Antiepileptic Drugs

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.