Anticonvulsant activity of original valproic acid aminoethers in cholinesterase inhibitor poisoning

Introduction. Cholinesterase inhibitors present in household chemicals, agrochemicals, and a number of medicinal products represent the most common cause of acute intoxications accompanied by the development of convulsive syndrome. Delayed and repeated administration of existing antidotes proves ineffective. Compounds that are promising for the development of alternative therapeutic agents include derivatives of valproic acid.

Objective. Evaluation of the anticonvulsant efficacy of original valproic acid aminoethers in intoxication with phenylcarbamate as a cholinesterase inhibitor.

Materials and methods. Experiments were conducted using outbred white male rats aged 3 months with a body weight of 200–240 g. The tabular express method by Prozorovsky was used to determine the median lethal doses of the new compounds. To model the convulsive syndrome, phenylcarbamate was administered intraperitoneally to male rats at a dose of 1 mg/kg bw. The anticonvulsant activity of valproic acid aminoethers — N-methyl-4-piperidinol (VAA), quinuclidinol (QVA), and tropinol (TVA) — was assessed. The preparations were administered at doses of 21.5 mg/kg bw and 43 mg/kg bw after the onset of convulsions. The study was conducted using four experimental groups: phenylcarbamate — P (n = 8), P+VAA (n = 16), P+TVA (n = 16), and P+QVA (n = 16). The test substances were dissolved in 0.9% sodium chloride solution and administered intraperitoneally, taking interspecies dose conversion into account. The volume of the intraperitoneally administered solution was 0.1 mL/100 g. The severity of the convulsive syndrome in the experiment was assessed using the Racine scale. The following efficacy indicators were taken into account: latent period, severity and duration of convulsive syndrome, and mortality. Statistical processing of the research results was performed using the Statistica 13.0 software package (Statsoft, USA).

Results. The established LD₅₀ values of the original valproic acid aminoethers under study correspond to class 3 of moderately toxic substances. At a dose of 21.5 mg/kg bw, the proportion of rats with severe convulsions significantly decreased in all groups; the fastest anticonvulsant effect was recorded in the QVA group (after 10 min, convulsions were absent). The efficacy of VAA and TVA at a dose of 43 mg/kg bw was comparable to the dose of 21.5 mg/kg bw; in the QVA group, the proportion of animals with convulsions remained high after 10 min. A significant reduction in the duration of convulsions was revealed in the QVA group at doses of 21.5 mg/kg bw and 43 mg/kg bw. A significant decrease in the intensity of convulsions was detected in the VAA and QVA groups at a dose of 21.5 mg/kg bw, and at a dose of 43 mg/kg bw in the VAA and TVA groups.

Conclusions. The new aminoethers of valproic acid exhibit anticonvulsant activity in intoxication with a reversible cholinesterase inhibitor. At a dose of 21.5 mg/kg bw, QVA is the most effective; however, at a dose of 43 mg/kg bw, manifestations of toxicity are observed and VAA is more effective. Despite animal mortality, TVA also demonstrates its efficacy at a dose of 43 mg/kg bw.

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