The Nature of the Toxicity of 2‐oxo‐oximes

Askew, Beryl M.; Davies, D. R.; Green, A. L.; Holmes, R.

doi:10.1111/j.1476-5381.1956.tb00010.x

Cited by 19 publications

(14 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since P-2-AM had no measurable effect on the inhibition produced by DFP it is difficult to see how the protection obtained by the combined use of atropine and P-2-AM could be entirely the result of enzyme reactivation. Askew (1956), who studied the antidotal properties of a series of oximes, was also unable to find any direct correlation between their potency as reactivators of sarin-inhibited cholinesterase in vitro and their effectiveness as antidotes of sarin poisoning of rats in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The results presented in this paper show that in the mouse pyridine-2-aldoxime methiodide (P-2-AM), which was the most active oxime found so far, was less effective in reactivating phosphorylated true cholinesterases in vivo than was indicated by the in vitro experiments. According to the findings of Askew, Davies, Green, and Holmes (1956) (Hobbiger, 1956;Davies and Green, 1956) has also to be considered in this connexion.…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps some of the differences observed in the experiments reported here are caused by them. Askew (1956) has-recently shown that the antidotal potency of a number of oximes varies between different species. This has to be borne in mind before the results in the mouse, especially the antidotal effects obtained by the combined use of atropine and P-2-AM, are generalized.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Hobbiger

1957

British Journal of Pharmacology and Chemotherapy

View full text Add to dashboard Cite

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 diisopropylphosphoryl 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 x I0D-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 I 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Hobbiger

1957

British Journal of Pharmacology and Chemotherapy

View full text Add to dashboard Cite

show abstract

“…The value of oximes administered with atropine in the treatment of organophosphate poisoning has been demonstrated by Kewitz and Wilson (1956), Kewitz, Wilson and Nachmansohn (1956), Hobbiger (1957), Wills, Kunkel, Brown and Groblewski (1957), Askew, Davies, and Green (1957), and Askew (1957). The toxicity of the more effective oximes is therefore a matter of some importance, particularly if they are to be used in man.…”

mentioning

confidence: 99%

“…respectively (unpublished observations). MINA is toxic because it is converted in the body into cyanide, a reaction which is probably specific to 2-oxo-aldoximes (Askew, Davies, Green, and Holmes, 1956).…”

mentioning

confidence: 99%

THE TOXICITY OF 2‐HYDROXYIMINOMETHYL‐NMETHYLPYRIDINIUM METHANESULPHONATE (P2S)

Davies¹,

Willey²

1958

British Journal of Pharmacology and Chemotherapy

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

John¹,

Blum

2011

Drug Testing and Analysis

View full text Add to dashboard Cite

Pralidoxime (2-PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2-PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2-PAM was introduced. In this time (mid-1950s until the end of the 1970s) 2-PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size-exclusion, reversed-phase, and ligand-exchange chromatography have been introduced. Today, the most popular method for 2-PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied. This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2-PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2-PAM are provided.

show abstract

The Nature of the Toxicity of 2‐oxo‐oximes

Cited by 19 publications

References 9 publications

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

THE TOXICITY OF 2‐HYDROXYIMINOMETHYL‐NMETHYLPYRIDINIUM METHANESULPHONATE (P2S)

Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

Contact Info

Product

Resources

About