Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers
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 refractor...
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doaj-14d93bd013764f8c9f5bd6edf0ae6bab2020-11-24T20:47:14ZengFrontiers Media S.A.Frontiers in Neurology1664-22952017-07-01810.3389/fneur.2017.00301275386Drug-Resistant Epilepsy: Multiple Hypotheses, Few AnswersFei Tang0Fei Tang1Anika M. S. Hartz2Anika M. S. Hartz3Björn Bauer4Björn Bauer5Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United StatesSanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United StatesDepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United StatesEpilepsy Center, University of Kentucky, Lexington, KY, United StatesEpilepsy 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.http://journal.frontiersin.org/article/10.3389/fneur.2017.00301/fullepilepsyrefractory epilepsyblood–brain barrierP-glycoproteintransporter hypothesistarget hypothesis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fei Tang Fei Tang Anika M. S. Hartz Anika M. S. Hartz Björn Bauer Björn Bauer |
spellingShingle |
Fei Tang Fei Tang Anika M. S. Hartz Anika M. S. Hartz Björn Bauer Björn Bauer Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers Frontiers in Neurology epilepsy refractory epilepsy blood–brain barrier P-glycoprotein transporter hypothesis target hypothesis |
author_facet |
Fei Tang Fei Tang Anika M. S. Hartz Anika M. S. Hartz Björn Bauer Björn Bauer |
author_sort |
Fei Tang |
title |
Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers |
title_short |
Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers |
title_full |
Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers |
title_fullStr |
Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers |
title_full_unstemmed |
Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers |
title_sort |
drug-resistant epilepsy: multiple hypotheses, few answers |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neurology |
issn |
1664-2295 |
publishDate |
2017-07-01 |
description |
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. |
topic |
epilepsy refractory epilepsy blood–brain barrier P-glycoprotein transporter hypothesis target hypothesis |
url |
http://journal.frontiersin.org/article/10.3389/fneur.2017.00301/full |
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