roland M

2016-11-25

One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of nerve agent treatment when administered as a pretreatment. In the present study soman-induced seizures were also substantially prevented when the animals were intravenously treated with tariquidar post-poisoning, in addition to HI-6 and atropine. In these animals, approximately twice as much AChE activity was present in their brain as compared to control rats. The finding that tariquidar did not affect distribution of soman to the brain indicates that the potentiating effects were a result of interactions of Pgp inhibition with drug distribution. In line with this, atropine appeared to be a substrate for Pgp in in vitro studies in a MDR1/MDCK cell model. This indicates that tariquidar might induce brain region specific effects on atropine distribution, which could contribute to the therapeutic efficacy increase found. Furthermore, the therapeutic enhancement by tariquidar was compared to that of the less specific and less potent Pgp inhibitor cyclosporine A. This compound appeared to induce a protective effect similar to tariquidar. In conclusion, treatment with a Pgp inhibitor resulted in enhanced therapeutic efficacy of HI-6 and atropine in a soman-induced seizure model in the rat. The mechanism underlying these effects should be further investigated. To that end, the potentiating effect of nerve agent treatment should be addressed against a broader range of nerve agents, for oximes and atropine separately, and for those at lower doses. In particular when efficacy against more nerve agents is shown, a Pgp inhibitor such as tariquidar might be a valid addition to nerve agent antidotes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Thermal Process Development

DTIC Science & Technology

1983-04-08

constraints and legislation, the methods used for disposing of military lethal agents such as GB, VX, and HD, have changed from land and sea burial to...uction is the most generally accepted method of destroying toxic organic materials for all cases where the toxicity is associated with the totality of...8217., preferred method can be based on estimates or determinations of the required incineration conditions and an appraisal of the requirement for

Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valdez, Carlos A.; Leif, Roald N.; Alcaraz, Armando

The effective methylation of phosphonic acids related to chemical warfare agents (CWAs) employing trimethyloxonium tetrafluoroborate (TMO·BF 4) for their qualitative detection and identification by gas chromatography-mass spectrometry (GC-MS) is presented. The methylation occurs in rapid fashion (1 h) and can be conveniently carried out at ambient temperature, thus providing a safer alternative to the universally employed diazomethane-based methylation protocols. Optimization of the methylation parameters led us to conclude that methylene chloride was the ideal solvent to carry out the derivatization, and that even though methylated products can be observed surfacing after only 1 h, additional time was not found tomore » be detrimental but beneficial to the process particularly when dealing with analytes at low concentrations (~10 μg mL -1). Due to its insolubility in methylene chloride, TMO·BF 4 conveniently settles to the bottom during the reaction and does not produce additional interfering by-products that may further complicate the GC-MS analysis. We demonstrated the method to successfully methylate a variety of Schedule 2 phosphonic acids, including their half esters, resulting in derivatives that were readily detected and identified using the instrument's spectral library. Most importantly, the method was shown to simultaneously methylate a mixture of the organophosphorus-based nerve agent hydrolysis products: pinacolyl methylphosphonate (PMPA), cyclohexyl methylphosphonate (CyMPA) and ethyl methylphosphonate (EMPA) (at a 10 μg mL -1 concentration each) in a fatty acid ester-rich organic matrix (OPCW-PT-O 3) featured in the 38th Organisation for the Prohibition of Chemical Weapons (OPCW) Proficiency Test. Additionally, the protocol was found to effectively methylate N,N-diethylamino ethanesulfonic acid and N,N-diisopropylamino ethanesulfonic acid that are products arising from the oxidative degradation of the V-series agents VR and VX respectively. This work described herein represents the first report on the use of TMO·BF 4 as a viable, stable and safe agent for the methylation of phosphonic acids and their half esters and within the context of an OPCW Proficiency Test sample analysis.« less

Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry

DOE PAGES

Valdez, Carlos A.; Leif, Roald N.; Alcaraz, Armando

2016-06-01

The effective methylation of phosphonic acids related to chemical warfare agents (CWAs) employing trimethyloxonium tetrafluoroborate (TMO·BF 4) for their qualitative detection and identification by gas chromatography-mass spectrometry (GC-MS) is presented. The methylation occurs in rapid fashion (1 h) and can be conveniently carried out at ambient temperature, thus providing a safer alternative to the universally employed diazomethane-based methylation protocols. Optimization of the methylation parameters led us to conclude that methylene chloride was the ideal solvent to carry out the derivatization, and that even though methylated products can be observed surfacing after only 1 h, additional time was not found tomore » be detrimental but beneficial to the process particularly when dealing with analytes at low concentrations (~10 μg mL -1). Due to its insolubility in methylene chloride, TMO·BF 4 conveniently settles to the bottom during the reaction and does not produce additional interfering by-products that may further complicate the GC-MS analysis. We demonstrated the method to successfully methylate a variety of Schedule 2 phosphonic acids, including their half esters, resulting in derivatives that were readily detected and identified using the instrument's spectral library. Most importantly, the method was shown to simultaneously methylate a mixture of the organophosphorus-based nerve agent hydrolysis products: pinacolyl methylphosphonate (PMPA), cyclohexyl methylphosphonate (CyMPA) and ethyl methylphosphonate (EMPA) (at a 10 μg mL -1 concentration each) in a fatty acid ester-rich organic matrix (OPCW-PT-O 3) featured in the 38th Organisation for the Prohibition of Chemical Weapons (OPCW) Proficiency Test. Additionally, the protocol was found to effectively methylate N,N-diethylamino ethanesulfonic acid and N,N-diisopropylamino ethanesulfonic acid that are products arising from the oxidative degradation of the V-series agents VR and VX respectively. This work described herein represents the first report on the use of TMO·BF 4 as a viable, stable and safe agent for the methylation of phosphonic acids and their half esters and within the context of an OPCW Proficiency Test sample analysis.« less

Rapid and Efficient Filtration-Based Procedure for Separation and Safe Analysis of CBRN Mixed Samples

PubMed Central

Bentahir, Mostafa; Laduron, Frederic; Irenge, Leonid; Ambroise, Jérôme; Gala, Jean-Luc

2014-01-01

Separating CBRN mixed samples that contain both chemical and biological warfare agents (CB mixed sample) in liquid and solid matrices remains a very challenging issue. Parameters were set up to assess the performance of a simple filtration-based method first optimized on separate C- and B-agents, and then assessed on a model of CB mixed sample. In this model, MS2 bacteriophage, Autographa californica nuclear polyhedrosis baculovirus (AcNPV), Bacillus atrophaeus and Bacillus subtilis spores were used as biological agent simulants whereas ethyl methylphosphonic acid (EMPA) and pinacolyl methylphophonic acid (PMPA) were used as VX and soman (GD) nerve agent surrogates, respectively. Nanoseparation centrifugal devices with various pore size cut-off (30 kD up to 0.45 µm) and three RNA extraction methods (Invisorb, EZ1 and Nuclisens) were compared. RNA (MS2) and DNA (AcNPV) quantification was carried out by means of specific and sensitive quantitative real-time PCRs (qPCR). Liquid chromatography coupled to time-of-flight mass spectrometry (LC/TOFMS) methods was used for quantifying EMPA and PMPA. Culture methods and qPCR demonstrated that membranes with a 30 kD cut-off retain more than 99.99% of biological agents (MS2, AcNPV, Bacillus Atrophaeus and Bacillus subtilis spores) tested separately. A rapid and reliable separation of CB mixed sample models (MS2/PEG-400 and MS2/EMPA/PMPA) contained in simple liquid or complex matrices such as sand and soil was also successfully achieved on a 30 kD filter with more than 99.99% retention of MS2 on the filter membrane, and up to 99% of PEG-400, EMPA and PMPA recovery in the filtrate. The whole separation process turnaround-time (TAT) was less than 10 minutes. The filtration method appears to be rapid, versatile and extremely efficient. The separation method developed in this work constitutes therefore a useful model for further evaluating and comparing additional separation alternative procedures for a safe handling and preparation of CB mixed samples. PMID:24505375

LC-MS/MS assay for the quantitation of the ATR kinase inhibitor VX-970 in human plasma.

PubMed

Kiesel, Brian F; Scemama, Jonas; Parise, Robert A; Villaruz, Liza; Iffland, Andre; Doyle, Austin; Ivy, Percy; Chu, Edward; Bakkenist, Christopher J; Beumer, Jan H

2017-11-30

DNA damaging chemotherapy and radiation are widely used standard-of-care modalities for the treatment of cancer. Nevertheless, the outcome for many patients remains poor and this may be attributed, at least in part, to highly effective DNA repair mechanisms. Ataxia-telangiectasia mutated and Rad3-related (ATR) is a key regulator of the DNA-damage response (DDR) that orchestrates the repair of damaged replication forks. ATR is a serine/threonine protein kinase and ATR kinase inhibitors potentiate chemotherapy and radiation. The ATR kinase inhibitor VX-970 (NSC 780162) is in clinical development in combination with primary cytotoxic agents and as a monotherapy for tumors harboring specific mutations. We have developed and validated an LC-MS/MS assay for the sensitive, accurate and precise quantitation of VX-970 in human plasma. A dilute-and-shoot method was used to precipitate proteins followed by chromatographic separation with a Phenomenex Polar-RP 80Å (4μm, 50×2mm) column and a gradient acetonitrile-water mobile phase containing 0.1% formic acid from a 50μL sample volume. Detection was achieved using an API 4000 mass spectrometer using electrospray positive ionization mode. The assay was linear from 3 to 5,000ng/mL, proved to be accurate (94.6-104.2%) and precise (<8.4% CV), and fulfilled criteria from the FDA guidance for bioanalytical method validation. This LC-MS/MS assay will be a crucial tool in defining the clinical pharmacokinetics and pharmacology of VX-970 as it progresses through clinical development. Copyright © 2017 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyo-Cheol; Chung, Jin Wook, E-mail: chungjw@snu.ac.kr; Choi, Seung Hong

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

Biomaterials for mediation of chemical and biological warfare agents.

PubMed

Russell, Alan J; Berberich, Jason A; Drevon, Geraldine F; Koepsel, Richard R

2003-01-01

Recent events have emphasized the threat from chemical and biological warfare agents. Within the efforts to counter this threat, the biocatalytic destruction and sensing of chemical and biological weapons has become an important area of focus. The specificity and high catalytic rates of biological catalysts make them appropriate for decommissioning nerve agent stockpiles, counteracting nerve agent attacks, and remediation of organophosphate spills. A number of materials have been prepared containing enzymes for the destruction of and protection against organophosphate nerve agents and biological warfare agents. This review discusses the major chemical and biological warfare agents, decontamination methods, and biomaterials that have potential for the preparation of decontamination wipes, gas filters, column packings, protective wear, and self-decontaminating paints and coatings.

A Gas Chromotographic-Mass Spectrometric Approach to Examining Stereoselective Interaction of Human Plasma Proteins with Soman

DTIC Science & Technology

2008-02-01

ABSTRACT See reprint. 15. SUBJECT TERMS Human plasma proteins, soman, nerve agent , bioscavenger, gas chromatography, mass spectrometry 16. SECURITY...usually referred to as nerve agents ) are tabun (ethyl dimethylamidocyanophosphate, or GA ), sarin (iso- propyl methylfluorophosphonate, or GB), soman...Pharmacology and toxicology of chemical warfare agents Ann. Acad. Med. Singapore 2&: 104-107 (1997). 11. C Macilwain. Study proves Iraq used nerve gas . Nature 3

Proceedings of the Annual Chemical Defense Bioscience Review (5th) Held at Columbia, Maryland on 29-31 May 1985. Appendix 2

DTIC Science & Technology

1985-06-01

biocompatible enzyme-like catalyst for the rapid and specific deactivation of sys- temically sorbed nerve agents . We plan to introduce catalytic groups (thiol...mustard, seizures, respiratory failure, atropine, 2-PAM chloride, neurobehavioral effects, nerve agents , soman, cyanide, animal models, chemical casualties...Animal Model ........ .. A-541 Dr. H.L. Williams Effects of Nerve Agents on the Respiratory and e Cardiovascular Systems

Degradation of Toxic Chemicals by Zero-Valent Metal Nanoparticles - A Literature Review

DTIC Science & Technology

2005-11-01

oxidative reactions. Oxidative reactions are of primary interest to us as they have the potential to degrade organophosphorous nerve agents as well...a) mustard and b) nerve agent (general structure). To decontaminate mustard there are two approaches, dechlorination or oxidation of the sulfur, the...later of which is preferable due to the reversibility of the former. To decontaminate the nerve agents oxidation is required to replace X2, X3 and

The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops)

DTIC Science & Technology

2007-01-01

M., and Mestries, 1. C. 1998. Nerve agent poisoning in primates: antilethal, anti -epileptic and neuroprotective effects of GK-11. Arch. Toxico/. 72...toxicity in African green monkeys (Chlorocebus aethiops) and is the first step in exploring the suitability of this species as a model for nerve agent ...rhesus monkey (Macaca mulatta) has traditionally served as the NHP research species of choice to assess nerve agent toxicity and the effectiveness of

Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression

PubMed Central

Veit, Guido; Avramescu, Radu G.; Perdomo, Doranda; Phuan, Puay-Wah; Bagdany, Miklos; Apaja, Pirjo M.; Borot, Florence; Szollosi, Daniel; Wu, Yu-Sheng; Finkbeiner, Walter E.; Hegedus, Tamas; Verkman, Alan S.; Lukacs, Gergely L.

2015-01-01

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770–induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)–NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF. PMID:25101887

Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

PubMed

Veit, Guido; Avramescu, Radu G; Perdomo, Doranda; Phuan, Puay-Wah; Bagdany, Miklos; Apaja, Pirjo M; Borot, Florence; Szollosi, Daniel; Wu, Yu-Sheng; Finkbeiner, Walter E; Hegedus, Tamas; Verkman, Alan S; Lukacs, Gergely L

2014-07-23

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF. Copyright © 2014, American Association for the Advancement of Science.

Multimodality Imaging of Ethiodized Oil–loaded Radiopaque Microspheres during Transarterial Embolization of Rabbits with VX2 Liver Tumors

PubMed Central

Tacher, Vania; Duran, Rafael; Lin, MingDe; Sohn, Jae Ho; Sharma, Karun V.; Wang, Zhijun; Chapiro, Julius; Gacchina Johnson, Carmen; Bhagat, Nikhil; Dreher, Matthew R.; Schäfer, Dirk; Woods, David L.; Lewis, Andrew L.; Tang, Yiqing; Grass, Michael; Wood, Bradford J.

2016-01-01

Purpose To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70–150-μm radiopaque microspheres in saline (radiopaque microsphere group), 70–150-μm radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70–150-μm radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P < .05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P < .05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. © RSNA, 2015 PMID:26678453

Matrine in association with FD-2 stimulates F508del-cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809

PubMed Central

Marengo, Barbara; Speciale, Andrea; Senatore, Lisa; Garibaldi, Silvano; Musumeci, Francesca; Nieddu, Erika; Pollarolo, Benedetta; Pronzato, Maria Adelaide; Schenone, Silvia; Mazzei, Mauro; Domenicotti, Cinzia

2017-01-01

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the predominant mutation is termed Phe508del (F508del). Therapy for F508del-CFTR patients is based on the use of Orkambi®, a combination of VX809 and VX770. However, though Orkambi leads to an improvement in the lung function of patients, a progressive reduction in its efficacy has been observed. In order to overcome this effect, the aim of the present study was to investigate the role of matrine and the in-house compound FD-2 in increasing the action of VX809 and VX770. Fischer rat thyroid cells overexpressing F508del-CFTR were treated with matrine, VX809 (corrector) and/or with a number of potentiators (VX770, FD-1 and FD-2). The results demonstrated that matrine was able to stimulate CFTR activity and, in association with FD-2, increased the functionality of the channel in the presence of VX809. Based on these results, it may be hypothesized that FD-2 may be a novel and more effective potentiator compared with VX770. PMID:29039559

Department of Defense Chemical and Biological Defense Program. Volume I: Annual Report to Congress

DTIC Science & Technology

2002-04-01

The M21 RSCAAL is an automatic scanning, passive infrared sensor that detects nerve ( GA , GB, and GD) and blister (H and L) agent vapor clouds based on...Point Detection GA - tabun, a nerve agent System GAO - General Accounting Office IPE - Individual Protective Equipment GAS - Group A Streptococcus...IPR - In-Process Review GB - sarin , a nerve agent IPT - Integrated Product Team GC - gas chromatography IR&D - Independent Research & Development GD

Comparison of Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to the Nerve Agents Cyclosarin and Tabun in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Comparison of extracellular striatal acetylcholine and brain seizure activity following...lethality; nerve agents; organophosphorus compounds; seizure activity ; tabun 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER...acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs John C

Evaluation of ADD392124 for the Delayed Treatment of Nerve Agent-Induced Status Epilepticus Seizures

DTIC Science & Technology

2011-09-01

Induced Status Epilepticus Seizures John H. McDonough Kerry E. Van Shura Megan E. Lyman Claire G. Eisner Amelia Mazza Robert K. Kan Tsung...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Evaluation of ADD392124 for the delayed treatment of nerve agent-induced status epilepticus seizures 5b... status epilepticus seizures. We evaluated the ability of ADD392124 to control seizures induced by the nerve agent soman. Rats were exposed to a

Nerve Agents: What They Are, How They Work, How to Counter Them.

PubMed

Costanzi, Stefano; Machado, John-Hanson; Mitchell, Moriah

2018-05-16

Nerve agents are organophosphorus chemical warfare agents that exert their action through the irreversible inhibition of acetylcholinesterase, with a consequent overstimulation of cholinergic transmission followed by its shutdown. Beyond warfare, they have notoriously been employed in acts of terrorism as well as high profile assassinations. After a brief historical introduction on the development and deployment of nerve agents, this review provides a survey of their chemistry, the way they affect cholinergic transmission, the available treatment options, and the current directions for their improvement. As the review illustrates, despite their merits, the currently available treatment options present several shortcomings. Current research directions involve the search for improved antidotes, antagonists of the nicotinic receptors, small-molecule pretreatment options, as well as bioscavengers as macromolecular pretreatment options. These efforts are making good progress in many different directions and, hopefully, will lead to a lower target susceptibility, thus reducing the appeal of nerve agents as chemical weapons.

Neurosteroids for the potential protection of humans against organophosphate toxicity.

PubMed

Reddy, Doodipala Samba

2016-08-01

This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA A receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA A receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure. © 2016 New York Academy of Sciences.

Low-Level Analytical Methodology Updates to Support Decontaminant Performance Evaluations

DTIC Science & Technology

2011-06-01

from EPDM and tire rubber coupon materials that were spiked with a known amount of the chemical agent VX, treated with bleach decontaminant, and...to evaluate the performance of bleach decontaminant on EPDM and tire rubber coupons. Dose-confirmation or Tool samples were collected by delivering...components • An aging or damaged analytical column • Dirty detector • Other factors related to general instrument and/or sample analysis performance

Dramatic Differences in Organophosphorus Hydrolase Activity between Human and Chimeric Recombinant Mammalian Paraoxonase-1 Enzymes

DTIC Science & Technology

2009-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Dramatic Differences in Organophosphorus Hydrolase Activity between Human and 5a... activity , V-agents, VX, bioscavenger, medical countermeasures 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...Organophosphorus Hydrolase Activity between Human and Chimeric Recombinant Mammalian Paraoxonase-1 Enzymes† Tamara C. Otto,‡ Christina K. Harsch,§ David T

Asymptotic behavior of the Kohn-Sham exchange potential at a metal surface

NASA Astrophysics Data System (ADS)

Qian, Zhixin

2012-03-01

The asymptotic structure of the Kohn-Sham exchange potential vx(r) in the classically forbidden region of a metal surface is investigated, together with that of the Slater exchange potential VxS(r) and those of the approximate Krieger-Li-Iafrate VxKLI(r) and Harbola-Sahni Wx(r) exchange potentials. Particularly, the former is shown to have the form of vx(z→∞)=-αx/z with αx a constant dependent only of bulk electron density. The same result in previous work is thus confirmed; in the meanwhile, a controversy raised recently gets resolved. The structure of the exchange hole ρx(r,r') is examined, and the delocalization of it in the metal bulk when the electron is at large distance from the metal surface is demonstrated with analytical expressions. The asymptotic structures of vx(r), VxS(r), VxKLI(r), and Wx(r) at a slab metal surface are also investigated. Particularly, vx(z→∞)=-1/z in the slab case. The distinction, in this respect, between the semi-infinite and the slab metal surfaces is elucidated.

In Search of an Effective in vivo Reactivator for Organophosphorus Nerve Agent-Inhibited Acetylcholinesterase in the Central Nervous System

DTIC Science & Technology

2012-01-01

monoisonitrosoacetone (MINA) crossed BBB, provided some degree of CNS AChE reactivation, enhanced survival, and mitigated the seizure activity following nerve agent...tissues (brain regions, diaphragm, heart, skeletal muscle) were collected. AChE activity was measured using the Ellman assay. In GB exposure, pro...therapy. Protecting and/or restoring AChE activity in the brain is a major goal in the treatment of nerve agent intoxication. Our long-term goal is to

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

PubMed

Newmark, Jonathan

2004-05-11

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

Detection of Co-Infection of Notocactus leninghausii f. cristatus with Six Virus Species in South Korea

PubMed Central

Park, Chung Hwa; Song, Eun Gyeong; Ryu, Ki Hyun

2018-01-01

Co-infection with two virus species was previously reported in some cactus plants. Here, we showed that Notocactus leninghausii f. cristatus can be co-infected with six different viruses: cactus mild mottle virus (CMMoV)-Nl, cactus virus X (CVX)-Nl, pitaya virus X (PiVX)-Nl, rattail cactus necrosis-associated virus (RCNaV)-Nl, schlumbergera virus X (SchVX)-Nl, and zygocactus virus X (ZyVX)-Nl. The coat protein sequences of these viruses were compared with those of previously reported viruses. CMMoV-Nl, CVX-Nl, PiVX-Nl, RCNaV-Nl, SchVX-Nl, and ZyVX-Nl showed the greatest nucleotide sequence homology to CMMoV-Kr (99.8% identity, GenBank accession NC_011803), CVX-Jeju (77.5% identity, GenBank accession LC12841), PiVX-P37 (98.4% identity, GenBank accession NC_024458), RCNaV (99.4% identity, GenBank accession NC_016442), SchVX-K11 (95.7% identity, GenBank accession NC_011659), and ZyVX-B1 (97.9% identity, GenBank accession NC_006059), respectively. This study is the first report of co-infection with six virus species in N. leninghausii f. cristatus in South Korea. PMID:29422789

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons.

PubMed

Tenn, Catherine C; Wang, Yushan

2007-05-01

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.

The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway.

PubMed

Do Carmo, Helison; Arjun, Sapna; Petrucci, Orlando; Yellon, Derek M; Davidson, Sean M

2018-04-01

Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC). Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC. VX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC. The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.

Molecular targets for organophosphates in the central nervous system. Midterm report, 18 May 1995-17 November 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albuquerque, E.X.

1996-11-01

In this study, the patch-clamp technique was used as an approach to evaluate the pre- and postsynaptic effects of VX and soman on synaptic currents of cultured hippocampal neurons. Compared to control, the frequency of the currents mediated by the activation of GABA or glutamate receptors was increased in a concentration-dependent manner from 200% to 550%, when exposed to VX from 10 nM to 1 pM. The effect of VX was observed in the presence of TTX and atropine, indicating that it was a presynaptic effect unrelated to the activation of muscarinic receptors. In addition, it was found that themore » dlhydron-B-erythroldine did not prevent or abolished the effects of VX. Because, either soman or acetylcholine at high concentrations, applied for 5 to 10 min to the cultured neurons did not mimic the potentiation of transmitter release induced by VX, it was concluded that the presynaptic effect of VX was unrelated to the inhibition of cholinesterase enzyme. At the concentrations studied, VX and soman did not change the post-synaptic properties of GABAA, NMDA, and AMPA receptors. The effect of VX was markedly reduced when the extracellular calcium was removed, but was unaffected when the calcium channel blocker verapamil was added to the preparation. The present findings shows that VX exerts a presynaptic effect unrelated to cholinesterase enzyme that is unaffected by the common antidote atropine used for treating intoxication with VX.« less

In vitro evaluation of Aurora kinase inhibitor—VX680—in formulation of PLA-TPGS nanoparticles

NASA Astrophysics Data System (ADS)

Thuy Duong Le, Thi; Thu Ha, Phuong; Hai Yen Tran, Thi; Nguyen, Dac Tu; Nguyen, Hoai Nam; Khanh Bui, Van; Nhung Hoang, My

2016-06-01

Polymeric nanoparticles prepared from poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS) were used as potential drug carries with many advantages to overcome the disadvantages of insoluble anticancer drugs and enhance blood circulation time and tissues. VX680 is an Aurora kinase inhibitor and is also the foremost Aurora kinase inhibitor to be studied in clinical trials. In this study, we aimed to investigate whether VX680-loaded PLA-TPGS nanoparticles (VX680-NPs) are able to effectively increase the toxicity of chemotherapy. Accordingly, we first synthesized VX680-loaded nanoparticles and NP characterizations of morphology, mean size, zeta potential, and encapsulation efficiency were spherical shape, 63 nm, -30 mV and 76%, respectively. Then, we investigated the effects on HeLa cells. The cell cytotoxicity was evaluated by the xCELLigence real-time cell analyzer allowing measurement of changes in electrical impedance on the surface of the E-plate. Analysis of nucleus morphology and level of histone H3 phosphorylation was observed by confocal fluorescence scanning microscopy. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Our results showed that VX680-NPs reduced cell viability with IC50 value lower 3.4 times compared to free VX680. Cell proliferation was inhibited by VX680-NPs accompanied by other effects such as high abnormal changes of nucleus, a decrease of phospho-histone H3 at Ser10 level, an increase of polyploid cells and resulted in higher apoptotic cells. These results demonstrated that VX680-NPs had more cytotoxicity than as treated with VX680 alone. Thus, VX680-NPs may be considered as promising drug delivery system for cancer treatment.

