Effect of PAM-2 Cl, HI-6, and HGG-12 in Poisoning by Tabun and Its Thiocholine-like Analog in the Rat

Ćetković, Slavko; Cvetković, Mirjana; Jandrić, Dušan; Ćosić, M.; Bošković, Bogdan

doi:10.1093/toxsci/4.2part2.116

Cited by 13 publications

(3 citation statements)

References 25 publications

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“…65 The only drawback of HI-6 is that this oxime cannot reactivate tabun-inhibited AChE. 129,130 The per se toxicity of HI-6 is low, actually the lowest among the aforementioned oximes. 65,97,131 HLö-7 reactivates AChE inhibited by any of the four major nerve agents.…”

Section: Drawbacks and Limitations Of Oxime Therapymentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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Section: Drawbacks and Limitations Of Oxime Therapymentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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“…Some nucleophilic oxime compounds, including the monopyridinium compound 2-PAM and the bispyridinium compounds TMB4, Lu ¨H6, and HI-6, were shown to reactivate OPinhibited AChE and greatly attenuate the toxicity of many OP compounds (1-5) (Chart 1). However, in many cases, little or no reactivation of the OP-enzyme conjugate could be achieved by these oximes, therein limiting their efficacy as antidotes (6)(7)(8).…”

mentioning

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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“…1) is a potent reactivator of soman inhibited acetylcholinesterase (DeJong and Wolfing 1980;DeJong et al 1989) but is ineffective in reactivating tabun inhibited acetylcholinesterase (Cetkovic et al 1984;DeJong et al 1989). A new oxime HL6-7 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice

Clement¹,

Hansen²,

Boulet³

1992

Arch Toxicol

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The toxicity and efficacy of two oximes, HLö-7 and pyrimidoxime, were evaluated in mice and compared to those obtained with HI-6. HLö-7 and pyrimidoxime produced 24 h LD50 values of 356 and 291 mg/kg (i.p.), respectively. In combination with atropine (17.4 mg/kg, i.p.), HLö-7 was a very efficient therapy against poisoning by 3 x LD50 dose of soman, sarin and GF and 2 x LD50 dose of tabun with ED50 values of 12.4, 0.31, 0.32 and 25.2 mg/kg, respectively. In contrast, pyrimidoxime was a relatively poor therapy which resulted in ED50 values of greater than 150, 5.88, 100 and 71 mg/kg against poisoning by soman, sarin, GF and tabun, respectively. HLö-7 produced significant (p less than 0.05) reactivation of phosphorylated acetylcholinesterase, in vivo, resulting in 47, 38, 27 and 10% reactivation of sarin, GF, soman and tabun inhibited mouse diaphragm acetylcholinesterase, respectively. HLö-7 also antagonized sarin-induced hypothermia in mice suggesting that it reactivated central acetylcholinesterase. The potential of HLö-7 as a replacement oxime for the treatment of nerve agent poisoning is discussed.

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Effect of PAM-2 Cl, HI-6, and HGG-12 in Poisoning by Tabun and Its Thiocholine-like Analog in the Rat

Cited by 13 publications

References 25 publications

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

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

Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice

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