The Chemotherapy of Poisoning by Organophosphate Anticholinesterases

Davies, D. R.; Green, A. L.

doi:10.1136/oem.16.2.128

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…Following the rapid conversion of Pro-2-PAM to 2-PAM (t 1/2 = 1 min) and the rapid elimination of Pro-2-PAM (t1/2 = 20 min), the resulting 2-PAM was able to reactivate somaninhibited AChE but did not ameliorate the survival rate (Bodor et al, 1978;Bosković et al, 1980;Clement, 1979;Davies and Green, 1959). Determination of the acute toxicity of Pro-2-PAM outlined some particularities: toxicity was similar to PAM after i.p.…”

Section: Consequences Of Increasing Oxime Bbb Penetrationmentioning

confidence: 94%

“…It has been demonstrated that cholinesterase reactivators, at least partially, potentiate atropine effects and significantly improve survival of OP intoxicated animals, beginning with the first experimental tests with compounds like diacetylmonooxime (DAM) or monoisonitrosoacetone (MINA) (Askew, 1957;Davies and Green, 1959;Hobbiger, 1961;Rajapurkar and Koelle, 1958). A series of experimental observations proved the inefficacy of the oximes with tertiary structure and their lack of efficacy in reactivation of AChE inhibited by super-toxic chemicals such as nerve agents (sarin, soman, tabun, VX).…”

Section: Introductionmentioning

confidence: 97%

“…This last effect is relevant for emphasizing the antidotal effects. Their effects at the peripheral tissue AChE level are widely recognized (Bajgar, 2004;Davies and Green, 1959;Dawson, 1994;Marrs, 1991).…”

Section: Introductionmentioning

confidence: 98%

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Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

Voicu

Bajgar

Medvedovici

et al. 2010

J of Applied Toxicology

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Undoubtedly, the use of oximes represents real progress in counteracting intoxications with organophosphates (OP), through potentiating antidotal effects of atropine. The penetration extent of these compounds through the blood-brain barrier (BBB) to significantly reactivate phosphorylated or phosphonylated acetylcholinesterase (AChE) in the brain still remains a debatable issue. Penetration of biological barriers by oximes was investigated mainly through determination of several quantitative parameters characterizing digestive absorption and BBB penetration. A weak penetration of biological barriers could be concluded from the available experimental data. The functional parameters/therapeutic effects following the penetration of oximes through BBB, more precisely the antagonism of OP-induced seizures and hypothermia, prevention of brain damage and respiratory center protection, leading to the final end-point, the survival of intoxicated organisms, are of high interest. It seems obvious that oximes are weakly penetrating the BBB, with minimal brain AChE reactivation (<5%) in important functional areas, such as the ponto-medullar. The cerebral protection achieved through administration of oximes is only partial, without major impact on the antagonism of OP-induced seizures, hypothermia and respiratory center inhibition. The antidotal effects probably result from synergic effects of other PD properties, different from the brain AChE reactivation process. Oxime structures especially designed for enhanced BBB penetration, through potentiating the hydrophobic characteristics, more often produce neurotoxic effects. Certainly, obtaining oximes with broad action spectrum (active against all OP types) would make a sense, but certainly, such a target is not achievable only through the increase in their penetrability in the brain.

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Section: Consequences Of Increasing Oxime Bbb Penetrationmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

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Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

Voicu

Bajgar

Medvedovici

et al. 2010

J of Applied Toxicology

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“…Furthermore, many studies of prophylactic and therapeutic treatmcnt in animals and therapeutic treatment in man havc indicated the efficacy of 2-PAM in the treatment of alkyl phosphate intoxica tion (24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

The Metabolism of the Alkylphosphate Antagonists and its Pharmacologic Implications

Way¹,

Way²

1968

Annu. Rev. Pharmacol.

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Studies on the metabolic disposition of chemical compounds have so accelerated in the past few years that if a general review of the subject for the last year were attempted, it would be possible to give no more than a sketchy summary of the voluminous literature in the space allocated. More comprehensive reviews on the general topic of drug metabolism are available as monographs (1-3). The present review, like many previous ones appear ing in this series on drug metabolism (4-6), is restricted to selected topics, and is primarily concerned with a descriptive and interpretive appraisal of the status of the alkylphosphate antagonists, also known as the cholinesterase reactivators. These compounds are of interest because of their ability to antagonize the toxic effects of the organophosphorous cholinesterase inhibi tors that are used as insecticides and war gases.All compounds in the alkylphosphate antagonist series are nucleophilic agents and are mainly oximes. Although the organic oximes have been em ployed by chemists for a number of years, very little is really known con cerning the biotransformation of this functional group. Yamafugi and co workers (7-9) have investigated the metabolism of organic oximes in plants, silkworms, and other animals. Mahadevan ( 10) has reported on the metabo lism of 3-indoleacetaldoxime from various plants and fungi. However, the impetus to investigate the biotransformation of oximes can be attributed primarily to the work of Wilson and co-workers (11)(12)(13)(14) and Childs et al. (15), who have made important contributions in the development of the cholinesterase reactivation properties of these compounds.Initially, it was believed that the alkylphosphates were such potent inhibitors of acetylcholinesterase as well as other esterases, that they pro duced an "irreversible" inhibition of this enzyme. Subsequent work, howl The survey of literature pertaining to this review was completed in May, 1967.

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“…The acid dissociation constant (pK a ) of the oxime group determines the concentration of oximate ion and thus the rate of reactivation. Studies by Porton scientists showed that under physiological conditions (pH 7.4, 37 8C) only oximes with a pK a around 8 reacted satisfactorily with organophosphorus compounds [8]. Oximes having a pK a much less than 8 did ionise but the anion was too feebly nucleophilic to enable reactivation to occur quickly.…”

Section: Introductionmentioning

confidence: 98%

Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

Timperley

Banks

Young

et al. 2011

Journal of Fluorine Chemistry

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The Chemotherapy of Poisoning by Organophosphate Anticholinesterases

Cited by 15 publications

References 40 publications

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

The Metabolism of the Alkylphosphate Antagonists and its Pharmacologic Implications

Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

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