[Federal Register: November 16, 2006 (Volume 71, Number 221)]
[Notices]
[Page 66788-66789]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16no06-84]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing
AGENCY: National Institutes of Health, Public Health Service, HHS.
ACTION: Notice.
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SUMMARY: The inventions listed below are owned by an agency of the U.S.
Government and are available for licensing in the U.S. in accordance
with 35 U.S.C. 207 to achieve expeditious commercialization of results
of federally-funded research and development. Foreign patent
applications are filed on selected inventions to extend market coverage
for companies and may also be available for licensing.
ADDRESSES: Licensing information and copies of the U.S. patent
applications listed below may be obtained by writing to the indicated
licensing contact at the Office of Technology Transfer, National
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville,
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A
signed Confidential Disclosure Agreement will be required to receive
copies of the patent applications.
Second Generation Nitric Oxide-Releasing Non-Steroidal Anti-
Inflammatory Drugs Possessing a Diazeniumdiolate Group (NONO-NSAIDs)
Description of Technology: Non-steroidal anti-inflammatory drugs
(NSAIDs) are one of the most useful clinical therapies for the
treatment of pain, fever and inflammation. It is estimated that more
than 30 million people take NSAIDs every day. However, the major
mechanism by which NSAIDs exert their anti-inflammatory activity is
also responsible for the gastrointestinal, renal and hepatic side
effects observed in patients undergoing long-term treatment of chronic
conditions. The most common side effects associated with NSAID
administration are gastroduodenal erosions and ulcerations affecting
around 15% of chronic NSAID users. While many of these clinical
manifestations are mild, they may develop into serious events such as
bleeding, perforation, obstruction, and sudden death. Therefore, the
gastric irritant effect of NSAIDs (particularly aspirin) can be a
deterrent to its long-term use for the prophylactic prevention of
adverse cardiovascular events such as stroke and myocardial infarction,
or as a safe chemopreventive agent to avoid the recurrence of
colorectal cancer (CRC).
One of the main strategies that have emerged to improve the safety
profile of NSAIDs is the linkage of a nitric oxide (NO)-releasing
moiety to the structure of classical NSAIDs (NO-NSAIDs). However, all
NO-releasing NSAIDs published so far have a nitrooxyalkyl group as the
NO-releasing group. An important drawback to this design is the fact
that production of NO (only one equivalent) from organic nitrate esters
requires a metabolic three-electron reduction in vivo, and this
activation decreases in efficiency on continued use of the drugs,
contributing to ``nitrate tolerance''.
This invention describes the design, synthesis and biological
evaluation of novel NO-releasing non-steroidal anti-inflammatory
prodrugs (NONO-NSAIDs) possessing a N-diazen-1-ium-1,2-diolate
(NONOate), which offers additional advantages compared with organic
nitrate-based NO-NSAIDs:
(a) Simultaneous release of the corresponding NSAID and NO.
(b) Production of two equivalents of NO (twice as much) by a first-
order rate.
(c) Metabolic activation (hydrolysis) mediated by non-specific
esterases, which unlike redox metabolism, is not expected to produce
tolerance upon long-term treatment.
Applications: This invention provides a group of anti-inflammatory,
analgesic, and gastrointestinal safe prodrugs, which are expected to be
a suitable alternative for the prophylactic prevention of adverse
cardiovascular
[[Page 66789]]
events such as stroke and myocardial infarction, as well as cancer
chemoprevention.
Market: (1) An estimated 60 million people in the United States use
NSAIDs regularly; (2) An estimated $5 billion are spent each year in
the United States on prescription NSAIDs and approximately $2 billion
are spent on over-the-counter NSAIDs.
Development Status: Pre-clinical data is available.
Inventors: Carlos Velazquez Martinez (NCI) et al.
Related Publication: C Velazquez, PN Praveen Rao, EE Knaus. Novel
nonsteroidal anti-inflammatory drugs possessing a nitric oxide donor
diazen-1-ium-1,2-diolate moiety: Design, synthesis, biological
evaluation, and nitric oxide release studies. J Med Chem. 2005
Jun16;48(12):4061-4067.
Patent Status: U.S. Provisional Application 60/794,421 filed 24 Apr
2006 (HHS Reference No. E-186-2006/0-US-01).
Licensing Status: Available for exclusive and non-exclusive
licensing.
