Antiepileptic Drugs: Pharmacology and Therapeutics by M.J. EadieAntiepileptic Drugs: Pharmacology and Therapeutics by M.J. Eadie

Antiepileptic Drugs: Pharmacology and Therapeutics

byM.J. EadieEditorF. Vajda

Paperback | September 22, 2011

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In 1985, volume 74 of the Springer-Verlag Handbook of Experimental Phar­ macology, under the editorship of H. -H. Frey and D. Janz, appeared. In this volume the then available data on the topic of antiepileptic drugs were col­ lated and analysed. Over the intervening years knowledge in this area has grown progressively. More new antiepileptic drugs than the total number of agents that were in common use 15 years ago have in the interval either come on to the market or are about to do so. As well, further agents are at a fairly advanced stage of development, whilst the already established drugs have by and large held their places in clinical practice. Knowledge of epileptogenesis has advanced considerably. The mechanisms of action of antiepileptic drugs at the molecular level and in various animal models of epileptic seizures and of the epileptic state are much better understood than they were previously. As well, more information is available concerning the natural history of human epilepsy, and this knowledge is important in making optimal use of the various agents that are now available. Therefore, it has seemed appropriate at this stage in the evolution of knowledge to produce a second volume dealing with Antiepileptic Drugs in the Handbook of Experimental Pharmacology series.
Title:Antiepileptic Drugs: Pharmacology and TherapeuticsFormat:PaperbackDimensions:631 pagesPublished:September 22, 2011Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

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ISBN - 10:3642642446

ISBN - 13:9783642642449

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Table of Contents

1 Classification of Epileptic Seizures and the Epilepsies and Drugs of Choice for Their Treatment.- A. Introduction.- B. The International Classification of Epileptic Seizures.- I. Partial Seizures.- II. Generalized Seizures.- C. Classification of the Epilepsies and Epileptic Syndromes.- I. Idiopathic Epilepsies.- 1. Idiopathic Epilepsies with Partial Seizures.- 2. Idiopathic Epilepsies with Generalized Seizures.- II. Symptomatic Epilepsies.- 1. Symptomatic Epilepsies with Partial Seizures.- 2. Symptomatic Epilepsies with Generalized Seizures.- III. Epilepsies That Are Difficult to Categorize.- 1. West's Syndrome.- 2. Lennox-Gastaut Syndrome.- 3. Acquired Epileptic Aphasia (the Landau-Kleffner Syndrome).- 4. Epilepsy with Continuous Spike-Wave during Slow Wave Sleep.- D. Influence of Technological Advances on the Understanding of Semiology.- I. Singular Nuclear Gene Disorders.- II. Complex Inheritance Disorders.- E. Drugs of Choice for Epileptic Seizures and the Epilepsies.- I. Drugs for Epileptic Seizures.- 1. Partial Seizures.- 2. Generalized Seizures.- II. Drugs for the Epilepsies.- 1. Idiopathic Epilepsies with Partial Seizures.- 2. Idiopathic Epilepsies with Generalized Seizures.- 3. Symptomatic Epilepsies with Localization-Related Seizures.- 4. Symptomatic Epilepsies with Generalized Seizures.- 5. Febrile Convulsions.- F. Conclusion.- References.- 2 Animal Models of Epilepsy and Epileptic Seizures.- A. Introduction.- B. Animal Models of Epilepsy.- I. Localization-Related (Focal, Local, Partial) Epilepsies.- 1. Idiopathic (Primary) Focal Epilepsies.- a) Dogs with Idiopathic Localization-Related Epilepsy.- 2. Symptomatic (Secondary) Focal Epilepsies.- a) The Kindling Model of Temporal Lobe Epilepsy.- b) The Kainate Model.- c) The Pilocarpine Model.- d) Chronic Epilepsy Following Status Epilepticus.- e) Spontaneous Focal Seizures Following Local Application of Metals, Chemical Convulsants or Toxins.- II. Generalized Epilepsies.- 1. Animal Models of Idiopathic Primary Generalized Epilepsies.- a) Epileptic Dogs.- b) Rats with Generalized Absence Epilepsy.- c) The Lethargic (lh/lh) Mouse.