Human plasma-derived BuChE as a stoichiometric bioscavenger for treatment of nerve agent poisoning

Mumford, Helen; Docx, Cerys; Price, Matthew E.; Green, A. Christopher; Tattersall, J.E.H.; Armstrong, Stuart J.

doi:10.1016/j.cbi.2012.08.018

Cited by 58 publications

(27 citation statements)

References 15 publications

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“…Recent work, primarily with the stoichiometric bioscavenger human BChE, investigated the potential for post-exposure prophylaxis (Mumford et al, 2013;Mumford and Troyer, 2011). Hereby, it became obvious that administration of a bioscavenger after nerve agent exposure is only effective before clinical signs of poisoning develop and the effectiveness of the bioscavenger drops dramatically thereafter (Mumford et al, 2013).…”

Section: Catalytic Bioscavengers: Concept Of Usementioning

confidence: 99%

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Catalytic bioscavengers in nerve agent poisoning: A promising approach?

Worek¹,

Thiermann²,

Wille³

2016

Toxicology Letters

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Section: Catalytic Bioscavengers: Concept Of Usementioning

confidence: 99%

“…Hereby, it became obvious that administration of a bioscavenger after nerve agent exposure is only effective before clinical signs of poisoning develop and the effectiveness of the bioscavenger drops dramatically thereafter (Mumford et al, 2013).…”

Section: Catalytic Bioscavengers: Concept Of Usementioning

confidence: 99%

Catalytic bioscavengers in nerve agent poisoning: A promising approach?

Worek¹,

Thiermann²,

Wille³

2016

Toxicology Letters

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“…Yet, stoichiometric scavengers would necessitate the administration of an enormous amount in humans and would only prevent signs of poisoning if administered before the poison reaches target tissues (Mumford et al 2013). Therefore, catalytic scavengers are being developed and show, in principal, feasibility for prophylaxis and therapy in nerve agent poisoning.…”

Section: Introductionmentioning

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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“…10,11 The second one is based on natural or engineered forms of AChE/butyrylcholinesterase (BChE) as suicide enzymes. [12][13][14] A transgenic-derived recombinant BChE in a pegylated form (Protexia TM ) is the only such agent entered in a Phase 1 clinical study, 15 which ended in 2009 (NCT00744146).…”

Section: Introductionmentioning

confidence: 99%