Oximes for acute organophosphate pesticide poisoning

Buckley, Nicholas A.; Eddleston, Michael; Li, Yang; Bevan, Marc; Robertson, Jane

doi:10.1002/14651858.cd005085.pub2

Cited by 104 publications

(54 citation statements)

References 46 publications

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“…NCX has been reported to be involved in neuroprotection, but its role is marred by contradictory reports [35, 36]. The clinical use of oximes is controversial because of the reported negative balance between benefits and harmful effects [37, 38]. …”

Section: Discussionmentioning

confidence: 99%

Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

et al. 2015

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Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase (AChE) and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene-diol (4R) and a caspase 9 inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5–10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices.

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Section: Discussionmentioning

confidence: 99%

Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

et al. 2015

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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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“…Based on clinical studies, pralidoxime is indicated for the treatment of nicotinic symptoms and moderate to severe muscarinic features following OPs poisoning. 11 Thus, indication for pralidoxime administration was remarked in the checklist as "Yes" or "No". Lastly, decision on the appropriateness of the pralidoxime administration was checked and endorsed by an attending medical toxicologist, and then frequency or percentage of appropriate or inappropriate use of pralidoxime was summarized as proper in tables or figures.…”

Section: Methodsmentioning

confidence: 99%

“…and reversing moderate to severe muscarinic symptoms. 11 Our study retrospectively evaluated rational use of pralidoxime under a direct consult and observation of an attending medical toxicologist in a teaching hospital. As demonstrated in the Table 1, and evident in the previous studies, 14,17 majority of pesticide poisoning occurs in young and economically active age group of patients in developing countries.…”

mentioning

confidence: 99%

“…Despite wasting resources due to irrational use, such medical errors expose patients to lifethreatening side effects of pralidoxime including hypertension, arrhythmias, and respiratory arrest. [18][19][20] In a meta-analysis performed by Buckley et al, 11 it was mentioned that there is insufficient evidence to illustrate whether oximes are beneficial or harmful. Also the findings of this meta-analysis did not support the pralidoxime regimen recommended by the WHO.…”

mentioning

confidence: 99%

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