- d) The Spontaneously Epileptic Double Mutant Rat.- e) Transgenic or Knockout Mice.- III. Undetermined Epilepsies.- 1. Tottering Mice.- IV. Special Syndromes.- a) Epileptic Gerbils.- b) Audiogenic Seizure Susceptible Mice.- c) Audiogenic Seizure Susceptible Rats.- d) Epileptic Baboons with Photomyoclonic Seizures.- e) El Mice.- C. Animal Models of Epileptic Seizures.- I. Animal Models of Partial (Focal, Local) Seizures.- 1. Epileptic Animals with Focal Seizures.- 2. Focal Seizures Induced in Normal, Non-epileptic Animals.- II. Animal Models of Generalized Seizures.- 1. Epileptic Animals with Primary Generalized Seizures.- a) Genetic Animal Models of Epilepsy with Generalized Convulsive Seizures.- b) Genetic Animal Models of Epilepsy with Generalized Non-convulsive Seizures).- 2. Primary Generalized Seizures Induced in Normal, Non-epileptic Animals.- a) Models of Convulsive Seizures.- b) Models of Absence or Myoclonic Seizures.- D. Conclusions.- References.- 3 Epileptogenesis: Electrophysiology.- A. Introduction.- B. Partial (Focal, or Lesional) Epilepsy.- I. Overview.- II. The Single Neuron: Normal Population.- III. The Single Neuron: Epileptic Population.- IV. Connectivity.- V. Other Processes.- C. Generalized Epilepsy: Absence Seizures.- I. Overview.- II. Cortical Processes.- III. Thalamic Processes.- IV. Human Studies.- D. Generalized Epilepsy: Convulsive Seizures.- I. Overview.- II. Excessive Excitation or Impaired Inhibition.- III. Anatomical Distribution of Convulsions: Cortex and Hippocampus.- IV. Electrophysiological Distribution of Convulsions: Cortex and Brain Stem.- V. Human Studies: Predisposing Brain Processes and a Synthesis.- References.- 4 Epileptogenesis: Biochemical Aspects.- A. Introduction.- B. Methods for Studying Epileptogenesis.- I. In Humans.- 1. Imaging Techniques.- 2. Neurophysiological Studies on Cortical Slices Maintained In Vitro.- 3. Microdialysis.- II. Animal Models.- 1. Kindling.- 2. Kainate Model.- 3. Genetic Strains.- III. Biochemical Techniques.- C. Role of Neurotransmitters in Epileptogenesis.- I. Amino Acids.- 1. L-Glutamate.- a) Glutamate Release and Reuptake.- b) Glutamate Receptors.- ?) NMDA Receptors.- ?) AMPA/Kainate Receptors.- ?) Metabotropic Glutamate Receptors.- 2. GABA.- a) GABA Synthesis and Storage.- b) GABA Transporters.- c) GABA Receptors.- ?) GABAA Receptors.- ?) GABAB Receptors.- II. Biogenic Amines.- 1. Noradrenaline.- 2. 5-Hydroxytryptamine.- 3. Acetylcholine.- III. Neuropeptides.- 1. Neuropeptide Y.- 2. Somatostatin.- 3. Cholecystokinin.- 4. Dynorphin.- IV. Purines.- V. Nitric Oxide.- D. Postsynaptic Effects.- I. Role of Ca2+ Channels and Ca2+ Binding Proteins.- II. Immediate Early Genes.- E. Neurotrophins and Neurogenesis.- I. Mossy Fibre Sprouting in the Hippocampus.- II. Neuronal Migration Disorders in the Cortex.- F. Conclusions.- References.- 5 Cellular Actions of Antiepileptic Drugs.- A. Introduction.- B. Established Antiepileptic Drug Mechanisms of Action.- I. Phenytoin and Carbamazepine.- II. Benzodiazepines and Barbiturates.- III. Ethosuximide and Trimethadione.- IV. Valproic Acid.- C. Newly Developed Antiepileptic Drug Mechanisms of Action.- I. Gabapentin.- II. Lamotrigine.- III. Oxcarbazepine.- IV. Vigabatrin.- V. Tiagabine.- VI. Topiramate.- VII. Felbamate.- References.- 6 The Search for New Anticonvulsants.- A. Introduction.- B. Pharmacological Strategies in the Search for New Anticonvulsants.- I. Rational Drug Design.- 1. Selective Enhancement of GABAergic Neurotransmission.- 2. Selective Attenuation or Blockade of Excitatory Aminoacidergic Neurotransmission.- 3. Selective Modulation of Ion Channels.- 4. Other Strategies for Rational Drug Design.- II. Random Screening or Molecular Structural Variation of Known Compounds.- 1. Retigabine.- 2. TV 1901.- 3. Dezinamide.- 4. MDL 27,192.- C. Clinical Evaluation of Preclinical Development Strategies.- D. Strategies for Future Drug Development.- I. Chemical Systems for Delivery of Antiepileptic Drugs to Regions of the Brain.- II. Rational Polytherapy.