Polymeric Sorbent with Controlled Surface Polarity: An Alternate for Solid-Phase Extraction of Nerve Agents and Their Markers from Organic Matrix.

PubMed

Roy, Kanchan Sinha; Purohit, Ajay Kumar; Chandra, Buddhadeb; Goud, D Raghavender; Pardasani, Deepak; Dubey, Devendra Kumar

2018-06-05

Extraction and identification of lethal nerve agents and their markers in complex organic background have a prime importance from the forensic and verification viewpoint of the Chemical Weapons Convention (CWC). Liquid-liquid extraction with acetonitrile and commercially available solid phase silica cartridges are extensively used for this purpose. Silica cartridges exhibit limited applicability for relatively polar analytes, and acetonitrile extraction shows limited efficacy toward relatively nonpolar analytes. The present study describes the synthesis of polymeric sorbents with tunable surface polarity, their application as a solid-phase extraction (SPE) material against nerve agents and their polar as well as nonpolar markers from nonpolar organic matrices. In comparison with the acetonitrile extraction and commercial silica cartridges, the new sorbent showed better extraction efficiency toward analytes of varying polarity. The extraction parameters were optimized for the proposed method, which included ethyl acetate as an extraction solvent and n-hexane as a washing solvent. Under optimized conditions, method linearity ranged from 0.10 to 10 μg mL -1 ( r 2 = 0.9327-0.9988) for organophosphorus esters and 0.05-20 μg mL -1 ( r 2 = 0.9976-0.9991) for nerve agents. Limits of detection (S:N = 3:1) in the SIM mode were found in the range of 0.03-0.075 μg mL -1 for organophosphorus esters and 0.015-0.025 μg mL -1 for nerve agents. Limits of quantification (S:N = 10:1) were found in the range of 0.100-0.25 μg mL -1 for organophosphorus esters and 0.05-0.100 μg mL -1 for nerve agents in the SIM mode. The recoveries of the nerve agents and their markers ranged from 90.0 to 98.0% and 75.0 to 95.0% respectively. The repeatability and reproducibility (with relative standard deviations (RSDs) %) for organophosphorus esters were found in the range of 1.35-8.61% and 2.30-9.25% respectively. For nerve agents, the repeatability range from 1.00 to 7.75% and reproducibility were found in the range of 2.17-6.90%.

Enhanced detectability of fluorinated derivatives of N,N-dialkylamino alcohols and precursors of nitrogen mustards by gas chromatography coupled to Fourier transform infrared spectroscopy analysis for verification of chemical weapons convention.

PubMed

Garg, Prabhat; Purohit, Ajay; Tak, Vijay K; Dubey, D K

2009-11-06

N,N-Dialkylamino alcohols, N-methyldiethanolamine, N-ethyldiethanolamine and triethanolamine are the precursors of VX type nerve agents and three different nitrogen mustards respectively. Their detection and identification is of paramount importance for verification analysis of chemical weapons convention. GC-FTIR is used as complimentary technique to GC-MS analysis for identification of these analytes. One constraint of GC-FTIR, its low sensitivity, was overcome by converting the analytes to their fluorinated derivatives. Owing to high absorptivity in IR region, these derivatives facilitated their detection by GC-FTIR analysis. Derivatizing reagents having trimethylsilyl, trifluoroacyl and heptafluorobutyryl groups on imidazole moiety were screened. Derivatives formed there were analyzed by GC-FTIR quantitatively. Of these reagents studied, heptafluorobutyrylimidazole (HFBI) produced the greatest increase in sensitivity by GC-FTIR detection. 60-125 folds of sensitivity enhancement were observed for the analytes by HFBI derivatization. Absorbance due to various functional groups responsible for enhanced sensitivity were compared by determining their corresponding relative molar extinction coefficients ( [Formula: see text] ) considering uniform optical path length. The RSDs for intraday repeatability and interday reproducibility for various derivatives were 0.2-1.1% and 0.3-1.8%. Limit of detection (LOD) was achieved up to 10-15ng and applicability of the method was tested with unknown samples obtained in international proficiency tests.

The kinetic study of the inhibition of human cholinesterases by demeton-S-methyl shows that cholinesterase-based titration methods are not suitable for this organophosphate.

PubMed

Bazire, Alexandre; Gillon, Emilie; Lockridge, Oksana; Vallet, Virginie; Nachon, Florian

2011-04-01

The organophosphorus insecticide, demeton-S-methyl (DSM), is considered as a good surrogate of the highly toxic nerve agent VX for skin absorption studies due to similar physico-chemical properties and in vitro percutaneous penetration profile. But, when skin distribution was estimated by measuring inhibition of cholinesterase activity, the results were poorly reproducible. The various grades of commercial DSM solutions were suspected to be the origin of the discrepancies. This hypothesis was tested by measuring inhibition of human acetyl- and butyrylcholinesterase by two commercial DSM solutions. The inhibition rate was independent on the enzyme concentration confirming pseudo-first order conditions. But complete inhibition of butyrylcholinesterase activity was achieved only when the DSM concentration was at least 1500-fold higher than the enzyme concentration. Besides, complete inhibition of acetylcholinesterase was never achieved. Mass spectrometry analysis of the inhibited butyrylcholinesterase adducts identified monomethoxyphosphorylated-serine, the aged product of inhibition by DSM or a derivative with a modified leaving group. Neither spontaneous reactivation nor aging of the dimethoxyphosphorylated-serine could account for the inhibition kinetics observed, suggesting an overly complicated kinetic scheme not compatible with the requirement of a titration experiment. In conclusion, cholinesterase-based analytical methods should be avoided for DSM titration in skin penetration studies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Two new Blazhko stars: XZ UMi and VX Scl

NASA Astrophysics Data System (ADS)

Skarka, M.; Dolinsky, J.; Jurysek, J.; Honkova, K.; Masek, M.; Liska, J.; Zejda, M.

2016-02-01

A brief report about a discovery of modulation in two RRab Lyrae stars XZ UMi and VX Scl is presented. The suspicion of modulation comes from our observations, but the modulation periods (41.1d for XZ UMi and 67.3d for VX Scl) were estimated based on the analysis of NSVS (XZ UMi) and SuperWASP data (VX Scl). Both stars show indications of period change. The peaks close to the basic pulsation frequency of VX Scl could be the signs of possible double modulation.

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

PubMed

Worek, F; Eyer, P; Aurbek, N; Szinicz, L; Thiermann, H

2007-03-01

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

In vitro and in vivo magnetic resonance imaging with chlorotoxin-conjugated superparamagnetic nanoprobes for targeting hepatocarcinoma.

PubMed

Chen, Zhu; Xiao, En-Hua; Kang, Zhen; Zeng, Wen-Bin; Tan, Hui-Long; Li, Hua-Bing; Bian, Du-Jun; Shang, Quan-Liang

2016-05-01

The present study aimed to assess the in vitro and in vivo magnetic resonance imaging (MRI) features of chlorotoxin (CTX)-conjugated superparamagnetic iron oxide (SPIO) nanoprobes. CTX-conjugated nanoprobes were composed of SPIO coated with polyethylene glycol (PEG) and conjugated with CTX. The nanoprobes were termed SPIO-PEG-CTX. MRI of the SPIO and SPIO-PEG-CTX solutions at a different concentration was performed with a 3.0-T MRI scanner (Philips Achieva 3.0T X Series; Phillips Healthcare, The Netherlands). Rabbit VX2 hepatocarcinoma was established by a traditional laparotomy method (injection of the tumor particles into the liver using a 15G syringe needle) following approval by the institutional animal care and use committee. Contrast-enhanced MRI of VX2 rabbits (n=8) was performed using the same MRI scanner with SPIO‑PEG-CTX solutions as the contrast agent. Data were analyzed with calibration curve and a paired t-test. The SPIO-PEG-CTX nanoparticles were successfully prepared. With increasing concentrations of the solutions, the MRI signal intensity was increased at T1WI, but decreased at T2WI, which were the same as that for SPIO. Rabbit VX2 carcinoma appeared as a low MRI signal at T1WI, and high at T2WI. After injection of the contrast agent, the MRI signal of carcinoma was decreased relative to that before injection at T2WI (1,161±331.5 vs. 1,346±300.5; P=0.004<0.05), while the signal of the adjacent normal hepatic tissues was unchanged (480.6±165.1 vs. 563.4±67.8; P=0.202>0.05). The SPIO-PEG-CTX nanoparticles showed MRI negative enhancement at T2WI and a targeting effect in liver cancer, which provides the theoretical basis for further study of the early diagnosis of hepatocellular carcinoma.

Effect of drop size on the degradation of VX in concrete.

PubMed

Wagner, George W; O'Connor, Richard J; Edwards, Jennifer L; Brevett, Carol A S

2004-08-17

The effect of drop size on the degradation rate of VX, O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonothioate, in fresh concrete has been examined using (31)P NMR. Drops of neat VX, ranging in size from 4 microL to 0.2 microL, applied to small concrete coupons (8 mm x 15 mm) were observed to degrade at different rates, with the 1 microL and smaller drops reacting in less than 4 days, and the larger droplets reacting in less than 11 days. Additionally, 4 microL VX predissolved in hexane to evenly spread it over the concrete coupon likewise reacted faster, degrading in less than 5 days. The fresh concrete, less than 2 months old, exhibited significantly faster VX degradation for all drop sizes than that observed for "aged" concrete in a previous study where VX persisted for months. The enhanced reactivity of the "fresh" concrete for VX was maintained for at least a 1-year period. The pH of water containing crushed "fresh" and "aged" concrete was 10.0 and 9.0, respectively. The higher pH of the "fresh" concrete is one reason for its enhanced reactivity toward VX. An additional contribution to the enhanced reactivity of the "fresh" concrete is suggested by the increased mobility of its sorbed VX as evidenced by its significantly narrower peak in (31)P NMR spectra.

Investigation of the Persistence of Nerve Agent Degradation ...

EPA Pesticide Factsheets

Journal Article The persistence of chemical warfare nerve agent degradation analytes on surfaces is important for reasons ranging from indicating the presence of nerve agent on that surface to environmental restoration of a site after nerve agent release. This study investigates the persistence of several chemical warfare nerve agent degradation analytes on a number of indoor surfaces and presents an approach for wipe sampling of surfaces, followed by wipe extraction and liquid chromatography-tandem mass spectrometry detection. Multiple commercially available wipe materials were investigated to determine optimal wipe recoveries. Tested surfaces, including several porous/permeable and largely nonporous/impermeable surfaces, were investigated to determine recoveries from these indoor surface materials. Wipe extracts were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and compared with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) results. UPLC provides a sensitive separation of targeted degradation analytes in addition to being nearly four times faster than HPLC, allowing for greater throughput during a widespread release concerning large-scale contamination and subsequent remediation events. Percent recoveries from nonporous/impermeable surfaces were 60-103% for isopropyl methylphosphonate (IMPA), 61-91 % for ethyl methylphosphonate (EMPA), and 60-98% for pinacolyl methylphosphona

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).

VX

MedlinePlus

... eating the contaminated food. VX is primarily a liquid exposure hazard, but if it is heated to very high temperatures, it can turn into vapor (gas). A person’s clothing can release VX after contact ...

Occupational Criteria for Chemical Agent VX

DTIC Science & Technology

1988-09-01

nervous system in mild exposures may include tension, anxiety, jitteriness, restlessness, m insomnia , or excessive dreaming. Higher exposures may cause ...toxic substance which can cause death at very low doses. It is both an inhalation and a skin contact hazard. Despite its low vapor m pressure, a...hen and cat can a syndrome similar to that in humans be induced (Gordon et al. 1983, Johnson 1975a). Abou-Donia (1981) states that potent cholin

Proceedings of the Army Science Conference (15th) Held at West Point, New York on 17-19 June 1986. Volume 2. Principal Authors H through L.

DTIC Science & Technology

1986-06-20

Page Leonard, Joseph M. See Seiders, Barbara A. B. V 189 Linden, Carol D. See Canonico, Peter G. 1 127 Little, James S. A Potential Nerve Agent II 271...Semi-Automated System for Testing 11 235 Waring, Paul P. the Efficacy of Nerve Agent Hawkins, George S. Protection/Decontamination Powanda, Michael...potential uses. Among them are: 1) detection of organofluoro- phosphate chemicals, 2) non-corrosive decontamination of nerve agent mate- rials

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 yielded two types of adducts, one of which was thiomethyl phosphonate, a modification not found after treatment with authentic soman and sarin.

Combination of aspartic acid and glutamic acid inhibits tumor cell proliferation.

PubMed

Yamaguchi, Yoshie; Yamamoto, Katsunori; Sato, Yoshinori; Inoue, Shinjiro; Morinaga, Tetsuo; Hirano, Eiichi

2016-01-01

Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.

Reactive decontamination of absorbing thin film polymer coatings: model development and parameter determination

NASA Astrophysics Data System (ADS)

Varady, Mark; Mantooth, Brent; Pearl, Thomas; Willis, Matthew

2014-03-01

A continuum model of reactive decontamination in absorbing polymeric thin film substrates exposed to the chemical warfare agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (known as VX) was developed to assess the performance of various decontaminants. Experiments were performed in conjunction with an inverse analysis method to obtain the necessary model parameters. The experiments involved contaminating a substrate with a fixed VX exposure, applying a decontaminant, followed by a time-resolved, liquid phase extraction of the absorbing substrate to measure the residual contaminant by chromatography. Decontamination model parameters were uniquely determined using the Levenberg-Marquardt nonlinear least squares fitting technique to best fit the experimental time evolution of extracted mass. The model was implemented numerically in both a 2D axisymmetric finite element program and a 1D finite difference code, and it was found that the more computationally efficient 1D implementation was sufficiently accurate. The resulting decontamination model provides an accurate quantification of contaminant concentration profile in the material, which is necessary to assess exposure hazards.

Changes in Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to Nerve Against in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Changes in extracellular striatal acetylcholine and brain seizure activity following...Acetylcholine, acetylcholinesterase, choline, guinea pig, in vivo microdialysis, nerve agents, organophosphorus compounds, sarin, seizure activity ...RESEARCH ARTICLE Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Potentiator VX-770 (Ivacaftor) Opens the Defective Channel Gate of Mutant CFTR in a Phosphorylation-dependent but ATP-independent Manner* ♦

PubMed Central

Eckford, Paul D. W.; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E.

2012-01-01

The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe. PMID:22942289

Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner.

PubMed

Eckford, Paul D W; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E

2012-10-26

The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collombet, Jean-Marc, E-mail: jmcollombet@imassa.fr

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 increasedmore » 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.« less

Analysis of Trace VX in Acidified VX Hydrolysate Samples

DTIC Science & Technology

2009-07-01

SUBJECT TERMS Mass spectrometry Gas chromatography VX hydrolysate Energetics Blue Grass VX reformation BGCAPP 16. SECURITY CLASSIFICATION OF: 17...SCWO ( supercritical water oxidation) reactors. Prior to feeding the blended hydrolysate mixture from the SCWO blend tank to the SCWO reactors, chloride...transported as fluid in the reactor under the SCWO processing conditions. Current design calls for adding these elements as 35% HCI, 93% H2SO4 and

Neurosciences and research on chemical weapons of mass destruction in Nazi Germany.

PubMed

Schmaltz, Florian

2006-09-01

As a side-product of industrial research, new chemical nerve agents (Tabun, Sarin, Soman) superior to those available to the Allied Forces were discovered in Nazi Germany. These agents were never used by Germany, even though they were produced at a large scale. This article explores the toxicological and physiological research into the mechanisms of action of these novel nerve agents, and the emergence of military research objectives in neurophysiological and neurotoxicological research. Recently declassified Allied military intelligence files document secret nerve agent research, leading to intensified research on anticholinesterase agents in the peripheral and the central nervous system. The article discusses the involvement of IG Farben scientists, educational, medical and military institutions, and of Nobel Prize laureate Richard Kuhn, director of the Kaiser Wilhelm Institute for Medical Research.

Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells.

PubMed

Ruffin, Manon; Roussel, Lucie; Maillé, Émilie; Rousseau, Simon; Brochiero, Emmanuelle

2018-04-01

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

Glutathione-S-transferase-oxidative stress relationship in the internal spermatic vein blood of infertile men with varicocele.

PubMed

Mostafa, T; Rashed, L A; Zeidan, A S; Hosni, A

2015-02-01

This study aimed to assess glutathione-S-transferase (GST) enzyme- oxidative stress (OS) relationship in the internal spermatic vein (ISV) of infertile men associated with varicocele (Vx). Ninety five infertile oligoasthenoteratozoospemic (OAT) men associated with Vx were subjected to history taking, clinical examination and semen analysis. During inguinal varicocelectomy, GST, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in the blood samples drawn from ISV and median cubital veins. The mean levels of GST, GPx were significantly decreased and the mean level of GPx was significantly increased in the ISV compared with the peripheral blood. The mean level of GST and GPx in the ISV was significantly decreased, and the mean level of MDA was significantly increased in Vx grade III compared with Vx grade II cases. There was nonsignificant difference in the mean level of GST in the ISV in unilateral Vx cases compared with bilateral Vx cases. There was significant positive correlation of GST with sperm count, sperm motility, GPx and significant negative correlation with sperm abnormal forms, MDA. It is concluded that ISV of infertile men associated with Vx has decreased levels of GST compared with peripheral venous circulation that is correlated with both OS and Vx grade. © 2014 Blackwell Verlag GmbH.

MICROCHIP ENZYMATIC ASSAY OF ORGANOPHOSPHATE NERVE AGENTS. (R830900)

EPA Science Inventory

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

Best time window for the use of calcium-modulating agents to improve functional recovery in injured peripheral nerves-An experiment in rats.

PubMed

Yan, Yuhui; Shen, Feng-Yi; Agresti, Michael; Zhang, Lin-Ling; Matloub, Hani S; LoGiudice, John A; Havlik, Robert; Li, Jifeng; Gu, Yu-Dong; Yan, Ji-Geng

2017-09-01

Peripheral nerve injury can have a devastating effect on daily life. Calcium concentrations in nerve fibers drastically increase after nerve injury, and this activates downstream processes leading to neuron death. Our previous studies showed that calcium-modulating agents decrease calcium accumulation, which aids in regeneration of injured peripheral nerves; however, the optimal therapeutic window for this application has not yet been identified. In this study, we show that calcium clearance after nerve injury is positively correlated with functional recovery in rats suffering from a crushed sciatic nerve injury. After the nerve injury, calcium accumulation increased. Peak volume is from 2 to 8 weeks post injury; calcium accumulation then gradually decreased over the following 24-week period. The compound muscle action potential (CMAP) measurement from the extensor digitorum longus muscle recovered to nearly normal levels in 24 weeks. Simultaneously, real-time polymerase chain reaction results showed that upregulation of calcium-ATPase (a membrane protein that transports calcium out of nerve fibers) mRNA peaked at 12 weeks. These results suggest that without intervention, the peak in calcium-ATPase mRNA expression in the injured nerve occurs after the peak in calcium accumulation, and CMAP recovery continues beyond 24 weeks. Immediately using calcium-modulating agents after crushed nerve injury improved functional recovery. These studies suggest that a crucial time frame in which to initiate effective clinical approaches to accelerate calcium clearance and nerve regeneration would be prior to 2 weeks post injury. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Stabilizing Acetylcholinesterase on Carbon Electrodes Using Peptide Nanotubes to Produce Effective Biosensors

DTIC Science & Technology

2012-03-22

of pesticide . Plans for the cleanup of nerve gas attacks involve hosing affected areas down with bleach and water, which may also lead to water...They have been widely used in agriculture as pesticides and are also used as deadly nerve agents in chemical weapons. Chromatography and...Amperometric Detection of Organophosphorus Pesticides and Nerve Agents ,” Electroanalysis 16, Nos. 1-2: 145-149 (2004). Norouzi, Parviz, Farnoush

Phase formation polycrystalline vanadium oxide via thermal annealing process under controlled nitrogen pressure

NASA Astrophysics Data System (ADS)

Jessadaluk, S.; Khemasiri, N.; Rahong, S.; Rangkasikorn, A.; Kayunkid, N.; Wirunchit, S.; Horprathum, M.; Chananonnawathron, C.; Klamchuen, A.; Nukeaw, J.

2017-09-01

This article provides an approach to improve and control crystal phases of the sputtering vanadium oxide (VxOy) thin films by post-thermal annealing process. Usually, as-deposited VxOy thin films at room temperature are amorphous phase: post-thermal annealing processes (400 °C, 2 hrs) under the various nitrogen (N2) pressures are applied to improve and control the crystal phase of VxOy thin films. The crystallinity of VxOy thin films changes from amorphous to α-V2O5 phase or V9O17 polycrystalline, which depend on the pressure of N2 carrier during annealing process. Moreover, the electrical resistivity of the VxOy thin films decrease from 105 Ω cm (amorphous) to 6×10-1 Ω cm (V9O17). Base on the results, our study show a simply method to improve and control phase formation of VxOy thin films.

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

EPA Science Inventory

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

Comparison of Four Skin Decontamination Procedures Using Reactive Skin Decontamination Lotion (RSDL) Following Cutaneous VX Exposure in Guinea Pigs

DTIC Science & Technology

2016-01-01

DC) product following cutaneous exposure to VX was affected by the DC procedure. Fur-clipped, male, unanesthetized guinea pigs were used as subjects...RSDL) Following Cutaneous VX Exposure in Guinea Pigs Irwin Koplovitz Susan Schulz Julia Morgan Robert Reed Edward Clarkson C. Gary Hurst...Decontamination Procedures Using Reactive Skin 5a. CONTRACT NUMBER Decontamination Lotion (RSDL) Following Cutaneous VX Exposure in Guinea Pigs 5b

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. Published by Elsevier B.V.

Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis

PubMed Central

Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham; Matalon, Sadis; Bebok, Zsuzsanna

2016-01-01

The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single “corrector”. Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER) form (band B) of ΔF508 CFTR with another corrector (Corr-4a.) Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi. PMID:27214033

Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry.

PubMed

Valdez, Carlos A; Leif, Roald N; Alcaraz, Armando

2016-08-24

The effective methylation of phosphonic acids related to chemical warfare agents (CWAs) employing trimethyloxonium tetrafluoroborate (TMO·BF4) for their qualitative detection and identification by gas chromatography-mass spectrometry (GC-MS) is presented. The methylation occurs in rapid fashion (1 h) and can be conveniently carried out at ambient temperature, thus providing a safer alternative to the universally employed diazomethane-based methylation protocols. Optimization of the methylation parameters led us to conclude that methylene chloride was the ideal solvent to carry out the derivatization, and that even though methylated products can be observed surfacing after only 1 h, additional time was not found to be detrimental but beneficial to the process particularly when dealing with analytes at low concentrations (∼10 μg mL(-1)). Due to its insolubility in methylene chloride, TMO·BF4 conveniently settles to the bottom during the reaction and does not produce additional interfering by-products that may further complicate the GC-MS analysis. The method was demonstrated to successfully methylate a variety of Schedule 2 phosphonic acids, including their half esters, resulting in derivatives that were readily detected and identified using the instrument's spectral library. Most importantly, the method was shown to simultaneously methylate a mixture of the organophosphorus-based nerve agent hydrolysis products: pinacolyl methylphosphonate (PMPA), cyclohexyl methylphosphonate (CyMPA) and ethyl methylphosphonate (EMPA) (at a 10 μg mL(-1) concentration each) in a fatty acid ester-rich organic matrix (OPCW-PT-O3) featured in the 38th Organisation for the Prohibition of Chemical Weapons (OPCW) Proficiency Test. In addition, the protocol was found to effectively methylate N,N-diethylamino ethanesulfonic acid and N,N-diisopropylamino ethanesulfonic acid that are products arising from the oxidative degradation of the V-series agents VR and VX respectively. The work described herein represents the first report on the use of TMO·BF4 as a viable, stable and safe agent for the methylation of phosphonic acids and their half esters and within the context of an OPCW Proficiency Test sample analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Zirconium Hydroxide-coated Nanofiber Mats for Nerve Agent Decontamination.

