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GM1, An Elixir of Life for a Damaged Dopamninergic System? UPDATED 7/2000 

Yesterdays Public Relation announcement on the Dr. Schneider's
GM1 ganglioside treatment of Parkinson's disease was an early pilot
study for the safety and efficacy of using GM1.

The initial trial consisted of 10 Parkinson's patients excluding those
with the presence of signs indicative of progressive supranuclear
palsy or suspected Parkinson-plus syndromes, focal or lateralized
abnormalities on neurologic examination (other than parkinsonism),
or history of any of the following: infective or inflammatory brain
disease; alcohol or drug abuse; recent acute myocardial infarct;
severe psychiatric disturbance; hepatic, renal, hematologic, or
endocrine disease; multiple episodes of head trauma associated
with sustained loss of conciousness; or Guillain-Barre syndrome
(GBS).

All patients received an IV loading dose if 1,000 mg GM1 administered
over a 30 minute period. Patients were sent home with a 4-week
supply of GM1, which they were trained to administer to themselves
by subcutaneous injection. They returned each 4 weeks for testing and
were sent home with another 4 week supply until the 12th week when
they were sent home with a 6 week supply. Each patient
self-administered two injections/day for a total daily dose of 200 mg
of GM1.

Two patients dropped out of the study. Eight patients completed
the full 18-week course of treatment.

When the individual items from UPDRS motor examination were
analyzed, most of the improvements resulted from decreased
rigidity and bradykinesia scores.

Several patients reported improvements in walking ability,
ability to dress themselves, overall level of energy, and manual
dexterity.

GM1 was provided by Fidia Pharmaceutical Corporation.

----------------- Start of Press Release ------------------------

06/22 0806  CLINICAL TRIALS BEAR OUT PROMISE OF NEW ...

 A pilot clinical trial  showed encouraging evidence that the
drug GM1 ganglioside is effective at substantially reducing
some of the functional impairments caused by  Parkinson's disease.
     Those results, reported in the June issue of Neurology, are
the basis for controlled trials being conducted at Medical
College of Pennsylvania and Hahnemann University (MCPHU),
Philadelphia.
     Unlike two controversial Parkinson's procedures recently
under public  discussion -- fetal cell transplant and pallidotomy
surgery -- GM1 ganglioside is non-invasive, self-administered and
potentially more accessible to Parkinson's patients.
     The drug appears to enhance the brain's ability to produce
the key  neurotransmitter dopamine; it is the lack of dopamine
that leads to the  tremors, rigidity and cognitive problems that
mark Parkinson's.
     "Though the precise mechanism is not clear, GM1 ganglioside
may rescue damaged dopamine neurons, stimulate them to repair
themselves, promote growth of new dopamine terminals on the
neurons -- and perhaps even stimulate remaining dopamine neurons
to produce more than their normal amount of dopamine," said the
study's lead author, Jay Schneider, Ph.D., professor of anatomy,
neurobiology and neurology, MCPHU.
     Dr. Schneider and his colleagues reported that the
functional improvements brought about by the drug continued for
the duration of the study.  Improvements in motor skills and
activities-of-daily-living included decreased rigidity and
bradykinesia (abnormally slow movement); reduced time required to
perform physical tasks; greater ease in walking and dressing, and
an increased energy level.  Cognitively, the patients were less
distractible.
     Parkinson's disease, a progressive neurological disorder
that destroys  muscular control, afflicts 1 percent of all
Americans over age 55.  It is marked by abnormally slow movement,
uncontrollable tremors, stooped posture and a shuffling gait.
     "Given a very long life, most people would suffer some
effects of the brain's naturally decreasing production of
dopamine," Dr. Schneider explained.  "Unfortunately, Parkinson's
causes a loss of dopamine-producing cells above and beyond that
seen in normal aging, and it accelerates the consequences of
having too little dopamine in the brain."
     Doctors currently treat most Parkinson's patients with
L-dopa, which acts as a replacement for their own dopamine.
"While L-dopa ameliorates the symptoms, it loses its efficacy
within a few years, often causes undesirable side effects, and
does not deal with the underlying loss of dopamine-producing
neurons," Dr. Schneider noted.
     Given that GM1 fosters repair and revitalization of
remaining neurons, but does not create new neurons, it may prove
most effective in early stages of the disease, he said.
"However, since laboratory research suggests that only a small
portion of the dopamine system needs to be spared or functionally
recovered to achieve normal motor and cognitive skills, GM1 could
benefit even patients with more established Parkinson's disease
-- providing there are enough dopamine neurons remaining for GM1
to act on," Dr. Schneider suggested.
     The Neurology report involved 10 patients with mild to
severe symptoms of the disease, most of whom had been taking
L-dopa.  At the outset, the patients were given a battery of
tests to assess their functional abilities; those tests were
repeated four times over an 18-week period.  Each patient
received a large intravenous dose of GM1 at the trial's
beginning, then self-administered 200 mg of the drug each day by
injection.  Eight patients completed the full 18-week treatment;
two patients dropped out early, feeling they were not benefitting
from the trial.
     Among those eight participants, significant improvements in
motor skills and ability to perform activities-of-daily-living
occurred in the first eight weeks of the trial and stabilized
over the remaining 10 weeks.
     "While the results of this initial study are encouraging, we
must be careful not to overstate the significance of these
findings," Dr. Schneider observed.  "Since the patients in this
study all knew they were receiving a new drug, their function may
have improved due to psychological factors unrelated to the
medication.  Yet, since some patients have maintained their
original improvement over almost two years now, it is hard to
argue these effects are due primarily to psychological factors."
     The current clinical trial is a double blind, placebo
controlled study of 50 patients.  If that trial also demonstrates
safety and effectiveness in GM1 treatment, the next step would be
a multicenter trial that could begin as early as 1996.
     The big question Dr. Schneider and his colleagues will
ultimately try to  answer as their research progresses is whether
early enough treatment with GM1 or related drugs could alter the
course of the underlying disease.
     GM1 ganglioside is a normal constituent of nerve cell
membranes and is known to moderate a number of neuron surface and
receptor activities. The type of GM1 used in this study was
extracted from cow brain.
     Dr. Schneider is also studying a semi-synthetic derivative
of GM1, called LIGA 20, which could prove even more effective in
restoring the function of the dopamine system.
     The MCPHU research was funded by the F.M. Kirby Foundation,
the Marion and Joseph Wesley Foundation, the Alzheimer's Disease
Research Center at Hahnemann, and through donations to the
Parkinson's Disease Research Fund at Hahnemann.
     Dr. Schneider's co-authors of the Neurology report were
MCPHU colleagues David Rothblat, Ph.D., Jillian Chapas-Crilly,
B.S., and Louisa Seraydarian, Ph.D.; David Roeltgen, M.D., of The
Health Education and Research Foundation of Williamsport (Pa.)
Hospital, and Jayaraman Rao, M.D., of Louisiana State University
Medical Center.