- III. Predictive Identification of Responders.- IV. Strategies for the Development of Drugs for Unresponsive Epilepsies.- V. Identification of Genetic Defects in Epilepsy.- E. Conclusions.- References.- 7 Measurement of Anticonvulsants and Their Metabolites in Biological Fluids.- A. Introduction.- B. Chromatographic Methods.- I. Gas Chromatography and High Performance Liquid Chromatography.- C. Capillary Electrophoresis and Micellar Electrokinetic Capillary Electrophoresis.- I. Antiepileptic Drug Analysis by Capillary Electrophoresis and Micellar Electrokinetic Capillary Electrophoresis.- D. Stereoselective Drug Analysis.- E. Immunoassay Methods.- I. Immunoassay Instrumentation.- II. Analytical Performance.- III. Non-laboratory Immunoassay Antiepileptic Drug Monitoring.- F. Free Drug Monitoring.- I. Saliva.- G. Quality Assurance.- References.- 8 Older Anticonvulsants Continuing in Use but with Limited Advance in Knowledge.- A. Introduction.- B. Phenobarbitone and Congeners.- I. Chemistry and Use.- 1. Chemistry.- 2. Use.- II. Pharmacodynamics.- 1. Animal Models of Epilepsy.- 2. Electrophysiological Actions.- 3. Biochemical Actions.- III. Pharmacokinetics.- 1. Absorption.- a) Phenobarbitone.- b) Methylphenobarbitone.- c) Primidone.- 2. Distribution.- a) Phenobarbitone.- b) Methylphenobarbitone.- c) Primidone.- 3. Elimination.- a) Metabolism.- ?) Phenobarbitone.- ?) Methylphenobarbitone.- ?) Primidone.- b) Elimination Parameters.- ?) Phenobarbitone.- ?) Methylphenobarbitone.- ?) Primidone.- 4. Applied Pharmacokinetics.- a) Phenobarbitone.- b) Methylphenobarbitone.- c) Primidone.- IV. Interactions.- 1. Pharmacodynamic Interactions.- 2. Pharmacokinetic Interactions.- a) Phenobarbitone Affecting Other Substances.- b) Other Substances Affecting Phenobarbitone.- ?) Methylphenobarbitone.- ?) Primidone.- V. Adverse Effects.- 1. Idiosyncratic Effects.- 2. Dose-Determined Effects.- 3. Effects on the Foetus and Neonate.- C. Succinimides.- I. Chemistry and Use.- 1. Chemistry.- 2. Use.- II. Pharmacodynamics.- 1. Animal Models of Epilepsy.- 2. Electrophysiological Studies.- 3. Biochemical Effects.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- 4. Applied Pharmacokinetics.- IV. Interactions.- 1. Pharmacodynamic Interactions.- 2. Pharmacokinetic Interactions.- V. Adverse Effects.- D. Sulthiame.- I. Chemistry and Use.- II. Pharmacodynamics.- III. Pharmacokinetics.- IV. Interactions.- V. Adverse Effects.- E. Acetazolamide.- I. Chemistry and Use.- II. Pharmacodynamics.- III. Pharmacokinetics.- IV. Interactions.- V. Adverse Effects.- F. Bromides.- I. Chemistry and Use.- II. Pharmacodynamics.- III. Pharmacokinetics.- IV. Interactions.- V. Adverse Effects.- References.- 9 Phenytoin and Congeners.- A. Phenytoin.- I. Introduction.- II. Chemistry and Use.- 1. Chemistry.- 2. Indications and Use.- III. Pharmacodynamics.- IV. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Elimination.- a) Metabolism.- ?) Pharmacogenetics.- b) Elimination Parameters.- 4. Clinical Pharmacokinetics.- a) Dose-Plasma Level Relationships.- b) Plasma Level-Effects Relationships.- ?) Beneficial Effects.- ?) Acute Toxic Effects.- ?) Initial Target Range Concentration.- V. Interactions.- VI. Adverse Effects.- 1. Acute Toxicity.- 2. Idiosyncratic Adverse Effects.- 3. Teratogenicity.- a) Folate, Anaemia, Teratogenesis.- b) Mechanisms of Idiosyncratic Toxicity and Teratogenicity.- 4. Chronic Toxicity.- a) Enzyme Induction.- B. Fosphenytoin.- I. Introduction.- II. Chemistry and Use.- 1. Chemistry.- 2. Indications and Use.- III. Pharmacodynamics.- IV. Pharmacokinetics.- 1. Absorption and Disposition.- 2. Metabolism.- 3. Clinical Pharmacokinetics.- V. Adverse Effects.- C. Mephenytoin.- I. Introduction.- II. Chemistry and Use.- 1. Chemistry.- 2. Indications and Use.- III. Pharmacodynamics.- IV Pharmacokinetics.- 1. Absorption and Disposition.- 2. Metabolism.- a) Pharmacogenetics.- 3. Clinical Pharmacokinetics.- a) Dose-Plasma Level Relationships.- b) Plasma Level-Effect Relationships.- ?) Beneficial Effects.- ?) Acute Toxic Effects.- V. Interactions.- VI. Adverse Effects.