Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach

Worek, Franz; Aurbek, Nadine; Wille, Timo; Eyer, Peter; Thiermann, Horst

doi:10.3109/14756366.2010.504673

Cited by 8 publications

(6 citation statements)

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“…In vitro reactivation constants allow model calculations to estimate minimum k r and K D values for achieving a sufficient reactivation level and to calculate necessary oxime concentrations to reach a certain reactivation level after a defined time (Worek et al 2011b ). From these calculations a reactivity constant k r of > 0.1 min −1 and a dissociation constant of K D < 100 µM were proposed.…”

Section: The Oxime Conceptmentioning

confidence: 99%

“…Eyer and co-workers presented models for the calculation of steady-state AChE activities in the presence of different OP and oxime concentrations and for the estimation of oxime concentrations necessary to achieve a defined level of AChE reactivation (Thiermann et al 1999 ; Eyer 2003 ; Worek et al 2011b , 2016b ). Here, the agent-specific reactivating potency of an oxime and the inhibitory potency of an OP are decisive for the required therapeutic oxime concentration, indicating that the necessary oxime concentration will vary for different OP.…”

Section: The Oxime Conceptmentioning

confidence: 99%

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Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

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Section: The Oxime Conceptmentioning

confidence: 99%

Section: The Oxime Conceptmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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“…The cationic oximes tested (2‐PAM, MMB4, and HI‐6) were expected to show reactivation of cholinesterases in blood and peripheral tissues but not the brain, whereas the neutral and ionizable oximes (MINA and RS194b) were presumed to enter the CNS more easily possibly leading to a greater reactivation of CNS AChE. As this study was conducted only in rats, it is worthwhile to note that AChE from other species can be selectively reactivated by different oximes 46,47 …”

Section: Introductionmentioning

confidence: 99%

“…As this study was conducted only in rats, it is worthwhile to note that AChE from other species can be selectively reactivated by different oximes. 46,47 The mechanisms in Figures 1 and 3, which may include other OP reactive esterases besides AChE, are active in vivo within blood, and also peripheral and central tissue domains to various extents ( Fig. 6, top row).…”

Section: Introductionmentioning

confidence: 99%

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [¹⁸F]‐VXS

Hayes

Blecha

Chao

et al. 2020

Annals of the New York Academy of Sciences

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Oxime antidotes regenerate organophosphate-inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [ 18 F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [ 18 F]-VXS was evaluated after an LD 50 dose (250 µg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [ 18 F]-VXS tracer alone had significantly higher radioactivity (two-to threefold) in the heart and lung than rats given LD 50 POX at 20 or 60 min prior to [ 18 F]-VXS. When rats were given LD 50 POX followed by 2-PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI-6 or MMB-4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX-treated rats. This new in vivo dynamic platform using [ 18 F]-VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats.

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“…While inhibition of AChE is the mechanism of toxicity for all OPs, the in vivo toxicokinetics and oxime responsiveness to different OP nerve agents and insecticides vary significantly in humans and in the same or different animal models (Worek et al, 2010(Worek et al, , 2011a(Worek et al, , 2011bLuo et al, 2010). For example, in contrast to the constitutively active nerve agents, many disabling phosphorothionate insecticides such as parathion, chlorpyrifos, and dimethoate, while highly toxic, are not active immediately upon exposure in vivo and require conversion by P450 in the liver from the thion to active oxon forms (Atterberry et al, 1997;Murray & Butler, 1994;Tang et al, 2001) exhibiting delayed toxicity and permitting more time to administer an oxime.…”

Section: Introductionmentioning

confidence: 99%

A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

Rosenberg¹,

Garcia

Diener

et al. 2023

Journal of Neurochemistry

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Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP‐inhibited AChE. However, animal model studies and recent clinical trials using insecticide‐poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood–brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP‐inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1–2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non‐invasive treatment, especially in isolated rural settings.image

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Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach

Cited by 8 publications

References 39 publications

Organophosphorus compounds and oximes: a critical review

Organophosphorus compounds and oximes: a critical review

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [¹⁸F]‐VXS

A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

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Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach

Cited by 8 publications

References 39 publications

Organophosphorus compounds and oximes: a critical review

Organophosphorus compounds and oximes: a critical review

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [18F]‐VXS

A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

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Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [¹⁸F]‐VXS