Investigation of kinetic interactions between approved oximes and human acetylcholinesterase inhibited by pesticide carbamates

Wille, Timo; Kaltenbach, Lisa A.; Thiermann, Horst; Worek, Franz

doi:10.1016/j.cbi.2013.08.004

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…Carbamates AchE inhibitors lethal and convulsive effect may be due to the participation of glutamergic mechanisms in its neurotoxicity (Dekundya et al, 2007). The carbamates mimic the action of acetylcholine (Ach) and enter the enzyme instead of Ach (Wille et al, 2013 andBaltazar et al, 2014). The hydroxyl attacks the carbonyl moiety of the carbamate.…”

Section: Discussionmentioning

confidence: 99%

Possible action of grape seed oil on brain toxicity induced by methomyl or imidacloprid of male rats.

Moeen

Amer

Ismail

et al. 2018

Journal of Scientific Research in Science

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The present study was planned to investigate the effect of methomyl or imidacloprid on the brain of male rats. The effect grape seeds oil as an antioxidant was also evaluated. Animals were administered orally with 1/10 and 1/20 of LD 50 methomyl and imidacloprid with 17 and 450 mg /kg bw for four and eight weeks. Grape seeds oil with 4 ml/kg b.wt. was used for protection from methomyl and imidacloprid toxicity. Brain cortex and hippocampus oxidative stress (glutathione S transferase GST, glutathione peroxidase GPX, superoxide dismutase SOD, malondialdhyde MDA and nitric oxide NO), Na + ,K + , ATPase and acetylcholinesterase AChE were determined. The result showed that GST, GPX, MDA, and NO 2 were increased significantly. But SOD, Na + K + ATPase and AChE were significantly reduced in comparison with the control. Grape seed oil induced a significant improvement for the pesticides brain toxicity but not to the level of control. The study suggested that the oil antioxidants not improve the brain toxicity induced by methomyl or imidacloprid.

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Section: Discussionmentioning

confidence: 99%

Possible action of grape seed oil on brain toxicity induced by methomyl or imidacloprid of male rats.

Moeen

Amer

Ismail

et al. 2018

Journal of Scientific Research in Science

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“…In clinical settings, the use of 2-PAM Cl is contraindicated (Wille et al, 2013) or at least controversial (Rosman et al, 2009) against some pesticide intoxication. In the present study, 2-PAM Cl offered significant survival protection against LD 85 challenges of GB, VX, and the pesticide oxons; however significant AChE reactivation was observed only for GB and VX.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

Wilhelm

Snider

Babin

et al. 2014

Toxicology and Applied Pharmacology

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The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.

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“…Pralidoxime (2-PAM) and obidoxime (OBD) are oximes that have been used to treat organophosphate poisoning. Poor efficacy has been reported with 2-PAM in treating organophosphate poisoning patients (Buckley et al, 2011; Eddleston et al, 2009; Peter et al, 2006; Wille et al, 2013). OBD, while showing somewhat better efficacy than 2-PAM, is not able to reactivate AChE sufficiently to protect the brain from organophosphate poisoning (Eyer et al, 2009; Thiermann et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

et al. 2016

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Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24 hours after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30 min before or 5 min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality.

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Investigation of kinetic interactions between approved oximes and human acetylcholinesterase inhibited by pesticide carbamates

Cited by 19 publications

References 24 publications

Possible action of grape seed oil on brain toxicity induced by methomyl or imidacloprid of male rats.

Possible action of grape seed oil on brain toxicity induced by methomyl or imidacloprid of male rats.

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

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