pralidoxime and 1-methylpyridinium

The soluble methanesulphonate of the oxime 2-hydroxyiminomethyl-N-methylpyridinium (P2S) has been used to treat animals poisoned with sarin or ethyl pyrophosphate. The effect of the size of the dose, and its time of administration in relation to poisoning, have been examined. This oxime is very efficient in conjunction with atropine when given either before or after poisoning. About 30 mg./kg. seems to be the optimum therapeutic dose of the methanesulphonate. The significance of this optimum is discussed in relation to the treatment of accidental poisoning by organophosphate insecticides in man.

Topics: Animals; Atropine; Diphosphates; Humans; Insecticides; Male; Mesylates; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Pyrans; Pyridinium Compounds; Sarin

Sixteen compounds of the general structure {HON: CH.C(5)H(4)N(+).[CH(2)](n).R(+)}2Br(-) have been synthesized in which the position of the oxime group in the pyridine ring, the second charged group R(+) and the number of methylene groups between the charged atoms have been varied. The rate at which these compounds reactivate cholinesterase inhibited by ethyl pyrophosphate has been studied and a number have been found which are more active than 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate. Since considerable variation in structure was found among those compounds which are better reactivators than the latter, the concept that 2-hydroxyiminomethyl-N-methylpyridinium salts are unique in their ability to fit the surface of the inhibited enzyme is no longer tenable. The reactivating power of these oximes correlated well with their ability, when given in conjunction with atropine, to save the lives of mice poisoned by ethyl pyrophosphate. The most effective compounds, NN'-trimethylenebis-(4-hydroxyiminomethylpyridinium bromide) and NN'-hexamethylenebis(2-hydroxyiminomethylpyridinium bromide), contained a further oxime group in R(+), but the second oxime group was not essential for high activity. These new oximes were also superior in saving the lives of mice poisoned with sarin (isopropyl methylphosphonofluoridate), but the improvement was not as dramatic as when the mice were poisoned with ethyl pyrophosphate. The toxicity of the compounds varied with both n and R(+) and was unrelated to the therapeutic potency.

Topics: Alkanes; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Hydroxylamines; Mice; Organophosphates; Oximes; Phosphates; Pralidoxime Compounds; Pyridines; Pyridinium Compounds; Salts

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.

Topics: Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Hydroxylamines; Isoflurophate; Mice; Neostigmine; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Pyrans; Pyridines; Pyridinium Compounds

Topics: Antidotes; Mesylates; Organophosphate Poisoning; Pralidoxime Compounds; Pyridines; Pyridinium Compounds

The toxicity of 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate (P2S) has been determined in a number of species by various routes. It is approximately equally toxic in the rat, mouse, and guinea-pig. It is much more toxic in the dog. Atropine influences the toxicity of P2S differently in different species. From the results obtained attempts have been made to assess the maximum safe dose which can be given intramuscularly to man.

Topics: Animals; Dogs; Guinea Pigs; Humans; Male; Mesylates; Mice; Pralidoxime Compounds; Pyridines; Pyridinium Compounds; Rats