SOLICITATION NOTICE
A -- Characterization of Novel Therapeutics for the Treatment and Prevention of Epilepsy and Other Neurological Disorders
- Notice Date
- 8/19/2003
- Notice Type
- Solicitation Notice
- Contracting Office
- Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke, 6001 Executive Boulevard, Neuroscience Center, Suite 3287, MSC 9531, Bethesda, MD, 20892-9531
- ZIP Code
- 20892-9531
- Solicitation Number
- NIH-NINDS-04-01
- Response Due
- 10/3/2003
- Archive Date
- 10/18/2003
- Point of Contact
- Helene Braun, Contract Specialist, Phone 301 496-1813, Fax 301 402-4225, - Helene Braun, Contract Specialist, Phone 301 496-1813, Fax 301 402-4225,
- E-Mail Address
-
braunh@ninds.nih.gov, braunh@ninds.nih.gov
- Description
- The NINDS intends to negotiate a follow-on contract with University of Utah to continue pharmacologic evaluations of potential anticonvulsant compounds. A new 5-year award (July 2004 -- July 2009) is anticipated. The Anticonvulsant Screening Project (ASP) conducts an extensive drug discovery and translational science effort aimed at identifying potential new antiepileptic agents to be developed and marketed for treatment of human epilepsy disorders. Active compounds are tested through a series of pharmacodynamic and pharmacokinetic evaluations (both in vivo and in vitro tests) that help define a candidate?s anticonvulsant profile including activity, neurotoxicity, effect on hepatic microsomal metabolizing enzymes and pharmacodynamic interactions. These efforts have been carried out under the contract mechanism since 1975 with the University of Utah. Approximately 800 compounds are evaluated for anticonvulsant activity per year. Overall testing requirements include, but are not limited to, the following: 1) Anticonvulsant Identification: Testing includes the evaluation of anticonvulsant activity and associated neurotoxicity in mice, following intraperitoneal administration of 100 mg/kg of test compound using the 6 Hz induced focal seizure test for approximately 800 candidate compounds. Compounds displaying significant anticonvulsant activity by the 6 Hz test may be further evaluated following intraperitoneal administration of 30, 100 and 300 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 in the MES, pentylenetetrazol and neurological deficit seizure tests. 2) Anticonvulsant Quantitation -- Candidate compounds found active in the identification screens shall be subjected to further testing designed to establish ED50's for the 6 Hz, MES, sc Met tests and TD50's for minimal motor impairment. The anticonvulsant activity and minimal motor impairment shall be quantitated following both intraperitoneal and oral administration to mice and rats at previously determined time of peak effects. 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 pentylenetetrazol 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 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 for a candidate substance to inhibit a battery of the major P-450 human liver isozymes are determined along with comparative assessment of the standard available anticonvulsants. 7) Mutagenicity ? The Ames will be employed to identify whether a compound is or has pro-mutagen activity and whether bioactivation in this screen is cytochrome P450 dependant. Comparison with known mutagens and pro-mutagens at various concentrations are required. 8) Lamotrigine Resistant Kindled Rat Test -. Animals will be kindled according to the procedure described by Postma et al. (2000). Seizures will be scored according to a Racine Scale (Racine, 1972). In addition, the seizure score and afterdischarge duration will be recorded for each animal. 9) AED Modulation of Axonal Neurotransmission - This will be assessed via two tests: Partial Ligation of the Sciatic Nerve and the Formalin Test: This model is ideally suited for efficacy of an investigational AED against the acute and chronic hyper-responsive neuronal discharges following activation of peripheral nerve fibers. Positive results in one or both of these models will: 1) support the broad-spectrum activity identified in the acute seizure models; and 2) imply activity for other non-epilepsy indications. Selected compounds will have summary reports prepared detailing all methodologies and comparative values to known anticonvulsants. During the past 28 years, the University of Utah has been able to successfully adopt specialized techniques, methods of evaluation and accumulation of extensive pharmacodynamic and pharmacokinetic profiles for all the current therapeutic agents and 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 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 nor an annoucement that a Request for Proposals (RFP) is available. See Numbered Notes 22 and 26.
- Place of Performance
- Address: University of Utah, Salt Lake City, Utah
- Zip Code: 84112
- Zip Code: 84112
- Record
- SN00406001-W 20030821/030819213517 (fbodaily.com)
- Source
-
FedBizOpps.gov Link to This Notice
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