Anticonvulsant Screening Program

Description of Testing Services

Evaluation begins with a structural comparison within our database of over 27,000 compounds. The structural diversity of this database and the wealth of associated biological data provide a wide range of parameters for structure-activity evaluation. This database possibly holds the most structurally varied collection of compounds specifically tested for anticonvulsant activity and toxicity in the world. Testing is performed in a series of successive stages. Compounds are screened in a variety of widely accepted models. Employing a battery of validated in vivo/in vitro models rather than any one single assay has proven to be highly predictive of efficacy in human condition. Unless a specific mechanism is known, qualitative anticonvulsant profiles are determined for each submission using two to three different animal models. If deemed biologically active or chemically unique, a compound proceeds into a series of screens designed to establish quantitative, mechanistic, and differentiation profiles for both activity and toxicity. The evaluation of new chemical entities for biological activity is a dynamic process. New assays are continually designed, validated and when appropriate are incorporated into the Program. This process is driven by technological advances and recommendations from expert ASP advisors. The Program Review Article provides a general overview of some of the tests used and basic approach applied in screening. Since the publication of the article several new assays have been incorporated including: the formalin and sciatic nerve ligation models, lamotrigine resistant model, in vitro slice electrophysiology studies and the minimal clonic seizure test (see Model Listings). Each stage of evaluation occurs with direct consultation with the participant(s) and ASP staff. The ASP provides prompt feedback on results, interpretation of generated data, as well as an assessment of the potential success of each particular compound or compound class. The most successful compounds receive a comprehensive profile report detailing all generated biological and comparative data. This document, known as a "Red Book," is frequently used as the original source of publications of the participants as well as documentation for early discussions with the Food and Drug Administration (FDA) and supporting evidence in submissions of Investigational New Drug (IND) applications.

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PANACHE Database

The ASP is in the process of developing a new web-based search tool called PANACHE (Public Access to Neuroactive & Anticonvulsant CHemical Evaluations) to provide access to years of previously protected nonproprietary data on hundreds of tested compounds. These include antiepileptic drugs (AEDs) as well as drugs used for other indications. The database will be useful to chemists, pharmacologists, and other investigators working with molecules of similar chemical structure. We eventually expect to provide baseline pharmacological data across several different models for most of the marketed AEDs. In addition, portions of the data will be released through PubChem to provide a quick reference to investigators.

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How to Participate

A signed confidentiality agreement between the NINDS and each potential participant is required before submission of compounds for evaluation. If interested in participating please contact an ASP staff member for additional information about the program. Based on your research goals, resources and timelines, we will determine how the ASP can best serve your specific needs. An agreement for submitting confidential material is provided for review. After you have contacted staff and submitted two original documents the NINDS will execute and return one of the originals retaining the other for our records. A registration form is also required for each sample submitted for evaluation. These are provided once the NINDS has approved the entity for program participation. Preliminary screening is normally performed using in vivo rodent models thus an initial sample size of approximately 350 to 500 mg is required unless prior knowledge of the compound's efficacy and toxicity are known. Directions for packaging and compound submission will also be provided prior to sample shipment.

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Confidentiality

Confidentiality is one of the hallmarks of the Program's long success. The trust and confidence in ASP's handling of the originator's intellectual property have helped to establish the partnering necessary to facilitate successful development of new drugs. Participation in the ASP begins only after the appropriate representatives from both the participant's organization and the NINDS sign the confidentiality agreement. This document defines the legal parameters for the partnership. All screening and other communication activities are performed in strict confidence to help safeguard the participant's intellectual property. Chemical structures are considered proprietary unless otherwise specified by the supplier. The only testing undertaken by the ASP is that agreed upon by participants in collaboration with ASP personnel. To further assure confidentiality each newly submitted compound has a unique ASP number code assigned. This ADD number is used in future communications, tracking, and analysis. All laboratory site personnel are blinded to both the structure and the source of submitted compounds. The data generated through screening activities are provided exclusively to the participating supplier.

ASP databases that store the test results and other proprietary information are protected and secured through the NIH intrusion detection system, firewall, and the NIH password policy.

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