PubMed

Kim, Sohee; Ying, Wu Bin; Jung, Hyunsook; Ryu, Sam Gon; Lee, Bumjae; Lee, Kyung Jin

2017-03-16

Diverse innovative fabrics with specific functionalities have been developed for requirements such as self-decontamination of chemical/biological pollutants and toxic nerve agents. In this work, Zr(OH) 4 -coated nylon-6,6 nanofiber mats were fabricated for the decontamination of nerve agents. Nylon-6,6 fabric was prepared via the electrospinning process, followed by coating with Zr(OH) 4 , which was obtained by the hydrolysis of Zr(OBu) 4 by a sol-gel reaction on nanofiber surfaces. The reaction conditions were optimized by varying the amounts of Zr(OBu) 4 ,the reaction time, and the temperature of the sol-gel reaction. The composite nanofibers show high decontamination efficiency against diisopropylfluorophosphate, which is a nerve agent analogue, due to its high nucleophilicity that aids in the catalysis of the hydrolysis of the phosphonate ester bonds. Composite nanofiber mats have a large potential and can be applied in specific fields such as military and medical markets. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection.

PubMed

Di Bisceglie, Adrian M; Sulkowski, Mark; Gane, Ed; Jacobson, Ira M; Nelson, David; DeSouza, Cynthia; Alves, Katia; George, Shelley; Kieffer, Tara; Zhang, Eileen Z; Kauffman, Robert; Asmal, Mohammed; Koziel, Margaret J

2014-07-01

To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. VX-222 (100 or 400 mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400 mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400 mg twice daily, respectively). These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle.

PubMed

Jih, Kang-Yang; Hwang, Tzyh-Chang

2013-03-12

Vx-770 (Ivacaftor), a Food and Drug Administration (FDA)-approved drug for clinical application to patients with cystic fibrosis (CF), shifts the paradigm from conventional symptomatic treatments to therapeutics directly tackling the root of the disease: functional defects of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel caused by pathogenic mutations. The underlying mechanism for the action of Vx-770 remains elusive partly because this compound not only increases the activity of wild-type (WT) channels whose gating is primarily controlled by ATP binding/hydrolysis, but also improves the function of G551D-CFTR, a disease-associated mutation that abolishes CFTR's responsiveness to ATP. Here we provide a unified theory to account for this dual effect of Vx-770. We found that Vx-770 enhances spontaneous, ATP-independent activity of WT-CFTR to a similar magnitude as its effects on G551D channels, a result essentially explaining Vx-770's effect on G551D-CFTR. Furthermore, Vx-770 increases the open time of WT-CFTR in an [ATP]-dependent manner. This distinct kinetic effect is accountable with a newly proposed CFTR gating model depicting an [ATP]-dependent "reentry" mechanism that allows CFTR shuffling among different open states by undergoing multiple rounds of ATP hydrolysis. We further examined the effect of Vx-770 on R352C-CFTR, a unique mutant that allows direct observation of hydrolysis-triggered gating events. Our data corroborate that Vx-770 increases the open time of WT-CFTR by stabilizing a posthydrolytic open state and thereby fosters decoupling between the gating cycle and ATP hydrolysis cycle. The current study also suggests that this unique mechanism of drug action can be further exploited to develop strategies that enhance the function of CFTR.

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle

PubMed Central

Jih, Kang-Yang; Hwang, Tzyh-Chang

2013-01-01

Vx-770 (Ivacaftor), a Food and Drug Administration (FDA)-approved drug for clinical application to patients with cystic fibrosis (CF), shifts the paradigm from conventional symptomatic treatments to therapeutics directly tackling the root of the disease: functional defects of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel caused by pathogenic mutations. The underlying mechanism for the action of Vx-770 remains elusive partly because this compound not only increases the activity of wild-type (WT) channels whose gating is primarily controlled by ATP binding/hydrolysis, but also improves the function of G551D-CFTR, a disease-associated mutation that abolishes CFTR’s responsiveness to ATP. Here we provide a unified theory to account for this dual effect of Vx-770. We found that Vx-770 enhances spontaneous, ATP-independent activity of WT-CFTR to a similar magnitude as its effects on G551D channels, a result essentially explaining Vx-770’s effect on G551D-CFTR. Furthermore, Vx-770 increases the open time of WT-CFTR in an [ATP]-dependent manner. This distinct kinetic effect is accountable with a newly proposed CFTR gating model depicting an [ATP]-dependent “reentry” mechanism that allows CFTR shuffling among different open states by undergoing multiple rounds of ATP hydrolysis. We further examined the effect of Vx-770 on R352C-CFTR, a unique mutant that allows direct observation of hydrolysis-triggered gating events. Our data corroborate that Vx-770 increases the open time of WT-CFTR by stabilizing a posthydrolytic open state and thereby fosters decoupling between the gating cycle and ATP hydrolysis cycle. The current study also suggests that this unique mechanism of drug action can be further exploited to develop strategies that enhance the function of CFTR. PMID:23440202

The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts.

PubMed

Timme, Cindy R; Rath, Barbara H; O'Neill, John W; Camphausen, Kevin; Tofilon, Philip J

2018-06-01

Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood-brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. Mol Cancer Ther; 17(6); 1207-16. ©2018 AACR . ©2018 American Association for Cancer Research.

Corrector VX-809 promotes interactions between cytoplasmic loop one and the first nucleotide-binding domain of CFTR.

PubMed

Loo, Tip W; Clarke, David M

2017-07-15

A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1). To investigate whether VX-809 promoted CL1/NBD1 interactions, we performed cysteine mutagenesis and disulfide cross-linking analysis of Cys-less TMD1 (residues 1-436) and ΔTMD1 (residues 437-1480; NBD1-R-TMD2-NBD2) truncation mutants. It was found that VX-809, but not bithiazole correctors, promoted maturation (exited endoplasmic reticulum for addition of complex carbohydrate in the Golgi) of the ΔTMD1 truncation mutant only when it was co-expressed in the presence of TMD1. Expression in the presence of VX-809 also promoted cross-linking between R170C (in CL1 of TMD1 protein) and L475C (in NBD1 of the ΔTMD1 truncation protein). Expression of the ΔTMD1 truncation mutant in the presence of TMD1 and VX-809 also increased the half-life of the mature protein in cells. The results suggest that the mechanism by which VX-809 promotes maturation and stability of CFTR is by promoting CL1/NBD1 interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

VX Her: Eclipsing Binary System or Single Variable Star

NASA Astrophysics Data System (ADS)

Perry, Kathleen; Castelaz, Michael; Henson, Gary; Boghozian, Andrew

2015-01-01

VX Her is a pulsating variable star with a period of .4556504 days. It is believed to be part of an eclipsing binary system (Fitch et al. 1966). This hypothesis originated from Fitch seeing VX Her's minimum point on its light curve reaching a 0.7 magnitude fainter than normal and remaining that way for nearly two hours. If VX Her were indeed a binary system, I would expect to see similar results with a fainter minimum and a broader, more horizontal dip. Having reduced and analyzed images from the Southeastern Association for Research in Astronomy Observatory in Chile and Kitt Peak, as well as images from a 0.15m reflector at East Tennessee State University, I found that VX Her has the standard light curve of the prototype variable star, RR Lyrae. Using photometry, I found no differing features in its light curve to suggest that it is indeed a binary system. However, more observations are needed in case VX Her is a wide binary.

Midazolam: An Improved Anticonvulsant Treatment for Nerve Agent-Induced Seizures

DTIC Science & Technology

2002-01-01

variety of compounds that different authors had championed as being capable of stopping or moderating nerve agent seizures (e.g., memantine , clonidine...e.g., memantine , neuroactive steroids; EEG seizures were still evident) or required such a narrow dose range or specific treatment conditions that

Army Science Conference Proceedings, 12-15 June 1990, Volume 2: Principal Authors G-M

DTIC Science & Technology

1990-07-30

The Excitatory Amino Acid Antagonist MK-801 Prevents Nerve Agent -induced Neuropathology Even When Given After the Onset of Convulsions See Johnson...Smejkal, Ruthann M. See Sharp, Edward J. See O’Neill, Timothy R. See Coffee, Terence P. Oxidative Decontamination of the Chemical Nerve Agent See...190, 1955. 5 Hoskin, F. C. G.,and Roush, A. H. "Hydrolysis of Nerve Gas by Squid Type Diisopropylphosphorofluoridate Hydrolyzing Enzyme on Agarose

Physics-Based Modeling of Permeation: Simulation of Low-Volatility Agent Permeation and Aerosol Vapor Liquid Assessment Group Experiments

DTIC Science & Technology

2015-06-01

methylphosphonothiolate (VX) through natural latex rubber and neoprene resulting from LVAP tests. 2. The permeation model is used to study the sensitivity of...Styrene–Butadiene– Rubber , Ethylene–Propylene–Diene Terpolymer, and Natural Rubber Versus Hydrocarbons (C8–C16). Macromolecules 1991, 24 (9), 2598–2605...22 14. Harogoppad, S.B.; Aminabhavi, T.M. Diffusion and Sorption of Organic Liquids through Polymer Membranes 2. Neoprene, SBR, EPDM , NBR, and

Extraction and Analysis of V-Type Agents (VX, RVX, CVX, and VM) from Various Food Matrices by Ultra-Performance Liquid Chromatography-Time-Of-Flight Mass Spectrometry

DTIC Science & Technology

2015-12-01

2% reduced fat milk, Egg Beaters egg whites, tomato sauce, and several meats, including hamburger meat (80% lean and 20% fat), hot dogs, chicken... Egg Whites and Tomato Sauce .....................................................3 2.3.3 Group 3: Hot Dogs, Chicken Nuggets, Turkey Deli Meat...Apple juice, orange juice, whole milk, 2% reduced fat milk, Egg Beaters processed egg whites, tomato sauce, precooked turkey deli meat (99% fat free

Methodology Investigation of Rapid Evaluation of Environmental Hazards: The Fate of VX and GB in the Dugway Proving Ground Environment

DTIC Science & Technology

1988-12-01

vegetation, freshly harvested living vegetation, and actively growing vegetation. Except for bean plants , the plant species used are indigenous to the DPG...desired concentration of agent/g of plant material. The flasks were stopped, thoroughly mixed, and stored at room temperature. C. Actively Growing Plants (1...light and 12 hours dark. Seedlings were grown in stainless steel trays containing the nutrient solution and the actively growing mature plants were

[Perspectives in the treatments of poisonings by organophosphorus insecticides and warfare nerve agents].

PubMed

Sogorb-Sánchez, M A; Vilanova-Gisbert, E; Carrera-González, V

Organophosphorus compounds are worldwide employed as insecticides and are yearly responsible of several millions of poisonings. The chemical structure of most of the warfare nerve agents also corresponds with an organophosphorus compound. Organophosphorus insecticides and warfare nerve agents exert their main toxicological effects through inhibition of acetylcholinesterase. Current treatments of patients poisoned with organophosphorus compounds include atropine (in order to protect muscarinic receptors), oximes (in order to accelerate the reactivation of the inhibited acetylcholinesterase) and benzodiazepines (in order to avoid convulsions). The administration of phosphotriesterases (enzymes involved in the detoxication of organophosphorus compounds through hydrolysis) is a very effective treatment against poisonings by organophosphorus insecticides and warfare nerve agents. There are experimental preventive treatments based on the simultaneous administration of carbamates and certain antimuscarinic drugs, different from atropine, which notably improve the efficacy of the classical treatments applied after poisonings by warfare nerve agents. The treatments based in the administration of phosphotriesterases might be the response to the call of the World Health Organization for searching new treatments with capability to reduce the high mortality recorded in the cases of poisonings by organophosphorus compounds. These treatments can be applied in a preventive way without the intrinsic neurotoxicity associated to the preventive treatments based on carbamates and antimuscarinic drugs. Therefore, these treatments are specially interesting for people susceptible to suffer severe exposures, i.e. sprayers in the farms.

A decontamination system for chemical weapons agents using a liquid solution on a solid sorbent.

PubMed

Waysbort, Daniel; McGarvey, David J; Creasy, William R; Morrissey, Kevin M; Hendrickson, David M; Durst, H Dupont

2009-01-30

A decontamination system for chemical warfare agents was developed and tested that combines a liquid decontamination reagent solution with solid sorbent particles. The components have fewer safety and environmental concerns than traditional chlorine bleach-based products or highly caustic solutions. The liquid solution, based on Decon Greentrade mark, has hydrogen peroxide and a carbonate buffer as active ingredients. The best solid sorbents were found to be a copolymer of ethylene glycol dimethacrylate and n-lauryl methacrylate (Polytrap 6603 Adsorber); or an allyl methacrylate cross-linked polymer (Poly-Pore E200 Adsorber). These solids are human and environmentally friendly and are commonly used in cosmetics. The decontaminant system was tested for reactivity with pinacolyl methylphosphonofluoridate (Soman, GD), bis(2-chloroethyl)sulfide (Mustard, HD), and S-(2-diisopropylaminoethyl) O-ethyl methylphosphonothioate (VX) by using NMR Spectroscopy. Molybdate ion (MoO(4)(-2)) was added to the decontaminant to catalyze the oxidation of HD. The molybdate ion provided a color change from pink to white when the oxidizing capacity of the system was exhausted. The decontaminant was effective for ratios of agent to decontaminant of up to 1:50 for VX (t(1/2) < or = 4 min), 1:10 for HD (t(1/2) < 2 min with molybdate), and 1:10 for GD (t(1/2) < 2 min). The vapor concentrations of GD above the dry sorbent and the sorbent with decontamination solution were measured to show that the sorbent decreased the vapor concentration of GD. The E200 sorbent had the additional advantage of absorbing aqueous decontamination solution without the addition of an organic co-solvent such as isopropanol, but the rate depended strongly on mixing for HD.

Application of cation-exchange solid-phase extraction for the analysis of amino alcohols from water and human plasma for verification of Chemical Weapons Convention.

PubMed

Kanaujia, Pankaj K; Tak, Vijay; Pardasani, Deepak; Gupta, A K; Dubey, D K

2008-03-28

The analysis of nitrogen containing amino alcohols, which are the precursors and degradation products of nitrogen mustards and nerve agent VX, constitutes an important aspect for verifying the compliance to the CWC (Chemical Weapons Convention). This work devotes on the development of solid-phase extraction method using silica- and polymer-based SCX (strong cation-exchange) and MCX (mixed-mode strong cation-exchange) cartridges for N,N-dialkylaminoethane-2-ols and alkyl N,N-diethanolamines, from water. The extracted analytes were analyzed by GC-MS (gas chromatography-mass spectrometry) in the full scan and selected ion monitoring modes. The extraction efficiencies of SCX and MCX cartridges were compared, and results revealed that SCX performed better. Extraction parameters, such as loading capacity, extraction solvent, its volume, and washing solvent were optimized. Best recoveries were obtained using 2 mL methanol containing 10% NH(4)OH and limits of detection could be achieved up to 5 x 10(-3) microg mL(-1) in the selected ion monitoring mode and 0.01 microg mL(-1) in full scan mode. The method was successfully employed for the detection and identification of amino alcohol present in water sample sent by Organization for Prohibition of Chemical Weapons (OPCW) in the official proficiency tests. The method was also applied to extract the analytes from human plasma. The SCX cartridge showed good recoveries of amino alcohols from human plasma after protein precipitation.

Department of Defense Chemical, Biological, Radiological, and Nuclear Defense Program, Annual Report to Congress, 2004

DTIC Science & Technology

2004-05-01

foldable/ portable emergency smoke hoods with extended gas sorption capabilities and regenerable, biological pathogen-destroying and gas-sorbing...traditional agents. • Cyanide Countermeasures – Potential pretreatment compounds (e.g., methemoglobin formers and sulfide donors) and regimen are being...evaluated for safety and efficacy as pretreatments. • Nerve agent antidotes – New nerve agent antidote compounds that are water soluble, have a broader

Identification and Characterization of Novel Catalytic Bioscavengers of Organophosphorus Nerve Agents

DTIC Science & Technology

2013-01-01

hydrolase activity . These strains are Ammoniphilus oxalaticus, Haloarcula sp., and Micromonospora aurantiaca. Lysates from A. oxalaticus had...warfare agents [1–3]. OP nerve agents readily bind covalently to the active site serine in acetylcho- linesterase (AChE), thereby inhibiting the ability...muscarinic receptors, whereas 2-pralidoxime chloride, an oxime nucleophile, reactivates AChE by displacing the phospho- nyl group left on the active site

Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs.

PubMed

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

2010-11-01

Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

Toxicology of organophosphorus compounds in view of an increasing terrorist threat.

PubMed

Worek, Franz; Wille, Timo; Koller, Marianne; Thiermann, Horst

2016-09-01

The implementation of the Chemical Weapon Convention (CWC), prohibiting the development, production, storage and use of chemical weapons by 192 nations and the ban of highly toxic OP pesticides, especially class I pesticides according to the WHO classification, by many countries constitutes a great success of the international community. However, the increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents new challenges to our societies. Almost seven decades of research on organophosphorus compound (OP) toxicology was mainly focused on a small number of OP nerve agents despite the fact that a huge number of OP analogues, many of these agents having comparable toxicity to classical nerve agents, were synthesized and published. Only limited physicochemical, toxicological and medical information on nerve agent analogues is available in the open literature. This implies potential gaps of our capabilities to detect, to decontaminate and to treat patients if nerve agent analogues are disseminated and may result in inadequate effectiveness of newly developed countermeasures. In summary, our societies may face new, up to now disregarded, threats by toxic OP which calls for increased awareness and appropriate preparedness of military and civilian CBRN defense, a broader approach for new physical and medical countermeasures and an integrated system of effective detection, decontamination, physical protection and treatment.

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

EPA Science Inventory

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

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

EPA Science Inventory

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

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

EPA Science Inventory

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

Using Nanotechnology to Detect Nerve Agents

DTIC Science & Technology

2011-01-01

56 | Air & Space Power Journal Air Force Institute of Technology Using Nanotechnology to Detect Nerve Agents Lt Col Mark N. Goltz , PhD, USAF...Retired Dr. Dong Shik Kim Maj LeeAnn Racz, PhD, USAF* *Lieutenant Colonel Goltz and Major Racz are faculty members in the Department of Systems and

Dawn of Aurora kinase inhibitors as anticancer drugs.

PubMed

Doggrell, Sheila A

2004-09-01

With the current standard chemotherapy regimens only approximately 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.

Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats.

PubMed

Harris, L W; Stitcher, D L

1983-01-01

Atropinized rats intoxicated with ethyl-S-2-diisopropyl aminoethyl methyl phosphonothioate (VX), 15 mg/kg iv, were divided into three groups and were treated with normal saline, iv, 30 mg/kg of 2-PAM C1, iv, and 30 mg/kg of HS-6, iv. One hr after administration of therapy they were decapitated and cholinesterase (ChE) activity was determined on blood, brain and diaphragm tissue. Both 2-PAM C1 and HS-6 markedly reactivated VX-inhibited blood and diaphragm ChE. Brain ChE activity was not significantly reactivated by either oxime. The effectiveness of these oximes in restoration of VX-inactivated ChE in vivo offers an explanation as to why conventional atropine/oxime therapy is so effective against VX intoxication.

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma.

PubMed

Dewerth, Alexander; Wonner, Timo; Lieber, Justus; Ellerkamp, Verena; Warmann, Steven W; Fuchs, Jörg; Armeanu-Ebinger, Sorin

2012-06-01

Hepatoblastoma (HB) has a poor prognosis in advanced stages. The aim of this study was to enhance effectiveness of chemotherapy with antineoplastic kinase inhibitors. Viability was monitored in HB cells (HUH6, HepT1) in monolayer and spheroid cultures treated with kinase inhibitors VX-680, Wee1-InhibitorII, and SU11274 alone or in combination with cisplatin (CDDP) using MTT assays. Apoptosis was revealed by Caspase-3 assay. Western blot and immunohistochemical analyses were performed to determine histone H3 phosphorylation. Among the kinase inhibitors strongest anti-proliferative effect on HB cells was documented for VX-680. HUH6 cells responded more sensitively to the Aurora kinase inhibitor as HepT1 cells (IC(50) 8 and 16.6 μM, respectively). While VX-680 and CDDP showed no additive effects, the combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. The inhibition with VX-680 led to reduced histone H3 phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei. The data provide evidence that VX-680 might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis.

Dynamic characteristics of MR diffusion-weighted imaging in a rabbit liver VX-2 tumor model.

PubMed

Yuan, You-Hong; Xiao, En-Hua; He, Zhong; Jin, Ke; Ma, Cong; Xiang, Jun; Xiao, Jian-Hua; Chen, Wei-Jian

2013-02-01

To investigate prospectively dynamic characteristics of the apparent diffusion coefficient (ADC) on MR diffusion-weighted imaging (DWI) in a rabbit VX-2 tumor model. Forty New Zealand rabbits were included in the study, and 47 rabbit VX-2 tumor models were developed by direct and intrahepatic implantation after opening the abdominal cavities. DWI was carried out periodically and respectively on days 7, 14 and 21 after implantation. The VX-2 tumor samples were studied by pathology. The distinction of VX-2 tumors on DWI was assessed by their ADC values by analysis of variance (ANOVA) using SPSS12.0 software. The ADC values (mean ± SD) × 10(-3) mm(2)/s of 47 VX-2 tumors in the peripheral and central areas were 2.18 ± 0.29, 1.96 ± 0.33, 1.80 ± 0.35, 2.20 ± 0.29, 2.05 ± 0.30 and 1.96 ± 0.48, respectively, on days 7, 14 and 21 after implantation. ADC values of 47 VX-2 tumors in the area of the tumor periphery, center and normal parenchyma were higher when the b-value was 100 s/mm(2) than those when the b-value was 300 s/mm(2) (F = 17.964, p < 0.001; F = 13.986, p < 0.001; F = 128.681, p < 0.001). ADC values in the area of normal liver parenchyma were higher than those in the area of the VX-2 tumor periphery and center when the b-value was 100 or 300 s/mm(2). ADCs of viable tumor cells in VX-2 tumors were lower on DWI than those in the area of normal liver parenchyma around the tumor, and ADCs of dead tumor cells in VX-2 tumors were unequal, including high, equal and low values, but they were higher than in the area of normal liver parenchyma around tumors after dead tumor cells had been liquefied or had become cystic. ADC is correlated with the tumor histology and degree of malignancy, and DWI has potential value for dynamically monitoring tumors and evaluating the degree of malignancy and therapeutic effect.

Gas-phase synthesis of singly and multiply charged polyoxovanadate anions employing electrospray ionization and collision induced dissociation.

PubMed

Al Hasan, Naila M; Johnson, Grant E; Laskin, Julia

2013-09-01

Electrospray ionization mass spectrometry (ESI-MS) combined with in-source fragmentation and tandem mass spectrometry (MS/MS) experiments were used to generate a wide range of singly and multiply charged vanadium oxide cluster anions including VxOy(n-) and VxOyCl(n-) ions (x = 1-14, y = 2-36, n = 1-3), protonated clusters, and ligand-bound polyoxovanadate anions. The cluster anions were produced by electrospraying a solution of tetradecavanadate, V14O36Cl(L)5 (L = Et4N(+), tetraethylammonium), in acetonitrile. Under mild source conditions, ESI-MS generates a distribution of doubly and triply charged VxOyCl(n-) and VxOyCl(L)((n-1)-) clusters predominantly containing 14 vanadium atoms as well as their protonated analogs. Accurate mass measurement using a high-resolution LTQ/Orbitrap mass spectrometer (m/Δm = 60,000 at m/z 410) enabled unambiguous assignment of the elemental composition of the majority of peaks in the ESI-MS spectrum. In addition, high-sensitivity mass spectrometry allowed the charge state of the cluster ions to be assigned based on the separation of the major from the much less abundant minor isotope of vanadium. In-source fragmentation resulted in facile formation of smaller VxOyCl((1-2)-) and VxOy ((1-2)-) anions. Collision-induced dissociation (CID) experiments enabled systematic study of the gas-phase fragmentation pathways of the cluster anions originating from solution and from in-source CID. Surprisingly simple fragmentation patterns were obtained for all singly and doubly charged VxOyCl and VxOy species generated through multiple MS/MS experiments. In contrast, cluster anions originating directly from solution produced comparatively complex CID spectra. These results are consistent with the formation of more stable structures of VxOyCl and VxOy anions through low-energy CID. Furthermore, our results demonstrate that solution-phase synthesis of one precursor cluster anion combined with gas-phase CID is an efficient approach for the top-down synthesis of a wide range of singly and multiply charged gas-phase metal oxide cluster anions for subsequent investigations of structure and reactivity using mass spectrometry and ion spectroscopy techniques.

