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PROTECTION AGAINST THE LETHAL EFFECTS OF ORGANO‐PHOSPHATES BY PYRIDINE‐2‐ALDOXIME METHIODIDE
Author(s) -
HOBBIGER F.
Publication year - 1957
Publication title -
british journal of pharmacology and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0366-0826
DOI - 10.1111/j.1476-5381.1957.tb00162.x
Subject(s) - methiodide , cholinesterase , organophosphate , chemistry , acetylcholinesterase , pharmacology , in vivo , oxime , antidote , enzyme , biochemistry , toxicity , biology , pesticide , microbiology and biotechnology , organic chemistry , agronomy
The mechanism responsible for the protection against lethal organophosphate poisoning by pyridine‐2‐aldoxime methiodide (P‐2‐AM) was studied in the mouse. Two types of organophosphates were used: ethyl pyrophosphate (TEPP), E 600, Ro 3–0340, and Ro 3–0422 which form with true cholinesterase a diethylphosphoryl enzyme (1) and DFP, D 600 and Ro 3–0351 which form with true cholinesterase a di iso propylphosphoryl enzyme (2). In vitro and under the experimental conditions used more than 50% reactivation of (1) was obtained within 1 hr. by concentrations of P‐2‐AM ranging from 0.5 to 1 × 10 −6 m ; 30 times higher concentrations of the oxime were required to achieve the same effect with (2). In vivo reactivation of phosphorylated true cholinesterases in blood amounted to 10 to 24% within the first 30 min. if 25 mg./kg. P‐2‐AM was injected (i.p.) 5 min. before a sublethal dose of TEPP, E 600, Ro 3–0340, or Ro 3–0422 and reactivation reached a maximum within 1 to 2 hr. after the injection of the oxime. P‐2‐AM was more effective when given 30 min. after the organophosphate. The effect of 25 mg./kg. P‐2‐AM on the phosphorylated true cholinesterase in brain (experiments with TEPP and E 600) was negligible. A dose of 25 mg./kg. P‐2‐AM had no consistent effect on the phosphorylated true cholinesterases in blood and brain of mice injected with sublethal doses of DFP, D 600, or Ro 3–0351. The protection by 25 mg./kg. P‐2‐AM against lethal doses of TEPP, E 600, Ro 3–0422, and Ro 3–0340 was greater than that obtained with 50 mg./kg. atropine sulphate, but the degree of protection was determined by the organophosphate itself and not its dialkylphosphoryl group. Protection by 25 mg./kg. P‐2‐AM against lethal doses of DFP, D 600, and Ro 3–0351 was negligible. The antidotal effect of P‐2‐AM was potentiated by atropine. Mice which were injected with atropine and P‐2‐AM were protected to a greater extent against DFP than against Ro 3–0422, and protection against DFP was only slightly less than protection against TEPP. This is difficult to reconcile with a specific action of P‐2‐AM on phosphorylated cholinesterases.