Spezifische Antidot-Behandlung bei protrahierter Vergiftung mit Alkylphosphaten (Paraoxon, Parathion, DFP) und Eserin an Meerschweinchen

Bethe, K.; Erdmann, W. D.; Lendle, L.; Schmidt, Gerhard

doi:10.1007/bf00246123

Cited by 28 publications

(7 citation statements)

References 14 publications

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“…Since atropine-like and neuromuscular blocking activities of pyridine-2-aldoxime methiodide have been demonstrated on isolated organs (Bethe, Erdmann, Lendle and Schmidt, 1957 ;Holmes and Robins, 1955), all oximes of polymethylenebispyridinium compounds'were investigated for such properties. No relationship was found between the atropine-like activity of the oximes and their ability to paralyse indirectly stimulated striped muscle on the one hand and their effectiveness as antidotes on the other.…”

Section: Resultsmentioning

confidence: 99%

Protection Against Lethal Organophosphate Poisoning by Quaternary Pyridine Aldoximes

Hobbiger

Sadler

1959

British Journal of Pharmacology and Chemotherapy

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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-isopropylphosphorylacetocholinesterase 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.The interaction between anticholinesterases of the organophosphate type and acetocholinesterase (also often referred to as true cholinesterase or acetylcholinesterase) yields phosphorylated acetocholinesterase which is enzymatically inactive and in many instances has a half-life ranging from several days to weeks. While cholinesterase is in a phosphorylated form acetylcholine accumulates and thus the administration of organophosphates is followed by muscarinic and nicotinic symptoms of acetylcholine poisoning.

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Section: Resultsmentioning

confidence: 99%

Protection Against Lethal Organophosphate Poisoning by Quaternary Pyridine Aldoximes

Hobbiger

Sadler

1959

British Journal of Pharmacology and Chemotherapy

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“…This possibility had to be considered because in higher concentrations both oxidoxime and pralidoxime have a peripheral atropine-like action and antagonize the contractions produced by acetylcholine and carbachol on isolated smooth muscle preparations (Bethe, Erdmann, Lendle & Schmidt, 1957;Hobbiger & Sadler, 1959;Lehmann, 1962;Kuhnen-Clausen, 1970). They may therefore also have a central atropine-like action.…”

Section: Discussionmentioning

confidence: 99%

A Central Vasodepressor Effect of Dyflos

Edery

Guertzenstein

1974

British J Pharmacology

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1 Cats were anaesthetized with pentobarbitone sodium and atropinized peripherally by intravenous injection of atropine methyl nitrate; the effect was examined of topical bilateral application of dyflos to the ventral surface of the medulla oblongata at a region lateral to the pyramids and caudal to the trapezoid bodies. Dyflos was applied by means of perspex rings; the volume of fluid placed in each ring was 10 gl.2 The topical application of dyflos (1-20 mg/ml) produced a fall in arterial blood pressure without changes in heart rate and, in experiments without artificial ventilation, tachypnoea with dissociation of thoracic and abdominal respiration. 3 Atropine methyl nitrate (50 mg/ml) applied topically in the same way as dyflos, prevented or abolished its vasodepressor effect. 4 The two reactivators of acetylcholinesterase, obidoxime (100-200 mg/ml) and pralidoxime mesylate (100-200 mg/ml), applied topically in the same way as dyflos, abolished its vasodepressor effect. The reactivator compound 30 (100 mg/ml), also a pyridinium aldoxime, did not have this effect. 5 Obidoxime and pralidoxime mesylate also reversed the vasodepression produced by carbachol applied to the ventral surface of the brain stem but not the vasodepression produced by glycine similarly applied. 6 The problem is discussed as to whether the reversal of the dyflos and carbachol-induced vasodepression by obidoxime and pralidoxime is due to acetylcholinesterase reactivation by dephosphorylation and decarbamylation respectively, to a central atropine-like action of these compounds or to a combination of both.

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“…Animals poisoned with eserine, which does not give a phosphorylated enzyme, or with tabun or OMPA, which give amidophosphoryl enzymes relatively resistant to reactivation, could not be satisfactorily treated with PAM (Kewitz, Wilson, and Nachmansohn, 1956;Bethe, Erdmann, Lendle, and Schmidt, 1957;Wilson and Sondheimer, 1957 Kewitz et at. (1956) i.…”

Section: Ho Nh2mentioning

confidence: 99%

“…Wilson and Sondheimer (1957) muscular block had previously been shown on isolated tissue preparations (Holmes and Robins, 1955). It will also counteract the bradycardia due to organophosphates and this too may contribute to its therapeutic activity (Bethe et al, 1957). The inability to overcome central respiratory depression may be due to failure of PAM, a quaternary salt, to penetrate into the central nervous system.…”

Section: Ho Nh2mentioning

confidence: 99%