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. 1959 Jun;14(2):192–201. doi: 10.1111/j.1476-5381.1959.tb01383.x

Protection against lethal organophosphate poisoning by quaternary pyridine aldoximes

F Hobbiger, P W Sadler
PMCID: PMC1481808  PMID: 13662573

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ASKEW B. M. Oximes and hydroxamic acids as antidotes in anticholinesterase poisoning. Br J Pharmacol Chemother. 1956 Dec;11(4):417–423. doi: 10.1111/j.1476-5381.1956.tb00009.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BAY E., KROP S., YATES L. F. Chemotherapeutic effectiveness of 1,1'-trimethylene bis (4-formylpyridinium bromide) di-oxime (TMB-4) in experimental anticholinesterase poisoning. Proc Soc Exp Biol Med. 1958 May;98(1):107–110. doi: 10.3181/00379727-98-23955. [DOI] [PubMed] [Google Scholar]
  3. BETHE K., ERDMANN W. D., LENDLE L., SCHMIDT G. Spezifische Antidot-Behandlung bei protrahierter Vergiftung mit Alkylphosphaten (Paraoxon, Parathion, DFP) und Eserin an Meerschweinchen. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1957;231(1):3–22. [PubMed] [Google Scholar]
  4. BURGEN A. S. V., HOBBIGER F. The inhibition of cholinesterases by alkyl-phosphates and alkylphenolphosphates. Br J Pharmacol Chemother. 1951 Dec;6(4):593–605. doi: 10.1111/j.1476-5381.1951.tb00670.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. CHILDS A. F., DAVIES D. R., GREEN A. L., RUTLAND J. P. The reactivation by oximes and hydroxamic acids of cholinesterase inhibited by organo-phosphorus compounds. Br J Pharmacol Chemother. 1955 Dec;10(4):462–465. doi: 10.1111/j.1476-5381.1955.tb00106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. CONLEY B. E. Incidence of injury with pesticides. J Am Med Assoc. 1957 Apr 13;163(15):1338–1340. doi: 10.1001/jama.1957.02970500022006. [DOI] [PubMed] [Google Scholar]
  7. DIGGLE W. M., GAGE J. C. Cholinesterase inhibition in vitro by OO-diethyl O-p-nitrophenyl thiophosphate (parathion, E 605). Biochem J. 1951 Sep;49(4):491–494. doi: 10.1042/bj0490491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. ERDMANN W. D., LENDLE L. Vergiftungen mit esteraseblockierenden Insecticiden aus der Gruppe der organischen Phosphorsäure-Ester (E 605 und Verwandte). Ergeb Inn Med Kinderheilkd. 1958;10:104–184. [PubMed] [Google Scholar]
  9. FLEISHER J. H., CORRIGAN J. P., HOWARD J. W. Potentiation of the response of frog rectus muscle to acetylcholine by isopropyl methyl phosphonofluoridate and its modification by pyridine-2-aldoxime methiodide. Br J Pharmacol Chemother. 1958 Sep;13(3):291–295. doi: 10.1111/j.1476-5381.1958.tb00905.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. GORDON A. S., FRYE C. W. Large doses of atropine; low toxicity and effectiveness in anticholinesterase intoxication. J Am Med Assoc. 1955 Nov 19;159(12):1181–1184. doi: 10.1001/jama.1955.02960290007003. [DOI] [PubMed] [Google Scholar]
  11. GROB D., JOHNS R. J. Treatment of anticholinesterase intoxication with oximes; use in normal subjects and in patients with myasthenia gravis. J Am Med Assoc. 1958 Apr 12;166(15):1855–1858. doi: 10.1001/jama.1958.62990150001011. [DOI] [PubMed] [Google Scholar]
  12. HERZFELD E., KRAUPP O., PATEISKY K., STUMPF C. Pharmakologische und klinische Wirkungen des Cholinesterasehemmkörpers Hexamethylen-bis(N-methyl-carbaminoly-1-methyl-3-oxypyridiniumbromid) BC 51). Wien Klin Wochenschr. 1957 Apr 5;69(14):245–248. [PubMed] [Google Scholar]
  13. HOBBIGER F., O'SULLIVAN D. G., SADLER P. W. New potent reactivators of acetocholinesterase inhibited by tetraethyl pyrophosphate. Nature. 1958 Nov 29;182(4648):1498–1499. doi: 10.1038/1821498a0. [DOI] [PubMed] [Google Scholar]
