An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?

INTRODUCTION: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored. AREAS COVERED: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective. EXPERT OPINION: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

Triclabendazole and clofazimine reduce replication and spermine uptake in vitro in Toxoplasma gondii.

Toxoplasmosis is a worldwide zoonosis caused by the protozoan parasite Toxoplasma gondii. Although this infection is generally asymptomatic in immunocompetent individuals, it can cause serious clinical manifestations in newborns with congenital infection or in immunocompromised patients. As current treatments are not always well tolerated, there is an urgent need to find new drugs against human toxoplasmosis. Drug repurposing has gained considerable momentum in the last decade and is a particularly attractive approach for the search of therapeutic alternatives to treat rare and neglected diseases. Thus, in this study, we investigated the antiproliferative effect of several repurposed drugs. Of these, clofazimine and triclabendazole displayed a higher selectivity against T. gondii, affecting its replication. Furthermore, both compounds inhibited spermine incorporation into the parasite, which is necessary for the formation of other polyamines. The data reported here indicate that clofazimine and triclabendazole could be used for the treatment of human toxoplasmosis and confirms that drug repurposing is an excellent strategy to find new therapeutic targets of intervention.