Contract Management Branch, National Institute of Neurological Disorders and Stroke, NIH, Federal Building, Room 901, 7550 Wisconsin Avenue, MSC 9190, Bethesda, Maryland 20892-9190

A -- THE EARLY EVALUATION OF ANTICONVULSANT DRUGS DUE 081198 POC Raina Cervantes, Contracting Officer, (301) 496-1813, fax #(301) 402-4225 E-MAIL: Laurie Leonard, ll44s@nih.gov. The NINDS intends to negotiate a follow-on contract with the University of Utah to continue pharmacologic evaluations of potential anticonvulsant compounds. A new 5-year award (June 1999 -- June 2004) is anticipated. The Epilepsy Branch, Division of Convulsive, Infectious and Immune Disorders (DCIID) conducts an extensive Epilepsy Therapeutics Research Program aimed at identifying potential new antiepileptic agents to be used in man. Active compounds are advanced through a series of pharmacodynamic and pharmacokinetic evaluations (in vivo and in vitro tests) which define the compound's anticonvulsant activity, neurotoxicity, effect on hepatic microsomal metabolizing enzymes and pharmacodynamic interactions. This Anticonvulsant Screening Project has been carried out under the contract mechanism since 1975 with the University of Utah. During these past 22 years, the University of Utah has been able to successfully adopt specialized techniques, methods of evaluation and accumulation of pharmacodynamic and pharmacokinetic profiles for current therapeutic agents and new investigational drugs. This accumulation of data and experiences is the basis by which all new compounds are compared. Approximately 800 compounds are evaluated for anticonvulsant activity per year. Overall testing requirements include, but are not limited to, the following: 1) Anticonvulsant Identification -- Annually the anticonvulsant activity of approximately 800 candidate compounds shall be identified in mice following intraperitoneal administration of 100 mg/kg using the threshold tonic extension (TTE) test. Neurotoxicity will be evaluated using the rotorod test. Compounds displaying significant anticonvulsant activity by the TTE test will be further evaluated following intraperitoneal administration of 3, 10 and 30 mg/kg using the supramaximal electroshock seizure pattern test (MES), the subcutaneous pentylenetetrazol (sc Met) threshold test and the rotorod test. Those compounds possessing significant anticonvulsant activity in mice shall also be evaluated in rats by the MES and pentylenetetrazol seizure tests. 2) Anticonvulsant Quantitation -- Candidate compounds found active in the identification screen shall be subjected to further testing designed to establish ED50's for the MES and sc Met tests and TD50's for minimal motor impairment. Anticonvulsant activity and minimal motor impairment shall be quantitated following intraperitoneal administration to mice and oral administration to rats at a previously determined time of peak effect. 3) Pharmacologic Differentiation -- An anticonvulsant profile shall be developed for selected candidate compounds wherein the efficacy of the novel agent will be compared with that of prototype drugs. As part of this process, the anticonvulsant efficacy of candidate compounds shall be quantitated in mice using seizures induced by bicuculline and picrotoxin. The anticonvulsant profile of candidate anticonvulsant compounds shall be further developed in rats by the gamma-butrylactone (GBL) spike-wave model of absence and by the rapid hippocampal kindling model of complex partial seizures. Candidate substances shall also be evaluated for their ability to block the expression of kindled seizures in the rapid hippocampal kindling model. A limited number of compounds shall additionally be tested for their ability to block the acquisition of kindled seizures induced by rapid hippocampal stimulation. The anticonvulsant profile of selected test substances shall also include a genetically susceptible model of reflex epilepsy. 4) Evaluation of Proconvulsant Potential -- The length of time taken for the first evidence of seizure activity following the infusion of pentylenetetrazole into the tail vein of mice shall be used as a measure of seizure threshold. 5) Evaluation of Mechanism of Action -- Studies directed toward elucidating anticonvulsant mechanism(s) of action shall be conducted on a limited number of test substances. These include the use of whole cell voltage-clamp recordings from cortical neurones in primary culture to characterize possible interactions with gaba and glutamate receptors. The effects of drugs on voltage-dependent sodium channels in NIE-115 neuroblastoma cells. Additional mechanistic studies are carried out by using depolarizing voltage steps from 60 mV in the cells with the expressed ion channels. 6) The Development of Tolerance, Toxicity and Potential for Drug-drug Interactions Following Multiple (Sub-chronic) Dosing -- Using whole-animal tests, it shall be determined whether an altered response to drug anticonvulsant effect might be due to an alteration in hepatic oxidative drug metabolism or in CNS sensitivity. The NINDS believes that the University of Utah is the only known source for this work by virtue of their experience, demonstrated expertise, availability of required staff of 11.6 persons/year, facilities and requisite resources. NINDS' requirement for consistency and compatibility of data derived from these screening procedures is paramount to the success of this program. Inability to produce compatible evaluation results to our existing data base would lead to delays in screening new compounds and incurrence of duplicate costs, both of which would be unacceptable to the Government and would disrupt the continuity of this work. Organizations that believe they have the qualifications and capabilities necessary to undertake this work should submit complete documentation of staffing, facilities, and methodologies currently in place to the Contracting Officer at the above address within 45 days from the date of this announcement. An organization must have an ongoing program with available staff with substantial experience in conducting the required tests, equipment, space and infrastructure in place to carry out work described above. Authority: 41 U.S.C. 253 (c)(1), as set forth in FAR 6.302-1. See Numbered Note 22. (0174)

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