Gas-Phase Synthesis of Singly and Multiply Charged Polyoxovanadate Anions Employing Electrospray Ionization and Collision Induced Dissociation

NASA Astrophysics Data System (ADS)

Al Hasan, Naila M.; Johnson, Grant E.; Laskin, Julia

2013-09-01

Electrospray ionization mass spectrometry (ESI-MS) combined with in-source fragmentation and tandem mass spectrometry (MS/MS) experiments were used to generate a wide range of singly and multiply charged vanadium oxide cluster anions including VxOy n- and VxOyCln- ions (x = 1-14, y = 2-36, n = 1-3), protonated clusters, and ligand-bound polyoxovanadate anions. The cluster anions were produced by electrospraying a solution of tetradecavanadate, V14O36Cl(L)5 (L = Et4N+, tetraethylammonium), in acetonitrile. Under mild source conditions, ESI-MS generates a distribution of doubly and triply charged VxOyCln- and VxOyCl(L)(n-1)- clusters predominantly containing 14 vanadium atoms as well as their protonated analogs. Accurate mass measurement using a high-resolution LTQ/Orbitrap mass spectrometer (m/Δm = 60,000 at m/z 410) enabled unambiguous assignment of the elemental composition of the majority of peaks in the ESI-MS spectrum. In addition, high-sensitivity mass spectrometry allowed the charge state of the cluster ions to be assigned based on the separation of the major from the much less abundant minor isotope of vanadium. In-source fragmentation resulted in facile formation of smaller VxOyCl(1-2)- and VxOy (1-2)- anions. Collision-induced dissociation (CID) experiments enabled systematic study of the gas-phase fragmentation pathways of the cluster anions originating from solution and from in-source CID. Surprisingly simple fragmentation patterns were obtained for all singly and doubly charged VxOyCl and VxOy species generated through multiple MS/MS experiments. In contrast, cluster anions originating directly from solution produced comparatively complex CID spectra. These results are consistent with the formation of more stable structures of VxOyCl and VxOy anions through low-energy CID. Furthermore, our results demonstrate that solution-phase synthesis of one precursor cluster anion combined with gas-phase CID is an efficient approach for the top-down synthesis of a wide range of singly and multiply charged gas-phase metal oxide cluster anions for subsequent investigations of structure and reactivity using mass spectrometry and ion spectroscopy techniques.

Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides

DTIC Science & Technology

2014-08-01

chemical warfare nerve agents (CWNA). Enzymes identified in these screens should be capable of catalytically neutralizing the target agent under...soluble form. 4. Large-scale production of selected enzyme candidates, and their kinetic, structural and pharmacological evaluation 6...employed, with an enzyme protein concentration of 0.5-2 mM in the assay cuvette, the activity measured was indistinguishable from the rate of

Passive Standoff Detection of Chemical Warfare Agents on Surfaces

NASA Astrophysics Data System (ADS)

Thériault, Jean-Marc; Puckrin, Eldon; Hancock, Jim; Lecavalier, Pierre; Lepage, Carmela Jackson; Jensen, James O.

2004-11-01

Results are presented on the passive standoff detection and identification of chemical warfare (CW) liquid agents on surfaces by the Fourier-transform IR radiometry. This study was performed during surface contamination trials at Defence Research and Development Canada-Suffield in September 2002. The goal was to verify that passive long-wave IR spectrometric sensors can potentially remotely detect surfaces contaminated with CW agents. The passive sensor, the Compact Atmospheric Sounding Interferometer, was used in the trial to obtain laboratory and field measurements of CW liquid agents, HD and VX. The agents were applied to high-reflectivity surfaces of aluminum, low-reflectivity surfaces of Mylar, and several other materials including an armored personnel carrier. The field measurements were obtained at a standoff distance of 60 m from the target surfaces. Results indicate that liquid contaminant agents deposited on high-reflectivity surfaces can be detected, identified, and possibly quantified with passive sensors. For low-reflectivity surfaces the presence of the contaminants can usually be detected; however, their identification based on simple correlations with the absorption spectrum of the pure contaminant is not possible.

A comparison of the reactivating and therapeutic efficacy of chosen combinations of oximes with individual oximes against VX in rats and mice.

PubMed

Kassa, Jiri; Karasova, Jana Zdarova; Sepsova, Vendula; Caisberger, Filip; Bajgar, Jiri

2011-10-01

The ability of 2 combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate VX-inhibited acetylcholinesterase and reduce acute toxicity of VX was compared with the reactivating and therapeutic efficacy of antidotal treatment involving a single oxime (HI-6, trimedoxime, K203) in rats and mice. Our results showed that the reactivating efficacy of both combinations of oximes studied in rats is significantly higher than the reactivating efficacy of all individual oximes in diaphragm and roughly corresponds to the most effective individual oxime in blood and brain. Both combinations of oximes were found to be more effective in the reduction of acute lethal toxicity of VX in mice than the antidotal treatment involving the most efficacious individual oxime although the difference is not significant. Based on the obtained data, we can conclude that the antidotal treatment involving the chosen combinations of oximes brings benefit for the reactivation of VX-inhibited acetylcholinesterase in rats and for the antidotal treatment of VX-induced acute poisoning in mice.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi

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{submore » 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.« less

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

PubMed

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

2009-08-15

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

Reversed enantioselectivity of diisopropyl fluorophosphatase against organophosphorus nerve agents by rational design.

PubMed

Melzer, Marco; Chen, Julian C-H; Heidenreich, Anne; Gäb, Jürgen; Koller, Marianne; Kehe, Kai; Blum, Marc-Michael

2009-12-02

Diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris is an efficient and robust biocatalyst for the hydrolysis of a range of highly toxic organophosphorus compounds including the nerve agents sarin, soman, and cyclosarin. In contrast to the substrate diisopropyl fluorophosphate (DFP) the nerve agents possess an asymmetric phosphorus atom, which leads to pairs of enantiomers that display markedly different toxicities. Wild-type DFPase prefers the less toxic stereoisomers of the substrates which leads to slower detoxification despite rapid hydrolysis. Enzyme engineering efforts based on rational design yielded two quadruple enzyme mutants with reversed enantioselectivity and overall enhanced activity against tested nerve agents. The reversed stereochemical preference is explained through modeling studies and the crystal structures of the two mutants. Using the engineered mutants in combination with wild-type DFPase leads to significantly enhanced activity and detoxification, which is especially important for personal decontamination. Our findings may also be of relevance for the structurally related enzyme human paraoxonase (PON), which is of considerable interest as a potential catalytic in vivo scavenger in case of organophosphorus poisoning.

VxWorks 6.9 for LEON

NASA Astrophysics Data System (ADS)

Cederman, Daniel; Hellstrom, Daniel

2016-08-01

The VxWorks operating system together with the Cobham Grislier LEON architectural port provides an efficient platform for the development of software for space applications. It supports both uni-and multiprocessor mode (SMP or AMP) and comes with an integrated development environment with several debugging and analysis tools. The LEON architectural port from Cobham Grislier supports LEON2/3/4 systems and includes drivers for all standard on-chip peripherals, as well as support for RASTA boards. In this paper we will highlight some the many features of VxWorks and the LEON architectural port. The latest version of the architectural port now supports VxWorks 6.9 (the previous version was for VxWorks 6.7) and has the support for the GR740, the commercially available quad-core LEON system, designed as the European Space Agency's Next Generation Microprocessor (NGMP).

The application of single particle aerosol mass spectrometry for the detection and identification of high explosives and chemical warfare agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Audrey Noreen

2006-01-01

Single Particle Aerosol Mass Spectrometry (SPAMS) was evaluated as a real-time detection technique for single particles of high explosives. Dual-polarity time-of-flight mass spectra were obtained for samples of 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitro-1,3,5-triazinane (RDX), and pentaerythritol tetranitrate (PETN); peaks indicative of each compound were identified. Composite explosives, Comp B, Semtex 1A, and Semtex 1H were also analyzed, and peaks due to the explosive components of each sample were present in each spectrum. Mass spectral variability with laser fluence is discussed. The ability of the SPAMS system to identify explosive components in a single complex explosive particle (~1 pg) without the need formore » consumables is demonstrated. SPAMS was also applied to the detection of Chemical Warfare Agent (CWA) simulants in the liquid and vapor phases. Liquid simulants for sarin, cyclosarin, tabun, and VX were analyzed; peaks indicative of each simulant were identified. Vapor phase CWA simulants were adsorbed onto alumina, silica, Zeolite, activated carbon, and metal powders which were directly analyzed using SPAMS. The use of metal powders as adsorbent materials was especially useful in the analysis of triethyl phosphate (TEP), a VX stimulant, which was undetectable using SPAMS in the liquid phase. The capability of SPAMS to detect high explosives and CWA simulants using one set of operational conditions is established.« less

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

PubMed

Clancy, J P; Rowe, Steven M; Accurso, Frank J; Aitken, Moira L; Amin, Raouf S; Ashlock, Melissa A; Ballmann, Manfred; Boyle, Michael P; Bronsveld, Inez; Campbell, Preston W; De Boeck, Kris; Donaldson, Scott H; Dorkin, Henry L; Dunitz, Jordan M; Durie, Peter R; Jain, Manu; Leonard, Anissa; McCoy, Karen S; Moss, Richard B; Pilewski, Joseph M; Rosenbluth, Daniel B; Rubenstein, Ronald C; Schechter, Michael S; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W

2012-01-01

VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. NCT00865904.

A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator

PubMed Central

Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham; Fu, Lianwu; Matalon, Sadis; Bebok, Zsuzsanna

2016-01-01

Synonymous mutations, such as I507-ATC→ATT, in deletion of Phe508 in cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR), the most frequent disease-associated mutant of CFTR, may affect protein biogenesis, structure, and function and contribute to an altered disease phenotype. Small-molecule drugs are being developed to correct ΔF508 CFTR. To understand correction mechanisms and the consequences of synonymous mutations, we analyzed the effect of mechanistically distinct correctors, corrector 4a (C4) and lumacaftor (VX-809), on I507-ATT and I507-ATC ΔF508 CFTR biogenesis and function. C4 stabilized I507-ATT ΔF508 CFTR band B, but without considerable biochemical and functional correction. VX-809 biochemically corrected ∼10% of both of the variants, leading to stable, forskolin+3-isobutyl-1-methylxanthine (IBMX)-activated whole-cell currents in the presence of the corrector. Omitting VX-809 during whole-cell recordings led to a spontaneous decline of the currents, suggesting posttranslational stabilization by VX-809. Treatment of cells with the C4+VX-809 combination resulted in enhanced rescue and 2-fold higher forskolin+IBMX–activated currents of both I507-ATT and I507-ATC ΔF508 CFTR, compared with VX-809 treatment alone. The lack of an effect of C4 on I507-ATC ΔF508 CFTR, but its additive effect in combination with VX-809, implies that C4 acted on VX-809–modified I507-ATC ΔF508 CFTR. Our results suggest that binding of C4 and VX-809 to ΔF508 CFTR is conformation specific and provide evidence that synonymous mutations can alter the drug sensitivity of proteins.—Bali, V., Lazrak, A., Guroji, P., Fu, L., Matalon, S., Bebok, Z. A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator. PMID:26336913

Evolution of and perspectives on therapeutic approaches to nerve agent poisoning.

PubMed

Masson, Patrick

2011-09-25

After more than 70 years of considerable efforts, research on medical defense against nerve agents has come to a standstill. Major progress in medical countermeasures was achieved between the 50s and 70s with the development of anticholinergic drugs and carbamate-based pretreatment, the introduction of pyridinium oximes as antidotes, and benzodiazepines in emergency treatments. These drugs ensure good protection of the peripheral nervous system and mitigate the acute effects of exposure to lethal doses of nerve agents. However, pyridostigmine and cholinesterase reactivators currently used in the armed forces do not protect/reactivate central acetylcholinesterases. Moreover, other drugs used are not sufficiently effective in protecting the central nervous system against seizures, irreversible brain damages and long-term sequelae of nerve agent poisoning.New developments of medical counter-measures focus on: (a) detoxification of organophosphorus molecules before they react with acetylcholinesterase and other physiological targets by administration of stoichiometric or catalytic scavengers; (b) protection and reactivation of central acetylcholinesterases, and (c) improvement of neuroprotection following delayed therapy.Future developments will aim at treatment of acute and long-term effects of low level exposure to nerve agents, research on alternative routes for optimizing drug delivery, and therapies. Though gene therapy for in situ generation of bioscavengers, and cell therapy based on neural progenitor engraftment for neuronal regeneration have been successfully explored, more studies are needed before practical medical applications can be made of these new approaches. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Exhaust Plume Measurements of the VASIMR VX-200

NASA Astrophysics Data System (ADS)

Longmier, Benjamin; Bering, Edgar, III; Squire, Jared; Glover, Tim; Chang-Diaz, Franklin; Brukardt, Michael

2008-11-01

Recent progress is discussed in the development of an advanced RF electric propulsion concept: the Variable Specific Impulse Magnetoplasma Rocket (VASIMR) VX-200 engine, a 200 kW flight-technology prototype. Results from high power Helicon only and Helicon with ICRH experiments are performed on the VX-200 using argon plasma. Recent measurements of axial plasma density and potential profiles, magnetic field-line shaping, charge exchange, and force measurements taken in the plume of the VX-200 exhaust are made within a new 125 cubic meter cryo-pumped vacuum chamber and are presented in the context of RF plasma thruster physics.

GenomeVx: simple web-based creation of editable circular chromosome maps.

PubMed

Conant, Gavin C; Wolfe, Kenneth H

2008-03-15

We describe GenomeVx, a web-based tool for making editable, publication-quality, maps of mitochondrial and chloroplast genomes and of large plasmids. These maps show the location of genes and chromosomal features as well as a position scale. The program takes as input either raw feature positions or GenBank records. In the latter case, features are automatically extracted and colored, an example of which is given. Output is in the Adobe Portable Document Format (PDF) and can be edited by programs such as Adobe Illustrator. GenomeVx is available at http://wolfe.gen.tcd.ie/GenomeVx

Combined treatment with ABT-737 and VX-680 induces apoptosis in Bcl-2- and c-FLIP-overexpressing breast carcinoma cells.

PubMed

Choi, Jung Eun; Woo, Seon Min; Min, Kyoung-Jin; Kang, Su Hwan; Lee, Soo Jung; Kwon, Taeg Kyu

2015-03-01

ABT-737, a BH3-mimetic small-molecule inhibitor, binds with very high affinity to Bcl-2, Bcl-xL and Bcl-w, and inhibits their activity. Aurora kinase is one of the serine/threonine kinase family members and is a vital and critical regulator of mitosis and meiosis. In the present study, we investigated the effects and mechanisms of a combined treatment of ABT-737 and VX-680 (Aurora kinase inhibitor) in human breast cancer MDA-MB‑435S cells. ABT-737 plus VX-680 induced caspase-dependent apoptosis in the human breast cancer cells. Combined treatment with ABT-737 and VX-680 led to the downregulation of Bcl-2 expression at the transcriptional level and the downregulation of c-FLIP and Mcl-1 expression at the post-transcriptional level. Overexpression of Bcl-2 or c-FLIP could not block the induction of apoptosis caused by the combined treatment with ABT-737 and VX-680. However, overexpression of Mcl-1 partially inhibited the induction of apoptosis. In contrast, the combined treatment with ABT-737 and VX680 had no effect on the apoptosis in normal cells. Taken together, our study demonstrated that combined treatment with ABT-737 and VX-680 induced apoptosis in anti‑apoptotic protein (Bcl-2 or c-FLIP)-overexpressing cells.

Development of a gas-cylinder-free plasma desorption/ionization system for on-site detection of chemical warfare agents.

PubMed

Iwai, Takahiro; Kakegawa, Ken; Aida, Mari; Nagashima, Hisayuki; Nagoya, Tomoki; Kanamori-Kataoka, Mieko; Miyahara, Hidekazu; Seto, Yasuo; Okino, Akitoshi

2015-06-02

A gas-cylinder-free plasma desorption/ionization system was developed to realize a mobile on-site analytical device for detection of chemical warfare agents (CWAs). In this system, the plasma source was directly connected to the inlet of a mass spectrometer. The plasma can be generated with ambient air, which is drawn into the discharge region by negative pressure in the mass spectrometer. High-power density pulsed plasma of 100 kW could be generated by using a microhollow cathode and a laboratory-built high-intensity pulsed power supply (pulse width: 10-20 μs; repetition frequency: 50 Hz). CWAs were desorbed and protonated in the enclosed space adjacent to the plasma source. Protonated sample molecules were introduced to the mass spectrometer by airflow through the discharge region. To evaluate the analytical performance of this device, helium and air plasma were directly irradiated to CWAs in the gas-cylinder-free plasma desorption/ionization system and the protonated molecules were analyzed by using an ion-trap mass spectrometer. A blister agent (nitrogen mustard 3) and nerve gases [cyclohexylsarin (GF), tabun (GA), and O-ethyl S-2-N,N-diisopropylaminoethyl methylphosphonothiolate (VX)] in solution in n-hexane were applied to the Teflon rod and used as test samples, after solvent evaporation. As a result, protonated molecules of CWAs were successfully observed as the characteristic ion peaks at m/z 204, 181, 163, and 268, respectively. In air plasma, the limits of detection were estimated to be 22, 20, 4.8, and 1.0 pmol, respectively, which were lower than those obtained with helium plasma. To achieve quantitative analysis, calibration curves were made by using CWA stimulant dipinacolyl methylphosphonate as an internal standard; straight correlation lines (R(2) = 0.9998) of the peak intensity ratios (target per internal standard) were obtained. Remarkably, GA and GF gave protonated dimer ions, and the ratios of the protonated dimer ions to the protonated monomers increased with the amount of GA and GF applied.

Galantamine is a novel post-exposure therapeutic against lethal VX challenge.

PubMed

Hilmas, Corey J; Poole, Melissa J; Finneran, Kathryn; Clark, Matthew G; Williams, Patrick T

2009-10-15

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 microg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).

Potentiator Ivacaftor Abrogates Pharmacological Correction of ΔF508 CFTR in Cystic Fibrosis

PubMed Central

Cholon, Deborah M.; Quinney, Nancy L.; Fulcher, M. Leslie; Esther, Charles R.; Das, Jhuma; Dokholyan, Nikolay V.; Randell, Scott H.; Boucher, Richard C.; Gentzsch, Martina

2014-01-01

Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed “correctors” such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and “potentiators” such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ΔF508. Thus, patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ΔF508 homozygous cultures. This result reflected the destabilization of corrected ΔF508 CFTR by VX-770, dramatically increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining of these drugs to maximize rescue of ΔF508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability. PMID:25101886

Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings.

PubMed

Genovese, Mark C; Yang, Fang; Østergaard, Mikkel; Kinnman, Nils

2016-11-01

To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA). This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system. ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p<0.01) and for RAMRIS osteitis scores (p<0.01) for VX-509 300 mg. Treatment was generally well tolerated. VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated. NCT01754935; results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.

PubMed

Matsushita, Takashi; Date, Mutsumi; Kano, Miyu; Mizumaki, Kie; Tennichi, Momoko; Kobayashi, Tadahiro; Hamaguchi, Yasuhito; Hasegawa, Minoru; Fujimoto, Manabu; Takehara, Kazuhiko

2017-04-01

Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702-treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4 + T cells, CD8 + T cells, and CD11b + cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblasts in vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Galantamine is a novel post-exposure therapeutic against lethal VX challenge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hilmas, Corey J.; Poole, Melissa J.; Finneran, Kathryn

2009-10-15

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 {mu}g/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicitedmore » muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI)« less

Delayed and Aberrant Presentation of VX2 Carcinoma in a Rabbit Model of Hepatic Neoplasia

PubMed Central

Hansen, Sarah A; Fink, Michael K; Upendran, Anandhi; Besch-Williford, Cynthia L; Livingston, Robert S; Amos-Landgraf, James M; Lattimer, Jimmy C; Kannan, Raghuraman

2015-01-01

A socially-housed New Zealand white rabbit presented with a large subcutaneous mass on the ventral thorax approximately 11 mo after the intrahepatic delivery of a suspension of VX2 carcinoma cells to induce hepatocellular carcinoma as part of a nanoparticle study. The mass and closely associated axillary lymph node were removed en bloc. Immunohistochemical staining identified the mass as an undifferentiated carcinoma. The rabbit demonstrated no appreciable pathology at the study end point at 16 mo after VX2 inoculation. An additional rabbit from the same VX2 injection cohort was found at necropsy to have an unanticipated intraabdominal mass, also identified as an undifferentiated carcinoma. This case report summarizes the molecular analysis of both tumors through a novel PCR assay, which identified the delayed and aberrant onset of VX2 carcinoma in an extended timeframe not previously reported. PMID:26473347

Large-Format Dual-Counter Pixelated X-Ray Detector Platform: Phase II Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Adam; Williams, George; Huntington, Andrew

2016-10-10

Within the program, a Voxtel led team demonstrated both prototype (48 x 48, 130-μm pitch, VX-798) and full-format (192 x 192, 100-μm pitch, VX-810) versions of a high-dynamic-range, x-ray photon-counting (HDR-XPC) sensor. Within the program the following tasks were completed: 1) integration and evaluation of the VX-798 prototype camera at the Advanced Photon Source beamline at Argonne National Labs; 2) the design, simulation, and fabrication of the full-format VX-810 ROIC was completed; 3) fabrication of thick, fully depleted silicon photodiodes optimized for x-ray photon collection; 4) hybridization of the VX-810 ROIC to the photodiode array in the creation of themore » optically sensitive FPA (FPA), and 4) development of an evaluation camera to enable electrical and optical characterization of the sensor.« less

Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

DTIC Science & Technology

2015-03-01

Analysis of seizure activity and dendritic spine density following exposure to sarin during puberty Methods Female rats were surgically implanted...effects were observed in rats exposed to GB on PND 7 or 21. This study shows that nerve agent exposure during puberty results in severe and life

Using NMR Spectroscopy to Investigate the Solution Behavior of Nerve Agents and Their Binding to Acetylcholinesterase

DTIC Science & Technology

2016-01-01

USING NMR SPECTROSCOPY TO INVESTIGATE THE SOLUTION BEHAVIOR OF NERVE AGENTS AND THEIR BINDING TO...XX-01-2016 2. REPORT TYPE Final 3. DATES COVERED (From - To) Jan – Jun 2015 4. TITLE AND SUBTITLE Using NMR Spectroscopy to Investigate the...MOLECULAR MOTIONS AND NMR SPECTROSCOPY ...................................................................................................3 4. THE

Chemical warfare and the Gulf War: a review of the impact on Gulf veterans' health.

PubMed

Riddle, James R; Brown, Mark; Smith, Tyler; Ritchie, Elspeth Cameron; Brix, Kelley Ann; Romano, James

2003-08-01

It is unlikely that Gulf War veterans are suffering chronic effects from illnesses caused by chemical warfare nerve agent exposure. Extensive investigation and review by several expert panels have determined that no evidence exists that chemical warfare nerve agents were used during the Gulf War. At no time before, during, or after the war was there confirmation of symptoms among anyone, military or civilian, caused by chemical warfare nerve agent exposure. However, studies of Gulf War veterans have found belief that chemical weapons were used, significantly associated with both severe and mild-moderate illnesses. The psychological impact of a chemical warfare attack, either actual or perceived, can result in immediate and long-term health consequences. The deployment or war-related health impact from life-threatening experiences of the Gulf War, including the perceived exposure to chemical warfare agents, should be considered as an important cause of morbidity among Gulf War veterans.

