The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats

Meek, Edward C.; Chambers, Howard W.; Pringle, Ronald B.; Chambers, Janice E.

doi:10.1016/j.tox.2015.08.002

Cited by 6 publications

(2 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lead oximes were converted by ion exchange from their original bromide salt form to mesylate salts for better aqueous solubility. The procedure for novel oxime synthesis has been described …”

Section: In Vivo Lethal Dosage Challenge Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Novel brain‐penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

Chambers

Meek

Chambers

2016

Annals of the New York Academy of Sciences

Self Cite

View full text Add to dashboard Cite

Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood–brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have invented novel substituted phenoxyalkyl pyridinium oximes (U.S. Patent 9,227,937 B2) that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, these novel oximes also showed an attenuation of seizure-like behavior compared to rats treated with 2-PAM, giving additional evidence of the ability of these oximes to penetrate the blood–brain barrier. Further, some of these oximes provided 24-hour survival superior to 2-PAM and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the concept of these life-saving oximes penetrating the brain.

show abstract

Section: In Vivo Lethal Dosage Challenge Studiesmentioning

confidence: 99%

“…The procedure for novel oxime synthesis has been described. 36 The surrogates were dissolved in Multisol and administered subcutaneously in the back of the neck. 35 (Multisol, a biocompatible vehicle, consists of 48.5% water, 40% propylene glycol, 10% ethanol, and 1.5% benzyl alcohol.)…”

Section: In Vivo Lethal Dosage Challenge Studiesmentioning

confidence: 99%

Novel brain‐penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

Chambers

Meek

Chambers

2016

Annals of the New York Academy of Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead

Iyengar

Pande

2016

Protein J

View full text Add to dashboard Cite

Nerve agents (NAs) are extremely neurotoxic synthetic organophosphate (OP) compounds exploited as weapons of mass destruction in terrorist attacks and chemical warfare. Considering the current world scenario, there is a persistent threat of NA-exposure to military personals and civilians. Various prophylactic and post-exposure treatments (such as atropine and oximes) available currently for NA-poisoning are inadequate and unsatisfactory and suffer from severe limitations. Hence, developing safe and effective treatment(s) against NA-poisoning is a critical necessity. With regards to counteracting NA-toxicity, the OP-hydrolyzing enzymes (OPHEs), which can hydrolyze and inactivate a variety of NAs, have emerged as promising candidates for the development of prophylactic therapy against NA-poisoning. However, there are many hurdles to be crossed before these enzymes can be brought to therapeutic use in humans. In this article, we have reviewed the various advancements in the field of development of OPHEs as prophylactic against NA-poisoning. The article majorly focuses on the toxic effects of NAs, various available therapies to counteract NA poisoning, the current status of OPHEs and attempts made to improve the various properties of these enzymes. Further, we have also briefly discussed about the prospective work that is needed to be undertaken for developing these OPHEs into those suitable for use in humans.

show abstract

Paraoxonase (PON1), detoxification of nerve agents, and modulation of their toxicity

Costa

Cole

Garrick

et al. 2020

Handbook of Toxicology of Chemical Warfare Agents

View full text Add to dashboard Cite

The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats

Cited by 6 publications

References 15 publications

Novel brain‐penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

Novel brain‐penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead

Paraoxonase (PON1), detoxification of nerve agents, and modulation of their toxicity

Contact Info

Product

Resources

About