The effect of 18 pyridinium
aldoximes on diethylphosphoryl-acetocholinesterase in vitro and the protection against lethal
poisoning by ethyl
pyrophosphate (
TEPP) in mice pretreated with 0.095 m.mole/kg. of these
oximes was investigated. Monoximes and dioximes of polymethylenebispyridinium compounds were studied in greater detail since they were up to 22 times more potent than
pyridine-2-aldoxime methiodide (2-hydroxyiminomethyl-N-methylpyridinium iodide) in reactivating diethylphosphoryl-acetocholinesterase in vitro and protected mice against lethal
poisoning by up to 15 LD100 of ethyl
pyrophosphate. These
oximes were also up to 52 times more potent than
pyridine-2-aldoxime methiodide in reactivating di-isopropylphosphoryl-acetocholinesterase in vitro and were effective in preventing lethal
poisoning by
dyflos (di-isopropyl phosphorofluoridate). The antidotal action against diethyl
phosphostigmine (Ro 3-0340) was even greater than that against ethyl
pyrophosphate. Some of the most effective
oximes had antidotal actions in
poisoning by ethyl
pyrophosphate, diethyl
phosphostigmine and
dyflos when given in 0.0095 m.mole/kg. and this effect was enhanced by 1 mg./kg.
atropine sulphate. In vivo reactivation of diethylphosphoryl-acetocholinesterases by 0.0095 or 0.095 m.mole/kg. of
oximes of polymethylenebispyridinium compounds was demonstrated in blood but not in brain.
Atropine-like and neuromuscular blocking activities were studied on isolated organs and protection against lethal doses of
neostigmine and related
anticholinesterases were also investigated. Some of the
oximes of polymethylenebispyridinium compounds have, relative to
pyridine-2-aldoxime methiodide, a higher therapeutic ratio in mice and considerably greater water-solubility. The possible advantages to be gained from their use in preference to
pyridine-2-aldoxime methiodide are discussed.