High Power Electric Propulsion Using The VASIMR VX-200: A Flight Technology Prototype

NASA Astrophysics Data System (ADS)

Bering, Edgar, III; Longmier, Benjamin; Glover, Tim; Chang-Diaz, Franklin; Squire, Jared; Brukardt, Michael

2008-11-01

The Variable Specific Impulse Magnetoplasma Rocket (VASIMR) is a high power magnetoplasma rocket, capable of Isp/thrust modulation at constant power. The plasma is produced by a helicon discharge. The bulk of the energy is added by ion cyclotron resonance heating (ICRH.) Axial momentum is obtained by adiabatic expansion of the plasma in a magnetic nozzle. Thrust/specific impulse ratio control in the VASIMR is primarily achieved by the partitioning of the RF power to the helicon and ICRH systems, with the proper adjustment of the propellant flow. Ion dynamics in the exhaust were studied using probes, gridded energy analyzers (RPA's), microwave interferometry and optical techniques. Results are summarize from high power ICRH experiments performed on the VX-100 using argon plasma during 2007, and on the VX-200 using argon plasma during 2008. The VX-100 has demonstrated ICRH antenna efficiency >90% and a total coupling efficiency of ˜75%. The rocket performance parameters inferred by integrating the moments of the ion energy distribution corresponds to a thrust of 2 N at an exhaust velocity of 20 km/s with the VX-100 device. The new VX-200 machine is described.

Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer.

PubMed

Leszczynska, Katarzyna B; Dobrynin, Greg; Leslie, Rhea E; Ient, Jonathan; Boumelha, Adam J; Senra, Joana M; Hawkins, Maria A; Maughan, Tim; Mukherjee, Somnath; Hammond, Ester M

2016-11-01

Esophageal cancer has a persistently low 5-year survival rate and has recently been classified as a cancer of unmet need by Cancer Research UK. Consequently, new approaches to therapy are urgently required. Here, we tested the hypothesis that an ATR inhibitor, VX-970, used in combination with standard therapies for esophageal cancer could improve treatment outcome. Using esophageal cancer cell lines we evaluated the efficacy of combining VX-970 with cisplatin and carboplatin in vitro and with radiation in vitro and in vivo. Radiation experiments were also carried out in hypoxic conditions to mimic the tumor microenvironment. Combining VX-970 with cisplatin, carboplatin and radiation increased tumor cell kill in vitro. A significant tumor growth delay was observed when VX-970 was combined with radiotherapy in vivo. VX-970 is an effective chemo/radiosensitizer which could be readily integrated in the current treatment paradigm to improve the treatment response in esophageal cancer and we plan to test it prospectively in the forthcoming phase I dose escalation safety study combining the ATR inhibitor VX-970 with chemoradiotherapy in esophageal cancer (EudraCT number: 2015-003965-27). Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Genotypic and Phenotypic Analyses of Hepatitis C Virus Variants Observed in Clinical Studies of VX-222, a Nonnucleoside NS5B Polymerase Inhibitor

PubMed Central

Zhang, Eileen Z.; Ardzinski, Andrzej; Tigges, Ann; Davis, Andrew; Sullivan, James C.; Nelson, Michelle; Spanks, Joan; Dorrian, Jennifer; Nicolas, Olivier; Bartels, Doug J.; Rao, B. Govinda; Rijnbrand, Rene; Kieffer, Tara L.

2014-01-01

VX-222, a thiophene-2-carboxylic acid derivative, is a selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV. To characterize the potential for selection of VX-222-resistant variants in HCV-infected patients, the HCV NS5B gene was sequenced at baseline and during and after 3 days of VX-222 dosing (monotherapy) in a phase 1 study. Variants with the substitutions L419C/I/M/P/S/V, R422K, M423I/T/V, I482L/N/T, A486S/T/V, and V494A were selected during VX-222 dosing, and their levels declined over time after the end of dosing. Phenotypic analysis of these variants was conducted using HCV replicons carrying site-directed mutations. Of the 17 variants, 14 showed reduced susceptibility to VX-222 compared with the wild type, with the L419C/S and R422K variants having higher levels of resistance (>200-fold) than the rest of the variants (6.8- to 76-fold). The M423I and A486S variants remained susceptible to VX-222. The 50% effective concentration (EC50) for the L419P variant could not be obtained due to the poor replication of this replicon. The majority of the variants (15/17) were less fit than the wild type. A subset of the variants, predominately the L419S and R422K variants, were observed when the efficacy and safety of VX-222- and telaprevir-based regimens given for 12 weeks were investigated in genotype 1 HCV-infected patients in a phase 2 study. The NS3 and NS5B variants selected during the dual combination therapy showed reduced susceptibility to both telaprevir and VX-222 and had a lower replication capacity than the wild type. The phase 1b study has the ClinicalTrials.gov identifier NCT00911963, and the phase 2a study has ClinicalTrials.gov identifier NCT01080222. PMID:24982088

Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor.

PubMed

Jiang, Min; Zhang, Eileen Z; Ardzinski, Andrzej; Tigges, Ann; Davis, Andrew; Sullivan, James C; Nelson, Michelle; Spanks, Joan; Dorrian, Jennifer; Nicolas, Olivier; Bartels, Doug J; Rao, B Govinda; Rijnbrand, Rene; Kieffer, Tara L

2014-09-01

VX-222, a thiophene-2-carboxylic acid derivative, is a selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV. To characterize the potential for selection of VX-222-resistant variants in HCV-infected patients, the HCV NS5B gene was sequenced at baseline and during and after 3 days of VX-222 dosing (monotherapy) in a phase 1 study. Variants with the substitutions L419C/I/M/P/S/V, R422K, M423I/T/V, I482L/N/T, A486S/T/V, and V494A were selected during VX-222 dosing, and their levels declined over time after the end of dosing. Phenotypic analysis of these variants was conducted using HCV replicons carrying site-directed mutations. Of the 17 variants, 14 showed reduced susceptibility to VX-222 compared with the wild type, with the L419C/S and R422K variants having higher levels of resistance (>200-fold) than the rest of the variants (6.8- to 76-fold). The M423I and A486S variants remained susceptible to VX-222. The 50% effective concentration (EC50) for the L419P variant could not be obtained due to the poor replication of this replicon. The majority of the variants (15/17) were less fit than the wild type. A subset of the variants, predominately the L419S and R422K variants, were observed when the efficacy and safety of VX-222- and telaprevir-based regimens given for 12 weeks were investigated in genotype 1 HCV-infected patients in a phase 2 study. The NS3 and NS5B variants selected during the dual combination therapy showed reduced susceptibility to both telaprevir and VX-222 and had a lower replication capacity than the wild type. The phase 1b study has the ClinicalTrials.gov identifier NCT00911963, and the phase 2a study has ClinicalTrials.gov identifier NCT01080222. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

PubMed Central

Antonijevic, Biljana; Stojiljkovic, Milos P.

2007-01-01

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX. TMB-4 and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of controlled clinical trials on the use of TMB-4 in human organophosphate pesticide poisoning, LüH-6 may be a better option. PMID:17456837

Multiagent MINICAMS Performance and Dependability Evaluation

DTIC Science & Technology

1991-05-17

obtain 1000 ml/min. 12 The recorder cables were connected from the recorder to tte MINICAMS, and the recorder was zeroed on each channel. The NCR ard...v.d.c.: FPD photomultiplier . 1400 + 51 TIMES sec.: Purge 0 - 120 Sample F r’ -𔃻,- Desorb 0 - 30 Columr - 79 T ’i ect 120 - 130 Tniel , FPD zero 5...Aqents GB ad X" TUBE Tena’< GC for Agent HD V-G conversion pads were installed abcve the inlet _heci ., *.,q fcr VX analyses. Injections for YX were

Comparison of oxime reactivation and aging of nerve agent-inhibited monkey and human acetylcholinesterases.

PubMed

Luo, Chunyuan; Tong, Min; Maxwell, Donald M; Saxena, Ashima

2008-09-25

Non-human primates are valuable animal models that are used for the evaluation of nerve agent toxicity as well as antidotes and results from animal experiments are extrapolated to humans. It has been demonstrated that the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited acetylcholinesterase (AChE). If the in vitro oxime reactivation of nerve agent-inhibited animal AChE is similar to that of human AChE, it is likely that the results of an in vivo animal study will reliably extrapolate to humans. Therefore, the goal of this study was to compare the aging and reactivation of human and different monkey (Rhesus, Cynomolgus, and African Green) AChEs inhibited by GF, GD, and VR. The oximes examined include the traditional oxime 2-PAM, two H-oximes HI-6 and HLo-7, and the new candidate oxime MMB4. Results indicate that oxime reactivation of all three monkey AChEs was very similar to human AChE. The maximum difference in the second-order reactivation rate constant between human and three monkey AChEs or between AChEs from different monkey species was 5-fold. Aging rate constants of GF-, GD-, and VR-inhibited monkey AChEs were very similar to human AChE except for GF-inhibited monkey AChEs, which aged 2-3 times faster than the human enzyme. The results of this study suggest that all three monkey species are suitable animal models for nerve agent antidote evaluation since monkey AChEs possess similar biochemical/pharmacological properties to human AChE.

Human Metabolism and Interactions of Deployment-Related Chemicals

DTIC Science & Technology

2003-08-01

with individual test compounds (final concentration, 100 PM), agent pyridostigmine bromide to protect against possible nerve gas NADPH-generating system...an insect repellent (N,N-diethyl-m- toluamide) a nerve gas prophyllactic (pyridostigmine bromide) did not cause the inhibition of trans-permethrin...mechanism of organophosphorus anticholinesterase agents , namely; covalent modification of the active site of the esterases in question. Carbaryl, another

Nerve Agent Sensing Biopolymer Wipe

DTIC Science & Technology

2003-04-01

3. Urease and BChE (at two concentrations) activity as function of pH. ..... 10 Figure 4. Reaction scheme Agentase nerve agent sensor...11 Figure 5. Signal development in Agentase’s Traffic Light Sensor Construct.......... 11 Figure 6. Effect of BChE/ urease ...between two competing enzyme reactions. BChE catalyzed butyrylcholine hydrolysis results in the production of acid (decreasing pH) while urease - catalyzed

Sorption of VX to Clay Minerals and Soils: Thermodynamic and Kinetic Studies

DTIC Science & Technology

2012-12-01

Suspengel 200, humus , and soil substrates for use in this study. In addition, the authors gratefully acknowledge the support of the ECBC Technical...sorption profiles for VX with clay substrates ..................................55 30. Initial kinetic sorption profiles for VX with humus ...naturally derived garden soil amendment, identified as humus , was purchased from Frey Brothers (Quarryville, PA). Two natural soils, identified as MCL lot

Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome.

PubMed

Bagley, Mark C; Davis, Terence; Dix, Matthew C; Fusillo, Vincenzo; Pigeaux, Morgane; Rokicki, Michal J; Kipling, David

2010-09-01

The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use. Microwave irradiation using a stop-flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C-S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield. This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.

The Parallax of the Red Hypergiant VX Sgr with Accurate Tropospheric Delay Calibration

NASA Astrophysics Data System (ADS)

Xu, Shuangjing; Zhang, Bo; Reid, Mark J.; Menten, Karl M.; Zheng, Xingwu; Wang, Guangli

2018-05-01

We report astrometric results of VLBI phase-referencing observations of 22 GHz H2O masers emission toward the red hypergiant VX Sgr, one of most massive and luminous red hypergiant stars in our Galaxy, using the Very Long Baseline Array. A background source, J1820‑2528, projected 4.°4 from the target VX Sgr, was used as the phase reference. For the low decl. of these sources, such a large separation normally would seriously degrade the relative astrometry. We use a two-step method of tropospheric delay calibration, which combines the VLBI geodetic-block (or Global Positioning System) calibration with an image-optimization calibration, to obtain a trigonometric parallax of 0.64 ± 0.04 mas, corresponding to a distance of {1.56}-0.10+0.11 kpc. The measured proper motion of VX Sgr is 0.36 ± 0.76 and ‑2.92 ± 0.78 mas yr‑1 in the eastward and northward directions. The parallax and proper motion confirms that VX Sgr belong to the Sgr OB1 association. Rescaling bolometric luminosities in the literature to our parallax distance, we find that the luminosity of VX Sgr is (1.95 ± 0.62) × 105 L ⊙, where the uncertainty is dominated by differing photometry measurements.

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.

High-Content Surface and Total Expression siRNA Kinase Library Screen with VX-809 Treatment Reveals Kinase Targets that Enhance F508del-CFTR Rescue.

PubMed

Perkins, Lydia A; Fisher, Gregory W; Naganbabu, Matharishwan; Schmidt, Brigitte F; Mun, Frederick; Bruchez, Marcel P

2018-03-05

The most promising F508del-CFTR corrector, VX-809, has been unsuccessful as an effective, stand-alone treatment for CF patients, but the rescue effect in combination with other drugs may confer an acceptable level of therapeutic benefit. Targeting cellular factors that modify trafficking may act to enhance the cell surface density of F508-CFTR with VX-809 correction. Our goal is to identify druggable kinases that enhance F508del-CFTR rescue and stabilization at the cell surface beyond that achievable with the VX-809 corrector alone. To achieve this goal, we implemented a new high-throughput screening paradigm that quickly and quantitatively measures surface density and total protein in the same cells. This allowed for rapid screening for increased surface targeting and proteostatic regulation. The assay utilizes fluorogen-activating-protein (FAP) technology with cell excluded and cell permeant fluorogenic dyes in a quick, wash-free fluorescent plate reader format on live cells to first measure F508del-CFTR expressed on the surface and then the total amount of F508del-CFTR protein present. To screen for kinase targets, we used Dharmacon's ON-TARGET plus SMARTpool siRNA Kinase library (715 target kinases) with and without 10 μM VX-809 treatment in triplicate at 37 °C. We identified several targets that had a significant interaction with VX-809 treatment in enhancing surface density with siRNA knockdown. Select small-molecule inhibitors of the kinase targets demonstrated augmented surface expression with VX-809 treatment.

VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

PubMed Central

Ren, Hong Yu; Grove, Diane E.; De La Rosa, Oxana; Houck, Scott A.; Sopha, Pattarawut; Van Goor, Fredrick; Hoffman, Beth J.; Cyr, Douglas M.

2013-01-01

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR. PMID:23924900

VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.

PubMed

Ren, Hong Yu; Grove, Diane E; De La Rosa, Oxana; Houck, Scott A; Sopha, Pattarawut; Van Goor, Fredrick; Hoffman, Beth J; Cyr, Douglas M

2013-10-01

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease.

PubMed

Mahajan, Sudipta; Hogan, James K; Shlyakhter, Dina; Oh, Luke; Salituro, Francesco G; Farmer, Luc; Hoock, Thomas C

2015-05-01

Cytokines, growth factors, and other chemical messengers rely on a class of intracellular nonreceptor tyrosine kinases known as Janus kinases (JAKs) to rapidly transduce intracellular signals. A number of these cytokines are critical for lymphocyte development and mediating immune responses. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on nonimmune physiology. The aim of this study was to evaluate the potency and selectivity of the investigational JAK3 inhibitor VX-509 (decernotinib) [(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide] against JAK3 kinase activity and inhibition of JAK3-mediated signaling in vitro and JAK3-dependent physiologic processes in vivo. These results demonstrate that VX-509 potently inhibits JAK3 in enzyme assays (Ki = 2.5 nM + 0.7 nM) and cellular assays dependent on JAK3 activity (IC50 range, 50-170 nM), with limited or no measurable potency against other JAK isotypes or non-JAK kinases. VX-509 also showed activity in two animal models of aberrant immune function. VX-509 treatment resulted in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores in the rat collagen-induced arthritis model. In a mouse model of oxazolone-induced delayed-type hypersensitivity, VX-509 reduced the T cell-mediated inflammatory response in skin. These findings demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and modulates proinflammatory response in models of immune-mediated diseases, such as collagen-induced arthritis and delayed-type hypersensitivity. The data support evaluation of VX-509 for treatment of patients with autoimmune and inflammatory diseases such as rheumatoid arthritis. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Validation of refraction and anterior segment parameters by a new multi-diagnostic platform (VX120).

PubMed

Gordon-Shaag, Ariela; Piñero, David P; Kahloun, Cyril; Markov, David; Parnes, Tzadok; Gantz, Liat; Shneor, Einat

2018-03-08

The VX120 (Visionix Luneau, France) is a novel multi-diagnostic platform that combines Hartmann-Shack based autorefraction, Placido-disk based corneal-topography and anterior segment measurements made with a stationary-Scheimpflug camera. We investigate the agreement between different parameters measured by the VX120 with accepted or gold-standard techniques to test if they are interchangeable, as well as to evaluate the repeatability and reproducibility. The right-eyes of healthy subjects were included in the study. Autorefraction of the VX120 was compared to subjective refraction. Agreement of anterior segment parameters was compared to the Sirius (CSO, Italy) including autokeratometry, central corneal thickness (CCT), iridiocorneal angle (IA). Inter and intra-test repeatability of the above parameters was assessed. Results were analyzed using Bland and Altman analyses. A total of 164 eyes were evaluated. The mean difference between VX120 autorefraction and subjective refraction for sphere, spherical equivalent (SE), and cylinder was 0.01±0.43D, 0.14±0.47D, and -0.26±0.30D, respectively and high correlation was found to all parameter (r>0.75) except for J 45 (r=0.61). The mean difference between VX120 and the Sirius system for CCT, IA, and keratometry (k1 and k2) was -3.51±8.64μm, 7.6±4.2°, 0.003±0.06mm and 0.004±0.04mm, respectively and high correlation was found to all parameter (r>0.97) except for IA (r=0.67). Intrasession repeatability of VX120 refraction, CCT, IA and keratometry yielded low within-subject standard deviations. Inter-session repeatability showed no statistically significant difference for most of the parameters measured. The VX120 provides consistent refraction and most anterior segment measurements in normal healthy eyes, with high levels of intra and inter-session repeatability. Copyright © 2018. Published by Elsevier España, S.L.U.

PET imaging of apoptosis in tumor-bearing mice and rabbits after paclitaxel treatment with 18F-Labeled recombinant human His10-annexin V

PubMed Central

Qin, Haidong; Zhang, Ming-Rong; Xie, Lin; Hou, Yanjie; Hua, Zichun; Hu, Minjin; Wang, Zizheng; Wang, Feng

2015-01-01

Monitoring response to chemo- or radiotherapy is of great importance in clinical practice. Apoptosis imaging serves as a very useful tool for the early evaluation of tumor response. The goal of this study was PET imaging of apoptosis with 18F-labeled recombinant human annexin V linked with 10 histidine tag (18F-rh-His10-annexin V) in nude mice bearing an A549 tumor and rabbits bearing a VX2 lung cancer after paclitaxel therapy. 18F-rh-His10-annexin V was prepared by conjugation of rh-His10-annexin V with N-succinimidyl 4-[18F]fluorobenzoate. Biodistribution was determined in mice by the dissection method and small-animal PET. Single-dose paclitaxel (175 mg/m2) was used to induce apoptosis in A549 and VX2 tumor models. 18F-rh-His10-annexin V was injected into A549 mice and VX rabbits to acquire dynamic and static PET images 72 h after paclitaxel treatment. The uptake of 18F-rh-His10-annexin V in apoptotic cells 4 h after induction was 6.45±0.52 fold higher than that in non-induced cells. High focal uptake of 18F-rh-His10-annexin V was visualized in A549 (SUVmax: 0.35±0.13) and VX2 (0.41±0.23) tumor models after paclitaxel treatment, whereas lower uptake was found in the corresponding tumors before treatment (A549 SUVmax: 0.04±0.02; VX2: 0.009±0.002). The apoptotic index was 75.61±11.56% in the treated VX2 cancer, much higher than that in the untreated VX2 (8.03±2.81%). This study demonstrated the feasibility of 18F-rh-His10-annexin V for the detection of apoptosis after chemotherapy in A549 and VX2 tumor models. PMID:25625024

Research in Progress 1 July 1990 - 30 June 1991

DTIC Science & Technology

1991-06-30

that encountered for diequatorial ring place- warfare agents , pesticides . explosives, etc. In addi- ment. In a more general sense both the theoretical...mustards but also for chlorodinitromethane was the major product. Nitration nerve agents . The advantages (and one disadvantage) of vinylidene chloride gave...resolution capillary gas The membrane potential of cultured rat sciatic nerve chromatography-mass spectrometry to obtain infor- Schwann cells was determined

Toxicity studies on agent GA (Phase 2): 90 day subchronic study of GA (Tabun) in cd rats. Appendices. Final report, July 1985-August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1992-03-01

The purpose of the report is to provide essential toxicologic information on Tabun administration over a 90 day period. This toxicologic information may be used to adjust the maximum-tolerated dose for subsequent dominant-lethal and two-generation reproduction studies. The objectives were to determine the toxic effects of nerve agent exposure (e.g., target organs); and to determine the effects of nerve agent GA on sperm morphology and motility and vaginal cytology.

Evaluation of Chemical Warfare Agent Wipe Sampling ...

EPA Pesticide Factsheets

Report This investigation tested specific (CWAs), including sarin (GB), soman (GD), cyclosarin (GF), sulfur mustard (HD), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) on the non-ideal (e.g., porous and permeable) surfaces of drywall, vinyl tile, wood, laminate, and coated glass. Pesticides (diazinon and malathion) were used so that a comparison is possible with existing literature data (1). Experiments included testing with coupons having surface areas of 10 cm2 and 100 cm2. The 10-cm2 coupons were of a size that could easily be extracted in a 2 oz jar (to provide comparative data for CWA recoveries generated by direct extraction) and the 100-cm2 coupons better represented the area of a surface that might typically be sampled by wipe extraction. In addition, CWA, at a normalized surface concentration of 0.1 µg per cm2 surface area, were spiked on coupons of the tested surfaces. Wipes were wetted with either dichloromethane (DCM) or isopropanol (IPA) before sampling for CWA. Experimental parameters include multiple wipe types, porous/permeable surfaces, coupon surface area, solvent used to wet the wipe (i.e., wetting solvent), and the utility of VX-d14 as an extracted internal standard.

Hazards of chemical weapons release during war: new perspectives.

PubMed Central

Reutter, S

1999-01-01

The two major threat classes of chemical weapons are mustard gas and the nerve agents, and this has not changed in over 50 years. Both types are commonly called gases, but they are actually liquids that are not remarkably volatile. These agents were designed specifically to harm people by any route of exposure and to be effective at low doses. Mustard gas was used in World War I, and the nerve agents were developed shortly before, during, and after World War II. Our perception of the potency of chemical weapons has changed, as well as our concern over potential effects of prolonged exposures to low doses and potential target populations that include women and children. Many of the toxicologic studies and human toxicity estimates for both mustard and nerve agents were designed for the purpose of quickly developing maximal casualties in the least sensitive male soldier. The "toxicity" of the chemical weapons has not changed, but our perception of "toxicity" has. PMID:10585902

Zen and the Art of Virtual Observatory Maintenance

NASA Astrophysics Data System (ADS)

Bargatze, L. F.

2014-12-01

The NASA Science Mission Directive Science Plan stresses that the primary goals of Heliophysics research focus on the understanding of the Sun's influence on the Earth and other bodies in the solar system. The NASA Heliophysics Division has adopted the Virtual Observatory, or VxO, concept in order to enable scientists to easily discover and access all data products relevant to these goals via web portals that act as clearinghouses. Furthermore, Heliophysics discipline scientists have defined the Space Physics Archive Search and Extract (SPASE) metadata schema in order to describe the contents of such applicable data products with detail extending all the way down to the parameter level. One SPASE metadata description file must be written to describe each data product at the global level. And the collection of such data product metadata description files, stored in repositories, provides the searchable content that the VxO web sites require in order to match the list of products to the unique needs of each researcher. The VxO metadata repository content also allows one to provide links to each unique data file contained in the full complement of files on a per data product basis. These links are contained within SPASE "Granule" description files and permit uniform access, worldwide, regardless of data server location thus permitting the VxO clearinghouse capability. The VxO concept is sound in theory but difficult in practice given that the Heliophysics data environment is diverse, ever expanding, and volatile. Thus, it is imperative to update the VxO metadata repositories in order to provide a complete, accurate, and current portrayal of the data environment. Such attention to detail is not a VxO desire but a necessity in order to support Heliophysics researchers and foster VxO user loyalty. An application of these basic tenets to the construction of a VxO repository dedicated to providing access to the CDF-formatted data collection hosted on the NASA Goddard CDAWeb data server. Note that the CDF format is self-describing and thus it provides a source of information for initiating SPASE metadata description at the data product level. Also, the CDAWeb data server provides high-quality data product tracking down to the individual data file level permitting easy updating of SPASE Granule metadata.

Letterman Army Institute of Research Annual Research Progress Report, FY 1981.

