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Pharmacoresistance in Epilepsy pp 47–57Cite as

Molecular Mechanisms of Pharmacoresistant Epilepsy

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Abstract

Epilepsy is a common neurological disorder and despite significant advances in therapy over recent decades, about 30–40 % of epileptic patients will remain refractory to pharmacological therapies despite optimized drug treatment. Taking a carefully reviewed definition of “drug-resistance” into account, two main concepts were proposed to explain the development of pharmacoresistance in epilepsy. The “target” hypothesis indicates that changes in the properties of the drug targets themselves may result in reduced sensitivity to antiepileptic drugs (AEDs). This hypothesis is supported by several pharmacodynamic modifications leading to loss of drugs’ effects in refractory epilepsy. However, it cannot explain the refractoriness observed after polytherapeutic trials using several recommended AEDs at appropriate doses. Consequently, a mechanism of multidrug resistance (MDR) as previously described in cancer could also explain—at least in part—the reason for this particular phenotype. The so-called “transporters” hypothesis suggests that functional over-expression of multidrug transporters in brain could reduce AEDs access to the central nervous system. Both mechanisms could be active simultaneously in refractory epilepsy and possibly also, not represent the only mechanisms involved.

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Author information

Authors and Affiliations

  1. INFIBIOC-FFyB-UBA-Universidad de Buenos Aires, Junín 856 (1113 AAD), Buenos Aires, Argentina

    Alberto Lazarowski M.S., Ph.D.

  2. Hospital Nacional de Pediatría “Juan P. Garrahan”, Combate de los Pozos 1245 (1245 AAM), Buenos Aires, Argentina

    Liliana Czornyj M.D.

Authors
  1. Alberto Lazarowski M.S., Ph.D.
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  2. Liliana Czornyj M.D.
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Corresponding author

Correspondence to Alberto Lazarowski M.S., Ph.D. .

Editor information

Editors and Affiliations

  1. , Pharmacobiology Department, Center for Research and Advanced Studies, Av. Instituto Politécnico Nacional 2508, Mexico City, 07360, Mexico

    Luisa Rocha

  2. , Disciplina de Neurologia Experimental, UNIFESP/EPM, Rua Botucatu 740, São Paulo, 04023-900, Brazil

    Esper A. Cavalheiro

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Lazarowski, A., Czornyj, L. (2013). Molecular Mechanisms of Pharmacoresistant Epilepsy. In: Rocha, L., Cavalheiro, E. (eds) Pharmacoresistance in Epilepsy. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6464-8_4

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