Finding a better drug for epilepsy: Preclinical screening strategies and experimental trial design.

Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Ferrara, and National Institute of Neuroscience, Ferrara, Italy Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine and Center for Systems Neuroscience, Hannover, Germany Epilepsy Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Department of Physiology, Salk School of Medicine, University of Utah, Salt Lake City, Utah, U.S.A. Departments of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, and the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. CNS Research, UCB Pharma, Braine-l'Alleud, Belgium Wayne State University, Detroit, Michigan, U.S.A. New York University Langone Medical Center and Colombia University, New York, New York, U.S.A. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Departments of Cell Biology & Anatomy, and Pediatrics, New York Medical College, Valhalla, New York, U.S.A.
Epilepsia (Impact Factor: 4.58). 06/2012; DOI: 10.1111/j.1528-1167.2012.03541.x
Source: PubMed

ABSTRACT The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past.


Available from: Libor Velíšek, Oct 07, 2014
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