Repetitive obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning: A case report

Steinritz, Dirk; Eyer, Florian; Worek, Franz; Thiermann, Horst; John, Harald

doi:10.1016/j.toxlet.2015.07.010

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…In any event, clearance is rapid and multiphasic, but the rapid clearance (short half‐life) persists for close to an hour, where the plasma concentration is 10 % or less of the original value. This short resident time in the plasma and rapid clearance would require multiple dosing for a sustained therapeutic action of a long‐acting organophosphate . It is noteworthy to mention that typically upon intramuscular (i.m.)…”

Section: Resultsmentioning

confidence: 99%

“…This short resident time in the plasma andr apid clearance would require multiple dosing for as ustained therapeutic action of al ongacting organophosphate. [14] It is noteworthy to mention that typicallyu pon intramuscular (i.m.) administration of aq uaternary oxime, there is as hort redistribution phase followed by the kinetics of elimination from the plasma.T hat redistribution Limits of detectionw ere % 2ngmL À1 ,50ngmL À1 and 100 ng mL À1 for 2A, 3A and 14A,respectively.…”

Section: Pharmacokinetics Of Lead Reactivators Of Phosphorylated Achementioning

confidence: 99%

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Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Kovarik

Kalisiak

Hrvat

et al. 2019

Chemistry A European J

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Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post‐exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun‐inhibited human AChE, and in vivo antidotal efficacies in tabun‐exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Pharmacokinetics Of Lead Reactivators Of Phosphorylated Achementioning

confidence: 99%

Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Kovarik

Kalisiak

Hrvat

et al. 2019

Chemistry A European J

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“…In the case of OP pesticides, humans administered a 2g loading dose plus a steady infusion of 2-PAM following poisoning with two diethylphosphoryl-containing pesticides, chlorpyrifos and quinalphos, variably reactivated BChE, but was not sustained past 10–12 hr (43). In addition, in the treatment of methamidophos poisoning in man, multiple dosing of a pyridinium aldoxime over a sustained period was required to reverse toxicity (11). …”

Section: Discussionmentioning

confidence: 99%

“…However, efficacy of these oximes is limited by steric constraints of an impacted active center gorge limiting pyridinium aldoxime attack, poor oral bioavailability, rapid clearance, and their inability to rapidly cross the blood-brain-barrier (BBB)(6–8). Recent clinical trials using pesticide-poisoned individuals have shown uneven clinical benefits with these oximes (9–11). …”

Section: Introductionmentioning

confidence: 99%

Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor

Rosenberg¹,

Mao²,

Jiang³

et al. 2017

Chemico-Biological Interactions

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Organophosphate (OP) nerve agents and pesticides trigger a common mechanism of neurotoxicity resulting from critical targeting and inhibition of acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Therapeutic countermeasures have thus focused on either administering an oxime post-exposure, that can rapidly reactivate OP-inhibited AChE, or by preventing OP poisoning through administering pre-exposure treatments that scavenge OPs before they inhibit their physiological AChE targets. While several pyridinium aldoxime antidotes are currently approved, their utility is impaired due to their inability to cross the blood-brain barrier (BBB) efficiently. The present study utilized a macaque (Ma) model to demonstrate the efficacy of a novel zwitterionic and centrally acting oxime RS194B to reactivate sarin- and paraoxon-inhibited macaque AChE and butyrylcholinesterase (BChE) in vitro and to further assess the capacity of RS194B to effect a reversal of clinical symptoms following sarin inhalation in vivo. In vitro, oxime reactivation of MaAChE and MaBChE was shown to be comparable to their human orthologs, while the macaque studies indicated that IM administration of 62.5mg/kg of RS194B and 0.28mg/kg atropine after continuous exposure to 49.6 ug/kg sarin vapor, rapidly reactivated the inhibited AChE and BChE in blood and reversed both early and advanced clinical symptoms of sarin-induced toxicity following pulmonary exposure within one hour. The rapid cessation of autonomic and central symptoms, including convulsions, observed in macaques bodes well for the use of RS194B as an intra- or post-exposure human treatment and validates the macaque model in generating efficacy and toxicology data required for approval under the FDA Animal rule.

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“…pralidoxime (2-PAM), HI-6, obidoxime, MMB4, to reactivate the OP-inhibited AChE, with/without a benzodiazepine anticonvulsant to control seizures (Hulse et al, 2014; Eddleston et al, 2008; Eddleston and Chowdhury., 2016; Shih et al, 2012). While oximes are widely used globally, several animal model studies and recent clinical trials using pesticide-poisoned individuals have shown uneven clinical benefits with those currently used (Buckley et al, 2011; Eddleston et al, 2009; Steinritz et al, 2016) and the value of administering an oxime has therefore been seriously debated. Limitations of antidotal function of most synthetic oxime reactivators relate to their quaternary structure and their inability to rapidly cross the blood-brain barrier (BBB), in addition to rapid clearance from the circulation.…”

Section: Introductionmentioning

confidence: 99%

Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques

Rosenberg¹,

Wang

Ooms

et al. 2018

Toxicology Letters

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Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40-100% in<1hr and BChE (40% in 8h). These findings will be used to develop a macaque model with RS194B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule.

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Repetitive obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning: A case report

Cited by 6 publications

References 10 publications

Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Reversal of Tabun Toxicity Enabled by a Triazole‐Annulated Oxime Library—Reactivators of Acetylcholinesterase

Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor

Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques

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