<i>In Vivo</i> Evaluation of Cholinesterase Activity, Oxidative Stress Markers, Cyto‐ and Genotoxicity of K048 Oxime – a Promising Antidote against Organophosphate Poisoning

Žunec, Suzana; Kopjar, Nevenka; Želježić, Davor; Kuča, Kamil; Musílek, Kamil; Vrdoljak, Ana Lucić

doi:10.1111/bcpt.12158

Cited by 17 publications

(17 citation statements)

References 58 publications

(99 reference statements)

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“…In the same experiment, obidoxime was shown to be less implicated in oxidative stress induction because of the decrease in TBARS (Drtinova & Pohanka, ). Newly developed K‐series oxime reactivators showed either no impact on oxidative stress parameters (K048) or increase in LMWA (K203) in rat plasma (Karasova et al, ; Žunec et al, ). Unfortunately, there is a lack of data from in vivo experiments to confirm the connection between oxime structure and oxidative stress‐mediated organ injury.…”

Section: Oxidative Stress In Organophosphate Antidotal Therapymentioning

confidence: 99%

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

Váňová

Pejchal

Herman

et al. 2018

J of Applied Toxicology

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Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.

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Section: Oxidative Stress In Organophosphate Antidotal Therapymentioning

confidence: 99%

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

Váňová

Pejchal

Herman

et al. 2018

J of Applied Toxicology

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“…The limitations of post‐exposure treatment of acute poisonings with highly toxic organophosphorus compounds, especially soman, are well recognized . In situations allowing the administration of prophylactic agents, better therapeutic effects can be achieved by pre‐treatment with reversible AChE inhibitors .…”

Section: Discussionmentioning

confidence: 99%

“…soman, are well recognized [3][4][5][6][19][20][21][22]. In situations allowing the administration of prophylactic agents, better therapeutic effects can be achieved by pre-treatment with reversible AChE inhibitors [12,23].…”

Section: Discussionmentioning

confidence: 99%

The Evaluation of Prophylactic Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A Comparison with Commonly Used Pyridostigmine

Kassa¹,

Korábečný²,

Šepsová³

et al. 2014

Basic Clin Pharma Tox

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The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD 50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising.

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“…administration is widely used to test the efficacy of oximes (Lucić Vrdoljak et al, 2006;Nakab et al, 2014;Žunec et al, 2014).…”

Section: Limitationsmentioning

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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In Vivo Evaluation of Cholinesterase Activity, Oxidative Stress Markers, Cyto‐ and Genotoxicity of K048 Oxime – a Promising Antidote against Organophosphate Poisoning

Cited by 17 publications

References 58 publications

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

The Evaluation of Prophylactic Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A Comparison with Commonly Used Pyridostigmine

Oximes as pretreatment before acute exposure to paraoxon

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