title: Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6.
abstract: 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.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937, Munich, Germany. timowille@bundeswehr.org.
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: von der Wellen
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D001665:Binding Sites; D001800:Blood Specimen Collection; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005615:Freezing; D006801:Humans; D008658:Inactivation, Metabolic; D009768:Obidoxime Chloride / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*
chemical_list: D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009768:Obidoxime Chloride; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; C009680:VX-agent; C022870:asoxime chloride
keywords: Blood; Nerve agent; Oxime; Pseudocatalytic; Scavenging