More MS news articles for Nov 2001

Pharmos Compounds Demonstrate Neuroprotection in Stroke and Parkinson's Disease Models

Mon, Nov 12 9:39 AM EST

ISELIN, N.J., Nov. 12 /PRNewswire/ -- 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-kappaB, 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 is less than 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 is less than 0.05).

Dexanabinol Inhibition of NF-kappaB

Dexanabinol exerts anti-inflammatory effects, including the ability to inhibit expression of tumor necrosis factor (TNF) alpha. The gene expression of TNFalpha and various other mediators of inflammation are regulated by NF-kappaB, 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-kappaB activation, U373 MG cells, an astrocytoma cell line, were transiently transfected with a reporter fusion gene that is under transcriptional control of NF-kappaB. Stimulation of NF-kappaB activity by TNFalpha, 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-kappaB activation and nuclear translocation by its ability to block the TNFalpha-induced degradation of the NF-kappaB inhibitor, IkappaBalpha. In summary, the results show that dexanabinol is capable of inhibiting the activation of NF-kappaB, 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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