Prompt recovery from severe cholinesterase-inhibitor poisoning — Remarks on classification and therapy of organophosphate poisoning

Wilde, de; Vogelaers, Dirk; Colardyn, Francis

doi:10.1007/bf01660960

Cited by 6 publications

(1 citation statement)

References 6 publications

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“…When large amounts of OP are present in vivo (such as in a megadose pesticide suicide), the POX formed by direct reaction of OP with oxime may accumulate fast enough to saturate PON activity and manifest its toxic effect. This may be the reason for the unexplained peripheral paralysis of respiratory muscle, the primary cause of death in the Intermediate Syndrome (IMS) observed during the treatment of poisoning by some OP pesticides and often correlated with a sharp drop of cholinesterase activity in the blood when it occurred ( − ). Therefore, oximes, such as LüH6 and TMB4, that may form relatively stable POXs and produce inhibition of reactivated enzyme during reactivation in vitro as confirmed by this study, or 2-PAM and MMB4, as indicated by several former studies ( 15−18 , 20 , 21 ), should be used with caution during the treatment of OP pesticide poisoning.…”

Section: Discussionmentioning

confidence: 99%

Phosphoryl Oxime Inhibition of Acetylcholinesterase during Oxime Reactivation Is Prevented by Edrophonium

et al. 1999

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Reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a key objective in the treatment of OP poisoning. This study with native, wild-type, and mutant recombinant DNA-expressed AChEs, each inhibited by representative OP compounds, establishes a relationship between edrophonium acceleration of oxime-induced reactivation of OP-AChE conjugates and phosphoryl oxime inhibition of the reactivated enzyme that occurs during reactivation by pyridinium oximes LüH6 and TMB4. No such recurring inhibition could be observed with HI-6 as the reactivator due to the extreme lability of the phosphoryl oximes formed by this oxime. Phosphoryl oximes formed during reactivation of the ethoxy methylphosphonyl-AChE conjugate by LüH6 and TMB4 were isolated for the first time and their structures confirmed by (31)P NMR. However, phosphoryl oximes formed during the reactivation of the diethylphosphoryl-AChE conjugate were not sufficiently stable to be detected by (31)P NMR. The purified ethoxy methylphosphonyl oximes formed during the reactivation of ethoxy methylphosphonyl-AChE conjugate with LüH6 and TMB4 are 10- to 22-fold more potent than MEPQ as inhibitors of AChE and stable for several hours at pH 7.2 in HEPES buffer. Reactivation of both ethoxy methylphosphonyl- and diethylphosphoryl-AChE by these two oximes was accelerated in the presence of rabbit serum paraoxonase, suggesting that organophosphorus hydrolase can hydrolyze phosphoryl oxime formed during the reactivation. Our results emphasize that certain oximes, such as LüH6 and TMB4, if used in the treatment of OP pesticide poisoning may cause prolonged inhibition of AChE due to formation of phosphoryl oximes.

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Section: Discussionmentioning

confidence: 99%

Phosphoryl Oxime Inhibition of Acetylcholinesterase during Oxime Reactivation Is Prevented by Edrophonium

et al. 1999

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Urinary excretion of diethylphosphorus metabolites in persons poisoned by quinalphos or chlorpyrifos

Vasilić

Drevenkar

Rumenjak

et al. 1992

Arch. Environ. Contam. Toxicol.

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The urinary excretion rates of diethyl phosphate and diethyl phosphorothioate and changes in blood cholinesterase activities were studied in fifteen persons self-poisoned either by the organophosphorus pesticide quinalphos (twelve persons) or by chlorpyrifos (three persons). The organophosphate poisoning was always indicated by a significant depression of serum and/or red blood cell cholinesterase activities. The return of serum cholinesterase activity in the range of referent values took more than 30 days and had a different course in different persons. The most rapid increase in red blood cell acetylcholinesterase activity was noted within 24 h after the first treatment with oximes Pralidoxime and/or HI-6. None of the spot urine samples, collected daily after admission of persons to hospital, contained measurable quantities of the parent pesticide. There was no correlation between the maximum concentration of total urinary diethylphosphorus metabolites normalized to creatinine and the initial inhibition of blood cholinesterase activities measured in samples collected on the day of admission to hospital. The excretion of metabolites followed the kinetics of a biphasic reaction. The half-time of urinary metabolites concentration decrease in the fast excretion phase in quinalphos poisoned persons was 5.5-14.2 h (eight persons) and 26.8-53.6 h (four persons) and in chlorpyrifos poisoned persons 3.5-5.5 h. The half-time for the slow excretion phase ranged from 66.5 to 127.9 h in all persons and for both compounds. For a given person, the rates of excretion of diethyl phosphate and diethyl phosphorothioate were about the same. However, in quinalphos poisoned persons the proportions of single metabolites in total diethylphosphorus metabolites varied with the initial maximum concentration of total metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

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The functional role of molecular forms of acetylcholinesterase in neuromuscular transmission

Busker

Wiel

et al. 1994

Neurochem Res

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The severity of poisoning following acetylcholinesterase (AChE) inhibition correlates weakly with total AChE activity. This may be partly due to the existence of functional and non-functional pools of AChE. AChE consists of several molecular forms. The aim of the present study was to investigate which of these forms will correlate best with neuromuscular transmission (NMT) remaining after partial inhibition of this enzyme. Following sublethal intoxication of rats with the irreversible AChE inhibitor soman, diaphragms were isolated after 0.5 or 3 h. It appeared that at 3 h after soman poisoning the percentage of G1 increased, while those of G4 and A12 decreased. NMT was inhibited more strongly than in preparations obtained from the 0.5 h rats with the same level of AChE inhibition, but with a normal ratio of molecular forms. NMT correlated positively with G4 as well as with A12, but inversely with G1. In vitro inhibition with the charged inhibitors DEMP and echothiophate resulted in higher levels of total AChE, relatively less G1 and more G4 and A12 than after incubation with soman, but led to less NMT. Treatment of soman-intoxicated rats with the reactivating compound HI-6 resulted in preferential reactivation of A12, persisting low levels of G1 and concurrent recovery of NMT as compared with saline-treated soman controls with equal total AChE activity. Apparently, in rat diaphragm G4 and A12 are the functional AChE forms.

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Prompt recovery from severe cholinesterase-inhibitor poisoning — Remarks on classification and therapy of organophosphate poisoning

Cited by 6 publications

References 6 publications

Phosphoryl Oxime Inhibition of Acetylcholinesterase during Oxime Reactivation Is Prevented by Edrophonium

Phosphoryl Oxime Inhibition of Acetylcholinesterase during Oxime Reactivation Is Prevented by Edrophonium

Urinary excretion of diethylphosphorus metabolites in persons poisoned by quinalphos or chlorpyrifos

The functional role of molecular forms of acetylcholinesterase in neuromuscular transmission

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