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On the Development of New Drugs for the Treatment of Drug-Resistant Epilepsy: An Update on Different Approaches to Different Hypotheses

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Pharmacoresistance in Epilepsy

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Abstract

Despite the continuous expansion of the available pharmacological options for the treatment of epilepsies and remarkable advances in understanding their pathophysiology, the proportion of refractory patients has remained roughly unchanged over the past 100 years.

In the last decade, hypotheses that try to explain the drug-resistant phenotype have increased in number and their scope has been more precisely specified, and some major advances related to some of these hypotheses have been realized, both at the preclinical and clinical levels. These include the use of gene therapies to revert the pharmacoresistant phenotype in animal models of epilepsy, advance into clinical trials and approval of tailored multitarget therapeutics (e.g., padsevonil and cenobamate) exhibiting encouraging results on refractory patients, approval of new drugs with new (and sometimes complex) mechanisms to address particularly severe and difficult-to-treat epileptic syndromes, and the first reports of applications of network analysis to rationally select combinations of antiseizure medications. The introduction of the Epilepsy Therapy Screening Program also constitutes a significant milepost that will possibly have a major impact on the development of new, more efficacious therapeutic options against epilepsy, as the focus of the international guidelines to screen for novel medications against epilepsy is now on refractory epilepsy and disease-modifying interventions.

This chapter, which intends to be a critical update of the one published back in the first edition of this volume, overviews the current hypotheses that intend to explain refractory epilepsy as well as plausible therapeutic strategies to address some of them.

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Acknowledgments

The author thanks CONICET, Incentivos UNLP, and FONCyT’s PICT 2019-1075.

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  1. Laboratory of Bioactive Compound Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Argentina

    Alan Talevi

  2. Argentinean National Council of Scientific and Technical Research (CONICET) – CCT La Plata, La Plata, Argentina

    Alan Talevi

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  1. Pharmacobiology Department, Center for Research and Advanced Studies, México, Mexico

    Luisa L. Rocha

  2. Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

    Alberto Lazarowski

  3. Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil

    Esper A. Cavalheiro

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Talevi, A. (2023). On the Development of New Drugs for the Treatment of Drug-Resistant Epilepsy: An Update on Different Approaches to Different Hypotheses. In: Rocha, L.L., Lazarowski, A., Cavalheiro, E.A. (eds) Pharmacoresistance in Epilepsy. Springer, Cham. https://doi.org/10.1007/978-3-031-36526-3_20

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