  14. HOBBIGER F., SADLER P. W. Protection by oximes of bis-pyridinium ions against lethal diisopropyl phosphonofluoridate poisoning. Nature. 1958 Dec 13;182(4650):1672–1673. doi: 10.1038/1821672a0. [DOI] [PubMed] [Google Scholar]
  15. HOBBIGER F. The mechanism of anticurare action of certain neostigmine analogues. Br J Pharmacol Chemother. 1952 Jun;7(2):223–236. doi: 10.1111/j.1476-5381.1952.tb01317.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. HOLMES R., ROBINS E. L. The reversal by oximes of neuromuscular block produced by anticholinesterases. Br J Pharmacol Chemother. 1955 Dec;10(4):490–495. doi: 10.1111/j.1476-5381.1955.tb00110.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. KEWITZ H., NACHMANSOHN D. A specific antidote against lethal alkyl phosphate intoxication. IV. Effects in brain. Arch Biochem Biophys. 1957 Feb;66(2):271–283. [PubMed] [Google Scholar]
  18. KEWITZ H., NACHMANSOHN D., WILSON I. B. A specific antidote against lethal alkyl phosphate intoxication. II. Antidotal properties. Arch Biochem Biophys. 1956 Oct;64(2):456–465. doi: 10.1016/0003-9861(56)90288-0. [DOI] [PubMed] [Google Scholar]
  19. KOELLE G. B. Histochemical demonstration of reactivation acetylcholinesterase in vivo. Science. 1957 Jun 14;125(3259):1195–1196. doi: 10.1126/science.125.3259.1195. [DOI] [PubMed] [Google Scholar]
  20. KOELLE G. B., STEINER E. C. The cerebral distributions of a tertiary and a quaternary anticholinesterase agent following intravenous and intraventricular injection. J Pharmacol Exp Ther. 1956 Dec;118(4):420–434. [PubMed] [Google Scholar]
  21. KRAUPP O., STUMPF C., HERZFELD E., PILLAT B. Pharmakologische Eigenschaften einiger langwirksamer Cholinesterasehemmkörper aus der Reihe der Polymethylen-bis-(Carbaminoyl-m-Trimethylammoniumphenole). Arch Int Pharmacodyn Ther. 1955 Jul 1;102(3):281–303. [PubMed] [Google Scholar]
  22. MARESCH W. Die Vergiftung durch Phosphorsäureester; E 605, Parathion, Thiophos. Arch Toxikol. 1957;16(5):285–319. [PubMed] [Google Scholar]
  23. NAMBA T., HIRAKI K. PAM (pyridine-2-aldoxime methiodide) therapy for alkyl-phosphate poisoning. J Am Med Assoc. 1958 Apr 12;166(15):1834–1839. doi: 10.1001/jama.1958.02990150030007. [DOI] [PubMed] [Google Scholar]
  24. PARKES M. W., SACRA P. Protection against the toxicity of cholinesterase inhibitors by acetylcholine antagonists. Br J Pharmacol Chemother. 1954 Sep;9(3):299–305. doi: 10.1111/j.1476-5381.1954.tb01685.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. PATON W. D. M., ZAIMIS E. The methonium. Pharmacol Rev. 1952 Sep;4(3):219–253. [PubMed] [Google Scholar]
  26. PRIBILLA O. Vergiftungen mit E 605 (O, O-Diätyl-O, p-nitrophenyl-thiophosphorsäureester); Sammelbericht über die bis 1.1. 55 publizierten und 10 eigene Todesfälle sowie über die theoretischen Grundlagen der Vergiftung und der Nachweismethoden. Arch Toxikol. 1955;15(4-5):210–284. [PubMed] [Google Scholar]
  27. QUINBY G. E., LEMMON A. B. Parathion residues as a cause of poisoning in crop workers. J Am Med Assoc. 1958 Feb 15;166(7):740–746. doi: 10.1001/jama.1958.02990070026007. [DOI] [PubMed] [Google Scholar]
  28. RUTLAND J. P. The effect of some oximes in sarin poisoning. Br J Pharmacol Chemother. 1958 Dec;13(4):399–403. doi: 10.1111/j.1476-5381.1958.tb00228.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. SCHOFFENIELS E., WILSON I. B., NACHMANSOHN D. Overshoot and block of conduction by lipid-soluble acetylcholine analogues. Biochim Biophys Acta. 1958 Mar;27(3):629–633. doi: 10.1016/0006-3002(58)90397-4. [DOI] [PubMed] [Google Scholar]
  30. WILSON I. B., GINSBURG B. A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim Biophys Acta. 1955 Sep;18(1):168–170. doi: 10.1016/0006-3002(55)90040-8. [DOI] [PubMed] [Google Scholar]

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