DTIC Science & Technology

1981-10-01

with physiology and mech- anisms of skin damage and repair. The mechanisms by which nerve agents and vesicants produce physiologic aberration and...enzyme vital for nerve function. Organophos- phates react rapidly and covalently with the enzyme to produce an in- active enzyme. Reactivation of the...warfare agents . These organic molecules may also alter the natural defense mechanism by activating or deactivating enzymes in the skin that destroy

Characterisation of a Cell Culture System for Investigating Nerve Agent Neurotoxicology. Part 1

DTIC Science & Technology

2012-03-01

eds. CRC Press), pp. 1-24. Sawyer,T.W., Weiss,M.T., and Unger,R.J. (1992). Anticholinesterase activity of organophosphate nerve agents in neuronal...were confirmed. The presence of muscarinic receptors and acetylcholinesterase activity was determined. Importantly, differential acetylcholinesterase... activity assays that will provide the basis for an ongoing research programme. The neuroblastoma cell lines chosen can potentially be used as a

Using an object-based grid system to evaluate a newly developed EP approach to formulate SVMs as applied to the classification of organophosphate nerve agents

NASA Astrophysics Data System (ADS)

Land, Walker H., Jr.; Lewis, Michael; Sadik, Omowunmi; Wong, Lut; Wanekaya, Adam; Gonzalez, Richard J.; Balan, Arun

2004-04-01

This paper extends the classification approaches described in reference [1] in the following way: (1.) developing and evaluating a new method for evolving organophosphate nerve agent Support Vector Machine (SVM) classifiers using Evolutionary Programming, (2.) conducting research experiments using a larger database of organophosphate nerve agents, and (3.) upgrading the architecture to an object-based grid system for evaluating the classification of EP derived SVMs. Due to the increased threats of chemical and biological weapons of mass destruction (WMD) by international terrorist organizations, a significant effort is underway to develop tools that can be used to detect and effectively combat biochemical warfare. This paper reports the integration of multi-array sensors with Support Vector Machines (SVMs) for the detection of organophosphates nerve agents using a grid computing system called Legion. Grid computing is the use of large collections of heterogeneous, distributed resources (including machines, databases, devices, and users) to support large-scale computations and wide-area data access. Finally, preliminary results using EP derived support vector machines designed to operate on distributed systems have provided accurate classification results. In addition, distributed training time architectures are 50 times faster when compared to standard iterative training time methods.

Corrector VX-809 stabilizes the first transmembrane domain of CFTR.

PubMed

Loo, Tip W; Bartlett, M Claire; Clarke, David M

2013-09-01

Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis (CF). A potential CF therapy would be to repair CFTR processing mutants. It has been demonstrated that processing mutants of P-glycoprotein (P-gp), CFTR's sister protein, can be efficiently repaired by a drug-rescue mechanism. Many arginine suppressors that mimic drug-rescue have been identified in the P-gp transmembrane (TM) domains (TMDs) that rescue by forming hydrogen bonds with residues in adjacent helices to promote packing of the TM segments. To test if CFTR mutants could be repaired by a drug-rescue mechanism, we used truncation mutants to test if corrector VX-809 interacted with the TMDs. VX-809 was selected for study because it is specific for CFTR, it is the most effective corrector identified to date, but it has limited clinical benefit. Identification of the VX-809 target domain will help to develop correctors with improved clinical benefits. It was found that VX-809 rescued truncation mutants lacking the NBD2 and R domains. When the remaining domains (TMD1, NBD1, TMD2) were expressed as separate polypeptides, VX-809 only increased the stability of TMD1. We then performed arginine mutagenesis on TM6 in TMD1. Although the results showed that TM6 had distinct lipid and aqueous faces, CFTR was different from P-gp as no arginine promoted maturation of CFTR processing mutants. The results suggest that TMD1 contains a VX-809 binding site, but its mechanism differed from P-gp drug-rescue. We also report that V510D acts as a universal suppressor to rescue CFTR processing mutants. Copyright © 2013 Elsevier Inc. All rights reserved.

Direct Binding of the Corrector VX-809 to Human CFTR NBD1: Evidence of an Allosteric Coupling between the Binding Site and the NBD1:CL4 Interface.

PubMed

Hudson, Rhea P; Dawson, Jennifer E; Chong, P Andrew; Yang, Zhengrong; Millen, Linda; Thomas, Philip J; Brouillette, Christie G; Forman-Kay, Julie D

2017-08-01

Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for the optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. We demonstrate the direct binding of VX-809 to the first nucleotide-binding domain (NBD1) of human CFTR. Disruption of the interaction between C-terminal helices and the NBD1 core upon VX-809 binding is observed from chemical shift changes in the NMR spectra of residues in the helices and on the surface of β -strands S3, S9, and S10. Binding to VX-809 leads to a significant negative shift in NBD1 thermal melting temperature (T m ), pointing to direct VX-809 interaction shifting the NBD1 conformational equilibrium. An inter-residue correlation analysis of the chemical shift changes provides evidence of allosteric coupling between the direct binding site and the NBD1:CL4 interface, thus enabling effects on the interface in the absence of direct binding in that location. These NMR binding data and the negative T m shifts are very similar to those previously reported by us for binding of the dual corrector-potentiator CFFT-001 to NBD1 (Hudson et al., 2012), suggesting that the two compounds may share some aspects of their mechanisms of action. Although previous studies have shown an important role for VX-809 in modulating the conformation of the first membrane spanning domain (Aleksandrov et al., 2012; Ren et al., 2013), this additional mode of VX-809 binding provides insight into conformational dynamics and allostery within CFTR. Copyright © 2017 by The Author(s).

Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR.

PubMed

Farinha, Carlos M; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D

2015-08-01

Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.

Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR

PubMed Central

Farinha, Carlos M; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D

2015-01-01

Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue. PMID:26171232

CFTR rescue with VX-809 and VX-770 favors the repair of primary airway epithelial cell cultures from patients with class II mutations in the presence of Pseudomonas aeruginosa exoproducts.

PubMed

Adam, Damien; Bilodeau, Claudia; Sognigbé, Laura; Maillé, Émilie; Ruffin, Manon; Brochiero, Emmanuelle

2018-04-13

Progressive airway damage due to bacterial infections, especially with Pseudomonas aeruginosa remains the first cause of morbidity and mortality in CF patients. Our previous work revealed a repair delay in CF airway epithelia compared to non-CF. This delay was partially prevented after CFTR correction (with VRT-325) in the absence of infection. Our goals were now to evaluate the effect of the Orkambi combination (CFTR VX-809 corrector + VX-770 potentiator) on the repair of CF primary airway epithelia, in infectious conditions. Primary airway epithelial cell cultures from patients with class II mutations were mechanically injured and wound healing rates and transepithelial resistances were monitored after CFTR rescue, in the absence and presence of P. aeruginosa exoproducts. Our data revealed that combined treatment with VX-809 and VX-770 elicited a greater beneficial impact on airway epithelial repair than VX-809 alone, in the absence of infection. The treatment with Orkambi was effective not only in airway epithelial cell cultures from patients homozygous for the F508del mutation but also from heterozygous patients carrying F508del and another class II mutation (N1303 K, I507del). The stimulatory effect of the Orkambi treatment was prevented by CFTR inhibition with GlyH101. Finally, Orkambi combination elicited a slight but significant improvement in airway epithelial repair and transepithelial resistance, despite the presence of P. aeruginosa exoproducts. Our findings indicate that Orkambi may favor airway epithelial integrity in CF patients with class II mutations. Complementary approaches would however be needed to further improve CFTR rescue and airway epithelial repair. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

PubMed Central

Bassil, Fares; Fernagut, Pierre-Olivier; Bezard, Erwan; Pruvost, Alain; Leste-Lasserre, Thierry; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.; Meissner, Wassilios G.

2016-01-01

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation. PMID:27482103

Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction

PubMed Central

Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B.; A.Shamsi, Shahab

2016-01-01

To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150–5,000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy. PMID:26460073

Molecular and bioinformatical characterization of a novel superfamily of cysteine-rich peptides from arthropods.

PubMed

Zeng, Xian-Chun; Nie, Yao; Luo, Xuesong; Wu, Shifen; Shi, Wanxia; Zhang, Lei; Liu, Yichen; Cao, Hanjun; Yang, Ye; Zhou, Jianping

2013-03-01

The full-length cDNA sequences of two novel cysteine-rich peptides (referred to as HsVx1 and MmKTx1) were obtained from scorpions. The two peptides represent a novel class of cysteine-rich peptides with a unique cysteine pattern. The genomic sequence of HsVx1 is composed of three exons interrupted by two introns that are localized in the mature peptide encoding region and inserted in phase 1 and phase 2, respectively. Such a genomic organization markedly differs from those of other peptides from scorpions described previously. Genome-wide search for the orthologs of HsVx1 identified 59 novel cysteine-rich peptides from arthropods. These peptides share a consistent cysteine pattern with HsVx1. Genomic comparison revealed extensive intron length differences and intronic number and position polymorphisms among the genes of these peptides. Further analysis identified 30 cases of intron sliding, 1 case of intron gain and 22 cases of intron loss occurred with the genes of the HsVx1 and HsVx1-like peptides. It is interesting to see that three HsVx1-like peptides XP_001658928, XP_001658929 and XP_001658930 were derived from a single gene (XP gene): the former two were generated from alternative splicing; the third one was encoded by a DNA region in the reverse complementary strand of the third intron of the XP gene. These findings strongly suggest that the genes of these cysteine-rich peptides were evolved by intron sliding, intron gain/loss, gene recombination and alternative splicing events in response to selective forces without changing their cysteine pattern. The evolution of these genes is dominated by intron sliding and intron loss. Copyright © 2012 Elsevier Inc. All rights reserved.

Supporting Real-Time Computer Vision Workloads using OpenVX on Multicore+GPU Platforms

DTIC Science & Technology

2015-05-01

a registered trademark of the NVIDIA Corporation . Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection...from NVIDIA , we adapted an alpha- version of an NVIDIA OpenVX implementation called VisionWorks® [3] to run atop PGMRT (a graph-based mid- dleware...time support to an OpenVX implementation by NVIDIA called VisionWorks. Our modifications were applied to an alpha-version of VisionWorks. This alpha

SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. | Office of Cancer Genomics

Cancer.gov

Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models.

Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2: evaluation of in vitro topical decontamination efficacy using undamaged skin.

PubMed

Dalton, Christopher H; Hall, Charlotte A; Lydon, Helen L; Chipman, J K; Graham, John S; Jenner, John; Chilcott, Robert P

2015-05-01

The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat™) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder-based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat™ should be subject to further evaluation using an in vitro model of damaged skin. Copyright © 2014 Crown copyright. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd.

Asymptotic behavior of exact exchange potential of slabs

NASA Astrophysics Data System (ADS)

Engel, E.

2014-06-01

In this contribution the exact exchange potential vx of density functional theory is examined for slabs such as graphene, for which one has a Bravais lattice in the x-y directions, while the electrons are confined to the finite region -L≤z≤L in the z direction. It is demonstrated analytically that the exact vx behaves as -e2/z for z ≫L. This result extends the corresponding statement of Horowitz, Proetto, and Rigamonti [Phys. Rev. Lett. 97, 026802 (2006), 10.1103/PhysRevLett.97.026802] for jellium slabs to slabs with arbitrary periodic density distributions. Application of the exact exchange to a Si(111) slab (within the Krieger-Li-Iafrate approximation) indicates that the corrugation of the exact vx is more pronounced than that of the local density approximation for vx.

Effects of Whole-Body VX Vapor Exposure on Lethality in Rats

DTIC Science & Technology

2007-01-01

J. "New Method for Hemoglobin Determination by Using Sodium Lauryl Sulfate (SLS)." Clin. Biochem. 15(1) 83-88 (1982). Prins, J, "Product and Process...regenerated VX-G and deuterated internal standard VX-G were eluted with I mL ethyl acetate that was collected and dried over anhydrous sodium sulfate ...anhydrous sodium sulfate . The ethyl acetate was removed from the collection tube and filtered through a 0.2 lim nylon Acrodisc syringe filter (Pall Gelman

An Automated Air Sampling System Comprising an OPTIC GC Injector II, Quantification of VX Vapour

DTIC Science & Technology

2006-01-01

Convention in 1989. In 1990 a Canadian research institute reported their work on the thermodesorption of VX using Tenax minitubes [3]. They obtained best...is to convert VX to a volatile derivative which is then trapped on Tenax and easily desorbed. This approach is used by Robert B. Walton [4] in...measure levels of 0.001 mg/m3 with a 20 minutes sampling time. With the Hapsite as well as with the abovementioned minitubes no cold trap is used

Evaluation of RSDL, M291 SDK, 0.5 Bleach, 1% Soapy Water and SERPACWA: Part 11: Challenge with EA4243 (VR, Russian VX)

DTIC Science & Technology

2016-01-01

listed decontamination products in the haired guinea pig model following exposure to VR (Russian VX, EA4243). 15. SUBJECT TERMS decontamination...the efficacy of the barrier skin cream SERPACWA and the four listed decontamination products in the haired guinea pig model following exposure to VR...four listed decontamination products and SERPACWA in the haired guinea pig model following exposure to VR (Russian VX, EA4243, Soviet V-gas

Imaging of Rabbit VX-2 Hepatic Cancer by Cold and Thermal Neutron Radiography

NASA Astrophysics Data System (ADS)

Tsuchiya, Yoshinori; Matsubayashi, Masahito; Takeda, Tohoru; Lwin, Thet Thet; Wu, Jin; Yoneyama, Akio; Matsumura, Akira; Hori, Tomiei; Itai, Yuji

2003-11-01

Neutron radiography is based on differences in neutron mass attenuation coefficients among the elements and is a non-destructive imaging method. To investigate biomedical applications of neutron radiography, imaging of rabbit VX-2 liver cancer was performed using thermal and cold neutron radiography with a neutron imaging plate. Hepatic vessels and VX-2 tumor were clearly observed by neutron radiography, especially by cold neutron imaging. The image contrast of this modality was better than that of absorption-contrast X-ray radiography.

Acute Toxicity Estimation and Operational Risk Management of Chemical Warfare Agent Exposures

DTIC Science & Technology

2004-05-01

Following absorption into the body, nerve agents bind with and inhibit the activity of cholinesterases (ChE) that are present in the blood and...other tissues. Blood ChE activity depression by itself is not considered an adverse effect but (particularly red blood cell cholinesterase (RBC-ChE...chemical, such as an organophosphate , that blocks nerve impulses by inhibiting the activity of the enzyme cholinesterase (adapted from University of

Fluoride Ion Regeneration of Cyclosarin (Gf) from Minipig Tissue and Fluids Following Whole Body GF Vapor Exposure

DTIC Science & Technology

2006-11-01

Quantitation of organophosphorus nerve agent metabolites in human urine using isotope dilution gas chromatography- tandem mass spectrometry. J. Anal...Recent developments to improve nerve agent biomarker techniques include methods for measuring fluoride regenerated Sarin (GB) in blood and tissue...Our efforts extend the fluoride ion regeneration method to be able to determine cyclosarin (GF) in red blood cells, plasma, and tissue of minipig

The Limitations of Diazepam as a Treatment for Nerve Agent-Induced Seizures and Neuropathology in Rats: Comparison with UBP302

DTIC Science & Technology

2014-11-01

to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the cur- rent US Food and Drug... status epilepticus (SE), which are initiated by the excessive stimulation of cholinergic receptors. If immediate death is prevented by adequate...5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid; PBS, phosphate-buffered saline; SE, status epilepticus ; UBP302, (S)-3-(2-carboxybenzyl

Effects of subacute pretreatment with carbamate together with acute adjunct pretreatment against nerve agent exposure. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, D.R.; Harris, L.W.; Lennox, W.J.

1991-12-31

Acute carbamate pretreatment, in conjunction with atropine pretreatment or followed by atropine and oxime therapy has been shown to protect rabbits, rats, guinea pigs and monkeys against multiple lethal doses of soman. In those experiments, pretreated animals were usually challenged with soman at the time of peak whole blood acetylcholinesterase (AChE) inhibition by the carbamate or when the concentration of carbamate in the blood was expected to be rapidly diminishing. However, soldiers in a chemical environment, having taken carbamate orally might well be exposed to nerve agent shortly thereafter. Thus, both active carbamate and nerve agent would be entering themore » blood simultaneously. In a recent study it was reported that subacute administration of physostigmine (Phy), via subcutaneously implanted 28 day osmotic minipump, afforded protection against an iv challenge of soman on the 27th day.« less

Hydrolysis of Nerve Agents by Model Nucleophiles: A Computational Study

PubMed Central

Beck, Jeremy M.

2008-01-01

Density functional theory calculations were employed to study the reaction of five nerve agents with model nucleophiles, including EtX− and EtXH (X = O, S, Se) for serine, cysteine and selenocysteine, respectively. Calculations at the B3LYP/6-311++G(2d,p) level of theory predict an exothermic reaction between ethoxide and all of the nerve agents studied. As compared to EtO− as a nucleophile, these reactions become ~30 kcal/mol more endothermic for EtS−, and by ~40 kcal/mol for EtSe−. The equivalent reactions with the neutral nucleophiles (EtXH) were more endothermic. The effect of solvation on the reaction thermochemistry was determined using a polarizable continuum model simulating the dielectric constant of chloroform. While there was a large exothermic shift for reactions involving charged nucleophiles with solvation modeling, the corresponding shift was minimal for the reaction with neutral nucleophiles. PMID:18538754

A common-path optical coherence tomography based electrode for structural imaging of nerves and recording of action potentials

NASA Astrophysics Data System (ADS)

Islam, M. Shahidul; Haque, Md. Rezuanul; Oh, Christian M.; Wang, Yan; Park, B. Hyle

2013-03-01

Current technologies for monitoring neural activity either use different variety of electrodes (electrical recording) or require contrast agents introduced exogenously or through genetic modification (optical imaging). Here we demonstrate an optical method for non-contact and contrast agent free detection of nerve activity using phase-resolved optical coherence tomography (pr-OCT). A common-path variation of the pr-OCT is recently implemented and the developed system demonstrated the capability to detect rapid transient structural changes that accompany neural spike propagation. No averaging over multiple trials was required, indicating its capability of single-shot detection of individual impulses from functionally stimulated Limulus optic nerve. The strength of this OCT-based optical electrode is that it is a contactless method and does not require any exogenous contrast agent. With further improvements in accuracy and sensitivity, this optical electrode will play a complementary role to the existing recording technologies in future.

Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-CFTR Mutation

PubMed Central

Accurso, Frank J.; Rowe, Steven M.; Clancy, J.P.; Boyle, Michael P.; Dunitz, Jordan M.; Durie, Peter R.; Sagel, Scott D.; Hornick, Douglas B.; Konstan, Michael W.; Donaldson, Scott H.; Moss, Richard B.; Pilewski, Joseph M.; Rubenstein, Ronald C.; Uluer, Ahmet Z.; Aitken, Moira L.; Freedman, Steven D.; Rose, Lynn M.; Mayer-Hamblett, Nicole; Dong, Qunming; Zha, Jiuhong; Stone, Anne J.; Olson, Eric R.; Ordoñez, Claudia L.; Campbell, Preston W.; Ashlock, Melissa A.; Ramsey, Bonnie W.

2010-01-01

BACKGROUND A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. METHODS We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). RESULTS At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was −3.5 mV (range, −8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. PMID:21083385

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

PubMed Central

Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.

2011-01-01

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR. PMID:21976485

Molecular and dissociative adsorption of DMMP, Sarin and Soman on dry and wet TiO2(110) using density functional theory

NASA Astrophysics Data System (ADS)

Quintero, Yenny Cardona; Nagarajan, Ramanathan

2018-09-01

Titania, among the metal oxides, has shown promising characteristics for the adsorption and decontamination of chemical warfare nerve agents, due to its high stability and rapid decomposition rates. In this study, the adsorption energy and geometry of the nerve agents Sarin and Soman, and their simulant dimethyl methyl phosphonate (DMMP) on TiO2 rutile (110) surface were calculated using density functional theory. The molecular and dissociative adsorption of the agents and simulant on dry as well as wet metal oxide surfaces were considered. For the wet system, computations were done for the cases of both molecularly adsorbed water (hydrated conformation) and dissociatively adsorbed water (hydroxylated conformation). DFT calculations show that dissociative adsorption of the agents and simulant is preferred over molecular adsorption for both dry and wet TiO2. The dissociative adsorption on hydrated TiO2 shows higher stability among the different configurations considered. The dissociative structure of DMMP on hydrated TiO2 (the most stable one) was identified as the dissociation of a methyl group and its adsorption on the TiO2 surface. For the nerve agents Sarin and Soman on hydrated TiO2 the dissociative structure was by the dissociation of the F atom from the molecule and its interaction with a Ti atom from the surface, which could indicate a reduction in the toxicity of the products. This study shows the relevance of water adsorption on the metal oxide surface for the stability and dissociation of the simulant DMMP and the nerve agents Sarin and Soman on TiO2.

Sarin Exposures in A Cohort of British Military Participants in Human Experimental Research at Porton Down 1945-1987.

PubMed

Keegan, Thomas J; Carpenter, Lucy M; Brooks, Claire; Langdon, Toby; Venables, Katherine M

2017-12-15

The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30000 participants drawn from the UK armed services has been undertaken. Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Six principal nerve agents were tested on humans between 1945 and 1987. Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans. © The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Fluorescent sensors for the detection of chemical warfare agents.

PubMed

Burnworth, Mark; Rowan, Stuart J; Weder, Christoph

2007-01-01

Along with biological and nuclear threats, chemical warfare agents are some of the most feared weapons of mass destruction. Compared to nuclear weapons they are relatively easy to access and deploy, which makes them in some aspects a greater threat to national and global security. A particularly hazardous class of chemical warfare agents are the nerve agents. Their rapid and severe effects on human health originate in their ability to block the function of acetylcholinesterase, an enzyme that is vital to the central nervous system. This article outlines recent activities regarding the development of molecular sensors that can visualize the presence of nerve agents (and related pesticides) through changes of their fluorescence properties. Three different sensing principles are discussed: enzyme-based sensors, chemically reactive sensors, and supramolecular sensors. Typical examples are presented for each class and different fluorescent sensors for the detection of chemical warfare agents are summarized and compared.

Nerve Agent Induced Status Epilepticus: From Seizure Onset to Long Lasting Pathology

DTIC Science & Technology

2014-01-31

of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev 25:297-323 168. Martin LF, Kem WR, Freedman R. 2004. Alpha-7...Pharmacol 82:931-42 220. Paxinos G, Watson C. 2005. The Rat Brain in Stereotaxic Coordinates. New York NY: Elsevier 221. Petras JM. 1981. Soman...neurotoxicity. Fundam Appl Toxicol 1 :242 222. Petras JM. 1994. Neurology and neuropathology of Soman-induced brain injury: an overview. J Exp Anal

Examination of plasma PON1 paraoxonase activity and genotype in Gulf War veterans

DTIC Science & Technology

2017-10-01

cholinergic” effects (e.g., personal pesticide use, exposure to OP nerve agents) in subgroups of veterans with different PON1192 genotype. (2...associations between GWI and GW-related exposures with the potential for “cholinergic” effects (e.g., personal pesticide use, exposure to OP nerve agents) in...learning and careers in science, technology, and the humanities . What do you plan to do during the next reporting period to accomplish the goals

The postwar hospitalization experience of Gulf War Veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq.

PubMed

Gray, G C; Smith, T C; Knoke, J D; Heller, J M

1999-09-01

Using Department of Defense hospital data, the authors examined the postwar hospitalization experience from March 1991 through September 1995 of US Gulf War veterans who were near Khamisiyah, Iraq, during nerve agent munition destruction in March 1991. Multiple sources of meteorologic, munition, and toxicology data were used to circumscribe geographic areas of low level, vaporized nerve agent for 4 days after the destruction. Plume estimates were overlaid on military unit positions, and exposure was estimated for the 349,291 US Army Gulf War veterans. Exposure was classified as not exposed (n = 224,804), uncertain low dose exposure (n = 75,717), and specific estimated subclinical exposure (n = 48,770) categorized into three groups for dose-response evaluation. Using Cox proportional hazard modeling, the authors compared the postwar experiences of these exposure groups for hospitalization due to any cause, for diagnoses in 15 unique categories, and for specific diagnoses an expert panel proposed as most likely to reflect latent disease from such subclinical exposure. There was little evidence that veterans possibly exposed to the nerve agent plumes experienced unusual postwar morbidity. While there were several differences in hospitalization risk, none of the models suggested a dose-response relation or neurologic sequelae. These data, having a number of limitations, do not support the hypothesis that Gulf War veterans are suffering postwar morbidity from subclinical nerve agent exposure.

Development of haemostatic decontaminants for treatment of wounds contaminated with chemical warfare agents. 3: Evaluation of in vitro topical decontamination efficacy using damaged skin.

