Effect of long-term administration of a novel anticonvulsant drug candidate (TP-315) on living organism

Epilepsy is a chronic neurological disorder affecting nearly 65-70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs, still nearly 30% of patients suffer from the pharmacoresistant form of the disease. In our recent studies, we have identified 4-alkyl-5-aryl-1,2,4-triazole-3-thiones as a promising group of antiepileptic drug candidates acting on the voltage-gated sodium channels. Their anticonvulsant properties were proved in animal models of tonic-clonic generalized seizures (MES test) and in the 6 Hz model of pharmacoresistant epilepsy. Although several preclinical studies confirmed their favorable pharmacological and toxicological profile, little is known about the effects of long-term administration of such compounds on the living organism. In our current studies, using the combined results of PAMPA-BBB, MES and 6 Hz tests, the most promising drug candidate - 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315), was selected for further experiments. After prolonged administration of TP-315 to adult Swiss-Albino mice, its effects on functional parameters of internal organs and cytochrome P450 enzyme system were evaluated. On the basis of both histopathological and biochemical examination, it was found that TP-315 does not exhibit hepatotoxic and nephrotoxic effects in mice. Moreover, TP-315 at the concentration determined in the blood of mice, did not significantly affect the activity of the studied CYP450 isoforms.

This research was supported by the National Science Centre (Poland) under Preludium funding scheme (Grant No. 2018/31/N/NZ7/02867).