Epilepsy research
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Despite the release of eight antiepileptic drugs (AEDs) during the last decade, the incidence of pharmacoresistant epilepsy has changed relatively little. Predicting efficacy and safety of AEDs in people with epilepsy from acute seizure models in rodents is difficult and risky. ⋯ In this review the use of pharmacogenomic and pharmacokinetic techniques in the development and monitoring of antiepileptic drug therapy is reviewed. Genetic techniques have the potential of identifying novel drug targets, predicting drug response, and identifying individuals at risk for serious idosyncratic reactions.
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Results of experiments performed in animal epilepsy models and human epilepsy during the past decade indicate that the epileptic brain is not a stable neuronal network, but undergoes modifications caused by the underlying etiology and/or recurrent seizures. In many forms of epilepsy, such as temporal lobe epilepsy, the underlying etiologic factor triggers a cascade of events (epileptogenesis) leading to spontaneous seizures and cognitive decline. In some patients, the condition progresses, due in part to recurrent seizures. ⋯ Here we review the available data regarding the neuroprotective effects of antiepileptic drugs (AEDs) at different phases of the epileptic process. Analysis of published data suggests that initial-insult modification and prevention of the progression of seizure-induced damage are candidate indications for treatment with AEDs. An understanding of the molecular mechanisms underlying the progression of epileptic process will eventually show what role AEDs have in the neuroprotective and antiepileptogenic treatment regimen.
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During the last decade, several new antiepileptic drugs (AEDs) have been introduced in Europe, the United States, or other parts of the world. Although the antiepileptic efficacy of these drugs is not superior to that of older AEDs, some of the new drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential with other drugs. However, the new AEDs have only a modest impact on patients with refractory epilepsies, so that about one third of patients with epilepsy continue to have seizures with current pharmacotherapies. ⋯ The discussion of this session, which was chaired by the authors, is summarized in this article. Main issues of the discussion were whether epilepsy is a progressive disease and whether refractory epilepsy is preventable, the use of acute versus chronic animal models in the discovery and development of new AEDs, models for drug-resistant epilepsy, mechanisms of drug resistance, alterations in adverse effect potential of AEDs by epilepsy, and advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy. Overall, it was felt that the current preclinical strategies for the discovery and development of new AEDs have to be redefined in order to identify agents that are clearly superior to current medications.
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Several rodent models are available to study the cellular mechanisms associated with the development of temporal lobe epilepsy (TLE), but few have been successfully transferred to inbred mouse strains commonly used in genetic mutation studies. We examined spontaneous seizure development and correlative axon sprouting in the dentate gyrus of CD-1 and C57BL/6 mice after systemic injection of pilocarpine. Pilocarpine induced seizures and status epilepticus (SE) after systemic injection in both strains, although SE onset latency was greater for C57BL/6 mice. ⋯ Mossy fiber sprouting and spontaneous seizures were not observed in mice that did not experience a period of SE. These results indicate that pilocarpine induces spontaneous seizures and mossy fiber sprouting in both CD-1 and C57BL/6 mouse strains. Unlike systemic kainic acid treatment, the pilocarpine model offers a potentially useful tool for studying TLE development in genetically modified mice raised on the C57BL/6 background.
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy.
To evaluate the efficacy, dose-response, tolerability, and withdrawal effects of levetiracetam (Keppra) as adjunctive therapy in adult patients with partial epilepsy. ⋯ Levetiracetam was effective and well-tolerated and decreased seizure frequency in a dose-dependent manner, with no evidence of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration.