Insights into the novel three 'D's of epilepsy treatment: drugs, delivery systems and devices.

Here, we review three 'D's--drugs, delivery systems and devices--that can selectively target not only brain regions but also abnormal cells in the epileptic nervous system. This review also offers insights into the novel molecular targets that enabled the development of new antiepileptic drugs with improved efficacy. Nanotechnology-based delivery systems and alert, diagnostic, surgical and brain stimulation devices designed for the control and management of epilepsy are also discussed. Although the application of the three 'D's continues to be valuable, this review also considers computer-aided software systems, with special emphasis on seizure detection and management. Finally, challenges that still loiter in the field and future prospects that, once accomplished, could lead to cures for epilepsy are addressed.

[1]  K. Nocka,et al.  The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Bates,et al.  P-Glycoprotein—a Clinical Target in Drug-Refractory Epilepsy? , 2008, Molecular Pharmacology.

[3]  Michael C Veronesi,et al.  Thyrotropin-releasing hormone d,l polylactide nanoparticles (TRH-NPs) protect against glutamate toxicity in vitro and kindling development in vivo , 2009, Brain Research.

[4]  W. Luo,et al.  Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin , 2008, Journal of clinical pharmacology.

[5]  R. Sharma,et al.  Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting. , 2006, Journal of pharmaceutical sciences.

[6]  Qi Xu,et al.  Protective Effect of Resveratrol against Kainate-induced Temporal Lobe Epilepsy in Rats , 2009, Neurochemical Research.

[7]  Y. Bozzi,et al.  Action of botulinum neurotoxins in the central nervous system: Antiepileptic effects , 2006, Neurotoxicity Research.

[8]  E. Perucca.  Extended-Release Formulations of Antiepileptic Drugs: Rationale and Comparative Value , 2009, Epilepsy currents.

[9]  R. Bodmeier,et al.  In vitro and in vivo evaluation of carbamazepine-loaded enteric microparticles. , 2007, International journal of pharmaceutics.

[10]  M. D. de Groot,et al.  Subtype‐selective targeting of voltage‐gated sodium channels , 2009, British journal of pharmacology.

[11]  Timothy A. Pedley,et al.  Epilepsy : a comprehensive textbook , 2008 .

[12]  Yüksel Özbay,et al.  A new approach for epileptic seizure detection using adaptive neural network , 2009, Expert Syst. Appl..

[13]  V. Venkateswarlu,et al.  Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[14]  N. Mori,et al.  Comparison of anticonvulsant effects of valproic acid entrapped in positively and negatively charged liposomes in amygdaloid-kindled rats , 1992, Brain Research.

[15]  M. Kubek,et al.  Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation , 1998, Brain Research.

[16]  Xue-feng Wang,et al.  Genes associated with idiopathic epilepsies: a current overview , 2009, Neurological research.

[17]  Holger Stark,et al.  Histamine H3 and H4 receptors as novel drug targets , 2009, Expert opinion on investigational drugs.

[18]  D. Markovic,et al.  TRIGEMINAL NERVE STIMULATION FOR EPILEPSY: LONG-TERM FEASIBILITY AND EFFICACY , 2009, Neurology.

[19]  C. Mulle,et al.  Kainate receptors in epilepsy and excitotoxicity , 2009, Neuroscience.

[20]  Betty M Tyler,et al.  The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats , 2002, Epilepsy Research.

[21]  S. Savić,et al.  Preparation and Characterisation of Phenytoin-Loaded Alginate and Alginate-Chitosan Microparticles , 2007, Drug delivery.

[22]  J. Kreuter,et al.  Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[23]  M. Trimble,et al.  Antiepileptic Drug-Induced Cognitive Adverse Effects , 2009, CNS drugs.

[24]  J. Engel,et al.  Commentary: Hormones, diet, and botanicals , 2009, Neurotherapeutics.

[25]  San-Yuan Chen,et al.  A flexible drug delivery chip for the magnetically-controlled release of anti-epileptic drugs. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[26]  H. Kumashiro,et al.  Anticonvulsant effect of liposome-entrapped superoxide dismutase in amygdaloid-kindled rats , 1992, Brain Research.

[27]  N. Delanty,et al.  Oxidative injury in epilepsy: potential for antioxidant therapy? , 2004, Expert review of neurotherapeutics.

[28]  E. Trinka.  What is the relative value of the standard anticonvulsants: Phenytoin and fosphenytoin, phenobarbital, valproate, and levetiracetam? , 2009, Epilepsia.

[29]  H. Onishi,et al.  [Development of semisolid dosage form of clonazepam for oral cavity administration]. , 2010, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[30]  C. Reid,et al.  Prediction by modeling that epilepsy may be caused by very small functional changes in ion channels. , 2009, Archives of neurology.

[31]  S. Picaud,et al.  Treatment of epilepsy: the GABA‐transaminase inhibitor, vigabatrin, induces neuronal plasticity in the mouse retina , 2008, The European journal of neuroscience.

[32]  R. Sakai,et al.  Cellular and subcellular localization of kainic acid in the marine red alga Digenea simplex , 2005, Cell and Tissue Research.

[33]  G. Cavallaro,et al.  Preparation and characterization of polyethyl-2-cyanoacrylate nanocapsules containing antiepileptic drugs. , 1996, Biomaterials.

[34]  M. Rogawski,et al.  New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels , 2008 .

[35]  Michael A. Rogawski,et al.  Molecular targets for antiepileptic drug development , 2011, Neurotherapeutics.

[36]  E. Scholl,et al.  Developing novel antiepileptic drugs: Characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models , 2009, Neurotherapeutics.

[37]  A. Schousboe,et al.  Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. , 2010, Pharmacology & therapeutics.

