Unmet Medical Needs

There are a number of unmet needs in the field of anticonvulsant drug therapy, not the least of which is a clearer understanding of the discrete mechanisms by which the various AEDs produce their anticonvulsant effects. As noted, with the exception of vigabatrin and tiagabine which were synthesized in the context of a defined molecular hypothesis to enhance GABAergic transmission, the majority of clinically used AEDs have among other properties multiple effects on ion channel function, none sufficiently potent to highlight any one of these channels as a clear target for de novo synthetic efforts.

Additional unmet needs include the spectrum of anticonvulsant in different types of AED and their therapeutic index. In many instances, side effect liabilities are an extension of the AED's, albeit unknown, anticonvulsant pharmacology. In other instances, side effects may be due to totally unknown properties of the AED. The generally micromolar molecular effects of these compounds would, in a classical target-based drug discovery approach, make them potentially early lead NCEs requiring additional medicinal chemistry efforts to improve their potency rather than finished IND candidates.

Concerns have been raised in regard to current screening paradigms used in AED discovery, e.g., the NINDS in vivo panel, that are viewed as generating AEDs of similar efficacy (and limitations) to those already in use.29,43 In the 10 years encompassing the 1990 Decade of the Brain, eight new AEDs were introduced, none of which appears to have had any impact on the treatment of intractable epileptic patients.43 This same period also saw a doubling of the finding for epilepsy research from $40 million to $80 million and, in 1999, a major White House initiative, 'Curing Epilepsy - Focus on the Future,' focused on translational research initiatives to use the evolving knowledge of basic brain function at the genomic and proteomic levels to develop new models that would lead to new treatments for epilepsy, new AEDs as well as possible cures and prevention of the disorder(s). Like many of the debatably successful outcomes from the Decade of the Brain,44 the transition of research findings to improved healthcare has been slow. Part of this has been due to the inherent complexity of the disease - which is viewed as providing a 'low impact' career in which to recruit research scientists - and also issues with the return on investment in commercially developing AEDs,43 a tangible issue given that the federally funded NINDS Anticonvulsant Screening Program27 represents the major path through which to identify NCEs in the epilepsy area. Additionally, the social stigma associated with epilepsy has resulted in it being a hidden, chronic condition with little focus in public awareness or concern despite the efforts of advocacy groups. Funding for epilepsy R&D in 2003 on a per person basis was a modest $38. Comparable numbers for diseases like autism, multiple sclerosis, and Parkinson's disease were in the range of $220-$248, with Alzheimer's disease R&D being funded at the level of $165 per affected individual.

An alternative to this somewhat pessimistic situation is the considerable potential, discovered in the clinic by serendipity, for the use of AEDs in neuropathic pain (see 6.14 Acute and Neuropathic Pain) and BAPD (see 6.03 Affective Disorders: Depression and Bipolar Disorders), which has increased interest in advancing AEDs to the clinic as multifactorial therapeutic agents and a renewed focus on understanding the mechanism(s) of action of these agents as anticonvulsants in order to understand the role of aberrant and spontaneous neuronal firing via epileptogenic-like foci in neuropathic pain (neuromas) and BAPD. Like chronic convulsive episodes, outcomes from chronic pain states include cell death, aberrant neuronal sprouting, and neuronal pathway remodeling (see 6.14 Acute and Neuropathic Pain).

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