Physiologically Based Pharmacokinetic Modeling of Chemical Warfare Agents

Gearhart, Jeffery M.; Robinson, Peter; Jakubowski, Edward M.

doi:10.1016/b978-0-12-800159-2.00058-0

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…5,6 The toxicity of G-type nerve agents arises from inhibition of proper muscle response, which depends on the behavior of acetylcholine (ACh) and acetylcholinesterase (AChE). 4,7 ACh binds to a muscle fiber receptor to transmit muscle contraction signals, while AChE catalyzes the breakdown of ACh at neuromuscular junctions. 7 Nerve agent binding to AChE results in overaccumulation of ACh.…”

Section: ■ Introductionmentioning

confidence: 99%

“…4,7 ACh binds to a muscle fiber receptor to transmit muscle contraction signals, while AChE catalyzes the breakdown of ACh at neuromuscular junctions. 7 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.…”

Section: ■ Introductionmentioning

confidence: 99%

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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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