Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning

Krishnan, Jishnu K.S.; Figueiredo, Taíza H.; Moffett, John R.; Arun, Peethambaran; Appu, Abhilash P.; Puthillathu, Narayanan; Braga, Maria F. M.; Flagg, Thomas P.; Namboodiri, Aryan M.A.

doi:10.1016/j.neuro.2017.09.009

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…8; and Supporting information, online only). It should be noted that despite being given an LD 50 dose of POX, many symptoms typically associated with OP toxicity were not observed owing to the protective effect of isoflurane 54 …”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that despite being given an LD 50 dose of POX, many symptoms typically associated with OP toxicity were not observed owing to the protective effect of isoflurane. 54 The box plots ( Figs. 7 and 8; Supporting information, online only) highlight the statistical significance variations, data spread, and provide a means to identify any data outliers, and are particularly useful for comparing distributions across groups, which is important in the determination of oxime efficacy.…”

Section: In Vivo Pet Imaging Tissue Evaluations Using the [ 18 F]-vxsmentioning

confidence: 99%

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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

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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Section: Resultsmentioning

confidence: 99%

Section: In Vivo Pet Imaging Tissue Evaluations Using the [ 18 F]-vxsmentioning

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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“…Isoflurane also acts through TASK-3 potassium channels to repolarize neuronal membranes ( Luethy et al, 2017 ) which may play some role in isoflurane’s neuroprotective effects. We have shown that very brief (4 min) high dose (3%–5%) isoflurane has potent anticonvulsant and neuroprotective efficacy in a paraoxon model of OP poisoning ( Krishnan et al, 2017 ). This short-duration, high-dose application of isoflurane is opposite of its use as an anesthetic, where low doses are given for extended periods to maintain surgical anesthesia.…”

Section: Introductionmentioning

confidence: 99%

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Puthillathu,

Moffett,

Korotcov

et al. 2023

Front. Pharmacol.

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Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABAA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%–5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30 min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5 min, ranging from 60 to 180 min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1 h after paraoxon, with diminishing effectiveness at 90, 120 and 180 min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1 h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.

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“…By 60 minutes the initial POX toxidrome decreases and the radioactivity levels would provide insights into the recovery process, although reactivation levels of POX-modified proteins would not be significant. OP-induced seizures are suppressed in animals treated with isoflurane ( Krishnan et al, 2017 ), but the overall mechanism of POX action is retained. Overall, rats were dosed with an LD 50 POX dose (250 μ g/kg), and in separate experiments the [ 11 C]POX tracer was given at 20 or 60 minutes, whereupon the radioactivity in the blood fractions was measured at 0.5, 1.0, 5.0, 10.0, and 30.0 minutes after tracer injection ( Fig.…”

Section: Resultsmentioning

confidence: 99%

[¹¹C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography Imaging in Rat

Hayes,

Chao,

Blecha

et al. 2023

J Pharmacol Exp Ther

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Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([ 11 C]POX) and profiling in live rats is reported. Naïve rats intravenously injected with [ 11 C]POX showed a rapid decrease in parent tracer to ∼1%, with an increase in radiolabeled serum proteins to 87% and red blood cells (RBCs) to 9%. Protein and RBC leveled over 60 minutes, reflecting covalent modification of proteins by [ 11 C]POX. Ex vivo biodistribution and imaging profiles in naïve rats had the highest radioactivity levels in lung followed by heart and kidney, and brain and liver the lowest. Brain radioactivity levels were low but observed immediately after injection and persisted over the 60-minute experiment. This showed for the first time that even low POX exposures (∼200 ng tracer) can rapidly enter brain. Rats given an LD 50 dose of nonradioactive paraoxon at the LD 50 20 or 60 minutes prior to [ 11 C]POX tracer revealed that protein pools were blocked. Blood radioactivity at 20 minutes was markedly lower than naïve levels due to rapid protein modification by nonradioactive POX; however, by 60 minutes the blood radioactivity returned to near naïve levels. Live rat tissue imaging-derived radioactivity values were 10%–37% of naïve levels in nonradioactive POX pretreated rats at 20 minutes, but by 60 minutes the area under the curve (AUC) values had recovered to 25%–80% of naïve. The live rat imaging supported blockade by nonradioactive POX pretreatment at 20 minutes and recovery of proteins by 60 minutes. SIGNIFICANCE STATEMENT Paraoxon (POX) is an organophosphorus (OP) compound and a powerful prototype and substitute for OP chemical warfare agents (CWAs) such as sarin, VX, etc. To study the distribution and penetration of POX into the central nervous system (CNS) and other tissues, a positron emission tomography (PET) tracer analog, carbon-11–labeled paraoxon ([ 11 C]POX), was prepared. Blood and tissue radioactivity levels in live rats demonstrated immediate penetration into the CNS and persistent radioactivity levels in tissues indicative of covalent target modification.

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Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning

Cited by 16 publications

References 27 publications

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

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

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

[¹¹C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography Imaging in Rat

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Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning

Cited by 16 publications

References 27 publications

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

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

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

[11C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography Imaging in Rat

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Product

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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

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

[¹¹C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography Imaging in Rat