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Antiepileptic drug therapy: Does mechanism of action matter?
Epilepsy & Behavior 21 (2011) 490
Contents lists available at ScienceDirect
Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h
Letter to the Editor Antiepileptic drug therapy: Does mechanism of action matter?
To the Editor: Thank you for giving us the opportunity to respond to Dr. Schmidt's Commentary [1]. We do, of course, appreciate that “antiepileptic” drugs (AEDs) should logically be termed “antiseizure” drugs because they address the symptoms and not the underlying pathophysiological processes, which in some patients are progressive. Nevertheless, we do have available a broad range of therapeutic agents that influence different pharmacological targets in the brain [2]. We are aware that there are a variety of mechanisms underpinning the occurrence of seizures in different syndromes and different patients, and we believe that knowledge of the pathways leading to seizure generation and propagation could facilitate individual targeting of treatment [3]. We agree that the development of drugs with antiepileptogenic properties could be valuable, but this is irrelevant to the issues addressed in our article. On the basis of the data available, our report focuses on those situations in which mechanism of action can matter and those in which it does not. The fact that a third of our patients still have refractory epilepsy is, arguably, dwarfed by the observation that AEDs control seizures in the majority of people despite our disappointing lack of ability to refine our clinical approach to modes of action. The development of more AEDs with novel pharmacological properties may be a better strategy for the future than placing our bets on identifying “antiepileptogenic agents,” an untested scenario that is hampered by lack of validated preclinical models, formidable obstacles in clinical testing, and likely substantial regulatory hurdles. There is no “holy grail” on the horizon, but just a steady chipping away
1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.04.053
at the slowly decreasing population of patients with refractory epilepsy. It is not magic, but rather the mechanisms of action of current AEDs that make two-thirds of people with epilepsy seizure free. References [1] Schmidt D. Antiepileptic drug discovery: does mechanism of action matter? [commentary]. Epilepsy Behav 2011. [2] White HS, Smith MA, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol 2007;81:85–107. [3] Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18–61.
Martin Brodie ⁎ Thanos Covanis Antonio Gil-Nagel Holger Lerche Emilio Perucca Graeme Sills Steve White University Division of Cardiovascular & Medical Sciences, Epilepsy Unit, Western Infirmary, Glasgow, UK ⁎ Corresponding author at: University Division of Cardiovascular & Medical Sciences, Epilepsy Unit, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK. Tel.: +44 211 2534; fax: + 44 211 2072. E-mail address: [email protected] (M. Brodie). 4 April 2011
Contents lists available at ScienceDirect
Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h
Letter to the Editor Antiepileptic drug therapy: Does mechanism of action matter?
To the Editor: Thank you for giving us the opportunity to respond to Dr. Schmidt's Commentary [1]. We do, of course, appreciate that “antiepileptic” drugs (AEDs) should logically be termed “antiseizure” drugs because they address the symptoms and not the underlying pathophysiological processes, which in some patients are progressive. Nevertheless, we do have available a broad range of therapeutic agents that influence different pharmacological targets in the brain [2]. We are aware that there are a variety of mechanisms underpinning the occurrence of seizures in different syndromes and different patients, and we believe that knowledge of the pathways leading to seizure generation and propagation could facilitate individual targeting of treatment [3]. We agree that the development of drugs with antiepileptogenic properties could be valuable, but this is irrelevant to the issues addressed in our article. On the basis of the data available, our report focuses on those situations in which mechanism of action can matter and those in which it does not. The fact that a third of our patients still have refractory epilepsy is, arguably, dwarfed by the observation that AEDs control seizures in the majority of people despite our disappointing lack of ability to refine our clinical approach to modes of action. The development of more AEDs with novel pharmacological properties may be a better strategy for the future than placing our bets on identifying “antiepileptogenic agents,” an untested scenario that is hampered by lack of validated preclinical models, formidable obstacles in clinical testing, and likely substantial regulatory hurdles. There is no “holy grail” on the horizon, but just a steady chipping away
1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.04.053
at the slowly decreasing population of patients with refractory epilepsy. It is not magic, but rather the mechanisms of action of current AEDs that make two-thirds of people with epilepsy seizure free. References [1] Schmidt D. Antiepileptic drug discovery: does mechanism of action matter? [commentary]. Epilepsy Behav 2011. [2] White HS, Smith MA, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol 2007;81:85–107. [3] Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18–61.
Martin Brodie ⁎ Thanos Covanis Antonio Gil-Nagel Holger Lerche Emilio Perucca Graeme Sills Steve White University Division of Cardiovascular & Medical Sciences, Epilepsy Unit, Western Infirmary, Glasgow, UK ⁎ Corresponding author at: University Division of Cardiovascular & Medical Sciences, Epilepsy Unit, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK. Tel.: +44 211 2534; fax: + 44 211 2072. E-mail address: [email protected] (M. Brodie). 4 April 2011