Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor

Antonijević, Evica; Musílek, Kamil; Kuča, Kamil; Djukic-Cosic, Danijela; Vučinić, Slavica; Antonijević, Biljana

doi:10.1016/j.neuro.2016.05.006

Cited by 24 publications

(17 citation statements)

References 53 publications

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“…Such approach may also help to overcome similar issue regarding organophosphorus pesticides. HI-6 has only limited reactivation efficacy towards chlorpyrifos, dichlorvos, methamidophos, and paraoxon [ 1 , 12 , 30 , 31 ]. Its combination with trimedoxime or K203 might not only improve these results but may also broaden the spectrum of reactivation towards leptophos-oxon and possibly other pesticides [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

The benefit of combinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damage in rats

Caisberger

Pejchal

Mišík

et al. 2018

BMC Pharmacol Toxicol

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BackgroundThe aim of our study was to compare the ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) with atropine to counteract acute sarin-induced brain damage with the efficacy of antidotal treatment involving single oxime (HI-6) and atropin using in vivo methods.MethodsBrain damage and neuroprotective effects of antidotal treatment were evaluated in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% LD50) using histopathological, Fluoro-Jade B and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis 24 h after sarin administration.ResultsBoth combinations of oximes reduce the number of rats that died before the end of experiment compared to non-treated sarin poisoning and sarin poisoning treated with HI-6 and atropine. In the case of treatment of sarin poisoning with HI-6 in combination with K203, all rats survived till the end of experiment. HI-6 with atropine was able to reduce sarin-induced brain damage, however, both combinations were slightly more effective.ConclusionsThe oxime HI-6 in combination with K203 and atropine seems to be the most effective. Thus, both tested oxime combinations bring a small benefit in elimination of acute sarin-induced brain damage compared to single oxime antidotal therapy.

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Section: Discussionmentioning

confidence: 99%

The benefit of combinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damage in rats

Caisberger

Pejchal

Mišík

et al. 2018

BMC Pharmacol Toxicol

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“…2 OPs that were developed as chemical warfare nerve agents (CWAs) are all highly toxic and dangerous. [3][4][5] OP nerve agents have been used and are most likely to be used in the future by terrorists and dictators around the world because of their relatively easy synthesis and availability of suitable delivery systems. 6 Warfare and terrorist use of CWAs include the Aum Shinrikyo terrorist attack in the Tokyo subway in 1995, the 1980-1988 Iraq-Iran war where Iraq reportedly used nerve agents against Iranian troops and later on Kurd civilians and the murder of a family member of the North Korea Leader, Kim Jong Nam on February 2017 in Kuala Lumpur.…”

Section: Introductionmentioning

confidence: 99%

“…atropine), which counteracts the excessive muscarinic stimulation, and also the administration of an AChE reactivator (pyridinium oximes), which reactivates the physiological function of AChE. 3,15,16 Successful reactivation of AChE can terminate overstimulation of the muscarinic and nicotinic receptors by ACh and thus prevent further neurotoxicity. However, several reports on efficacy testing of experimental oximes claimed that the oximes have difficulty in reactivating the AChE located in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

et al. 2020

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“…Oximes are molecules that function as AChE reactivators, through the nucleophilic attack of the oxime to the OP‐AChE complex, promoting enzymatic reactivation and therefore the restoration of normal nerve function . However, both experimental and clinical findings demonstrate an inconsistent efficacy of oximes against OP poisoning since their efficiency depends on the chemical identity between the oxime and OP . In this way, the synthesis, safety evaluation and pharmacological properties of new molecules or alternative approaches are appropriate.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 However, both experimental and clinical findings demonstrate an inconsistent efficacy of oximes against OP poisoning since their efficiency depends on the chemical identity between the oxime and OP. [17][18][19] In this way, the synthesis, safety evaluation and pharmacological properties of new molecules or alternative approaches are appropriate.…”

Section: Introductionmentioning

confidence: 99%

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

Savall

Fidélis

Gutierrez

et al. 2019

Basic Clin Pharma Tox

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The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE‐reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)‐5‐chloro‐3‐(hydroxyimino) indolin‐2‐one oxime (Cℓ‐HIN) and 2‐(5‐chloro‐2‐oxoindolin‐3‐ylidene)‐hydrazinecarbothioamide (Cℓ‐OXHS) was higher than 1000 µM while to 3‐(phenylhydrazono) butan‐2‐one oxime (PHBO) was 38 µM. Our screening showed that Cℓ‐HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ‐HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ‐HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase‐1 (PON‐1) activity among groups treated. In conclusion, Cℓ‐HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ‐HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.

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Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor

Cited by 24 publications

References 53 publications

The benefit of combinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damage in rats

The benefit of combinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damage in rats

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

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