A Comparison of the Efficacy of Acetylcholinesterase Reactivators against Cyclohexyl Methylphosphonofluoridate (GF Agent) by in vitro and in vivo Methods

Abstract

The purpose of this study was to compare the therapeutic efficacy of a new acetylcholinesterase reactivator, designated BI-6 (1-(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-2-butene dibromide), with presently used oximes (pralidoxime, obidoxime, methoxime) and H-oximes (HI-6, HLo-7) by in vitro and in vivo methods. In vitro, methoxime seems to be the most efficacious reactivator of OF agent-inhibited acetylcholinesterase because the phosphonylation of acetylcholinesterase by OF agent markedly increases its affinity for the enzyme. The oxime BI-6 is more efficacious than other presently used oximes (pralidoxime, obidoxime) but its reactivating efficacy does not reach the efficacy of H-oximes tested. On the other hand, obidoxime and pralidoxime appear to be very poor reactivators of OF agentinhibited acetylcholinesterase because the phosphonylation of acetylcholinesterase by OF agent markedly decreases their affinity to the enzyme. In vivo, H oximes (HI-6, HLo-7) are the most efficacious antidotes for the treatment of acute poisoning with OF agent in rats while the presently used oximes such as pralidoxime and obidoxime are practically ineffective. BI-6 and methoxime are more efficacious than pralidoxime and obidoxime, nevertheless their therapeutic efficacy does not reach the efficacy of H oximes. Our results show that the ability of oximes to reactivate OF agentinhibited acetylcholinesterase in vitro usually corresponds to their therapeutic effects against OF agent in vivo.

A Comparison of the Neuroprotective Efficacy of Newly Developed Oximes (K156, K203) and Currently Available Oximes (Obidoxime, HI-6) in Cyclosarin-poisoned Rats

“…This is due to the fact that the oxime group of both newly synthesized oximes is situated in position 4. The oxime HI-6 having an oxime group in position 2 generally showed markedly higher reactivating and therapeutic efficacy against cyclosarin than other commonly used oximes (6,8,9), although the differences between the neuroprotective efficacy of the oxime HI-6 and other oximes studied are not as high in this study.…”

“…On the other hand, the number of aldoxime groups is not so important. The oxime HI-6 has only one oxime group but it is significantly more efficacious to reactivate cyclosarin-inhibited AChE than bispyridinium oximes with two aldoxime groups, such as obidoxime, methoxime or trimedoxime (6,9). The chain linking the two quaternary nitrogens in bispyridinium oximes exerts a great influence on the reactivating and therapeutic efficacy, although this part of the oxime reactivator molecule does not play any role in the dephosphorylation process.…”

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…Even the oxime HI-6 that is considered to be the best reactivator of cyclosarin-inhibited AChE (6,9,10,20,21) is not satisfactorily effective oxime for the elimination of cyclosarin-induced neurotoxic signs and symptoms due to low penetration through BBB and low reactivating efficacy in the CNS (6,22). On the other hand, it is known that the oximes may also attentuate nerve agent-induced brain insult via different mechanisms other than AChE reactivation (35).…”

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…Similar results were obtained for obidoxime. Obidoxime has no ability to reactivate cyclosarin-inhibited AChE in vitro, and its potency to reactivate tabun-inhibited AChE in vitro is poor [9]. Currently the most promising AChE reactivator, oxime HI-6, is the strongest in vitro and in vivo reactivator against almost all of the nerve agents [5,10].…”