Standard therapy of Organophosphorus Compound (OPC) poisoning with
oxime-type acetylcholinesterase (AChE) reactivators is unsatisfactory. New bispyridinium
oximes have therefore been synthesized. This review summarizes in vitro characteristics
of established (pralidoxime, obidoxime, trimedoxime, HI-6) and experimental (K-)oximes,
and compares their protective efficacy in vivo, when administered shortly after exposure
to Diisopropylfluorophosphate (DFP) and three OPC pesticides (ethyl-paraoxon, methylparaoxon,
azinphos-methyl) in the same experimental setting.
In addition to reactivating cholinesterase, oximes also inhibit this enzyme; strongest
AChE inhibition (IC50 rat blood: 1-9 µM) is observed in vitro for the oximes with a xylene
linker (K-107, K-108, K-113). AChE inhibition is weakest for K-27, K-48 and HI-6 (IC50
>500 µM). Intrinsic AChE inhibition of oximes in vitro (IC50, rat) is strongly correlated with their LD50 (rat):
oximes with a high IC50 (K-27, K-48, pralidoxime, obidoxime) also show a high LD50, making them relatively
non-toxic, whereas oximes K-107, K-108 and K-113 (low IC50 and LD50) are far more toxic.
When given in vivo after OP exposure, best protection is conferred by K-27, reducing the relative risk of death
to 16-58% of controls, which is significantly superior to pralidoxime in DFP-, ethyl-paraoxon- and methylparaoxon-
exposure, and to obidoxime in ethyl-paraoxon- and methyl-paraoxon-exposure. Marked reduction in
mortality is also achieved by K-48, K-53, K-74 and K-75, whereas K-107, K-108 and K-113 have no or only a
very weak mortality-reducing effect. K-27 is the most promising K-oxime due to its strong reactivation potency,
weak cholinesterase inhibition and high LD50, allowing administration in large, very efficacious dosages.
In vitro reactivation of trichlorfon-inhibited butyrylcholinesterase using HI-6, obidoxime, pralidoxime and K048