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

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

doi:10.1016/j.jchromb.2011.07.031

Cited by 39 publications

(21 citation statements)

References 51 publications

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“…As a short-term solution, administration of the licensed obidoxime or HI-6 as oxime in advanced development together with additionalby itself stoichiometric-AChE and/or BChE from blood products is a practical approach to elevate the oximemediated pseudocatalytic breakdown of VX in the vascular compartment to decrease the toxic body load and improve physical recovery. We used 100 nM VX as multiple LD 50 and a possible blood concentration after extensive inhalational uptake (Reiter et al 2011). This represents a concentration overwhelming the endogenous scavenging capacity and mechanisms by a simple binding to free ChEs and proteins and provided complete and stable inhibition during the experiment duration (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Within the first minute, approximately half of the labeled sarin was in the form of IMPA. The highest concentrations of sarin and its (Nakajima et al, 1998;Katagi et al, 1999;Jokanović, 2001Jokanović, , 2009Evans et al, 2008;Black, 2010;Tenberken et al, 2010;Reiter et al, 2011;Black and Read, 2013;Kranawetvogl et al, 2013). metabolites were found in the kidneys. Lower concentrations of IMPA and MPA were detected in the liver, suggesting a minor role for the liver in detoxification of sarin.…”

Section: Chemical Aspects Of Biotransformation Of Wnasmentioning

confidence: 98%

“…The presence of EA2192 metabolite in humans is important because it retains the 2-diisopropylaminoethylthio substituent that confirms exposure to VX (Black and Read, 2013). After intravenous and dermal administration of sublethal doses of VX to swine, both VX and EA2192 could be quantified during 540 min after exposure (Reiter et al, 2011). In addition, there are two nonphosphorus metabolites of VX: DAET and its methylation product DAEMS identified in human serum from a victim of the Osaka VX accident (Tsuchihashi et al, 1998).…”

Section: Chemical Aspects Of Biotransformation Of Wnasmentioning

confidence: 99%

“…In addition, there are two nonphosphorus metabolites of VX: DAET and its methylation product DAEMS identified in human serum from a victim of the Osaka VX accident (Tsuchihashi et al, 1998). The conversion from DAET to DAEMS is catalyzed by thiol S-methyltransferase (EC 2.1.1.9) (Reiter et al, 2011). Benschop et al (2000) and van der Schans et al (2003) studied the toxicokinetics of VX stereoisomers in hairless guinea pigs and marmosets.…”

Section: Chemical Aspects Of Biotransformation Of Wnasmentioning

confidence: 99%

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Biotransformation of Warfare Nerve Agents

Jokanović¹

2015

Handbook of Toxicology of Chemical Warfare Agents

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“…However, today these compounds are banned by the Chemical Weapons Convention (CWC) comprising strict surveillance by the Organization for the Prohibition of Chemical Weapons (OPCW, Nobel Peace Prize 2013) [3] . For this purpose, reliable analytical methods are required allowing verification of an alleged use of CWA [5][6][7][8] . For this purpose, reliable analytical methods are required allowing verification of an alleged use of CWA [5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

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

Kranawetvogl

Küppers

Gütschow

et al. 2017

Drug Testing and Analysis

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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.

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

Cited by 39 publications

References 51 publications

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

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

Biotransformation of Warfare Nerve Agents

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

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