- D. Ethotoin.- I. Introduction.- II. Chemistry and Use.- 1. Chemistry.- 2. Indications and Use.- III. Pharmacodynamics.- IV. Pharmacokinetics.- 1. Absorption and Disposition.- 2. Metabolism.- 3. Clinical Pharmacokinetics.- a) Dose-Plasma Level Relationships.- b) Plasma Level-Effects Relationships.- ?) Beneficial Effects.- ?) Acute Toxic Effects.- V. Interactions.- VI. Adverse Effects.- E. Phenacetamide.- I. Introduction.- II. Chemistry and Use.- 1. Chemistry.- 2. Indications and Use.- III. Pharmacodynamics.- IV. Pharmacokinetics.- 1. Absorption and Disposition.- 2. Metabolism.- 3. Clinical Pharmacokinetics.- a) Dose, Plasma Level and Effect Relationships.- V. Interactions.- VI. Adverse Effects.- F. Albutoin.- I. Introduction.- II. Chemistry and Use.- III. Pharmacology.- 1. Animal Pharmacology.- 2. Human Use.- References.- 10 Carbamazepine.- A. Introduction.- B. Chemistry and Use.- I. Chemistry.- II. Use.- C. Pharmacodynamics.- I. Biochemical Effects.- 1. Ion Channels and Receptors.- a) Na+ Channels.- b) Benzodiazepine Receptors.- c) Ca2+ Channels.- d) Adenosine Receptors.- 2. Effects on Neurotransmitters.- a) GABA.- b) Catecholamines.- c) Serotonin.- d) Acetylcholine.- e) Substance P.- f) Glutamate.- g) Somatostatin.- 3. Other Biochemical Changes.- II. Electrophysiological Effects.- 1. Effects at the Cellular Level.- 2. Effects on Neuronal Pools.- III. Effects in Animal Models of Epilepsy.- 1. Models of Generalized Epilepsy.- 2. Models of Partial Epilepsy.- IV. Human Studies.- D. Pharmacokinetics.- I. Absorption.- II. Distribution.- 1. Apparent Volume of Distribution.- 2. Plasma Protein Binding.- 3. Body Fluid and Tissue Distribution.- a) Blood.- b) Cerebrospinal Fluid.- c) Saliva.- d) Milk.- e) Foetal Blood and Amniotic Fluid.- f) Body Tissues.- III. Elimination.- 1. Metabolism.- 2. Elimination Parameters.- a) Half-life.- b) Clearance.- c) Carbamazepine-10,11-epoxide.- IV. Clinical Pharmacokinetics.- a) Pregnancy.- b) Disease States.- E. Interactions.- I. Pharmacodynamic Interactions.- II. Pharmacokinetic Interactions.- 1. Interactions Which Lower Plasma Carbamazepine Concentrations.- 2. Interactions Which Raise Plasma Carbamazepine Concentrations.- 3. Interactions in Which Carbamazepine Lowers the Plasma Concentrations, or Increases the Clearances, of Other Drugs.- 4. Interactions Leading to Raised Concentrations of Other Drugs.- F. Adverse Effects.- I. Biochemical Abnormalities.- II. Dose-Determined Adverse Effects.- 1. Hyponatraemia.- III. Idiosyncratic Adverse Effects.- 1. Aromatic Anticonvulsant Hypersensitivity Syndrome.- 2. Skin.- 3. Nervous System.- 4. Haematological.- 5. Cardiovascular.- 6. Respiratory.- 7. Alimentary Tract.- 8. Liver.- 9. Pancreas.- 10. Kidneys.- 11. Bone.- 12. Porphyria.- 13. Thyroid.- IV. Foetal Toxicity.- References.- 11 Oxcarbazepine.- A. Introduction.- B. Chemistry and Use.- C. Pharmacodynamics.- I. Biochemical Pharmacology.- II. Animal Models of Epilepsy.- III. Human Epilepsies.- 1. Monotherapy Trials.- a) Controlled Monotherapy Trials in Newly Diagnosed or Previously Untreated Patients.- ?) Study Designs.- ?) Enrolment Information.- ?) Results.- ?) Conclusions.- b) Pre-surgery Trials.- 2. Add-on and Open-label, Long-term Trials.- D. Pharmacokinetics.- I. Absorption, Bioavailability, and Distribution.- II. Elimination.- 1. Metabolism.- 2. Elimination Parameters.- III. Clinical Pharmacokinetics.- 1. Special Patient Groups.- a) Hepatic and Renal Impairment.- b) The Elderly and Children.- E. Interactions.- I. Effects on Other Drugs.- II. Effects of Other Drugs on Oxcarbazepine.- F. Adverse Effects.- I. Animal Studies.- 1. Acute Exposure.- 2. Teratogenicity/Carcinogenicity/Mutagenicity.- II. Human Studies.- 1. Add-on, Open-label Trials.- 2. Monotherapy Trials in Newly Diagnosed or Previously Untreated Patients.- III. Particular Adverse Effects in Humans.- 1. Rashes.- 2. Overdosage.- IV. Laboratory Abnormalities.- V. Pregnancy.- References.- 12 Lamotrigine.- A. Introduction.- B. Chemistry and Use.- I. Chemistry.- 1. Analytical Methods.- II. Use.