PubMed

Lydon, Helen L; Hall, Charlotte A; Dalton, Christopher H; Chipman, J Kevin; Graham, John S; Chilcott, Robert P

2017-08-01

Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

An Unstable Arch Model of a Solar Flare

DTIC Science & Technology

1976-08-10

where the Euler-Lagrange equation becomes singular. We now expand f(r) and g(r) around the singular point r. Thus k JA + - p x, (3.20) m where x...current layer, etc.) can result only from convection. The equations we will use are ()B E 2 - VX(vXB)- _ VX(1TV XB), (4.8) E+ vX B=77j (4.9) C and curl (P...d- curl (J ( curl B) X B+pg . (4.10) Since the treatment is principally concerned with resistive instabilities whose growth times are long compared to

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.

VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis.

PubMed

Genovese, Mark C; van Vollenhoven, Ronald F; Pacheco-Tena, César; Zhang, Yanqiong; Kinnman, Nils

2016-01-01

To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed. VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels. © 2016, American College of Rheumatology.

Synergistic Potentiation of Cystic Fibrosis Transmembrane Conductance Regulator Gating by Two Chemically Distinct Potentiators, Ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate.

PubMed

Lin, Wen-Ying; Sohma, Yoshiro; Hwang, Tzyh-Chang

2016-09-01

Cystic fibrosis (CF) is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a phosphorylation-activated but ATP-gated chloride channel. Previous studies suggested that VX-770 [ivacaftor, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide], a CFTR potentiator now used in clinics, increases the open probability of CFTR by shifting the gating conformational changes to favor the open channel configuration. Recently the chloride channel blocker and CFTR potentiator 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) has been reported to enhance CFTR activity by a mechanism that exploits the ATP hydrolysis-driven, nonequilibrium gating mechanism unique to CFTR. Surprisingly however, NPPB increased the activity of nonhydrolytic G551D-CFTR, the third most common disease-associated mutation. Here, we further investigated the mechanism of NPPB's effects on CFTR gating by assessing its interaction with well-studied VX-770. Interestingly, once G551D-CFTR was maximally potentiated by VX-770, NPPB further increased its activity. However, quantitative analysis of this drug-drug interaction suggests that this pharmacologic synergism is not due to independent actions of NPPB and VX-770 on CFTR gating; instead, our data support a dependent mechanism involving two distinct binding sites. This latter idea is further supported by the observation that the locked-open time of a hydrolysis-deficient mutant K1250A was shortened by NPPB but prolonged by VX-770. In addition, the effectiveness of NPPB, but not of VX-770, was greatly diminished in a mutant whose second nucleotide-binding domain was completely removed. Interpreting these results under the framework of current understanding of CFTR gating not only reveals insights into the mechanism of action for different CFTR potentiators but also brings us one step forward to a more complete schematic for CFTR gating. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Synergistic Potentiation of Cystic Fibrosis Transmembrane Conductance Regulator Gating by Two Chemically Distinct Potentiators, Ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate

PubMed Central

Lin, Wen-Ying; Sohma, Yoshiro

2016-01-01

Cystic fibrosis (CF) is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a phosphorylation-activated but ATP-gated chloride channel. Previous studies suggested that VX-770 [ivacaftor, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide], a CFTR potentiator now used in clinics, increases the open probability of CFTR by shifting the gating conformational changes to favor the open channel configuration. Recently the chloride channel blocker and CFTR potentiator 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) has been reported to enhance CFTR activity by a mechanism that exploits the ATP hydrolysis-driven, nonequilibrium gating mechanism unique to CFTR. Surprisingly however, NPPB increased the activity of nonhydrolytic G551D-CFTR, the third most common disease-associated mutation. Here, we further investigated the mechanism of NPPB’s effects on CFTR gating by assessing its interaction with well-studied VX-770. Interestingly, once G551D-CFTR was maximally potentiated by VX-770, NPPB further increased its activity. However, quantitative analysis of this drug–drug interaction suggests that this pharmacologic synergism is not due to independent actions of NPPB and VX-770 on CFTR gating; instead, our data support a dependent mechanism involving two distinct binding sites. This latter idea is further supported by the observation that the locked-open time of a hydrolysis-deficient mutant K1250A was shortened by NPPB but prolonged by VX-770. In addition, the effectiveness of NPPB, but not of VX-770, was greatly diminished in a mutant whose second nucleotide-binding domain was completely removed. Interpreting these results under the framework of current understanding of CFTR gating not only reveals insights into the mechanism of action for different CFTR potentiators but also brings us one step forward to a more complete schematic for CFTR gating. PMID:27413118

The impact of skin decontamination on the time window for effective treatment of percutaneous VX exposure.

PubMed

Joosen, M J A; van den Berg, R M; de Jong, A L; van der Schans, M J; Noort, D; Langenberg, J P

2017-04-01

The main goal of the present study was to obtain insight into depot formation and penetration following percutaneous VX poisoning, in order to identify an appropriate decontamination window that can enhance or support medical countermeasures. The study was executed in two phases, using the hairless guinea pig as an animal model. In the first phase the effect of various decontamination regimens on levels of free VX in skin and plasma were studied as well as on blood cholinesterase levels. Animals were exposed to 0.5 mg/kg VX and were not decontaminated (control), decontaminated with RSDL once at 15 or 90 min after exposure or three times at 15, 25 and 35 (10-min interval) or 15, 45 and 75 min after exposure (30-min interval). There was no significant effect of any of the decontamination regimens on the 6-h survival rate of the animals. However, all animals that had been decontaminated 15 min after exposure, showed a survival rate of more than 90%, compared to 50-60% in animals that were not decontaminated or decontaminated at 90 min after exposure. In the second phase of the study, hairless guinea pigs were exposed to 1 mg/kg VX on the shoulder, followed either by decontamination with RSDL (10 min interval), conventional treatment on indication of clinical signs or a combination thereof. It appeared that a thorough, repeated decontamination alone could not save the majority of the animals. A 100% survival rate was observed in the group that received a combination of decontamination and treatment. In conclusion, the effects of VX exposure could be influenced by various RSDL decontamination regimens. The results in freely moving animals showed that skin decontamination, although not fully effective in removing all VX from the skin and skin depot is crucial to support pharmacological intervention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-04-04

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. 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. 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 molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents.

Period Variations of the Eclipsing Binary Systems T LMi and VX Lac

NASA Astrophysics Data System (ADS)

Yılmaz, M.; İzci, D. D.; Gümüş, D.; Özavci, İ.; Selam, S. O.

2015-07-01

We present a period analysis of the two Algol-type eclipsing binary systems T LMi and VX Lac using all available times of minimum in the literature, as well as new minima obtained at the Ankara University Kreiken Observatory. The period analysis of T LMi suggests mass transfer between the components and also a third body that is dynamically bound to the binary system. The analysis of VX Lac also suggests mass transfer between the components, and the presence of a third and a fourth body under the assumption of a Light-Time Effect. In addition, the periodic variation of VX Lac was examined under the hypothesis of magnetic activity, and the corresponding parameters were derived. We report here the orbital parameters for both systems, along with the ones related to mass transfer, and those for the third and fourth bodies.

Portable Sensor for Chemical Nerve Agents and Organophosphorus Compounds

DTIC Science & Technology

2015-08-18

as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of the high toxicity and the...agents have been exploited for use as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

PubMed Central

2016-01-01

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

PubMed

Lockridge, Oksana; Norgren, Robert B; Johnson, Rudolph C; Blake, Thomas A

2016-09-19

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franz, D.R.

1986-12-01

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

Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

DTIC Science & Technology

2013-08-01

GFAP,IL6,CCL2, TNF, L118, Lif, IL10 Hip, Ctx Ctx Ctx CORT=corticosterone;(200mg/L) for days 7-14 P8= pyridostigmine bromide ;P8(2.5 mg/kg/day, s.c...reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB), the insect repellent DEET and, potentially, the nerve agent, sarin. These...acetylcholinesterase (AChE) inhibitor, pyridostigmine bromide (PB), the insect repellent, DEET, and, potentially, acutely to the nerve agent sarin. Previously, we

Stoichiometric and Catalytic Scavengers as Protection Against Nerve Agent Toxicity: A Mini Review

DTIC Science & Technology

2007-01-01

signs of nerve agent toxicity following exposure . Assessments of motor activity , coordination, and acquisition of spatial memory were performed for 2...serious side occur before endogenous AChE is affected (approxi- effects if administered in the absence of cholinesterase mately 2 min after exposure to an...after guinea pigs of cholinesterase in the blood and the level of protec- were administered 60mg/kg of HuBuChE (-󈧎-fold tion against OP poisoning

Enhanced catalytic activity through the tuning of micropore environment and supercritical CO2 processing: Al(porphyrin)-based porous organic polymers for the degradation of a nerve agent simulant.

PubMed

Totten, Ryan K; Kim, Ye-Seong; Weston, Mitchell H; Farha, Omar K; Hupp, Joseph T; Nguyen, SonBinh T

2013-08-14

An Al(porphyrin) functionalized with a large axial ligand was incorporated into a porous organic polymer (POP) using a cobalt-catalyzed acetylene trimerization strategy. Removal of the axial ligand afforded a microporous POP that is catalytically active in the methanolysis of a nerve agent simulant. Supercritical CO2 processing of the POP dramatically increased the pore size and volume, allowing for significantly higher catalytic activities.

Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus Nerve Agent Poisoning

DTIC Science & Technology

2010-11-01

particular nerve agent and oxime uti- lized in the treatment regimen. Atropine is the universal treatment for organophospho- rus anticholinesterase poisoning...general, to the recovery of AChE activity either through decarbamylation of PB protected enzyme or by use of an effective oxime. The results against...this protected enzyme in the first few minutes after intoxication and treat- ment provides sufficient enzyme activity to sustain survival.̂ ’"* A

Improving the Catalytic Activity of Hyperthermophilic Pyrococcus horikoshii Prolidase for Detoxification of Organophosphorus Nerve Agents over a Broad Range of Temperatures

DTIC Science & Technology

2011-01-01

affinity for metal, and increased thermostability compared to P. furiosus prolidase, Pf prol (PF1343). To obtain a better enzyme for OP nerve agent...decontamination and to investigate the structural factors that may influence protein thermostability and thermoactivity, randomly mutated Ph1prol enzymes ...Introduction Pyrococcus horikoshii and Pyrococcus furiosus are both hyper- thermophilic archaea, growing optimally at 98 –100◦C that were isolated from a

Subacute Low Dose Nerve Agent Exposure Causes DNA Fragmentation in Guinea Pig Leukocytes

DTIC Science & Technology

2005-10-01

1 SUBACUTE LOW DOSE NERVE AGENT EXPOSURE CAUSES DNA FRAGMENTATION IN GUINEA PIG LEUKOCYTES. Jitendra R. Dave1, John R. Moffett1, Sally M...DNA fragmentation in blood leukocytes from guinea pigs by ‘Comet’ assay after exposure to soman at doses ranging from 0.1LD50 to 0.4 LD50, once per...computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA treated guinea pigs as

Dual-cavity basket promotes encapsulation in water in an allosteric fashion.

PubMed

Chen, Shigui; Yamasaki, Makoto; Polen, Shane; Gallucci, Judith; Hadad, Christopher M; Badjić, Jovica D

2015-09-30

We prepared dual-cavity basket 1 to carry six (S)-alanine residues at the entrance of its two juxtaposed cavities (289 Å(3)). With the assistance of (1)H NMR spectroscopy and calorimetry, we found that 1 could trap a single molecule of 4 (K1 = 1.45 ± 0.40 × 10(4) M(-1), ITC), akin in size (241 Å(3)) and polar characteristics to nerve agent VX (289 Å(3)). The results of density functional theory calculations (DFT, M06-2X/6-31G*) and experiments ((1)H NMR spectroscopy) suggest that the negative homotropic allosterism arises from the guest forming C-H···π contacts with all three of the aromatic walls of the occupied basket's cavity. In response, the other cavity increases its size and turns rigid to prevent the formation of the ternary complex. A smaller guest 6 (180 Å(3)), akin in size and polar characteristics to soman (186 Å(3)), was also found to bind to dual-cavity 1, although giving both binary [1⊂6] and ternary [1⊂62] complexes (K1 = 7910 M(-1) and K2 = 2374 M(-1), (1)H NMR spectroscopy). In this case, the computational and experimental ((1)H NMR spectroscopy) results suggest that only two aromatic walls of the occupied basket's cavity form C-H···π contacts with the guest to render the singly occupied host flexible enough to undergo additional structural changes necessary for receiving another guest molecule. The structural adaptivity of dual-cavity baskets of type 1 is unique and important for designing multivalent hosts capable of effectively sequestering targeted guests in an allosteric manner to give stable supramolecular polymers.

Study of Degradation Kinetics of Parathion Methyl On Mixed Nanocrystalline Titania-Zirconium and Titania-Cerium Oxides

NASA Astrophysics Data System (ADS)

Kuráň, Pavel; Pšenička, Martin; Šťastný, Martin; Benkocká, Monika; Janoš, Pavel

2016-10-01

The unique surface properties of some nanocrystalline metal oxides and their application for removal of various toxic compounds were reported in early 1990s. Recently, a reliable method for the preparation of reactive cerium dioxide sorbent and its application for degradation of the organophosphate pesticides, such as parathion methyl, chlorpyrifos, dichlofenthion, fenchlorphos, and prothiofos, as well as of some chemical warfare agents-nerve gases soman and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) was published. This paper reports on the kinetics study of degradation of parathion methyl as a representative organophosphate on nanocrystalline metal oxides TiO2, ZrO2, CeO2 and their mixtures in different molar ratios of particular elements. The tested sorbents except of CeO2 were prepared by different methods (e.g. sol-gel, precipitation) in cooperation with Institute of Inorganic Chemistry (Rez, Czech Republic). The degradation kinetics of parathion methyl on tested sorbents was followed by HPLC equipped with diode array detector. The basic kinetics parameters (half-lives of parathion methyl degradation, rate constants of degradation product formation) were calculated for each sorbent from Weber-Morris equation of 1st order diffusion kinetic model. The results proved the ability of prepared sorbents to degrade parathion methyl under formation of 4-nitrophenol as the main degradation product. The most efficient sorbents were TiCe (2:8), TiCe (1:1), TiCe (0:1) (50-70 %) followed by TiZr (1:1), TiCe (8:2), TiZr (8:2), TiZr (2:8) (20-30%) and TiO2, ZrO2 (less than 5 %).

A Nerve Clamp Electrode Design for Indirect Stimulation of Skeletal Muscle

DTIC Science & Technology

2010-10-01

neurons. This device enables stimulation of muscle contraction indirectly as opposed to contraction from direct muscle stimulation. The electrode is able...to stimulate indirect muscle contraction when tested on ex vivo preparations from rodent phrenic nerve-hemidiaphragm muscle in similar fashion to...unsuccessful in stimulating indirect muscle contraction . Therefore, this novel electrode is useful for physiological assessment of nerve agents and

Effect of anticholinesterase agents on airway epithelial function. Annual report, 15 July 1888-14 August 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marin, M.G.

1989-09-15

Irreversible anticholinesterase compounds have potential serious health effects when employed as chemical warfare agents. Intoxication with these agents will cause an accumulation of acetylcholine at nerve muscle and nerve-gland junctions. Because tracheal glands have rich cholinergic innervation, we hypothesized that exposure to anticholinesterase agents, such as soman, would stimulate glandular secretion. This would cause pathological changes in the important lung defense mechanism of mucociliary clearance. Initial work on this contract revealed a dose-related increase in mucociliary transport in the ferret in response to soman. This effect could be inhibited by atropine but not by pralidoxime. The investigation described in thismore » report relates to the effects of soman and its antidotes on glycoconjugate secretion of ferret trachea in vitro.« less

Detoxification of organophosphate nerve agents by bacterial phosphotriesterase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghanem, Eman; Raushel, Frank M.

2005-09-01

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

Effects of anesthetic agents on in vivo axonal HCN current in normal mice.

PubMed

Osaki, Yusuke; Nodera, Hiroyuki; Banzrai, Chimeglkham; Endo, Sachiko; Takayasu, Hirokazu; Mori, Atsuko; Shimatani, Yoshimitsu; Kaji, Ryuji

2015-10-01

The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. Anesthetic agents affected responses to long hyperpolarizing currents. Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Part 3: Solid phase extraction of Russian VX and its chemical attribution signatures in food matrices and their detection by GC-MS and LC-MS.

PubMed

Williams, Audrey M; Vu, Alexander K; Mayer, Brian P; Hok, Saphon; Valdez, Carlos A; Alcaraz, Armando

2018-08-15

Chemical attribution signatures indicative of O-isobutyl S-(2-diethylaminoethyl) methylphosphonothioate (Russian VX) synthetic routes were investigated in spiked food samples. Attribution signatures were identified using a multifaceted approach: Russian VX was synthesized using six synthetic routes and the chemical attribution signatures identified by GC-MS and LC-MS. Three synthetic routes were then down selected and spiked into complex matrices: bottled water, baby food, milk, liquid eggs, and hot dogs. Sampling and extraction methodologies were developed for these materials and used to isolate the attribution signatures and Russian VX from each matrix. Recoveries greater than 60% were achieved for most signatures in all matrices; some signatures provided recoveries greater than 100%, indicating some degradation during sample preparation. A chemometric model was then developed and validated with the concatenated data from GC-MS and LC-MS analyses of the signatures; the classification results of the model were > 75% for all samples. This work is part three of a three-part series in this issue of the United States-Sweden collaborative efforts towards the understanding of the chemical attribution signatures of Russian VX in crude materials and in food matrices. Copyright © 2018 Elsevier B.V. All rights reserved.

Epidemiologic evidence of health effects from long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War.

PubMed

Haley, Robert W; Tuite, James J

2013-01-01

Military intelligence data published in a companion paper explain how chemical fallout from US and Coalition bombing of Iraqi chemical weapons facilities early in the air campaign transited long distance, triggering nerve agent alarms and exposing US troops. We report the findings of a population-based survey designed to test competing hypotheses on the impact on chronic Gulf War illness of nerve agent from early-war bombing versus post-war demolition. The US Military Health Survey performed computer-assisted telephone interviews of a stratified random sample of Gulf War-era veterans (n = 8,020). Early-war exposure was measured by having heard nerve agent alarms and post-war exposure, by the computer-generated plume from the Khamisiyah demolition. Gulf War illness was measured by two widely published case definitions. The OR (95% CI) for the association of alarms with the Factor case definition was 4.13 (95% CI 2.51-6.80) compared with 1.21 (95% CI 0.86-1.69) for the Khamisiyah plume. There was a dose-related trend for the number of alarms (p(trend) < 0.001) but not for the number of days in the Khamisiyah plume (p(trend) = 0.17). Exposure to low-level sarin nerve agent in fallout from bombing early in the air campaign contributed more to chronic illness than post-war demolition. Copyright © 2012 S. Karger AG, Basel.

Effect of O-methyl-β-cyclodextrin-modified magnetic nanoparticles on the uptake and extracellular level of l-glutamate in brain nerve terminals.

PubMed

Horák, Daniel; Beneš, Milan; Procházková, Zuzana; Trchová, Miroslava; Borysov, Arsenii; Pastukhov, Artem; Paliienko, Konstantin; Borisova, Tatiana

2017-01-01

Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe 2 O 3 ) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe 2 O 3 provides a relatively stable colloid product containing 48μmol of MCDg -1 . MCD-modified γ-Fe 2 O 3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[ 14 C]glutamate and increase the extracellular l-[ 14 C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol. Copyright © 2016 Elsevier B.V. All rights reserved.

Primary screen for potential sheep scab control agents.

PubMed

Dunn, J A; Prickett, J C; Collins, D A; Weaver, R J

2016-07-15

The efficacy of potential acaricidal agents were assessed against the sheep scab mite Psoroptes ovis using a series of in vitro assays in modified test arenas designed initially to maintain P. ovis off-host. The mortality effects of 45 control agents, including essential oils, detergents, desiccants, growth regulators, lipid synthesis inhibitors, nerve action/energy metabolism disruptors and ecdysteroids were assessed against adults and nymphs. The most effective candidates were the desiccants (diatomaceous earth, nanoclay and sorex), the growth regulators (buprofezin, hexythiazox and teflubenzuron), the lipid synthesis inhibitors (spirodiclofen, spirotetramat and spiromesifen) and the nerve action and energy metabolism inhibitors (fenpyroximate, spinosad, tolfenpyrad, and chlorantraniliprole). Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Catalytic degradation of organophosphorous nerve agent simulants by polymer beads@graphene oxide with organophosphorus hydrolase-like activity based on rational design of functional bimetallic nuclear ligand.

PubMed

Ma, Xuejuan; Zhang, Lin; Xia, Mengfan; Zhang, Xiaohong; Zhang, Yaodong

2018-05-15

The degradation of organophosphorous nerve agents is of primary concern due to the severe toxicity of these agents. Based on the active center of organophosphorus hydrolase (OPH), a bimetallic nuclear ligand, (5-vinyl-1,3-phenylene)bis(di(1H-imidazol-2-yl) methanol) (VPIM), was designed and synthesized, which contains four imidazole groups to mimic the four histidines at OPH active center. By grafting VPIM on graphene oxide (GO) surface via polymerization, the VPIM-polymer beads@GO was produced. The obtained OPH mimics has an impressive activity in dephosphorylation reactions (turnover frequency (TOF) towards paraoxon: 2.3 s -1 ). The synergistic catalytic effect of the bimetallic Zn 2+ nuclear center and carboxyl groups on surface of GO possibly contributes to the high hydrolysis on organophosphate substrate. Thus, a biomimetic catalyst for efficient degradation of some organophosphorous nerve agent simulants, such as paraoxon and chlorpyrifos, was prepared by constructing catalytic active sites. The proposed mechanism and general synthetic strategy open new avenues for the engineering of functional GOs for biomimetic catalysts. Copyright © 2018 Elsevier B.V. All rights reserved.

Sensitive detection of chemical agents and toxic industrial chemicals using active open-path FTIRs

NASA Astrophysics Data System (ADS)

Walter, William T.

2004-03-01

Active open-path FTIR sensors provide more sensitive detection of chemical agents than passive FTIRs, such as the M21 RSCAAL and JSLSCAD, and at the same time identify and quantify toxic industrial chemicals (TIC). Passive FTIRs are bistatic sensors relying on infrared sources of opportunity. Utilization of earth-based sources of opportunity limits the source temperatures available for passive chemical-agent FTIR sensors to 300° K. Active FTIR chemical-agent sensors utilize silicon carbide sources, which can be operated at 1500° K. The higher source temperature provides more than an 80-times increase in the infrared radiant flux emitted per unit area in the 7 to 14 micron spectral fingerprint region. Minimum detection limits are better than 5 μgm/m3 for GA, GB, GD, GF and VX. Active FTIR sensors can (1) assist first responders and emergency response teams in their assessment of and reaction to a terrorist threat, (2) provide information on the identification of the TIC present and their concentrations and (3) contribute to the understanding and prevention of debilitating disorders analogous to the Gulf War Syndrome for military and civilian personnel.

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.

Stable adducts of nerve agents sarin, soman and cyclosarin with TRIS, TES and related buffer compounds--characterization by LC-ESI-MS/MS and NMR and implications for analytical chemistry.

PubMed

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

2010-05-15

Buffering compounds like TRIS are frequently used in chemical, biochemical and biomedical applications to control pH in solution. One of the prerequisites of a buffer compound, in addition to sufficient buffering capacity and pH stability over time, is its non-reactivity with other constituents of the solution. This is especially important in the field of analytical chemistry where analytes are to be determined quantitatively. Investigating the enzymatic hydrolysis of G-type nerve agents sarin, soman and cyclosarin in buffered solution we have identified stable buffer adducts of TRIS, TES and other buffer compounds with the nerve agents. We identified the molecular structure of these adducts as phosphonic diesters using 1D (1)H-(31)P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates with TRIS and TES are fast enough to compete with spontaneous hydrolysis in aqueous solution and to yield substantial amounts (up to 20-40%) of buffer adduct over the course of several hours. A reaction mechanism is proposed in which the amino function of the buffer serves as an intramolecular proton acceptor rendering the buffer hydroxyl groups nucleophilic enough for attack on the phosphorus atom of the agents. Results show that similar buffer adducts are formed with a range of hydroxyl and amino function containing buffers including TES, BES, TRIS, BIS-TRIS, BIS-TRIS propane, Tricine, Bicine, HEPES and triethanol amine. It is recommended to use alternative buffers like MOPS, MES and CHES when working with G-type nerve agents especially at higher concentrations and over prolonged times. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Human Metabolism and Interactions of Deployment-Related Chemicals

DTIC Science & Technology

2008-08-01

metabolic detoxification pathway for permethrin. Other deployment related compounds, an insect repellent (N,N-diethyl-m- toluamide) a nerve gas ...Leo, K. U. 1997. Metabolism of proposed nerve agent pretreatment, pyridostigmine bromine. Walter Reed Army Institute of Research Report No. NTIS/AD...against possible nerve gas attack. It has been reported that chlorpyrifos and DEET are metabo- lized by human P450s (Tang et al., 2001; Usmani et al., 2002

The de-epoxidase and epoxidase reactions of Mantoniella squamata (Prasinophyceae) exhibit different substrate-specific reaction kinetics compared to spinach.