-------------------------- End of Press Release --------------------

Jefferson Researchers Provide Leads to Potential Parkinson’s Treatment

A natural substance in the cell membrane may either protect or stimulate brain cell activity.

A naturally occurring substance in the cell’s membrane may improve symptoms in Parkinson’s disease patients and perhaps even help slow down the progression of Parkinson’s, according to studies by researchers at Jefferson Medical College of Thomas Jefferson University in Philadelphia.

Jay S. Schneider, Ph.D., professor of pathology, cell biology and anatomy and neurology and his co-workers compared a drug, GM1 ganglioside, with a placebo in 45 patients with Parkinson’s disease receiving a 16-week course of treatment.

"At the end of the study, test scores in the Unified Parkinson’s Disease Rating Scale, which is a standard scale to measure motor abilities, showed a significant difference between those who received the drug and those who did not," says Dr. Schneider. He and his colleagues at Jefferson report their findings in the June issue of the journal Neurology.

The study was a double-blind trial, with neither the researchers nor the patients knowing who receives the drug. GM1 ganglioside is a normal part of the cell membrane that plays an important role in cell growth, development, signal transduction and repair after injury.

According to Dr. Schneider, many of the patients’ symptoms, such as rigidity and slow movement, improved during participation in the trial. Patients also reported that they were able to function better in performing daily living activities, such as dressing and handling eating utensils. "Overall, every patient receiving GM1 improved to some degree," he says. "They had less stiffness, less bradykinesia or slowness of movement, and better manual dexterity and motor coordination."

While some participants in the placebo group also slightly improved, the condition of the majority of those who did not receive the drug remained unchanged.

Dr. Schneider and his group continue to follow 21 patients who wanted to continue taking the drug upon study completion. "Most of these patients have received GM1 treatment now for at least two years," he notes. "The condition of 18 of these 21 patients is better now than it was two years ago when they first began the trial. Although they have improved with the treatment, the improvements in many patients have leveled off."

Dr. Schneider recently presented these findings of the long-term follow-up of these patients at the annual meeting of the American Academy of Neurology.

"Some patients report significant improvements in the quality of their life, though others say improvements have been more modest," he says. "For many patients who have used GM1 for two years or more, it’s not so much that they feel that symptoms continue to improve, but they don’t feel they are getting substantially worse. For a progressive disease, that’s something."