- C. Pharmacodynamics.- I. Anticonvulsant Effects.- 1. Animal Models of Epilepsy.- a) Maximal Electroshock Seizures.- b) Chemoconvulsant Tests.- c) Afterdischarge Tests.- d) Electrically Induced Kindling.- e) Genetic Seizure Models.- f) Models of Status Epilepticus.- 2. Mechanism of Action.- a) Neurochemical Actions.- b) Ionic Conductances.- ?) Na+ Channels.- ?) Ca2+ Channels.- ?) K+ Channels.- c) Ligand Binding to Receptors.- II. Other Central Nervous System Effects.- 1. Effects on the EEG and Sleep.- 2. Memory and Long-Term Potentiation.- 3. Excitotoxic and Ischaemic Neuronal Injury.- 4. Effects on Involuntary Movement Disorders.- 5. Morphine Withdrawal.- 6. Increased Atmospheric Pressure.- 7. Anxiolytic Effects.- III. Effects Outside the Central Nervous System.- 1. Effects on Peripheral Nerves and Analgesic Effects.- 2. Other Effects.- D. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Elimination.- 1. Elimination Parameters.- 2. Metabolism.- IV. Clinical Pharmacokinetics.- E. Interactions.- I. Pharmacodynamic Interactions.- II. Pharmacokinetic Interactions.- F. Adverse Effects.- I. Animal Toxicity.- II. Human Toxicity.- References.- 13 Valproate.- A. Introduction.- B. Chemistry and Use.- I. Chemistry.- II. Use.- C. Pharmacodynamics.- I. Experimental Animal Studies.- II. Biochemical Pharmacology.- D. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Elimination.- 1. Clearence Parameters.- 2. Metabolism.- E. Interactions.- I. Other Drugs Affecting Valproate.- II. Valproate Affecting Other Drugs.- F. Adverse Effects.- References.- 14 Vigabatrin.- A. Chemistry and Use.- I. Chemical Characteristics.- 1. Enantiomers.- II. Use.- B. Pharmacodynamics.- I. Biochemical Pharmacology.- 1. Effects on GABA and Other Amino Acids.- II. Animal Models.- 1. Anticonvulsive Effects.- 2. Prevention of Epileptogenesis.- 3. Neuroprotective Effects.- III. Humans.- 1. CSF and Brain Concentrations of GABA and Other Amino Acids.- 2. Magnetic Resonance Spectroscopy.- 3. Effects on Platelets.- 4. Human Epilepsy.- a) Adults with Partial Seizures.- ?) Major Single-Blind Studies.- ?) Major Double-Blind Studies.- ?) Monotherapy Studies.- ?) Long-term Studies.- b) Children with Partial Seizures.- c) Children with Infantile Spasms.- d) Children with the Lennox-Gastaut Syndrome.- C. Pharmacokinetics.- I. Absorption and Bioavailability.- II. Distribution.- 1. Body Tissues and Fluids.- 2. Placental Transfer.- III. Elimination.- 1. Metabolism.- 2. Elimination Parameters.- IV. Clinical Pharmacokinetics.- D. Interactions.- E. Adverse Effects.- I. General Effects.- II. Psychosis.- III. Visual Field Defects.- IV Teratogenicity.- F. Use in Clinical Practice.- I. Dosage.- II. Dose Titration.- III. Laboratory Monitoring.- References.- 15 Benzodiazepines.- A. Introduction.- B. Pharmacodynamics of Benzodiazepines in General.- I. Animal Models of Epilepsy.- II. Biochemical Pharmacology.- C. Benzodiazepine Adverse Effects and Their Mechanisms.- D. Diazepam.- I. Chemistry.- II. Pharmacodynamics.- 1. Humans.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- a) Cerebrospinal Fluid.- b) Brain.- c) Plasma Protein Binding.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- c) Excretion.- 4. Clinical Pharmacokinetics.- a) Plasma Concentration: Clinical Effect Relationships.- b) Treatment of Status Epilepticus.- IV. Interactions.- V. Adverse Effects.- E. Clobazam.- I. Chemistry.- II. Pharmacodynamics.- 1. Mechanism of Action.- 2. Animal Models.- 3. Human Studies.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- a) Protein Binding.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- 4. Clinical Pharmacokinetics.- IV. Interactions.- V. Adverse Effects.- F. Clonazepam.- I. Chemistry and Use.- 1. Chemistry.- 2. Use.- II. Pharmacodynamics.- 1. Tolerance.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- IV. Interactions.- V. Adverse Effects.- G. Lorazepam.- H. Nitrazepam.- I. Midazolam.- References.- 16 Gabapentin.- A. Introduction.- B. Chemistry and Use.- I. Chemical Structure and Properties.- II. Analytical Methods for Measuring Gabapentin.