The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice.

Jiří Kassa,Eugenie Nepovimová,Jan Korábečný

doi:10.14712/18059694.2017.45

Jiří Kassa, Eugenie Nepovimová + Show 1 more

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https://doi.org/10.14712/18059694.2017.45

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Abstract

The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2.

Highlights

The highly toxic organophosphorus compounds, called nerve agents, are still considered to be the most dangerous chemical warfare agents
The results show that the acute toxicity of newly prepared reversible inhibitors of AChE is quite different
While the acute toxicity of 7-phenoxytacrine, compound 2 and, especially, compound 1 is relatively low, the acute toxicity of 6-chlorotacrine is markedly higher it is still lower than the acute toxicity of commonly used pyridostigmine

Summary

Introduction

The highly toxic organophosphorus compounds, called nerve agents, are still considered to be the most dangerous chemical warfare agents. They pose potential threats to both military and civilian populations, as evidenced in terroristic attacks in Japan [1]. Organophosphorus nerve agents exert their toxic effects mainly by inhibiting acetylcholinesterase (AChE, EC 3.1.1.7) and subsequent accumulation of acetylcholine (ACh) in the central and peripheral nervous systems and stimulation of both muscarinic and nicotinic cholinergic receptors. Anticholinergics (mainly atropine) are used for relieving muscarinic signs and symptoms whereas AChE reactivators (generally nucleophilic compounds with high affinity for phosphorus), called oximes, are used to repair the biochemical lesion by dephosphonylation of AChE and restoring its activity. The antidotes against nerve agents and organophosphorus insecticides have been developed based on the knowledge of above-mentioned basic mechanism of acute toxicity, their efficacy is limited [4,5]

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