New avenues for anti-epileptic drug discovery and development

Löscher, Wolfgang; Klitgaard, Henrik; Twyman, Roy E.; Schmidt, Dieter

doi:10.1038/nrd4126

Cited by 519 publications

(478 citation statements)

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“…Previous publications have addressed the predictability of key models used in therapy development, their appropriateness for certain types of seizures or epilepsies, and suggested changes in the way these are used in therapy development 5, 6, 7, 8, 9, 10, 11, 50, 51, 52, 53…”

Section: Opportunities To Narrow the Preclinical‐clinical Trial Gap Amentioning

confidence: 99%

“…Rigor and transparency issues have been covered extensively in other previous publications 5, 6, 7, 8, 9, 10, 11, 50, 51, 52, 53. Assuming that appropriate rigor has been applied in the studies, preclinical findings may not be confirmed in clinical trials either because they have no true clinical relevance or because clinical trials do not test the appropriate scenarios.…”

Section: Opportunities To Narrow the Preclinical‐clinical Trial Gap Amentioning

confidence: 99%

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Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Galanopoulou

Mowrey

2016

Epilepsia Open

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SummaryPreclinical studies have produced numerous drugs with antiseizure properties that currently are the standard of care. One third of the human population with epilepsy still continues to have seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease‐modifying treatments, and treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to reevaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may affect the quality, interpretation, and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design; research practices that affect rigor (such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs, and preclinical‐clinical studies); the need to harmonize research methods and outcome assessment; and the importance of improving translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in future success.

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Section: Opportunities To Narrow the Preclinical‐clinical Trial Gap Amentioning

confidence: 99%

Section: Opportunities To Narrow the Preclinical‐clinical Trial Gap Amentioning

confidence: 99%

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Galanopoulou

Mowrey

2016

Epilepsia Open

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“…Animal models have, since 1937, been the foundation on which many new therapies have been identified for the treatment of symptomatic epilepsy [1][2][3]. The successful identification of several new antiepileptic (or anti-seizure) drugs (AEDs) since the 1990s clearly supports the value of animal models in the early identification of promising new drugs for the patient with epilepsy [1].…”

Section: Introductionmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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“…These manipulations result largely in “me‐too” drugs with similar efficacy rather than in a fundamental change to much‐needed, substantially more effective or better‐tolerated drugs compared with current medications 4, 5. A much more promising method, currently gaining momentum, is to design drugs to modify a molecular target presumed to be involved in seizure generation 4, 5. Such target‐based strategies offer the potential for more fundamental advance than simply manipulating the structure of existing drugs.…”

Section: Today's Theories and Practices Which May Not Withstand The Tmentioning

confidence: 99%

“…Also, other aspects affect response but cannot have any relationship to drug target or transporters, for instance: etiology of the epilepsy, epilepsy syndrome, extent or position of a brain lesion, environmental factors such as nutrition, lack of sleep, hepatic enzyme induction, drug receptor regulation, drug dose, pharmacokinetics, and comedication. In fact, none of the commonly proposed theories is able to convincingly explain drug resistance in focal epilepsy 4, 5…”

Section: Today's Theories and Practices Which May Not Withstand The Tmentioning

confidence: 99%

The right and the wrong with epilepsy and her science

Shorvon

Schmidt²

2016

Epilepsia Open

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SummaryThis is a commentary and an opinion paper attempting a critical reassessment of the methods and practices of epilepsy research as we see it. The enormous progress in the field of epilepsy in recent years is a cause of celebration. Advances have been made on most fronts, and the position of patients with epilepsy in society has greatly improved. However, there have also been culs‐de‐sac and dead ends of modern science and clinical practice which are also intriguing. It may be true that we can learn more from our mistakes than from our successes. In this opinion paper, we have listed some of the successes and some of the failures of past epilepsy practice, and also areas of current practice and theory which we feel are likely to prove mistaken. The underlying reasons for misdirected practices and theories include, in our view, the influence of fashion, bad science, and the bureaucracies of practice and academic medicine. As a result, some findings are far from objective. Recognition is the first step to remediation, and hopefully future research will minimize some of the pitfalls mentioned in this article and bring the “End of Epilepsy,” as defined and predicted by Oswei Temkin, closer than it is today.

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New avenues for anti-epileptic drug discovery and development

Cited by 519 publications

References 153 publications

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

The right and the wrong with epilepsy and her science

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