- III. Use.- C. Pharmacodynamics.- I. Biochemical Pharmacology.- 1. Effects on GABAergic Mechanisms.- a) Effects on GABA Accumulation.- b) Effects on GABA and Glutamate Metabolic Pathways.- c) Effects on Receptors and Ion Channels.- 2. Effects on Membrane Amino Acid Transport.- 3. Studies on the Gabapentin Binding Site in Animal Brains.- a) Distribution of Gabapentin Specific Binding Sites.- 4. Overview of Biochemical Pharmacology.- II. Studies at a Cell or Tissue Level.- 1. Hippocampal Slices.- 2. Cultured Neurons.- III. Animal Models of Epilepsy.- 1. Spectrum of Activity.- 2. Standard Seizure Models in Mice and Rats.- a) Maximal Electroshock Testing.- b) Seizures Induced by Glutamate, Aspartate and Kainic Acid.- c) Hippocampal Kindled Seizures.- d) Audiogenic Seizures in Mice.- e) Seizures in the Photosensitive Baboon.- f) Reflex Epilepsy.- g) Classical Absences.- IV. Antinociceptive Effects.- V. Antispasticity Effects.- VI. Human Studies.- D. Pharmacokinetics.- I. Pharmacokinetics in Animals.- II. Pharmacokinetics in Humans.- 1. Absorption and Bioavailability.- 2. Distribution.- a) Brain, CSF and Plasma Gabapentin Concentration Relationships.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- 4. Clinical Pharmacokinetics.- a) Plasma Concentration-Dose Relationships.- b) Effects of Food, Multiple Dosing, Age and Disease.- c) Gabapentin and Renal Function.- d) Plasma Gabapentin Concentrations and Therapeutic Effects.- E. Interactions.- I. Effect of Gabapentin on Other Drugs.- 1. Other Antiepileptic Drugs.- a) Multiple Drug Interactions.- 2. Oral Contraceptives.- II. Effects of Other Drugs on Gabapentin.- F. Adverse Effects.- I. Animal Studies.- 1. Acute Exposure.- 2. Subacute Exposure.- 3. Chronic Exposure.- 4. Mutagenicity.- 5. Carcinogenicity.- 6. Teratogenicity.- II. Human Studies.- 1. Add-on Pivotal Placebo-Controlled Studies in Refractory Patients.- 2. Monotherapy Trials in Previously Untreated Patients.- 3. Particular Adverse Effects in Humans.- a) Quality of Life.- 4. Overdosage.- 5. Laboratory Abnormalities.- 6. Pregnancy.- References.- 17 Tiagabine.- A. Introduction.- B. Chemistry and Use.- C. Pharmocodynamics.- I. Biochemical Pharmacology.- II. Electrophysiology.- III. Animal Seizure Models.- 1. Electrically and Chemically Induced Epilepsy Models.- 2. Genetic Epilepsy Models.- 3. Anxiolytic Effects.- 4. Analgesic Effects.- 5. Effect on Cerebral Ischaemia.- IV. Human Studies.- 1. Adult Add-on, Parallel-Design Trials.- a) Study Designs.- b) Enrolment Information.- c) Results.- 2. Open-label, Long-term Treatment.- 3. Monotherapy Studies.- a) Dose-Ranging, Tiagabine-Substitution Study.- b) Multicentre High-Versus Low-Dose Study.- 4. Paediatric Trials.- D. Pharmacokinetics.- I. Animal Pharmacokinetics.- II. Human Pharmacokinetics.- 1. Absorption and Bioavailability.- 2. Distribution.- 3. Elimination.- a) Metabolism.- b) Elimination Parameters.- 4. Applied Pharmacokinetics.- 5. Special Patient Groups.- a) Hepatic and Renal Impairment.- b) The Elderly and Children.- E. Interactions.- I. Pharmacodynamic Interactions.- II Pharmacokinetic Interactions.- 1. Effect of Tiagabine on the Pharmacokinetics of Other Drugs.- 2. Effects of Other Drugs on the Pharmacokinetics of Tiagabine.- F. Adverse Effects.- I. Animal Animal Toxicology.- 1. Acute Toxicity.- 2. Chronic Toxicity.- 3. Teratogenicity, Carcinogenicity, Mutagenicity.- II. Human Studies.- 1. Add-on, Parallel-Group Studies.- 2. Monotherapy Trials.- 3. Long-term Studies.- 4. Special Safety Issues in Humans.- a) Death.- b) Rash, Psychosis, Status Epilepticus.- c) Overdosage.- d) Laboratory Values.- e) Neuropsychological Function and Cognitive Effects.- f) Pregnancy.- References.- 18 Topiramate.- A. Introduction.- B. Chemistry.- C. Pharmacodynamics.- I. Animal Models of Epilepsy.- II. Biochemical Pharmacology.- 1. Na+ Channels.- 2. GABA-Mediated Cl- Influx.- 3. Glutamate Receptors.- 4. Carbonic Anhydrase.- 5. Other Actions.- III. Toxicology.- 1. Systemic Toxicity.- 2. Carcinogenicity.- 3. Reproductive and Teratology Studies.