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COMMERCE BUSINESS DAILY ISSUE OF DECEMBER 29,1997 PSA#2000Contract 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 021098 POC Raina
Cervantes, Contracting Officer, 301-496-1813 E-MAIL: Laurie Leonard,
ll44s@nih.gov. 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 (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-wavemodel 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
neuronesin primary culture to characterize possible interactions with
gaba and glutamate receptors. 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. (0357) Loren Data Corp. http://www.ld.com (SYN# 0009 19971229\A-0009.SOL)
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