Toxicity of organophosphate nerve agents and related phosphonylated oximes compared to their anticholinesterase activity in neuron cultures

Sawyer, Thomas W.; Weiss, M.; Boulet, Camille A.; Hansen, Arnold S.

doi:10.1016/0272-0590(91)90252-y

Cited by 21 publications

(4 citation statements)

References 15 publications

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“…OPNAs include a wide array of molecules, including G-series agents such as Soman (GD), Sarin (GB), and cyclosarin (GF), V-series agents such as VX and VG, GV series, and Novichok [ 7 , 8 ]. These NAs cause cholinergic toxicity through the irreversible inhibition of acetylcholinesterase (AChE), accumulation of acetylcholine (ACh) at the synapses, and overactivation of ACh receptors [ 9 , 10 , 11 ]. This leads to a wide variety of symptoms, such as bronchoconstriction, salivation, lacrimation, bradycardia, gastrointestinal distress, and convulsions [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

et al. 2021

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Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the protective effects of saracatinib (AZD0530), a Src kinase inhibitor, in mixed-sex or male-only Sprague Dawley rats exposed to 4–5 mg/kg DFP followed by 2 mg/kg atropine and 25 mg/kg 2-pralidoxime. Midazolam (3 mg/kg) was given to the mixed-sex cohort (1 h post-DFP) and male-only cohort (~30 min post-DFP). Saracatinib (20 mg/kg, oral, daily for 7 days) or vehicle was given two hours later and euthanized eight days or ten weeks post-DFP. Brain immunohistochemistry (IHC) showed increased microgliosis, astrogliosis, and neurodegeneration in DFP-treated animals. In the 10-week post-DFP male-only group, there were no significant differences between groups in the novel object recognition, Morris water maze, rotarod, or forced swim test. Brain IHC revealed significant mitigation by saracatinib in contrast to vehicle-treated DFP animals in microgliosis, astrogliosis, neurodegeneration, and nitro-oxidative stressors, such as inducible nitric oxide synthase, GP91phox, and 3-Nitrotyrosine. These findings suggest the protective effects of saracatinib on brain pathology seem to depend on the initial SE severity. Further studies on dose optimization, including extended treatment regimen depending on the SE severity, are required to determine its disease-modifying potential in OPNA models.

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Section: Introductionmentioning

confidence: 99%

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

et al. 2021

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“…RSDL reacts rapidly and completely with G-agents, V-agents, mustard and lewisite producing relatively nontoxic products. 10,11 RSDL is commercially available and recently has been approved for use as a medical device by the US Food and Drug Administration, and adopted by a number of armies.…”

Section: Introductionmentioning

confidence: 99%

Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller's earth in domestic swine

et al. 2007

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Research in skin decontamination and therapy of chemical warfare agents has been a difficult problem due to the simultaneous requirement of rapid action and non-aggressive behaviour. The aim of this study was to compare the performance of two decontaminating systems: the Canadian Reactive Skin Decontaminant Lotion (RSDL) and the Fuller's Earth (FE). The experiment was conducted with domestic swine, as a good model for extrapolation to human skin. RSDL and FE were tested against sulphur mustard (SM), a powerful vesicant, and VX, a potent and persistent cholinesterase inhibitor. When used 5 min after contamination, the results clearly showed that both systems were active against SM (10.1 mg/cm2) and VX (0.06 mg/cm2). The potency of the RSDL/sponge was statistically better than FE against skin injury induced by SM, observed 3 days post-exposure. RSDL was rather more efficient than FE in reducing the formation of perinuclear vacuoles and inflammation processes in the epidermis and dermis. Against a severe inhibition (67%) of plasmatic cholinesterases induced by VX poisoning, the potencies of the RSDL/sponge and FE were similar. Both systems completely prevented cholinesterase inhibition, which indirectly indicates a prevention of toxic absorption through the skin. Human & Experimental Toxicology (2007) 26, 135-141

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“…Chemical structure and IC50 of organophosphate cholinesterase inhibitors assessed for human red blood cell (*, **, ***), bovine red blood cell (****) or mouse cultured neuronal (*****) acetylcholinesterase. * [56], ** [57], *** [58], **** [59], ***** [60]. [2].…”

Section: In Vitro Versus In Vivo Resultsmentioning

confidence: 98%

Comparison of the Ability of Pyridinium Aldoximes to Reactivate Human Red Blood Cell Acetylcholinesterases Inhibited by ethyl- and methyl-paraoxon

Petroianu

Lorke

Kalász

2012

COC

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Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). They are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is, however, disappointing. This paper reviews available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl-and methyl-paraoxon.The intrinsic toxicity of oximes is quantified in vitro by measuring the concentration required to inhibit red blood cell (RBC) cholinesterase activity by 50% (IC50). Reactivation ability is assessed in vitro via the IC50 shift graph. The slope of the shift graph (tan ) is used to quantify the magnitude of the protective effect (nM IC50 increase per M reactivator).The ranking of reactivating potencies of the examined oximes determined with methyl-paraoxon as an inhibitor is essentially the same as the ranking obtained using ethyl-paraoxon as an inhibitor. In the in vitro model used, the presence of ethyl versus methyl substituents does not seem to significantly alter the ability of the examined oximes to reactivate the esterase.In vitro derived results were subsequently validated in vivo in rats using ethyl-paraoxon and methyl-paraoxon as cholinesterase inhibitors and various oximes as reactivators. Mortality data were compared and hazard ratios calculated using Cox proportional hazards model. Overall, the ability of in vitro testing (tan determinations) to predict in vivo protection by oximes is limited. POISONING WITH ORGANOPHOSPHORUS INHIBITORS OF CHOLINESTERASE (OPICHE)Organophosphorus esters (organophosphates and organophosphonates) are serine esterase and protease inhibitors widely used in agriculture as insecticides and acaricides, in industry and technology as softening agents and additives to lubricants, and some of them are classified as chemical warfare agents. The acute toxicity of these compounds is due to inhibition of the enzyme acetylcholinesterase (AChE), which metabolizes the neurotransmitter acetylcholine (ACh), see [1][2][3][4][5] for review. Sarin (GB) and VX were involved in terrorist attacks in Japan, illustrating that these compounds represent a major terrorist threat. The likelihood of the use of organophosphorus inhibitors of cholinesterase (OPIChE) by terrorist organizations is related to the relative ease of production of these substances, certainly within the means of even moderately sophisticated organizations [6]. The inhibition of esterases (butyrylcholinesterase: 3.1.1.8 and acetylcholinesterase: 3.1.1.7) results from reacting covalently with the active centre serine (by phosphylation, i.e. either phosphorylation or phosphonylation) and translates into an "endogenous acetylcholine poisoning" [5,7,8].

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Toxicity of organophosphate nerve agents and related phosphonylated oximes compared to their anticholinesterase activity in neuron cultures

Cited by 21 publications

References 15 publications

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller's earth in domestic swine

Comparison of the Ability of Pyridinium Aldoximes to Reactivate Human Red Blood Cell Acetylcholinesterases Inhibited by ethyl- and methyl-paraoxon

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