- IV. Human Studies.- 1. Placebo-Controlled Double-blind Add-on Trials.- 2. Non-Controlled Add-on Trials.- 3. Monotherapy Studies.- 4. Add-on Therapy for Generalized Seizures.- 5. The Lennox-Gastaut Syndrome.- D. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Elimination.- 1. No Interacting Drug Present.- 2. Interacting Drugs Present.- IV. Special Situations.- E. Interactions.- I. Pharmacodynamic Interactions.- II. Pharmacokinetic Interactions.- 1. Effects of Other Drugs on Topiramate.- 2. Effects of Topiramate on Various Drugs.- a) Antiepileptic Drugs.- b) Other Drugs.- F. Adverse Effects.- G. Clinical Use.- I. Indications.- II. Dosage and Administration.- 1. Dosage Titration.- 2. Patient Monitoring.- 3. Overdosage.- 4. Discontinuation of Topiramate.- H. Conclusions.- References.- 19 Zonisamide.- A. Chemistry and Use.- B. Pharmacodynamics.- I. Studies in Animals.- II. Studies in Humans.- 1. Efficacy in Localization-Related Epilepsies.- 2. Efficacy in Generalized Epilepsies.- III. Measurement in Biological Fluids.- C. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Elimination.- 1. Elimination Parameters.- 2. Metabolism and Excretion.- D. Interactions.- I. Pharmacokinetic Interactions.- E. Adverse Effects.- I. Clinical Trials.- II. Overdosage.- III. Teratogenicity.- F. Dose and Administration.- References.- 20 Felbamate.- A. Introduction.- B. Chemistry and Use.- C. Pharmacodynamic Studies.- I. Animal Models of Epilepsy.- II. Biochemical Actions.- III. Human Studies.- 1. Partial Epilepsy.- 2. Generalized Epilepsy.- D. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Elimination.- E. Interactions.- F. Adverse Effects.- I. Dose-Related Adverse Effects.- II. Idiosyncratic Adverse Effects.- G. Use of Felbamate in Practice.- I. Role of Felbamate Blood Levels.- II. Managing Drug Interactions.- III. Stopping Felbamate.- H. onclusions.- References.- 21 Drugs Under Clinical Trial.- A. Introduction.- B. Levetiracetam.- I. Chemistry.- II. Pharmacodynamics.- 1. Anticonvulsant Activity in Animal Models.- 2. Mechanism of Action.- 3. Other Pharmacological Effects and Toxicology Data.- III. Pharmacokinetics.- IV. Drug Interactions.- V. Antiepileptic Efficacy and Adverse Effects.- C Losigamone.- I. Chemistry.- II. Pharmacodynamics.- 1. Anticonvulsant Activity in Animal Models.- 2. Mechanism of Action.- 3. Other Pharmacological Effects and Toxicology Data.- III. Pharmacokinetics.- IV. Drug Interactions.- V. Antiepileptic Efficacy and Adverse Effects.- D. Remacemide.- I. Chemistry.- II. Pharmacodynamics.- 1. Anticonvulsant Activity in Animal Models.- 2. Mechanism of Action.- 3. Other Pharmacological Effects and Toxicology Data.- III. Pharmacokinetics.- IV. Drug Interactions.- V. Antiepileptic Efficacy and Adverse Effects.- E. Rufinamide.- I. Pharmacodynamics.- II. Pharmacokinetics and Drug Interactions.- III. Antiepileptic Efficacy and Adverse Effects.- F. Stiripentol.- I. Chemistry.- II. Pharmacodynamics.- 1. Anticonvulsant Activity in Animal Models.- 2. Mechanism of Action.- 3. Other Pharmacological Effects and Toxicology Data.- III. Pharmacokinetics.- IV. Drug Interactions.- V. Efficacy and Adverse Effects.- G. Drugs in Early Clinical Development.- I. 534U87.- II. Abecarnil.- III. Anti-epilepsirine.- IV. AWD-140-190.- V. D-2916 (Soretolide).- VI. D-23129 (Retigabine).- VII. Dezinamide.- VIII. Ganaxolone.- IX. Isobutyl-GABA (Pregabalin).- X. LY300164.- XI. Monohydroxycarbazepine.- XII. PNU-151774.- XIII. N-Valproyl-glycinamide.- XIV. SB-204269.- H. Conclusion.- References.- 22 Anticonvulsant Combinations and Interactions.- A. Introduction.- B. Extent of the Problem.- C. Pharmacokinetic Interactions.- I. Cytochrome P450.- D. Pharmacodynamic Interactions.- E. Interactions of the Generally Available Anticonvulsant Drugs.- I. Pharmacokinetic Interactions.- 1. Phenobarbitone.- a) Interactions Affecting Phenobarbitone.- ?) Valproic Acid.- ?) Phenytoin.- ?) Miscellaneous Interactions.- b) Interactions Where Phenobarbitone Affects Other Drugs.- ?) Anticoagulants.- ?) Calcium Antagonists.- ?) Oral Contraceptives.