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

Hobbiger, F.

doi:10.1111/j.1476-5381.1957.tb00162.x

Cited by 47 publications

(16 citation statements)

References 25 publications

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“…Thus, while most of the alkylphosphates would readily distribute to the central nervous system, the polarity of 2-PAM limits its penetration into the CNS. The reports are conflicting with respect to whether the compound is or is not detectable in the brain, and whether the amounts found there are sufficient to contribute to their anti dotal effects (20,23,26,56,(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77). In large part, these contradictions merely reflect different dosages and degrees of sensitivity of the procedures for 2-PAM.…”

Section: Metabolismmentioning

confidence: 83%

“…Although Poziomek and co-workers (17)(18)(19) have pointed out several objections to the theories of molecular complimentarity upon which 2-PAM was developed and to the proposed mechanism of reactivation, the fact re mains that 2-PAM is effective as an acetylcholinesterase reactivator, both in vitro (20)(21)(22) and in vivo (20,23). 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).…”

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confidence: 95%

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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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Section: Metabolismmentioning

confidence: 83%

mentioning

confidence: 95%

The Metabolism of the Alkylphosphate Antagonists and its Pharmacologic Implications

Way¹,

Way²

1968

Annu. Rev. Pharmacol.

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“…These agents cause ACh to accumulate at cholinergic receptor sites and thus are potentially capable of producing effects equivalent to continuous stimulation of cholinergic fibers throughout the central (CNS) and peripheral nervous systems. The current standard treatment for OP antiChE compounds in the United States consists of the combined administration of atropine sulfate to block the effects of ACh at muscarinic receptor sites and the oxime pralidoxime-2-chloride (2-PAM) to reactivate the inhibited AChE (Kewitz and Wilson 1956;Hobbiger 1957;Fleisher et al 1970).…”

Section: Introductionmentioning

confidence: 99%

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

Shih¹

1993

Arch Toxicol

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The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 micrograms/kg, SC; equivalent to 0.9 x LD50 dose) and treated 1 min later with one of these oximes (100 or 200 mumol/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93-96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (ranging from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. In contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than HI-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximes reactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. HI-6 reactivated soman-inhibited ChE in all tissues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman. However, treatment with the high dose (200 mumol/kg) of ICD-467 depressed respiration and two of the six rats died in 10 min. These observations indicate that MMB-4 is completely ineffective in protecting and/or reactivating soman-inhibited ChE, HI-6 is an effective ChE reactivator as reported earlier in rats and other species, and the imidazolium oxime ICD-467 is a powerful reactivator of soman-inhibited ChE; however, its toxic interactions with soman may not be related to tissue ChE levels.

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“…1971;Wecker et a/. 1977) and belong to the organophosphates forming complexes which can be reactivated by oxime type reactivators (Hobbiger 1957(Hobbiger & 1963Karlog 1967), but they differ in time of onset of intoxication, D F P being the more rapidly acting poison. OMPA has to be metabolized to the active compound (Du Bois er a/.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Atropine and Dexetimide in Treatment of Intoxications by Selected Organophosphates

Lüllmann

Schmaus

Staemmler

et al. 1982

Acta Pharmacologica et Toxicologica

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Mice and guinea pigs were intoxicated by three different organophosphates: DFP, paraoxon, and OMPA. After onset of intoxication the animals were treated by either a mixture of atropine plus obidoxim or dexetimide plus obidoxim. The combination of dexetimide plus reactivator proved to be superior to the combination of atropine plus reactivator in case of DFP intoxication. In guinea pig the LD50 of DFP could be increased from about 20 to 1300 μm/kg b.wt. by dexetimide plus obidoxim when applied after the onset of intoxication. Concerning the paraoxon intoxication both antidote mixtures were found to be equally potent, whereas the purely peripheral intoxication induced by OMPA could only be influenced to a minor degree. The tissue distribution of atropine and dexetimide differs markedly, dexetimide being accumulated faster and to a higher degree. Thus the higher penetration rate of dexetimide into the central nervous system is considered to be the reason of its superiority in the treatment of an organophosphate intoxication of rapid onset.

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

Cited by 47 publications

References 25 publications

The Metabolism of the Alkylphosphate Antagonists and its Pharmacologic Implications

The Metabolism of the Alkylphosphate Antagonists and its Pharmacologic Implications

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

Comparison of Atropine and Dexetimide in Treatment of Intoxications by Selected Organophosphates

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