Licensing Contact: Norbert Pontzer, PhD, J.D.; 301/435-5502;
pontzern@mail.nih.gov.
Collaborative Research Opportunity: The Chemistry Section of the
Laboratory of Comparative Carcinogenesis is seeking statements of
capability or interest from parties interested in collaborative
research to further develop, evaluate, or commercialize the prodrugs
described, as new and safer analgesic, anti-inflammatory, anti-
thrombotic, and cancer chemopreventive agents. Please contact Betty
Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.
Rat or Mouse Exhibiting Behaviors Associated With Human Schizophrenia
Description of Technology: A newly developed animal model for
schizophrenia is valuable for assaying pharmaceutical compounds for
treating this disorder. Schizophrenia is a neuropsychiatric disorder
characterized by cognitive deficits, bizarre behavior and/or
hallucinations. Presently, there has been no satisfactory animal model
for testing promising therapies for this disorder.
This invention provides a unique and surprisingly accurate animal
model for human schizophrenia. The animals are brain damaged while
prepubescent. The brain damage consists of a ventral hippocampus lesion
induced by exposure of the hippocampus region to a neurotoxin. When the
animal reaches puberty, abnormal behavior and a number of biological
phenomena associated with schizophrenic symptoms emerge.
The present invention also provides methods of assaying the anti-
schizophrenic potential of pharmaceutical compositions. The methods
involve (a) Inducing or creating a lesion in the ventral hippocampus of
a prepubescent mammal, (b) nurturing or raising the mammal until
postpuberty, (c) administering to the mammal a pharmaceutical
composition thought to have anti-schizophrenic properties; and (d)
determining the mammal's response to the pharmaceutical composition.
The anti-schizophrenic potential of the pharmaceutical composition is
assessed by objectively measuring the mammal's behavior following
administration of the pharmaceutical composition. The behaviors which
are measured typically include the following: locomotor activity in a
cage, in unfamiliar or novel environments, after injection or
administration of drugs (e.g., amphetamines), after mild electric
shock, after exposure to sensory stimuli (e.g., noise), in water (swim
test), after immobilization, in social interactions, and in various
learning and reward paradigms.
The neurotoxin used can be selected from a number of known agents
which lethally affect neurons usually, but not exclusively, by over-
exciting their glummate receptors. Examples of such neurotoxins include
ibotenic acid, N-methyl-D-aspartic acid, kainic acid, dihydrokainate,
DL-homocysteate, L-cysteate, L-aspartate, L-glutamate, colchicine,
ferric chloride, omega-conotoxin GVIA, 6-hydroxy-dopamine.
Advantage: This is the first model showing postpubertal emergence
of abnormalities similar to those reported in schizophrenia.
Applications: (1) Animal model for human schizophrenia; (2)
Screening methods for Anti-schizophrenics.
Development Status: Validated, well characterized and ready for
use.
Inventors: Daniel R. Weinberger, Barbara K. Lipska, and George E.
Jaskiw (NIMH).
Publications:
1. AHC Wong, BK Lipska, O Likhodi, E Boffa, DR Weinberger, JL
Kennedy, HHM Van Tol. Cortical gene expression in the neonatal ventral-
hippocampal lesion rat model. Schizophr Res. 2005 Sep 15;77(2-3):261-
270.
2. BK Lipska. Using animal models to test a neurodevelopmental
hypothesis of schizophrenia. J Psychiatry Neurosci. 2004 Jul;29(4):282-
286.
3. BK Lipska and DR Weinberger. To model a psychiatric disorder in
animals: schizophrenia as a reality test. Neuropsychopharmacology 2000
Sep;23(3):223-239.
4. BK Lipska, GE Jaskiw, DR Weinberger. Postpubertal emergence of
hyperresponsiveness to stress and to amphetamine after neonatal
excitotoxic damage: a potential animal model of schizophrenia.
Neuropsychopharmacology 1993 Aug;9(1):67-75.
Patent Status: U.S. Patent No. 5,549,884 issued 27 Aug 1996 (HHS
Reference No. E-013-1993/0-US-01).
Availability: Available for non-exclusive licensing.
Licensing Contact: Norbert Pontzer, Ph.D., J.D.; 301/435-5502;
pontzern@mail.nih.gov.
Dated: November 8, 2006.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. E6-19408 Filed 11-15-06; 8:45 am]
BILLING CODE 4140-01-P