Pharmos
Compounds Demonstrate Neuroprotection in Stroke and Parkinson's
Disease Models
Iselin,
NJ, November 12, 2001 - Pharmos Corporation (Nasdaq:
PARS and Nasdaq Europe: PHRM) is presenting this week
at the Society for Neuroscience Annual Meeting in San
Diego three papers demonstrating the potential activity
of its non-psychotropic dextrocannabinoids as agents to
treat neuro-inflammatory disorders. Two of the papers
present positive preclinical results in animal models
for stroke and Parkinson's Disease. For stroke, PRS-211,095
was shown to induce significant dose-dependent functional
recovery as well as reduction in brain infarct size following
transient middle cerebral artery occlusion (MCAo) in rats.
In a Parkinson's Disease mouse model, dexanabinol protected
dopaminergic neurons of the central nervous system from
MPTP toxicity.
"The
positive results we are obtaining with our compounds in
animal models for various neurological indications support
our decision to invest greater resources in this area
of development. The sale of our ophthalmic business to
Bausch & Lomb last month will help us advance promising
early-stage programs into development and thereby strengthen
our neurological pipeline," said Dr. George Fink,
Vice President of Research at Pharmos.
The
third paper extends scientific understanding of the mechanisms
of action of Pharmos' dextrocannabinoids. Collaborative
studies with Drs. Marcus Schwaninger and Eric Juettler
(Department of Neurology, University of Heidelberg) show
for the first time that dexanabinol inhibits NF-kB, an
important transcription factor in neuroinflammatory processes.
Fink explained, "These results and data to be announced
in the future demonstrate that our dextrocannabinoids
affect cell signaling, particularly via gene regulation,
cytokines and chemokines, and strengthen our ability to
optimize our lead compounds and identify new clinical
indications."
Stroke
Study
Stroke was induced in rats by a 120-minute occlusion of
the MCA, a standard animal model for focal ischemia. The
animals were treated with a single intravenous injection
of 0.5, 2.5, 5 or 10 mg/kg PRS-211,095 or vehicle alone
at the end of MCAo. The neuroprotective efficacy of the
compound was evaluated by brain infarct volume and by
neurological outcome tested in the "staircase test,"
which measures a combination of sensory and motor skills
similar to those impaired in humans who suffer a stroke.
A dose-related improvement in performance in the staircase
test was seen with PRS-211,095 (40-80% compared with vehicle
alone, p<0.05 at 0.5, 5 and 10 mg/kg). Infarct volume
was reduced with all doses of PRS-211,095, with the 5
mg/kg dose showing a 44% reduction compared with vehicle
alone.
Parkinson's
Disease Study
MPTP is a toxin that induces a severe and irreversible
Parkinson's Disease-like syndrome. In mice the agent causes
a massive loss of the tyrosine hydroxylase (TH) immunoreactive
(dopaminergic) cells in the substantia nigra, a key motor-control
center of the brain that undergoes degeneration in Parkinson's
Disease. Mice were injected with either MPTP toxin or
saline four times at two-hour intervals. The MPTP-injected
mice were treated with either dexanabinol (10, 20, 30
mg/kg) or its vehicle just before the first MPTP injection.
One group of MPTP-injected mice was left untreated. After
seven days, brain sections were analyzed for TH-positive
cells by immunohistochemistry. Brain sections from mice
treated with 20 mg/kg dexanabinol had 25-30% more TH-positive
cells in the substantia nigra than sections from mice
treated with vehicle alone (p<0.05).
Dexanabinol Inhibition of NF-kB
Dexanabinol exerts anti-inflammatory effects, including
the ability to inhibit expression of tumor necrosis factor
(TNF) a. The gene expression of TNFa and various other
mediators of inflammation are regulated by NF-kB, an essential
transcription factor for many genes involved in the pathophysiology
of brain damage, including cerebral ischemia and neural
cell death. To investigate the effect of dexanabinol on
NF-kB activation, U373 MG cells, an astrocytoma cell line,
were transiently transfected with a reporter fusion gene
that is under transcriptional control of NF-kB. Stimulation
of NF-kB activity by TNFa, detected by luciferase assay,
was inhibited by dexanabinol in a concentration-dependent
manner. Western blot and gelshift assays were also employed
and indicated dexanabinol inhibited NF-kB activation and
nuclear translocation by its ability to block the TNFa
- induced degradation of the NF-kB inhibitor, IkBa. In
summary, the results show that dexanabinol is capable
of inhibiting the activation of NF-kB, a mechanism by
which dexanabinol could protect neuronal and other cells
during neuroinflammation or ischemia.
Synthetic
Non-Psychotropic Dextrocannabinoid Library
Pharmos is conducting both clinical and preclinical studies
with neuroprotective compounds from its library of proprietary,
synthetic, non-psychotropic dextrocannabinoids. The most
advanced compound, dexanabinol, is in a pivotal Phase
III clinical trial to treat traumatic brain injury (TBI).
Another compound from the company's technology platform
is in last-stage preclinical development for stroke. Beyond
TBI and stroke, Pharmos believes its technology holds
great promise in the development of safe and effective
treatments for neuropathic pain, multiple sclerosis (MS)
and other neurological and autoimmune conditions in which
neuroinflammation is central to the pathology.
Pharmos
Corporation discovers and develops novel therapeutics
to treat a range of neurological disorders, in particular
those in which inflammation plays a role, such as traumatic
brain injury and stroke. The Company has an extensive
portfolio of drug candidates under development, as well
as discovery, preclinical and clinical capabilities.
Statements
made in this press release related to operational expectations
and projections of the Company are forward-looking and
are made pursuant to the safe harbor provisions of the
Securities Litigation Reform Act of 1995. Such statements
involve risks and uncertainties which may cause results
to differ materially from those set forth in these statements.
Additional economic, competitive, governmental, technological,
marketing and other factors identified in Pharmos' filings
with the Securities and Exchange Commission could affect
such results.
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