Drug Resistance in Epilepsy: Which Prospect to Tame its Stubbornness?
Main Article Content
Abstract
Epilepsy is a major health problem, it being among the most common chronic neurologic pathologies. Its basic therapy is via anti-seizure drugs (ASDs), of which nearly two dozen are currently available for symptomatic treatment of epileptic seizures. But, notwithstanding the increasing ASD options, about one-third of epileptic patients remain drug-refractory, and this fraction did not diminish over decades. This paper reviews the subject of drug resistance in epilepsy (DRE), in view of exploring the prospect to overcome its persistence. The survey of various hypotheses about DRE origin and mechanisms notices that any of them alone does not fully account the DRE, their multitude deriving from the lack of solution to this bad medical need. The non-pharmacological (neurosurgical, brain stimulation, focal treatments and dietary) approaches of drug-intractable epilepsy are also surveyed, with the sober conclusion that, in a predictable future, the mainstay of epilepsy therapy will likely remain the drugs. The vast multiplicity of molecular changes associated with DRE suggests that its pharmacological resolution might arise only from integrative, systemic approaches, beyond the reductionist single-target paradigm that dominated the ASD discovery, in the last several decades. A conceivable lessening of DRE might be brought about by precision (personalized) medicine, assisted by complex systems biology description of individual epileptic pathology. In a longer run, the emergent network pharmacology might led to genuine innovative multi-potent antiepileptic drugs, able to treat distinct subpopulations of current refractory patients.
Keywords:
mechanisms of drug resistance, non-pharmacological antiepileptic treatments, precision medicine, network pharmacology, multi-potent drug
Article Details
How to Cite
MARGINEANU, Doru Georg.
Drug Resistance in Epilepsy: Which Prospect to Tame its Stubbornness?.
Medical Research Archives, [S.l.], v. 9, n. 8, aug. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2514>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i8.2514.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Magiorkinis E, Sidiropoulou K, Diamantis A. Hallmarks in the history of epilepsy: epilepsy in antiquity. Epilepsy Behav. 2010;17(1),103–108.
4. Kinnier Wilson JV, Reynolds EH. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med Hist. 1990;34(2):185–198.
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6. Lai CW, Lai YHC. History of epilepsy in Chinese traditional medicine. Epilepsia 1991;32(3):299-302.
7. Magiorkinis E, Diamantis A, Sidiropoulou K, Panteliadis C. Highlights in the history of epilepsy: the last 200 years. Epilepsy Res Treat. 2014, Article ID 582039. Doi: http://dx.doi.org/10.1155/2014/582039
8. Reynolds EH, Rodin E. The clinical concept of epilepsy. Epilepsia 2009;50(3):2–7.
9. Golyala A, Kwan P. Drug development for refractory epilepsy: the past 25 years and beyond. Seizure Jan 2017;44:147–156.
10. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606–638.
11. Fisher RS, van Emde Boas W, Blume W, Elger C., Genton P., Lee P., Engel J., Jr. Epileptic seizures and epilepsy: definitions proposed by the ILAE and the IBE. Epilepsia 2005;46(4):470–472.
12. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–482.
13. Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, Pringsheim T, Lorenzetti DL, Jetté N. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017;88(3):296–303.
14. Brodie M.J., Kwan P. Staged approach to epilepsy management. Neurology 2002;58(8, Suppl 5):S2–S8.
15. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 2005;46(6):858–877.
16. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78(20):1548–1554.
17. Berg AT. Identification of pharmacoresistant epilepsy. Neurol Clin. 2009;27(4):1003–1013.
18. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077.
19. Elger CE. Pharmacoresistance: modern concept and basic data derived from human brain tissue. Epilepsia 2003;44(Suppl 5):9–15.
20. Neligan A, Bell GS, Sander JW, Shorvon SD. How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res. 2011;96(3):225–230.
21. Gorter JA, Potschka H. Drug Resistance. In: Noebels JL, Avoli M, Rogawski MA et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US) 2012; Drug Resistance - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
22. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301. Doi: 10.3389/fneur.2017.00301
23. Pérez-Pérez D, Frías-Soria CL, Rocha L. Drug-resistant epilepsy: from multiple hypotheses to an integral explanation using preclinical resources. Epilepsy Behav. Aug 2019;106430 https://doi.org/10.1016/j.yebeh.2019.07.031.
24. Margineanu DG, Klitgaard H. Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery. Expert Opin Drug Disc. 2009;4(1):23–32.
25. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005; 6(8):591–602.
26. Baltes S, Fedrowitz M, Luna Tortos C, Potschka H, Löscher W. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther. 2007;320(1):331–343.
27. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacol. 2007;52(2):333–346.
28. Remy S, Gabriel S, Urban BW, Dietrich D, Lehmann TN, Elger CE, Heinemann U, Beck H. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol. 2003;53(4):469–479.
29. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 2006;129(1):18-35.
30. Remy S, Urban BW, Elger CE, Beck H. Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. Eur J Neurosci. 2003;17(12):2648–2658.
31. Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr. 2008;8(5):127–130.
32. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia 2013;54(Suppl 2):33–40.
33. Schmidt D, Löscher W. New developments in antiepileptic drug resistance: an integrative view. Epilepsy Curr. 2009;9(2):47–52.
34. Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D’Giano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007;48 (Suppl 5):140–149.
35. Fang M, Xi ZQ, Wu Y, Wang XF. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 2011;76(6):871–876.
36. Scheffer IE, Berkovic SF. The genetics of human epilepsy. Trends Pharmacol Sci. 2003;24(8):428–433.
37. Pal DK, Strug LJ, Greenberg DA. Evaluating candidate genes in common epilepsies and the nature of evidence. Epilepsia 2008;49(3):386–392.
38. Helbig I, Heinzen EL, Mefford HC on behalf of the ILAE Genetics Commission. The building blocks of epilepsy genetics. Epilepsia 2016;57(6):861–868.
39. Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. Feb 2018;667:27–39.
40. Koeleman BPC. What do genetic studies tell us about the heritable basis of common epilepsy? Polygenic or complex epilepsy? Neurosci Lett. Feb 2018;667:10–16.
41. Cardenas‑Rodriguez N, Carmona‑Aparicio L, Pérez-Lozano DL et al. Genetic variations associated with pharmacoresistant epilepsy. Molec Med Rep. 2020;21(4):1685–1701.
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