Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase

Kuča, Kamil; Musílek, Kamil; Jun, Daniel; Pohanka, Miroslav; Ghosh, Kallol K.; Hrabinová, Martina

doi:10.3109/14756360903357569

Cited by 27 publications

(13 citation statements)

References 46 publications

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“…Structurally, they are bispyridinium oximes that differ in the length of the connection chain between two pyridinium rings, the position of the oxime group, and the number of oxime groups in a molecule. Promising results using several of the previously mentioned oximes were obtained for poisoning by the nerve agent tabun, as well as in the case of pesticide poisoning (8,14,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Although the use of OP pesticides is under restriction in most parts of the world, especially in developed countries, some, such as parathion, are still widely (mis)used (30).…”

Section: Resultsmentioning

confidence: 97%

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

et al. 2010

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The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD 50 ) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD 50 =21.4 mg kg -1 ) to mice, while monoxime K027 was the least toxic (LD 50 =672.8 mg kg -1 ). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD 50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.

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Section: Resultsmentioning

confidence: 97%

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

et al. 2010

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“…In contrast, oximes either do not enter the brain at all, or only a very small percentage passes the blood-brain barrier Lorke, Kalasz, Petroianu, & Tekes, 2008). K-27 belongs to a group of newly developed oxime-type AChE reactivators (Kuča et al, 2010;Kuča & Cabal, 2004;Kuča, Cabal, & Kassa, 2005;Kuča & Kassa, 2004;Lorke, Nurulain, et al, 2008;Petroianu, Lorke, & Kalasz, 2012), which efficiently reduce OPCinduced mortality, when administered after OPC exposure (Kassa, Kuča, Cabal, & Paar, 2006;Lorke, Kalasz, et al, 2008;Nurulain et al, 2009;. These K-oximes include K-27, K-48 and K-203 ( Figure 1), bisquaternary asymmetric pyridinium aldoximes containing only one functional aldoxime group in position 4 of the pyridine ring (Kassa et al, 2006;Kuča, Bielavsky, Cabal, & Bielavska, 2003) as well as K-53, K-74 and K-75, bispyridinium oximes with two aldoxime groups Musilek et al, 2007).…”

Section: Figurementioning

confidence: 99%

Oximes as pretreatment before acute exposure to paraoxon

Lorke

Nurulain

Al‐Hasan³

et al. 2019

J of Applied Toxicology

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Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01) the prophylactic efficacy of five experimental (K‐48, K‐53, K‐74, K‐75, K‐203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10‐methylacridine) and after the FDA‐approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon‐induced mortality. Best protection was conferred by the experimental oxime K‐48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K‐203), 0.21 (K‐74), 0.24 (K‐75) and 0.26 (pralidoxime), which were significantly more efficacious than 10‐methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

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“…A prodrug of pralidoxime is pro‐PAM (Bodor et al ., ). In an attempt to improve the antidote efficacy of these compounds, a wide range of PyAls, such as K027, (Kuca et al ., , ), K048 (Kuca et al ., ), K074 (Kuca et al ., , ), K075 (Kuca et al ., 2005), K117 (Kim et al ., ), K127 (Kim et al ., ), K156 (Kuca et al ., , ), K203 (Musilek et al ., , , ) and KR‐22836 (a fluorinated analogue of K203) (Jeong et al ., ; Kassa et al ., , ) were synthesized (Table ).…”

Section: Introductionmentioning

confidence: 99%

Mini review on blood–brain barrier penetration of pyridinium aldoximes

Kalász

Nurulain

Veress³

et al. 2014

J of Applied Toxicology

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This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration.

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Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase

Cited by 27 publications

References 46 publications

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

Oximes as pretreatment before acute exposure to paraoxon

Mini review on blood–brain barrier penetration of pyridinium aldoximes

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