Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis

Worek, Franz; Eyer, Peter; Aurbek, Nadine; Szinicz, L.; Thiermann, Horst

doi:10.1016/j.taap.2006.10.001

Cited by 115 publications

(70 citation statements)

References 64 publications

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“…At present, the most important oximes in antidotal treatment of OPC poisoning (Kuca et al, 2007;Worek et al, 2007) are pralidoxime (2-PAM), obidoxime, trimedoxime, methoxime and HI-6 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl‐fluorophosphate

Lorke

Al‐Hasan

Arafat

et al. 2008

J of Applied Toxicology

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Oximes are enzyme reactivators used in treating poisoning with organophosphorus cholinesterase (AChE) inhibitors. The oxime dose which can be safely administered is limited by the intrinsic toxicity of the substances such as their own AChE-inhibiting tendency. Clinical experience with the available oximes is disappointing. To meet this need, new AChE reactivators of potential clinical utility have been developed. The purpose of the study was to estimate in vitro both the intrinsic toxicity and the extent of possible protection conferred by established (pralidoxime, obidoxime, HI-6, methoxime, trimedoxime) and experimental (K-type) oximes, using diisopropyl-fluoro-phosphate (DFP) as an AChE inhibitor. The IC50 of DFP against human red blood cell AChE was determined ( approximately 120 nm). Measurements were then repeated in the presence of increasing oxime concentrations, leading to an apparent increase in DFP IC50. Calculated IC50 values were plotted against oxime concentrations to obtain an IC50 shift curve. The slope of this shift curve (tan alpha) was used to quantify the magnitude of the protective effect (nm IC50 increase per microm oxime). We show that, in the case of a linear relationship between oxime concentration and IC50, the binding constant K, determined using the Schild equation, equals IC50/DFP/tan alpha. Based on the values of tan alpha and of the binding constant K, some of the new K-oxime reactivators are far superior to pralidoxime (tan alpha = 0.8), obidoxime (1.5), HI-6 (0.8), trimedoxime (2.9) and methoxime (5.9), with K-107 (17), K-108 (20), and K-113 (16) being the outstanding compounds.

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Section: Introductionmentioning

confidence: 99%

In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl‐fluorophosphate

Lorke

Al‐Hasan

Arafat

et al. 2008

J of Applied Toxicology

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“…107,108 Thus, the current therapy in case of OP nerve agent poisonings includes an AChE reactivator of the quaternary pyridinium oxime family. 109,110 However, due to their permanent positive charge, these compounds do not readily cross the blood-brain barrier and thus cannot reactivate AChE in the central nervous system. 111 Therefore, attempts have been made to develop centrally acting reactivators using click-chemistry approach.…”

Section: 102-104mentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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“…Obidoxime ( Figure 1) was first used in the early 1960s 8 followed by trimedoxime (TMB-4, Figure 1) 9 while HI-6 ( Figure 1) was tested only in few cases of OP pesticide poisoning 10 . Although only very few oximes are used clinically a huge number of oximes were synthesized in the past decades mainly in Germany, USA, Croatia, Israel, Czech Republic, and Korea 7,11 . The main purpose of these oxime development programs was to find oximes which are more effective than the clinically used compounds in nerve agent poisoning.…”

Section: Introductionmentioning

confidence: 99%

“…Further factors include pre-treatment, OP body load and competing acetylcholine concentration, time interval between poisoning and onset of treatment, oxime dosing and duration of treatment. In view of multiple factors influencing the efficacy of oximes in OP-poisoning there is an ongoing debate on the benefit of oximes and on the necessity to develop more effective oximes as antidotes against pesticide and nerve agent poisoning [2][3][4]11,[28][29][30][31] . These controversies prompted us to use theoretical models, based on kinetic data obtained under identical experimental conditions, to characterize the requirements of an oxime as an effective antidote in OPpoisoning.…”

mentioning

confidence: 99%

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

Worek¹,

Aurbek²,

Wille³

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis

Cited by 115 publications

References 64 publications

In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl‐fluorophosphate

In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl‐fluorophosphate

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

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

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