Description
The National Institute of Neurological Disorders and Stroke (NINDS) intends to negotiate a two-year extension of the Anticonvulsant Screening Program's (ASP) contract with University of Utah in order to coincide with the expiration of the second component of the contract which was incorporated into the CounterAct Program funded by non-NIH sources to the same site. The purpose of the extension is to provide continued screening services while establishing a coincident expiration of the two screening components. Both screening components, which require significant resources in terms of personnel, facilities and materials requires extensive coordination of scientific data evaluation and administrative management. Virtually all compounds being submitted for evaluation within the CounterACT component are also screened in the ASP program. Both components focus on cessation of seizures although different types. It is essential from both a resource and operational management perspective to have both components run concurrent to each other. Negotiating an extension of the current contract for two years will provide concurrent evaluation and testing paradigms and will allow for a coincident contract expiration date. This action will significantly contribute to management efficiencies as well as streamlining program evaluation and review of solicitations for projected future renewals of two efforts. The primary goal of the ASP's contract is to evaluate novel compounds intended primarily as therapeutic interventions as anticonvulsants, neuroprotectants and for treatment of neuropathic pain. The ASP conducts extensive testing to facilitate drug discovery and translational activities aimed at identifying, optimizing and translating such discoveries into therapeutics for affected patients. Active compounds are identified and tested through a series of pharmacodynamic and pharmacokinetic evaluations (both in vivo and in vitro tests) that help define anticonvulsant or related disease profiles of candidate compounds. Test parameters include but are not limited to: Baseline assessments of anti-seizure activity, neurotoxicity, effects on hepatic microsomal metabolizing enzymes, pharmacodynamic interactions, brain slice survival rates and chronic EEG monitoring. These efforts have been carried out under the contract mechanism since 1975 with the University of Utah. Approximately 750 compounds are evaluated annually for anticonvulsant and related activities. Overall testing requirements include the following: 1) Anticonvulsant Identification: evaluation of anticonvulsant activity and associated neurotoxicity in mice, following intraperitoneal administration using the 6 Hz induced focal seizures. 2) Compounds displaying significant activity may be further evaluated with subsequent quantitation 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 using similar models but via different routes of administration. Both activity and toxicity shall be quantitated at previously determined time of peak effects. 3) Pharmacologic Differentiation -- Anticonvulsant profiles are developed wherein the efficacy will be compared with that of the prototype drugs. As part of this process, the efficacy is quantitated using seizures induced by bicuculline and picrotoxin. Anticonvulsant profiles of candidate anticonvulsant compounds are also developed in rats by the gammabutrylactone (GBL) spike-wave model of absence and by the rapid hippocampal-kindling model of complex partial seizures. Candidate substances are evaluated for their ability to block the expression of kindled seizures in the rapid hippocampal kindling model. A limited number shall additionally be tested the ability to block the acquisition of kindled seizures induced by rapid hippocampal stimulation. Profiles for selected test substances will include a genetically susceptible model of reflex epilepsy. 4) Proconvulsant Potential -The endpoint being length of time taken for evidence of seizure activity following the infusion of pentylenetetrazol into the tail vein of mice. 5) Mechanism of Action -- Studies to elucidate 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 neurons in primary culture to characterize possible interactions with GABA and glutamate receptors. 6) Drug Interaction Studies - The metabolic potential for drug-drug interactions are determined using human liver microsomes. The potential to inhibit a battery of the major P-450 human liver isozymes are determined along with comparative assessment of the standard available anticonvulsants. 7) Lamotrigine Resistant Kindled Rat Test -. Animals will be kindled according to the procedure described by Postma et al. (2000) with seizures scored according to a Racine Scale (Racine, 1972). Seizure scores and afterdischarge durations will be recorded for each animal. 8) AED Modulation of Axonal Neurotransmission - This will be assessed via two tests: Partial Ligation of the Sciatic Nerve and the Formalin Test: Used to determine efficacy of an investigational AED against the acute and chronic hyper-responsive neuronal discharges following activation of peripheral nerve fibers. Slice electrophysiology studies and 24 hour EEG recordings are performed on a select number of candidates. Comprehensive summary are prepared for the best candidates (approximately 12 per yr.) During the past 32 years, the University of Utah has been able to successfully adopt specialized techniques, methods of evaluation, model development and accumulation of extensive pharmacodynamic and pharmacokinetic profiles for all the current therapeutic agents and most new investigational drugs. This accumulation of data and experiences is the basis by which all new test compounds are pharmacologically compared. The NINDS believes that the University of Utah is the only known source for performing these comprehensive evaluations by virtue of their experience, demonstrated expertise, availability of required staff, laboratory and animal facilities and requisite trained personnel and 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 the work described above. Authority: 41 U.S.C. 253 (c)(1), as set forth in FAR 6.302-1. This is not a formal solicitation or an announcement that a Request for Proposals (RFP) is available. See Numbered Notes 22 and 26.