Human Toxicity of Various Oximes

Calesnick, Benjamin; Christensen, Henrik I.; Richter, M.

doi:10.1080/00039896.1967.10664975

Cited by 67 publications

(10 citation statements)

References 8 publications

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“…Data on toxicity of oximes in non-poisoned humans are sparse and are mainly a by-product of pharmacokinetic investigations. Only 2-PAM (P2S), TMB-4, obidoxime and HI-6 were tested in humans at doses related to the assumed therapeutic dose and only mild to moderate side effects (circulatory, gastrointestinal, sensory) were observed, TMB-4 being considered to be the most toxic of these oximes Calculations are based on experimental reactivation constants of obidoxime (tabun: k r 0.04 min −1 , K D 97.3 µM; sarin: k r 0.937 min −1 , K D 31.3 µM) and 2-PAM (tabun: k r 0.01 min −1 , K D 695 µM; sarin: k r 0.25 min −1 , K D 27.6 µM) and the bimolecular inhibi-tion rate constants k i of tabun (7.4 × 10 6 M −1 min −1 ) and sarin (2.7 × 10 7 M −1 min −1 ) (Worek et al 2004) (Calesnick et al 1967;Wiezorek et al 1968;Sidell and Groff 1970;Erdmann et al 1965;Holland and Parkes 1976;Xue et al 1985;Clement et al 1995).…”

Section: Impact Of Oxime Toxicitymentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

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Section: Impact Of Oxime Toxicitymentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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“…But in actual condition of OP exposure among Humans, 2-PAM, 30 mg/Kg (1 g -2 g) is administered by i.v. therapy over 15 min -30 min, repeated in 1 h if necessary 17 . Likewise, in order to evaluate HNK-102 oxime via i.v.…”

Section: Discussionmentioning

confidence: 99%

Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

et al. 2016

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Having established the antidotal efficacy of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (HNK oximes) against Diisopropylphosphorofluoridate (DFP) and sarin poisoning. Toxicity of HNK series and 2-PAM oximes on Human cell lines and Swiss male mice i.e. in vitro and in vivo to reported. Toxicity of the oximes was investigated in Hela, Hep G2 and HEK 293 cell lines and compared with most commonly used 2-PAM. Median lethal doses (LD50) of the oximes (2-PAM, HNK-102, HNK-106, and HNK-111) were also determined following intramuscular, intraperitoneal, intravenous and oral routes of administration. All tested oximes showed no cytotoxic effect on all three cell lines in concentrations up to 0.05 mg/mL. At higher dose (0.5 mg/mL), HNK-102 found to be less toxic thus safer than 2-PAM and other oximes in all the three cell lines. In corroboration with in vitro finding, HNK-102 was found to be least toxic compared to other oximes via intra-peritoneal and intravenous routes of administration. Also, HNK-102 was found to be unequivocally safer compared to that of 2-PAM through i.m. and i.p. routes. For all tested oximes, toxicity following oral route, was found to be lower compared to injections, signifying that these are safer and convenient compounds for administration. These finding also suggested that HNK-102 is safer and better lead as an antidote compared to 2-PAM, against OP intoxicants.

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“…Numerous early publications are focused on the characterization of 2‐PAM in terms of in vitro stability and pharmacokinetics in diverse species including man, cat, dog, rabbit, and guinea pig . These studies were conducted with related variants of spectroscopic procedures to quantify specimens of whole blood, plasma, urine, aqueous humour, tissue, and faeces.…”

Section: Introductionmentioning

confidence: 99%

Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

John¹,

Blum

2011

Drug Testing and Analysis

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Pralidoxime (2-PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2-PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2-PAM was introduced. In this time (mid-1950s until the end of the 1970s) 2-PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size-exclusion, reversed-phase, and ligand-exchange chromatography have been introduced. Today, the most popular method for 2-PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied. This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2-PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2-PAM are provided.

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Human Toxicity of Various Oximes

Cited by 67 publications

References 8 publications

Organophosphorus compounds and oximes: a critical review

Organophosphorus compounds and oximes: a critical review

Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

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