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. 2018 Feb 21;19(1):8.
doi: 10.1186/s40360-018-0196-3.

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Kamil Kuca  1   2 , Kamil Musilek  3   4 , Daniel Jun  3   5 , Jana Zdarova-Karasova  3   5 , Eugenie Nepovimova  3   4 , Ondrej Soukup  3   5 , Martina Hrabinova  3   5 , John Mikler  6 , Tanos C C Franca  7   8 , Elaine F F Da Cunha  9 , Alexandre A De Castro  9 , Martin Valis  10 , Teodorico C Ramalho  7   9
Affiliations

A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase

Kamil Kuca et al. BMC Pharmacol Toxicol. .

Abstract

Background: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes.

Methods: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6).

Results: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE.

Discussion: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

Keywords: Antidotes; Chemical warfare agents; Oxime; Poisoning; Reactivator; Treatment.

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Conflict of interest statement

Ethics approval and consent to participate

Experiments were approved in compliance with relevant laws and institutional guidelines and were approved by the Ethics Committee of the Faculty of Military Health Sciences in Hradec Kralove (Czech Republic).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Chemical structure of tabun
Fig. 2
Fig. 2
Developmental strategy of the AChE reactivator K203
Fig. 3
Fig. 3
Currently commercially available oximes
Fig. 4
Fig. 4
The effectiveness of oximes at varying concentrations to reactivate tabun-inhibited human cholinesterase. Cholinesterase activity measured in human brain homogenate is shown as a percentage of control activity. Tabun was incubated with brain homogenate for 30 min prior to the addition of the oxime. Reactivation was carried out for 10 min. All experiments were carried out at pH 7.6 and 25 °C. Each point represents the mean±SEM for 2 measurements
Fig. 5
Fig. 5
Structural requirements for reactivators of tabun-inhibited AChE
Fig. 6
Fig. 6
Interactions performed by K203 in the MmAChE (a) and HssAChE (b) active site
Fig. 7
Fig. 7
Interactions performed by Obidoxime in the MmAChE (a) and HssAChE (b) active site
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