- ?) Paracetamol.- ?) Valproic Acid.- ?) Miscellaneous Interactions.- 2. Phenytoin.- a) Interactions Affecting Phenytoin.- ?) Alcohol.- ?) Amiodarone.- ?) Antiulcer Agents.- ?) Carbamazepine.- ?) Isoniazid.- ?) Phenobarbitone.- ?) Valproic Acid.- ?) Miscellaneous Interactions.- b) Interactions Where Phenytoin Affects Other Drugs.- ?) Anticoagulant Drugs.- ?) Dexamethasone.- ?) Theophylline.- ?) Miscellaneous Interactions.- 3. Primidone.- a) Interactions Affecting Primidone.- b) Interactions Where Primidone Affects Other Drugs.- 4. Ethosuximide.- a) Interactions Affecting Ethosuximide.- b) Interactions Where Ethosuximide Affects Other Drugs.- 5. Carbamazepine.- a) Interactions Affecting Carbamazepine.- ?) Antibiotics.- ?) Antidepressants.- ?) Anticonvulsant Drugs (Enzyme-Inducing).- ?) Calcium Channel Blockers.- ?) Cimetidine.- ?) Imidazole Drugs.- ?) Valproic Acid.- ?) Miscellaneous Interactions.- b) Interactions Where Carbamazepine Affects Other Drugs.- 6. Diazepam.- a) Interactions Affecting Diazepam.- b) Interactions Where Diazepam Affects Other Drugs.- 7. Clonazepam.- a) Interactions Affecting Clonazepam.- b) Interactions Where Clonazepam Affects Other Drugs.- 8. Valproic Acid.- a) Interactions Affecting Valproic Acid.- b) Interactions Where Valproic Acid Affects Other Drugs.- 9. Clobazam.- a) Interactions Affecting Clobazam.- b) Interactions Where Clobazam Affects Other Drugs.- II. Pharmacodynamic Interactions.- 1. Interactions Between Anticonvulsant Drugs.- 2. Interactions Between Anticonvulsant Drugs and Other Drugs.- F. Interactions of the Recently Licensed Anticonvulsant Drugs.- I. Pharmacokinetic Interactions.- 1. Vigabatrin.- a) Interactions Affecting Vigabatrin.- b) Interactions Where Vigabatrin Affects Other Drugs.- 2. Lamotrigine.- a) Interactions Affecting Lamotrigine.- b) Interactions Where Lamotrigine Affects Other Drugs.- 3. Gabapentin.- a) Interactions Affecting Gabapentin.- b) Interactions Where Gabapentin Affects Other Drugs.- 4. Topiramate.- a) Interactions Affecting Topiramate.- b) Interactions Where Topiramate Affects Other Drugs.- 5. Felbamate.- a) Interactions Affecting Febamate.- b) Interactions Where Felbamate Affects Other Drugs.- 6. Oxcarbazepine.- a) Interactions Affecting Oxcarbazepine.- b) Interactions Where Oxcarbazepine Affects Other Drugs.- 7. Tiagabine.- a) Interactions Affecting Tiagabine.- b) Interactions Where Tiagabine Affects Other Drugs.- 8. Zonisamide.- a) Interactions Affecting Zonisamide.- b) Interactions Where Zonisamide Affects Other Drugs.- II. Pharmacodynamic Interactions.- 1. Interactions Between Anticonvulsant Drugs.- 2. Interactions Between Anticonvulsant Drugs and Other Drugs.- G. Conclusions.- References.- 23 The Use of Antiepileptic Drugs in Clinical Practice.- A. Introduction.- B. Changes in Antiepileptic Drug Use for Epilepsy.- I. Increased Knowledge of the Natural History of Epilepsy.- II. A More Critical Application of Pharmacokinetic Concepts.- III. The Availability of New Antiepileptic Drugs.- IV. A Better Understanding of the Mechanisms of Action of Antiepileptic Drugs.- V. The Maturing of the Surgical Therapy of Epilepsy.- C. The Decision to Prescribe Antiepileptic Drug Therapy.- I. Prevention of Anticipated (Usually Situation-Related) Seizures.- II. After a Solitary Seizure.- III. Definite Epilepsy.- D. The Choice of an Antiepileptic Drug.- E. Initiating Drug Therapy.- F. Continuing Drug Therapy.- I. No Further Seizures and No Adverse Effects Occur.- II. Adverse Effects Occur.- III. Seizures Continue Despite Therapy.- IV. Antiepileptic Drug Monotherapy Fails.- 1. Antiepileptic Drug Combinations.- 2. Pharmacokinetic Interactions Between Anticonvulsants.- V. The Patient's Physiological Status Alters.- 1. Age.- 2. Menstrual Cycle.- 3. Pregnancy.- 4. Intercurrent Illness.- VI. Status Epilepticus Occurs.- 1. Generalized Convulsive Status Epilepticus.- 2. Non-convulsive Status Epilepticus.- G. Duration of Therapy.- H. Withdrawal of Therapy.- I. Use of Antiepileptic Drugs for Indications Other than Epilepsy.- References.