Abstract
Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.
Document Type
Review
Publication Date
7-6-2017
Digital Object Identifier (DOI)
https://doi.org/10.3389/fneur.2017.00301
Funding Information
The project described was supported by grant number 1 R01NS079507 from the National Institute of Neurological Disorders and Stroke (to BB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.
Repository Citation
Tang, Fei; Hartz, Anika M. S.; and Bauer, Björn, "Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers" (2017). Pharmaceutical Sciences Faculty Publications. 99.
https://uknowledge.uky.edu/ps_facpub/99
Included in
Molecular and Cellular Neuroscience Commons, Neurology Commons, Pharmaceutics and Drug Design Commons
Notes/Citation Information
Published in Frontiers in Neurology, v. 8, 301, p. 1-19.
© 2017 Tang, Hartz and Bauer.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.