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

Abstract

A B ST R AC T Aim: 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. Methods: 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 LD 50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. Results: 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. Conclusion: 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. K E Y WO R D S soman; reversible inhibitors of acetylcholinesterase; antidotes; pharmacological pretreatment; mice

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

“…Our study confirms the negligible prophylactic value of pyridostigmine: the protective ratio was 0.92 as pretreatment and 1.02 with post-exposure therapy. Previously published studies bring similar results (Bajgar et al 2019;Kassa et al 2017). This limitation may be related to insufficient brain penetration.…”

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

“…A few years ago, a novel reversible inhibitor of AChE -6-chlorotacrine (6-chloro-1,2,3,4-tetrahydroacridine-9-amine hydrochloride) (Figure 1) was synthesized at our Department of Toxicology and Military Pharmacy to improve the efficacy of pharmacological pretreatment against nerve agents and potentially for the treatment of Alzheimer`s disease. Recently, a promising ability of 6-chlorotacrine to increase the resistance of soman-poisoned mice and the efficacy of post-exposure antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice was found (15). However, the dose of 6-chlorotacrine used in this study was too small to reach optimal inhibition of the brain AChE.…”

“…lethal toxicity of soman and to increase the therapeutic efficacy of standard antidotal treatment of acute soman poisoning. It was found to be more effective and less toxic than commonly used pyridostigmine bromide (15). The effect of reversible inhibitors of AChE administered prior nerve agent exposure strongly depends on their ability to protect enough peripheral and central AChE from irreversible inhibition by nerve agents.…”

“…The LD 50 value of 6-chlorotacrine (10.08 mg/kg) was assessed using probit-logarithmical analysis of death occurring within 24 hours after i.m. administration of 6-chlorotacrine at five doses with eight mice per dose (16) and published in our previous paper (15). The doses of tested reversible inhibitor of AChE were chosen to be sufficiently safe to avoid the potential adverse drug reactions in the peripheral as well as central compartment.…”

Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings

“…Furthermore, it might also be used as the post-exposure treatment via the antagonism of the overstimulated nicotinic receptors. 20 …”