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Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs
Authors:H Steve White
Institution:Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
Abstract:Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABAA receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.
Keywords:Anticonvulsants  Drug screening  Neurotransmitters  Phenytoin  Ethosuximide  Topiramate  Valproate  Benzodiazepines  Barbiturates  Vigabatrin  Lamotrigine  Gabapentin  Felbamate  Tiagabine
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