The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-oximes bearing a (E)-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested oximes was equally effective against all used OPs. In addition, the data indicate that a (E)-but-2-ene linker decreased in most cases the reactivating potency in comparison to oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs.

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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.

High dose lipid emulsions and glucose derivatives stabilised organophosphorus compounds in vitro.

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