Formation and disposition of diethylphosphoryl-obidoxime, a potent anticholinesterase that is hydrolyzed by human paraoxonase (PON1)

Kiderlen, Daniela; Eyer, Peter; Worek, Franz

doi:10.1016/j.bcp.2005.04.003

Cited by 42 publications

(35 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hereby, the addition of HI 6 slightly improved reactivation. Under the conditions used in this study, the formation of phosphoryloxime during the reactivation of paraoxon-inhibited AChE by obidoxime, which was shown to be rather stable and highly reactive (Kiderlen et al, 2005), is to be expected and may explain the deviation of the reactivation curve. Reducing the obidoxime concentration to 10 μM resulted in a moderate decrease in reactivation.…”

Section: Discussionmentioning

confidence: 92%

Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

Worek

Aurbek

Thiermann

2007

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

Highly toxic organophosphorus-type (OP) chemical warfare agents (nerve agents) and OP pesticides may be used by terrorists and during military conflicts emphasizing the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators (oximes) is considered to be ineffective with certain nerve agents due to low oxime efficacy. Despite research over decades none of the oximes has turned out to be a broad spectrum reactivator to cover the whole range of potential threat agents. The prospective oxime HI 6 is a weak reactivator of tabun- and pesticide-inhibited AChE, while the established oxime obidoxime mainly lacks efficacy with cyclosarin-inhibited enzyme. In order to investigate the feasibility of combining obidoxime and HI 6, human AChE inhibited by sarin, cyclosarin, VX, tabun and paraoxon was reactivated by these oximes either alone or in combination. Two major findings of this study were that a combination of HI 6 and obidoxime did not impair reactivation, compared with HI 6 or obidoxime alone, but broadened the spectrum compared with the individual oximes. By using different oxime concentrations a combination of oxime doses may be suggested which could be an alternative to individual obidoxime or HI 6 autoinjectors.

show abstract

Section: Discussionmentioning

confidence: 92%

Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

Worek

Aurbek

Thiermann

2007

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was shown that phosphyloximes of 2-substituted pyridinium compounds (2-PAM and HI-6) are rather unstable while those of 4-pyridinium aldoximes are more stable [21][22][23].…”

Section: Basic Reactions Of Reactivator In the Organismmentioning

confidence: 99%

Cholinesterase Reactivators: The Fate and Effects in the Organism Poisoned with Organophosphates/Nerve Agents

Bajgar

Kuča

Jun³

et al. 2007

CDM

View full text Add to dashboard Cite

Understanding the mechanism of action of organophosphates (OP)/nerve agents -irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed. Their distribution patterns and some metabolic and pharmacological effects are described with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisonig, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.

show abstract

“…Rather reactivating agents with intermediate affinities would be desired. Should phospho-oximes form and persist, trace amounts of phosphotriesterases or paraoxonases should ensure their removal (Kiderlen et al, 2005).…”

Section: Design Of a Second Generation Of Nucleophilic Reactivatorsmentioning

confidence: 99%

Acetylcholinesterase: Converting a vulnerable target to a template for antidotes and detection of inhibitor exposure

et al. 2007

View full text Add to dashboard Cite

Applications of recombinant DNA technology, chemical synthesis on biological templates and fluorescence detection of organophosphorylation provide unexplored avenues for development of antidotes and approaches for remote detection of organophosphate nerve agents and pesticides. We discuss here how acetylcholinesterase (AChE), through appropriate mutations, becomes more susceptible to oxime reactivation. Since the reaction between organophosphate and the mutated enzyme remains rapid, regeneration of active enzyme by oxime becomes the rate-limiting step in the process to complete a catalytic cycle for generation of active enzyme. Accordingly, "Oxime-assisted Catalysis" by AChE provides a potential means for catalyzing the hydrolysis of organophosphates in plasma prior to their reaching the cellular target site. In turn, AChE, when conjugated with organophosphate, is employed as a template for 'click-chemistry, freeze-frame' synthesis of new nucleophilic reactivating agents that could potentially prove useful in AChE reactivation at the target site as well as in catalytic scavenging of organophosphates in plasma. Finally, substituted AChE molecules can be conjugated to fluorophores giving rise to shifts in emission spectra for detection of dispersed organophosphates. Since external reagents do not have to be added to detect the fluorescence change, the modified enzyme would serve as a remote sensor.

show abstract

Formation and disposition of diethylphosphoryl-obidoxime, a potent anticholinesterase that is hydrolyzed by human paraoxonase (PON1)

Cited by 42 publications

References 38 publications

Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

Cholinesterase Reactivators: The Fate and Effects in the Organism Poisoned with Organophosphates/Nerve Agents

Acetylcholinesterase: Converting a vulnerable target to a template for antidotes and detection of inhibitor exposure

Contact Info

Product

Resources

About