Toxicokinetics and toxicodynamics of DFP

Sogorb, Miguel A.; Estévez, Jorge; Vilanova, E.

doi:10.1016/b978-0-12-819090-6.00053-2

Cited by 2 publications

(2 citation statements)

References 129 publications

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“…Nerve agent binding to AChE results in overaccumulation of ACh. In turn, the accumulation causes unregulated and continuous muscle contraction, leading to convulsions, respiratory difficulties, and in fatal cases, death by asphyxiation. ,, Therefore, it is imperative to mitigate the damaging health effects caused by these nerve agents.…”

Section: Introductionmentioning

confidence: 99%

Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal–Organic Frameworks

Liao

Sheridan

Liu

et al. 2021

ACS Appl. Mater. Interfaces

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Rapid degradation/destruction of chemical warfare agents, especially ones containing a phosphorous−fluorine bond, is of notable interest due to their extreme toxicity and typically rapid rate of human incapacitation. Recent studies of the hydrolytic destruction of a key nerve agent simulant, dimethyl 4-nitrophenylphosphate (DMNP), catalyzed by Zr 6 -based metal−organic frameworks (MOFs), have suggested deactivation of the active sites due to inhibition by the products as the reaction progresses. In this study, the interactions of two MOFs, NU-1000 and MOF-808, and two hydrolysis products, dimethyl phosphate (DMP) and ethyl methyl phosphonate (EMP), from the hydrolysis of the simulant (DMNP) and nerve agent ethyl methylphosphonofluoridate (EMPF), resembling the hydrolysis degradation product of the G-series nerve agent, Sarin (GB), have been investigated to deconvolute the effect of product inhibition from other effects on catalytic activity. Kinetic studies via in situ nuclear magnetic resonance spectroscopy indicated substantial product inhibition upon catalyst activity after several tens to several thousand turnovers, depending on specific conditions. Apparent product binding constants were obtained by fitting initial reaction rates at pH 7.0 and pH 10.5 to a Langmuir−Freundlich binding/adsorption model. For the fits, varying amounts/concentrations of candidate inhibitors were introduced before the start of catalytic hydrolysis. The derived binding constants proved suitable for quantitatively describing product inhibition effects upon reaction rates over the extended time course of simulant hydrolysis by aqua-ligand-bearing hexa-zirconium(IV) nodes.

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Section: Introductionmentioning

confidence: 99%

Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal–Organic Frameworks

Liao

Sheridan

Liu

et al. 2021

ACS Appl. Mater. Interfaces

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“…Preclinical models are critical tools in drug discovery, and the rat model of acute intoxication with diisopropylfluorophosphate (DFP) is increasingly being used to test candidate therapeutics for efficacy in mitigating the immediate and long-term consequences of acute OP intoxication (Deshpande et al, 2010;Pessah et al, 2016;Pouliot et al, 2016). While less potent than the OP warfare agents, DFP has nearly identical neurotoxic effects (Pouliot et al, 2016;Siso et al, 2017;Sogorb et al, 2015), and is itself considered a credible threat agent (Jett and Spriggs, 2018). The rat model of acute DFP intoxication typically includes pretreatment with the carbamate pyridostigmine bromide (PB) (Deshpande et al, 2010;Li et al, 2011;Pouliot et al, 2016) to enhance survival of intoxicated animals (Kim et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Pretreatment with pyridostigmine bromide has no effect on seizure behavior or 24 hour survival in the rat model of acute diisopropylfluorophosphate intoxication

et al. 2019

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Acute intoxication with organophosphate cholinesterase inhibitors (OPs) is a significant human health threat, and current medical countermeasures for OP poisoning are of limited therapeutic efficacy. The rat model of acute intoxication with diisopropylfluorophosphate (DFP) is increasingly being used to test candidate compounds for efficacy in protecting against the immediate and long-term consequences of acute OP toxicity. In this model, rats are typically pretreated with pyridostigmine bromide (PB), a reversible cholinesterase inhibitor, to enhance survival. However, PB pretreatment is not likely in most scenarios of civilian exposure to acutely neurotoxic levels of OPs. Therefore, the goal of this study was to determine whether PB pretreatment significantly increases survival in DFP-intoxicated rats. Adult male Sprague Dawley rats were injected with DFP (4 mg/kg, s.c.) or vehicle (VEH) followed 1 min later by combined i.m. injection of atropine sulfate (2 mg/kg) and 2-pralidoxime (25 mg/kg). Animals were pretreated 30 min prior to these injections with PB (0.1 mg/kg, i.m.) or an equal volume of saline. DFP triggered rapid and sustained seizure behavior irrespective of PB pretreatment, and there was no significant difference in average seizure behavior score during the first 4 h following injection between DFP animals pretreated with PB or not. PB pretreatment also had no significant effect on survival or brain AChE activity at 24 h post-DFP exposure. In summary, PB pretreatment is not necessary to ensure survival of rats acutely intoxicated with DFP, and eliminating PB pretreatment in the rat model of acute DFP intoxication would increase its relevance to acute OP intoxication in civilians.

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Toxicokinetics and toxicodynamics of DFP

Cited by 2 publications

References 129 publications

Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal–Organic Frameworks

Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal–Organic Frameworks

Pretreatment with pyridostigmine bromide has no effect on seizure behavior or 24 hour survival in the rat model of acute diisopropylfluorophosphate intoxication

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