PubMed

Frommolt, R; Goss, R; Wilhelm, C

2001-07-01

In vivo the prasinophyceaen alga Mantoniella squamata Manton et Parke uses an incomplete violaxanthin (Vx) cycle, leading to a strong accumulation of antheraxanthin (Ax) under conditions of high light. Here, we show that this zeaxanthin (Zx)-depleted Vx/Ax cycle is caused by an extremely slow second de-epoxidation step from Ax to Zx, and a fast epoxidation from Ax back to Vx in the light. The rate constant of Ax epoxidation is 5 to 6 times higher than the rate constant of Zx formation, implying that Ax is efficiently converted back to Vx before it can be de-epoxidated to Zx. It is, however, only half the rate constant of the first de-epoxidation step from Vx to Ax, thus explaining the observed net accumulation of Ax during periods of strong illumination. When comparing the rate constant of the second de-epoxidation step in M. squamata with Zx formation in spinach (Spinacia oleracea L.) thylakoids, we find a 20-fold reduction in the reaction kinetics of the former. This extremely slow Ax de-epoxidation, which is also exhibited by the isolated Mantoniella violaxanthin de-epoxidase (VDE), is due to a reduced substrate affinity of M. squamata VDE for Ax compared with the VDE of higher plants. Mantoniella VDE, which has a similar Km value for Vx, shows a substantially increased Km for the substrate Ax in comparison with spinach VDE. Our results furthermore explain why Zx formation in Mantoniella cells can only be found at low pH values that represent the pH optimum of VDE. A pH of 5 blocks the epoxidation reaction and, consequently, leads to a slow but appreciable accumulation of Zx.

Neural control of renal tubular sodium reabsorption of the dog.

PubMed

DiBona, G F

1978-04-01

The evidence supporting a role for direct neurogenic control of renal tubular sodium reabsorption is reviewed. Electron microscopic and fluorescence histochemical studies demonstrate adrenergic nerve terminals in direct contact with basement membranes of mammalian renal tubular epithelial cells. Low level direct or baroreceptor reflex stimulation of renal sympathetic nerves produces an increase in renal tubular sodium reabsorption without alterations in glomerular filtration rate, renal blood flow, or intrarenal distribution of blood flow. The antinatriuresis is prevented by prior treatment of the kidney with guanethidine or phenoxybenzamine. Possible indirect mediation of the antinatriuresis by other humoral agents known to be released from the kidney upon renal nerve stimulation (angiotensin II, prostaglandin) was excluded by experiments with appropriate blocking agents. Reflex diminutions in renal nerve activity (left atrial distention, stellate ganglion stimulation) produce a decrease in renal tubular sodium reabsorption independent of glomerular filtration rate or renal blood flow. The anatomically described adrenergic innervation of the renal tubules participates in the direct regulation of renal tubular sodium reabsorption.

Delisting toxicity evaluation of HTH and oxone(trade name) decontaminated VX. Final report, July 1989-March 1990

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manthei, J.H.; Heitkamp, D.H.; Buettner, L.C.

1992-07-01

The acute percutaneous (bare skin) LD50 was determined for EA 2192 in the rabbit. Also established were the effective doses (ED50s) for the major toxic signs observed. Dermal, Department of Transportation (DOT), tests with rabbits indicated that VX/HTH decontaminated waste is a Class B poison after being aged only 24 hr following initiation of the decontamination procedure. The same reaction, when allowed to age through about 2 half-lives (28-30 days), was no longer a Class B poison and was nonhazardous by Code of Maryland Regulations (COMAR) toxicity criteria. The DOT tests with OXONE decontaminated/neutralized VX showed this solution to bemore » less than a Class B poison by all three routes of administration (rat oral, rat inhalation, and rabbit dermal) after only 24-hr aging and a nonhazardous material by COMAR toxicity criteria.... vx, Rat, Half-life, ED50, EA 2192, Rabbit, COMAR, Decontaminated/Neutralized, HTH, OXONE, LD50.« less

Advanced nodal neutron diffusion method with space-dependent cross sections: ILLICO-VX

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rajic, H.L.; Ougouag, A.M.

1987-01-01

Advanced transverse integrated nodal methods for neutron diffusion developed since the 1970s require that node- or assembly-homogenized cross sections be known. The underlying structural heterogeneity can be accurately accounted for in homogenization procedures by the use of heterogeneity or discontinuity factors. Other (milder) types of heterogeneity, burnup-induced or due to thermal-hydraulic feedback, can be resolved by explicitly accounting for the spatial variations of material properties. This can be done during the nodal computations via nonlinear iterations. The new method has been implemented in the code ILLICO-VX (ILLICO variable cross-section method). Numerous numerical tests were performed. As expected, the convergence ratemore » of ILLICO-VX is lower than that of ILLICO, requiring approx. 30% more outer iterations per k/sub eff/ computation. The methodology has also been implemented as the NOMAD-VX option of the NOMAD, multicycle, multigroup, two- and three-dimensional nodal diffusion depletion code. The burnup-induced heterogeneities (space dependence of cross sections) are calculated during the burnup steps.« less

Interferometric phase-contrast X-ray CT imaging of VX2 rabbit cancer at 35keV X-ray energy

NASA Astrophysics Data System (ADS)

Takeda, Tohoru; Wu, Jin; Tsuchiya, Yoshinori; Yoneyama, Akio; Lwin, Thet-Thet; Hyodo, Kazuyuki; Itai, Yuji

2004-05-01

Imaging of large objects at 17.7-keV low x-ray energy causes huge x-ray exposure to the objects even using interferometric phase-contrast x-ray CT (PCCT). Thus, we tried to obtain PCCT images at high x-ray energy of 35keV and examined the image quality using a formalin-fixed VX2 rabbit cancer specimen with 15-mm in diameter. The PCCT system consisted of an asymmetrically cut silicon (220) crystal, a monolithic x-ray interferometer, a phase-shifter, an object cell and an x-ray CCD camera. The PCCT at 35 keV clearly visualized various inner structures of VX2 rabbit cancer such as necrosis, cancer, the surrounding tumor vessels, and normal liver tissue. Besides, image-contrast was not degraded significantly. These results suggest that the PCCT at 35 KeV is sufficient to clearly depict the histopathological morphology of VX2 rabbit cancer specimen.

2010 Department of Defense (DoD) Chemical and Biological Defense Program (CBDP) Portfolio

DTIC Science & Technology

2010-03-01

a new oxime and (2) obtaining approval for use of pyridostigmine bromide , the component of Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) for...Pralidoxime Chloride Autoinjector N/A 6505-01-125-3248 11704-620-01 N/A DLA 8 Pyridostigmine Bromide Tabs USP 30 mg I.S. (SNAPP) N/A 6505-01-178-7903 N...Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) N/A 6505-01-483-7162 N/A N/A N/A N/A Vaccines Anthrax Vaccine Adsorbed (AVA) N/A 6505-01-399

Soman Induces Ictogenesis in the Amygdala and Interictal Activity in the Hippocampus That Are Blocked by a GluR5 Kainate Receptor Antagonist In Vitro

DTIC Science & Technology

2009-01-01

to organophosphorus nerve agents in- uces brain seizures, which can cause profound brain dam- ge resulting in death or long-term cognitive deficits...The mygdala and the hippocampus are two of the most seizure- rone brain structures, but their relative contribution to the eneration of seizures after...nerve agent exposure is unclear. ere, we report that application of 1 M soman for 30 min, in at coronal brain slices containing both the hippocampus

Assessing Protection Against OP Pesticides and Nerve Agents Provided by Wild-Type HuPON1 Purified from Trichoplusia ni Larvae or Induced via Adenoviral Infection

DTIC Science & Technology

2013-01-01

times the median lethal dose (LD50) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic...metabolite of the OP pesticide chlorpyrifos . In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then...mice are dramati- cally more susceptible to the toxic metabolites of the OP pesticides diazinon and chlorpyrifos (diazoxon and chlorpyrifos oxon

Studies on centrifugal clutch judder behavior and the design of frictional lining materials

NASA Astrophysics Data System (ADS)

Li, Tse-Chang; Huang, Yu-Wen; Lin, Jen-Fin

2016-01-01

This study examines the judder behavior of a centrifugal clutch from the start of hot spots in the conformal contact, then the repeated developments of thermoelastic instability, and finally the formation of cyclic undulations in the vibrations, friction coefficient and torque. This behavior is proved to be consistent with the testing results. Using the Taguchi method, 18 kinds of frictional lining specimens were prepared in order to investigate their performance in judder resistance and establish a relationship between judder behavior and the Ts/Td (Ts: static torque; Td: dynamic torque) and dμ/dVx (μ: friction coefficient; Vx: relative sliding velocity of frictional lining and clutch drum) parameters. These specimens are also provided to examine the effects and profitability with regard to the centrifugal clutch, and find the relative importance of the various control factors. Theoretical models for the friction coefficient (μ), the critical sliding velocity (Vc) with clutch judder, and the contact pressure ratio p* /pbar (p*: pressure undulation w.r.t. pbar; pbar: mean contact pressure) and temperature corresponding to judder behavior are developed. The parameters of the contact pressure ratio and temperature are shown to be helpful to explain the occurrence of judder. The frictional torque and the rotational speeds of the driveline, clutch, and clutch drum as functions of engagement time for 100 clutch cycles are obtained experimentally to evaluate dμ/dVx and Ts/Td. A sharp rise in the maximum p* /pbar occurred when the relative sliding velocity reached the critical velocity, Vc. An increase in the maximum p* /pbar generally led to an increase of the (initially negative) dμ/dVx value, and thus the severity of judder. The fluctuation intensity of dμ/dVx becomes a governing factor of the growth of dμ/dVx itself in the engagement process. The mean values of dμ/dVx and Ts/Td for the clutching tests with 100 cycles can be roughly divided into three groups dependent on the fluctuation intensities of these two parameters, for each of which there is a linear relationship.

Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

PubMed

Bornia, Elaine Cs; Correia-de-Sá, Paulo; Alves-Do-Prado, Wilson

2011-03-01

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 μmol/L)-, cisatracurium (0.32 μmol/L)- and vecuronium (0.36 μmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 μmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

Algorithm Design of CPCI Backboard's Interrupts Management Based on VxWorks' Multi-Tasks

NASA Astrophysics Data System (ADS)

Cheng, Jingyuan; An, Qi; Yang, Junfeng

2006-09-01

This paper begins with a brief introduction of the embedded real-time operating system VxWorks and CompactPCI standard, then gives the programming interfaces of Peripheral Controller Interface (PCI) configuring, interrupts handling and multi-tasks programming interface under VxWorks, and then emphasis is placed on the software frameworks of CPCI interrupt management based on multi-tasks. This method is sound in design and easy to adapt, ensures that all possible interrupts are handled in time, which makes it suitable for data acquisition systems with multi-channels, a high data rate, and hard real-time high energy physics.

Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.

PubMed

Boyd, Michael J; Bandarage, Upul K; Bennett, Hamilton; Byrn, Randal R; Davies, Ioana; Gu, Wenxin; Jacobs, Marc; Ledeboer, Mark W; Ledford, Brian; Leeman, Joshua R; Perola, Emanuele; Wang, Tiansheng; Bennani, Youssef; Clark, Michael P; Charifson, Paul S

2015-05-01

VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species. Copyright © 2015 Elsevier Ltd. All rights reserved.

NRL (Naval Research Laboratory) Plasma Formulary. Revised.

DTIC Science & Technology

1983-01-01

EQUATIONS Name Rationalized inks Gaussian Faday’s law V xE -- !-s VxE--l1p .aD -l3D 4i" Ampere’slta xH-VxH -- +J VxH -- .- +- J at C at C Poison’s eqution...energy density Froude Fr t V (gL ) 1/2 (Inertial forces/gravitational or VINL buoyancy forces) t/2 Gay- Lussac Ga I/PA T (Relative volume change...112 Alfvin speed a Newton’s- law heat coefficient, k x " aA T aix Volumetric expansion coefficient, dV/ V - )dT r Bulk modulus (units m/it 2 ) AR, A

Temporary Blindness after Inferior Alveolar Nerve Block.

PubMed

Barodiya, Animesh; Thukral, Rishi; Agrawal, Shaila Mahendra; Rai, Anshul; Singh, Siddharth

2017-03-01

Inferior Alveolar Nerve Block (IANB) anaesthesia is one of the common procedures in dental clinic. This procedure is safe, but complications may still occur. Ocular complications such as diplopia, loss of vision, or ophthalmoplegia are extremely rare. This case report explains an event where due to individual anatomic variation of the sympathetic vasoconstrictor nerve and maxillary and middle meningeal arteries, intravascular administration of anaesthetic agent caused unusual ocular signs and symptoms such as temporary blindness.

VizieR Online Data Catalog: 22GHz observations of VX Sgr (Murakawa+, 2003)

NASA Astrophysics Data System (ADS)

Murakawa, K.; Yates, J. A.; Richards, A. M. S.; Cohen, R. J.

2012-07-01

The 22-GHz H2O maser emission from VX Sgr was observed on 1994 26 and 1999 January 16 for 5 and 7hr, respectively, in both left and right circular polarization, using 5 antennas of MERLIN. (3 data files).

Photocatalytic ozonation of terephthalic acid: a by-product-oriented decomposition study.

PubMed

Fuentes, Iliana; Rodríguez, Julia L; Poznyak, Tatyana; Chairez, Isaac

2014-11-01

Terephthalic acid (TA) is considered as a refractory model compound. For this reason, the TA degradation usually requires a prolonged reaction time to achieve mineralization. In this study, vanadium oxide (VxOy) supported on titanium oxide (TiO2) served as a photocatalyst in the ozonation of the TA with light-emitting diodes (LEDs), having a bandwidth centered at 452 nm. The modified catalyst (VxOy/TiO2) in combination with ozone and LEDs improved the TA degradation and its by-products. The results obtained by this system were compared with photolysis, single ozonation, catalytic ozonation, and photocatalytic ozonation of VxOy/TiO2 with UV lamp. The LED-based photocatalytic ozonation showed almost the same decomposition efficiency of the TA, but it was better in comparison with the use of UV lamp. The oxalic acid accumulation, as the final product of the TA decomposition, was directly influenced by either the presence of VxOy or/and the LED irradiation. Several by-products formed during the TA degradation, such as muconic, fumaric, and oxalic acids, were identified. Besides, two unidentified by-products were completely removed during the observed time (60 min). It was proposed that the TA elimination in the presence of VxOy/TiO2 as catalyst was carried out by the combination of different mechanisms: molecular ozone reaction, indirect mechanism conducted by ·OH, and the surface complex formation.

First measurement of the B$$0\\atop{2}$$ semileptonic branching ratio to an orbitally excited d$$**\\atop{s}$$ state, Br(B$$0\\atop{2}$$ → D$$-\\atop{s1}$$(2536)μ +vX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rieger, Jason

2007-12-08

In a data sample of approximately 1.3 fb -1 collected with the D0 detector between 2002 and 2006, the orbitally excited charm state Dmore » $$±\\atop{s1}$$(2536)has been observed with a measured mass of 2535.7 ± 0.6(stat) ± 0.5(syst) MeV/c 2 via the decay mode B$$0\\atop{s}$$ → D$$-\\atop{s1}$$(2536)μ +vX followed by D$$±\\atop{s1}$$(2536) → D *±K$$0\\atop{S}$$. By normalizing to the known branching ratio Br($$\\bar{b}$$ → D* - μ +vX) and to the number of reconstructed D* mesons with an associated identified muon, a first-ever measurement is made of the product branching ratio ($$\\bar{b}$$ →} D$$-\\atop{s1}$$(2536)μ +vX) • Br(D$$-\\atop{s1}$$ → D* -K$$0\\atop{S}$$). Assuming that D$$-\\atop{s1}$$(2536) production in semileptonic decay is entirely from B$$0\\atop{s}$$, an extraction of the semileptonic branching ratio Br(B$$0\\atop{s}$$ → D$$-\\atop{s1}$$(2536)μ +vX) is made. Comparisons are made with theoretical expectations.« less

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 molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents. PMID:24708580

Functionalized polymer nanofibre membranes for protection from chemical warfare stimulants

NASA Astrophysics Data System (ADS)

Ramaseshan, Ramakrishnan; Sundarrajan, Subramanian; Liu, Yingjun; Barhate, R. S.; Lala, Neeta L.; Ramakrishna, S.

2006-06-01

A catalyst for the detoxification of nerve agents is synthesized from β-cyclodextrin (β-CD) and o-iodosobenzoic acid (IBA). Functionalized polymer nanofibre membranes from PVC polymer are fabricated with β-CD, IBA, a blend of β-CD+IBA, and the synthesized catalyst. These functionalized nanofibres are then tested for the decontamination of paraoxon, a nerve agent stimulant, and it is observed that the stimulant gets hydrolysed. The kinetics of hydrolysis is investigated using UV spectroscopy. The rates of hydrolysis for different organophosphate hydrolyzing agents are compared. The reactivity and amount of adsorption of these catalysts are of higher capacity than the conventionally used activated charcoal. A new design for protective wear is proposed based on the functionalized nanofibre membrane.

Domain Visualization Using VxInsight[R] for Science and Technology Management.

ERIC Educational Resources Information Center

Boyack, Kevin W.; Wylie, Brian N.; Davidson, George S.

2002-01-01

Presents the application of a knowledge visualization tool, VxInsight[R], to enable domain analysis for science and technology management. Uses data mining from sources of bibliographic information to define subsets of relevant information and discusses citation mapping, text mapping, and journal mapping. (Author/LRW)

Biosensor Based on Self-Assembling Acetylcholinesterase on Carbon Nanotubes for Flow injection/Amperometric Detection of Organophosphate Pesticides and Nerve Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Guodong; Lin, Yuehe

A highly sensitive flow-injection amperometric biosensor for organophosphate pesticides and nerve agents based on self-assembly of acetylcholinesterase (AChE) on carbon nanotube (CNT)-modified glassy carbon (GC) electrode is described. AChE is immobilized on the negatively-charged CNT surface by alternatively assembling a cationic polydiallyldimethylammonium chloride (PDDA) layer and an AChE layer. Transmission electron microscopy images confirm the formation of layer-by-layer nanostructures on carboxyl functionalized CNTs. The unique sandwich-like structure (PDDA/AChE/PDDA) on the CNT surface formed by self-assembly provides a favorable microenvironment to keep the bioactivity of AChE and to prevent enzyme molecule leakage. The electrocatalytic activity of CNT leads to a greatlymore » improved electrochemical detection of the enzymatically generated thiocholine product, including a low oxidation overvoltage (+150 mV), higher sensitivity, and stability. The developed PDDA/AChE/PDDA/CNT/GC biosensor integrated into a flow injection system was used to monitor organophosphate pesticides and nerve agents, such as paraoxon. The sensor performance, including inhibition time and regeneration conditions, was optimized with respect to operating conditions. Under the optimal conditions, the biosensor was used to measure as low as 0.4 pM paraoxon with a 6-min inhibition time. The biosensor had excellent operational lifetime stability with no decrease in the activity of enzymes for more than 20 repeated measurements over a 1-week period. The developed biosensor system is an ideal tool for online monitoring of organophosphate pesticides and nerve agents.« less

Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review.

PubMed

Rodgers, G C; Condurache, C T

2010-09-01

This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area.

A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions

PubMed Central

Rosenberg, Yvonne J.; Walker, Jeremy; Jiang, Xiaoming; Donahue, Scott; Robosky, Jason; Sack, Markus; Lees, Jonathan; Urban, Lori

2015-01-01

Although recent innovations in transient plant systems have enabled gram quantities of proteins in 1–2 weeks, very few have been translated into applications due to technical challenges and high downstream processing costs. Here we report high-level production, using a Nicotiana benthamiana/p19 system, of an engineered recombinant human acetylcholinesterase (rAChE) that is highly stable in a minimally processed leaf extract. Lyophylized clarified extracts withstand prolonged storage at 70 °C and, upon reconstitution, can be used in several devices to detect organophosphate (OP) nerve agents and pesticides on surfaces ranging from 0 °C to 50 °C. The recent use of sarin in Syria highlights the urgent need for nerve agent detection and countermeasures necessary for preparedness and emergency responses. Bypassing cumbersome and expensive downstream processes has enabled us to fully exploit the speed, low cost and scalability of transient production systems resulting in the first successful implementation of plant-produced rAChE into a commercial biotechnology product. PMID:26268538

A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions.

PubMed

Rosenberg, Yvonne J; Walker, Jeremy; Jiang, Xiaoming; Donahue, Scott; Robosky, Jason; Sack, Markus; Lees, Jonathan; Urban, Lori

2015-08-13

Although recent innovations in transient plant systems have enabled gram quantities of proteins in 1-2 weeks, very few have been translated into applications due to technical challenges and high downstream processing costs. Here we report high-level production, using a Nicotiana benthamiana/p19 system, of an engineered recombinant human acetylcholinesterase (rAChE) that is highly stable in a minimally processed leaf extract. Lyophylized clarified extracts withstand prolonged storage at 70 °C and, upon reconstitution, can be used in several devices to detect organophosphate (OP) nerve agents and pesticides on surfaces ranging from 0 °C to 50 °C. The recent use of sarin in Syria highlights the urgent need for nerve agent detection and countermeasures necessary for preparedness and emergency responses. Bypassing cumbersome and expensive downstream processes has enabled us to fully exploit the speed, low cost and scalability of transient production systems resulting in the first successful implementation of plant-produced rAChE into a commercial biotechnology product.

Graphene oxide/MnO2 nanocomposite as destructive adsorbent of nerve-agent simulants in aqueous media

NASA Astrophysics Data System (ADS)

Šťastný, Martin; Tolasz, Jakub; Štengl, Václav; Henych, Jiří; Žižka, David

2017-08-01

Graphene oxide/MnO2 nanocomposite was prepared by thermal hydrolysis of potassium permanganate (KMnO4) and 2-chloroacetamide aqueous solutions with graphene oxide (GO) suspension. The synthesized samples were characterized by specific surface area (BET) and porosity determination (BJH), X-ray Diffraction (XRD) and high-resolution electron microscopes (HRSEM, HRTEM). These nanocomposites were used in an experimental evaluation of their adsorption activity with nerve agent simulants dimethyl methyl phosphonate (DMMP) and triethyl phosphate (TEP) in aqueous media. The nanocomposites exhibited enhanced adsorptive degradation ability compared to pure manganese oxide (MnO2) and GO. The GO amount in the nanocomposites affected their degradation activity substantially. The best adsorption efficiency was observed for samples with moderate GO amount. Three methods were used to observe the mechanism of the nerve-agent simulants deactivation: Gas chromatography with mass spectrometry (GC-MS), High-Performance Liquid Chromatography (HPLC) and in situ Infrared spectroscopy (FTIR). It was shown that the hydrolysis on the surface of prepared nanocomposites yields volatile primary alcohols (methanol and ethanol) as the main hydrolysis products.

[Mucoviscidosis: CFTR mutation-specific therapy: a ray of sunshine in a cloudy sky].

PubMed

Leonard, A; Leal, T; Lebecque, P

2013-01-01

There is a need to find a cure for pulmonary disease in cystic fibrosis (CF), though full benefit of this approach will be restricted to those patients with well-preserved lungs. The most promising route is currently that of a pharmacological mutation-specific approach aiming at correcting the mechanism by which mutations lead to impairment of chloride conductance across respiratory epithelial cells. In the past 14years, 7 candidate drugs (CPX, 4PBA, gentamicin, PTC124, VX-770 or Ivacaftor, VX-809 or Lumacaftor, and Miglustat) have been investigated in CF patients. A postulate of 14 out of the 15 published studies has been that an effective agent had to improve total chloride secretion as assessed in vivo by nasal potential difference measurements. The present review casts a critical look at these studies. Apparent inconsistencies are discussed as well as possible limitations of nasal potential difference measurements as outcome parameters in these trials. Primarily targeting a mutation carried by less than 2% of French CF patients, the 2 Ivacaftor studies could well be a milestone on the long road toward a cure for CF. However, further data on safety and long-term efficacy are obviously needed and the current price of this medication in the US would make it unaffordable for European patients. Copyright © 2012 Elsevier Masson SAS. All rights reserved.