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Chemical structure of oximes.
Source publication
The potency of bispyridinium acetylcholinesterase reactivator KR-22934 in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with the oxime K203 and commonly used oximes. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed...
Contexts in source publication
Context 1
... the replacement of commonly used oximes (pra- lidoxime, obidoxime) as well as H-oximes (the oxime HI-6) with a more effective oxime has been a long-standing goal for the treatment of tabun poisoning. For this reason, the new bispyridinium oxime K203 [1-(4-carbamoylpyridinium)-4- (4-hydroxyiminomethylpyridinium)-but-2-ene-dibromide] ( Figure 1) was synthesized at our department several years ago ) to improve the efficacy of the anti- dotal treatment in reactivating tabun-inhibited AChE and eliminating tabun-induced lethal toxicity. The oxime K203 was considered to be a promising reactivator of tabun- inhibited AChE; nevertheless, the differences between the reactivating and therapeutic efficacy of K203 and some com- monly used bispyridinium oximes (obidoxime, trimedoxime) are relatively small ( Kassa et al. 2008). ...
Context 2
... oxime K203 was considered to be a promising reactivator of tabun- inhibited AChE; nevertheless, the differences between the reactivating and therapeutic efficacy of K203 and some com- monly used bispyridinium oximes (obidoxime, trimedoxime) are relatively small ( Kassa et al. 2008). Another bispyridin- ium oxime, KR-22934 [1-(4-carbamoylpyridinium)-3-(4- hydroxyiminomethylpyridinium)-2-oxapropan-dichloride] ( Figure 1) was synthesized in Korea to improve the reactivat- ing and therapeutic efficacy of antidotal treatment of tabun poisoning. ...
Similar publications
This study compares the abilities of the newly developed bispyridinium oxime K203 with currently available oximes (HI-6, obidoxime, and trimedoxime) in the reactivation of sarin-inhibited acetylcholinesterase and the reduction of the acute toxicity of sarin. The percentage of reactivation of sarin-inhibited rat blood and tissue acetylcholinesterase...
The reactivating and therapeutic efficacy of two combinations ofoximes (HI-6 + trimedoxime and HI-6 + K203) was compared with the effectiveness of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase in...
Citations
... k r values. d From [13]. e From [16]. f No reactivation of tabun-inhibited AChE up to 5 mM HI 6. Wolring!1984!;!Worek,!Reiter"et"al.!2002!;!Worek,!Eyer"et"al.! 2007! ;! Worek,! Aurbek" et" al.! 2011 (Luo,! Tong" et" al.! 2008! ;! Worek,! Aurbek" et" al.! 2011). !Malheureusement,!l ! Kovarik,! Vrdoljak"et"al.! 2009! ;! Berend,! Radic"et"al.! 2010! ;! Kassa,! Karasova" et" al.! 2011 Harris!1965!;!Talbot,!Anderson"et"al.!1988).! ! 54! Maxwell!2003),!l'acétylcholinestérase !!(Wolfe,!Rush"et"al.!1987!;!Doctor,!Blick"et"al.! 1993! ;! Sweeney! and! Maxwell! 2003! ;)! et! la! butyrylcholinestérase!(Raveh, !Grunwald"et"al.!1993!;." ...
Organophosphate pesticides and chemical warfare are responsible for poisoning that pose to health security issues. The research of therapeutic solutions to overcome the lack of effective means to counter these poisonings is essential. Acetylcholinesterase (AChE), the enzyme involved in the regulation of nerve impulses, is the main target. ln this thesis, we have, first, set up a strategy for designing molecules that can reactivate aged cholinesterases. To this purpose, severa! dozen molecules have been designed and synthesized. Evaluation in silico by molecular docking and in vitro by rneasuring affinity for the enzyme and crystallographic study did not observe the desired realkylation. But this work opened new perspectives.Secondly, our crystallographic work on the inhibition of human butyrylcholinesterase by V-agents and sarin shows that cholinesterase has altered enantioselectivity for these chiral inhibitors of human AChE. This implies that larger amounts of enzyme are required for the desired protection and thus, a significant additional cost. Human AChE seems finally a more suitable neurotoxic bioscavenger.
... During the last several years, we have synthesized two new AChE reactivators (K033 and K027) at our department (Figure 2) [11,12]. Based on their potencies in reactivating rat brain AChE inhibited by several nerve agents (sarin, tabun, VX and cyclosarin) in vitro, they would be expected to be promising AChE reactivators [13,14]. Unfortunately, all in vitro reactivation tests were only done with the rat-brain homogenate. ...
... AChE reactivators (pralidoxime and obidoxime) were purchased from Leciva (Czech Republic) and Merck (Germany), respectively . HI-6 and the new oximes, K033 and K027, were synthesized at our department [11,12,13,16]. The purity of all AChE reactivators was tested using TLC (DC-Alufolien Cellulose F; mobile phase n-butanol: acetic acid: water—5:1:2; Detection: Dragendorff reagent). ...
... In this study, we have tested three currently used AChE reactivators (pralidoxime, obidoxime, and HI-6) in comparison with our newly developed AChE reactivators (K033 and K027) [11,12]. We have previously tested their potencies on rat brain homogenate [13,14]. The use of different animal species makes the effects of AChE reactivators in humans more predictable [15,25]. ...
The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of acetylcholine at muscarinic receptors and AChE reactivators (pralidoxime or obidoxime) to reactivate inhibited AChE. At the Department of Toxicology, the strategy of the development of new more potent AChE reactivators consists of several steps: description of the nerve agent intoxication mechanism on the molecular basis (molecular design), prediction of the biological active structure of AChE reactivators (artificial neural networks), their synthesis, in vitro evaluation of their potencies (potentiometric titration and Ellman's method), in vivo studies (therapeutic index, LD(50) of newly synthesized reactivators, reactivation in different tissues, neuroprotective efficacy).
Abstract:
Background: The widespread use of organophosphorus compounds in agriculture and their existence in some military arsenals present continuous threats.
Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds.
Objective:
The in vivo experimental pharmacokinetic properties of K-868, a novel bis-chlorinated, bis-pyridinium mono-aldoxime are detailed and put in context with regard to similar compounds described earlier.
Methods:
Rats received 30 µmol K-868 i.m. and were sacrificed at various time points following treatment. Blood, cerebrospinal fluid and tear were collected, while the brains, eyes, kidneys, livers, lungs and testes were removed, dissected and homogenized. K-868 concentrations were determined using high performance liquid chromatography with ultraviolet absorption detection.
Results:
K-868 was detected in the eyes, kidneys, lungs and tear within 5 minutes in maximal serum concentrations attained 15 minutes following administration. Elimination was slow for K-868 which remained detectable at 120 minutes in the blood and the kidneys, and at 60 minutes in the eyes, lungs and tear following its administration. Nevertheless, its distribution was overall poor with areas under the 120-minute concentration curves (AUC120) showing close similarity in the blood and the kidneys, while reaching just approximately 5% of serum AUC120 in the eyes and lungs.
Conclusion:
K-868 is a potent candidate antidote against organophosphate poisoining with a prolonged presence in the circulation.
For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.
The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%).
Reactivation potency of three newly developed oximes K027, K033 and K048 was tested using standard in vitro and in vivo reactivation tests. K027 and K048 seem to be efficacious reactivators of tabun-inhibited acetylcholinesterase. K033 is sufficient reactivator of cyclosarin-inhibited AChE. However, its potency is poor compared with current "gold standard" oxime HI-6.