[38]  A. Shende,et al.  Microemulsion of lamotrigine for nasal delivery , 2007 .

[39]  H. Kumashiro,et al.  Anticonvulsant Effect of Systemically Administered γ-Aminobutyric Acid (GABA)-Containing Liposomes in Rats Induced to Seizure by Amygdaloid Electrical Stimulation , 1992 .

[40]  R. Reed,et al.  Once-daily dosing is appropriate for extended-release divalproex over a wide dose range, but not for enteric-coated, delayed-release divalproex: Evidence via computer simulations and implications for epilepsy therapy , 2009, Epilepsy Research.

[41]  Tangui Maurice,et al.  The pharmacology of sigma-1 receptors. , 2009, Pharmacology & therapeutics.

[42]  René H. Levy,et al.  Progress report on new antiepileptic drugs: A summary of the Ninth Eilat Conference (EILAT IX) , 2009, Epilepsy Research.

[43]  David A. Boas,et al.  Dynamic physiological modeling for functional diffuse optical tomography , 2006, NeuroImage.

[44]  F Schottler,et al.  Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats. , 2001, Journal of neurosurgery.

[45]  R. Sankar,et al.  Galanin – 25 years with a multitalented neuropeptide , 2008, Cellular and Molecular Life Sciences.

[46]  Y. Awasthi,et al.  RLIP76, a non-ABC transporter, and drug resistance in epilepsy , 2005, BMC Neuroscience.

[47]  D. Vohora,et al.  Comparative efficacy of liposome-entrapped amiloride and free amiloride in animal models of seizures and serum potassium in mice , 2007, European Neuropsychopharmacology.

[48]  Rex Moats,et al.  Functionalized magnetonanoparticles for MRI diagnosis and localization in epilepsy , 2008, Epilepsia.

[49]  Pallavi Sethi,et al.  Curcumin protects against electrobehavioral progression of seizures in the iron-induced experimental model of epileptogenesis , 2009, Epilepsy & Behavior.

[50]  M. Rogawski,et al.  Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA , 2007, Journal of Pharmacology and Experimental Therapeutics.

[51]  M. Bialer,et al.  Valproic acid: Second generation , 2011, Neurotherapeutics.

[52]  D. Friedman,et al.  Enhanced Transdermal Delivery of Diazepam by Submicron Emulsion (SME) Creams , 1995, Pharmaceutical Research.

[53]  Mosby.  Mosby's medical dictionary , 1987 .

[54]  T. Friedrich,et al.  Molecular Determinants of KCNQ (Kv7) K+ Channel Sensitivity to the Anticonvulsant Retigabine , 2005, The Journal of Neuroscience.

[55]  S. Shorvon.  Drug treatment of epilepsy in the century of the ILAE: The first 50 years, 1909–1958 , 2009, Epilepsia.

[56]  G. Abdelbary,et al.  Diazepam-Loaded Solid Lipid Nanoparticles: Design and Characterization , 2009, AAPS PharmSciTech.

[57]  M. Erion,et al.  Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy. , 1999, The Journal of pharmacology and experimental therapeutics.

[58]  T. Baram,et al.  Hyperpolarization activated cyclic-nucleotide gated (HCN) channels in developing neuronal networks , 2008, Progress in Neurobiology.

[59]  N. Belyaev,et al.  Sodium valproate: an old drug with new roles. , 2009, Trends in pharmacological sciences.

[60]  S. Shorvon.  Drug treatment of epilepsy in the century of the ILAE: The second 50 years, 1959–2009 , 2009, Epilepsia.

[61]  Robert S Fisher,et al.  An automated drug delivery system for focal epilepsy , 2000, Epilepsy Research.

[62]  R. Sankar,et al.  Galanin and epilepsy. , 2010, Experientia supplementum.

[63]  S. Davis,et al.  The release of diazepam from poly(hydroxybutyrate-hydroxyvalerate) microspheres , 2002, Journal of Microencapsulation.

[64]  F. Ahmad,et al.  CNS drug delivery systems: novel approaches. , 2009, Recent patents on drug delivery & formulation.

[65]  W. Mark Saltzman,et al.  Nanotechnology for delivery of drugs to the brain for epilepsy , 2009, Neurotherapeutics.

[66]  J. Guttag,et al.  Advances in the Application of Technology to Epilepsy: The CIMIT/NIO Epilepsy Innovation Summit , 2009, Epilepsy & Behavior.

[67]  Dieter Schmidt,et al.  Drug treatment of epilepsy: Options and limitations , 2009, Epilepsy & Behavior.

[68]  Eleanor M. Pritchard,et al.  Antiepileptic effects of silk-polymer based adenosine release in kindled rats , 2009, Experimental Neurology.

[69]  B. Youan,et al.  Formulation of spray-dried phenytoin loaded poly(epsilon-caprolactone) microcarrier intended for brain delivery to treat epilepsy. , 2007, Journal of pharmaceutical sciences.

[70]  A. El-Kamel,et al.  Thermally Reversible In Situ Gelling Carbamazepine Liquid Suppository , 2006, Drug delivery.

[71]  Horst Bischof,et al.  A practical procedure for real-time functional mapping of eloquent cortex using electrocorticographic signals in humans , 2009, Epilepsy & Behavior.

[72]  Sydney S Cash,et al.  From ion channels to complex networks: magic bullet versus magic shotgun approaches to anticonvulsant pharmacotherapy. , 2009, Medical hypotheses.

[73]  Indranil Nandi,et al.  Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam. , 2002, International journal of pharmaceutics.

[74]  R. Gonzalez,et al.  A nanostructured titania bioceramic implantable device capable of drug delivery to the temporal lobe of the brain , 2007 .