Protection Against Lethal Organophosphate Poisoning by Quaternary Pyridine Aldoximes

Hobbiger, F.; Sadler, P. W.

doi:10.1111/j.1476-5381.1959.tb01383.x

Cited by 53 publications

(29 citation statements)

References 33 publications

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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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Section: Discussionmentioning

confidence: 99%

A Central Vasodepressor Effect of Dyflos

Edery

Guertzenstein

1974

British J Pharmacology

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“…On the other hand, it is well known that TMB-4 possesses curare-and atropine-like effects and exerts hypotension in experimental animals. Hobbiger & Sadler (1959) showed that TMB-4 reduced sensitivity of small intestine to acetylcholine in guinea pigs while Bošković & Stern (1963) proved its direct effect on the activity of the rat striated muscle. Results of Lindgren & Sundwall (1960) confirmed its strong parasympatholytic effect in animals not exposed to organophosphates.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos or Monocrotophos

Antonijević

Bokonjić²,

Stojiljković³

et al. 2005

Basic Clin Pharma Tox

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The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos Ͼ heptenophos Ͼ dichlorvos. Administration of the oxime produced a significant reactivation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of monocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organophosphorus compounds, although the biochemical findings were quite different.

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“…This probably is the consequence of a blocking action of the drug on postjunctional nicotinic cholinoceptors (Hobbiger & Sadler, 1959;Fleisher et al, 1960) and comparable to the antagonism of twitch potentiation by tubocurarine (Brown, Dale & Feldberg, 1936).…”

Section: Discussionmentioning

confidence: 99%

Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations

Clark

Hobbiger

1983

British J Pharmacology

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1Twitch potentiation produced by anticholinesterases has been variously attributed to the prolonged postjunctional action of acetylcholine (ACh), a prejunctional action of ACh involving the initiation of antidromic firing (ADF) in the nerve or a direct action of the anticholinesterases on nerve terminals initiating ADF.2 The organophosphate anticholinesterases, paraoxon (diethyl-4-nitrophenylphosphate) and DFP (diisopropyl fluorophosphate), when applied to rat isolated diaphragm preparations for 30 min, produced twitch potentiation which subsequently declined. 3 The rates of onset and decline of twitch potentiation were directly related to the concentration of the organophosphates and the reversibility of their effects was in line with the reactivation of the phosphorylated enzymes formed by them, whether reactivation was spontaneous or induced by the oxime, N,N'-trimethylene-1, 3-bis (pyridinium-4-aldoxime). 4 Reducing the output of ACh from nerve terminals (by reducing the ratio of calcium: magnesium ions in the bathing solution) or reducing the affinity of ACh for the nicotinic cholinoceptor (using the disulphide bond reducing agent, dithiothreitol) produced the same effects as did lowering the concentration of the organophosphates. 5 It is concluded that the twitch potentiation produced by paraoxon and DFP, and its failure to be maintained when the higher concentrations of the organophosphates were used, were the direct result of the excess of ACh in the synaptic cleft, following inhibition of acetylcholinesterase.

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Protection Against Lethal Organophosphate Poisoning by Quaternary Pyridine Aldoximes

Cited by 53 publications

References 33 publications

A Central Vasodepressor Effect of Dyflos

A Central Vasodepressor Effect of Dyflos

Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos or Monocrotophos

Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations

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