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Oximes and atropine in sarin poisoning.

Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.

Animals↗

The effect of some oximes in sarin poisoning.

The effects of monoisonitrosoacetone (MINA), diacetylmonoxime (DAM) and pyridine-2-aldoxime methiodide (P2AM) upon the cholinesterase of sarin poisoned rats have been studied. Monoisonitrosoacetone and diacetylmonoxime given before sarin protected blood and brain cholinesterase from inhibition. Monoisonitrosoacetone given after the appearance of signs of poisoning caused a rapid reactivation of brain cholinesterase. Diacetylmonoxime, at an equimolar dose, produced only a slight increase in enzyme activity, and pyridine-2-aldoxime methiodide, the best reactivator in vitro, reactivated blood but not brain cholinesterase. There is a relationship between protection and reactivation of brain cholinesterase and prevention and alleviation of signs of poisoning.

Animals↗

Potentiation of the response of frog rectus muscle to acetylcholine by isopropyl methyl phosphonofluoridate and its modification by pyridine-2-aldoxime methiodide.

Pyridine-2-aldoxime methiodide (P2AM) was used to study the relation between the recovery of cholinesterase activity of isolated frog rectus abdominis muscle and the change of isotonic response to acetylcholine after previous treatment with the anticholinesterase, isopropyl methyl phosphonofluoridate (sarin). Addition of P2AM to muscle which had been incubated with sarin produced an 88% decrease in potentiation to acetylcholine. This was accompanied by 71% and 35% recoveries of the cholinesterase activity of the intact and finely ground muscle respectively compared with controls from the contralateral muscle. Following pre-treatment with sarin, a two-hour rinsing with acetylcholine (3 mug./ml.) produced a 61% decrease in potentiation to acetylcholine accompanied by 24% and 4.5% recoveries of cholinesterase activity in intact and in ground muscle respectively. Since control experiments showed absence of uncombined sarin in the muscle after rinsing with acetylcholine solution, the results indicate a greater effectiveness of P2AM and acetylcholine in reactivating superficially situated cholinesterase of the frog rectus abdominis as compared with enzyme within the interior of the muscle.

Acetylcholine↗

Protection against lethal organophosphate poisoning by quaternary pyridine aldoximes.

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.

Animals↗