Why? One reason, he explains, could be that the drug somehow stimulates remaining dopamine-producing nerve cells to work better or causes regrowth or sprouting of dopamine nerve endings in the brain. He would like to find out if GM1 is playing either a neuroprotective or neurostimulatory role in patients’ improvements.

More than one million people in the United States suffer from Parkinson’s disease. It commonly strikes people over 50. Symptoms include hand tremor, slowness in movement, difficulty initiating movements, difficulty walking, shuffling feet, decrease in speech volume, fatigue, and balance problems. In Parkinson’s, sufferers lack the brain chemical dopamine due to the death of dopamine-producing nerve cells and their endings.

Dr. Schneider is "proposing to do another double-blind trial, but this time get images of the patients’ brains to visualize and count the number of dopamine nerve terminals before the start of the study, and then again after six months, one year, and two years being on therapy." He notes that "by comparing brain images with the clinical status of these patients, we can see if there is any nerve end sprouting or regrowth that can explain clinical improvement. In addition, over time we will be able to see if GM1-treated patients have a slowed loss of dopamine nerve terminals and slowed symptom progression compared to Parkinson’s patients, matched for age and disease duration, who don’t take GM1."

He explains, " We would expect to see a natural decline in dopamine nerve terminal in these patients, and in the GM1 group, we would hope to see either no decline, or a best, a slight increase. This might be fairly definitive evidence of the drug’s beneficial effects."

In earlier animal studies, Dr. Schneider and his coworkers found that injecting GM1 ganglioside improved Parkinsonian symptoms, increased levels of dopamine in the brain and stimulated nerve terminal sprouting. "It possibly saved damaged dopamine cells from dying," he notes.

Published: 6-22-98
Contact: Steve Benowitz or Phyllis Fisher
Phone: 215/955-6300
After Hours: 215/955-6060

The following are other abstracts on the previous hypothsis and usages
of GM1.

<1>
Authors
  Schneider JS.  Yuwiler A.
Institution
  Department of Neurology, Hahnemann University School of Medicine,
  Philadelphia, Pennsylvania 19102.
Title
  GM1 ganglioside treatment promotes recovery of striatal dopamine
  concentrations in the mouse model of MPTP-induced parkinsonism.
Source
  Experimental Neurology.  105(2):177-83, 1989 Aug.
Abstract
  GM1 ganglioside (GM1) has in the past been reported to promote
  regenerative sprouting and functional recovery in both central and
  peripheral nervous systems. The present experiments were performed in
  order to investigate whether GM1 might have any therapeutic effect on
  young mice who had been exposed to the Parkinson-producing neurotoxin
  MPTP. GM1 caused moderate to dramatic increases in striatal dopamine
  levels, depending upon duration of exposure to GM1, in animals previously
  exposed to MPTP. Furthermore, the effects of GM1 on enhancing striatal
  dopamine levels were apparent when GM1 administration was delayed until 3
  days after the last MPTP injection was given and these effects were not
  reversed when GM1 was withdrawn. Tyrosine hydroxylase (TH)
  immunohistochemistry of the striatum demonstrated increased numbers of
  TH-positive fibers and TH-positive terminal fields in GM1-treated animals
  as compared to animals that received only MPTP. TH immunohistochemistry of
  the substantia nigra revealed little or no loss of parts compacta neurons
  in the MPTP-treated mice. On the basis of these observations, GM1 appears
  to increase the dopamine content of the striatum by promoting or
  stimulating regenerative sprouting of dopaminergic terminals and perhaps
  collateral sprouting from remaining intact fibers in the MPTP model of
  Parkinsonism in the young mouse. We suggest that GM1 ganglioside may hold
  some promise as a potential adjunct in the treatment of Parkinson's
  Disease.

<2>
Authors
  Chapman J.  Sela BA.  Wertman E.  Michaelson DM.
Institution
  Department of Biochemistry, Faculty of Life Sciences, Tel-Aviv University,
  Ramat, Israel.
Title
  Antibodies to ganglioside GM1 in patients with Alzheimer's disease.
Source
  Neuroscience Letters.  86(2):235-40, 1988 Mar 31.
Abstract
  Gangliosides are thought to have a role in neuronal development and
  regeneration while anti-ganglioside antibodies have been shown to impair
  these processes. In the present work we examined whether the neuronal
  degeneration in Alzheimer's disease is associated with the presence of
  anti-ganglioside antibodies. A significant level of antibodies specific to
  ganglioside GM1 but not to other gangliosides (GD1a, GD1b, GT1b and GQ1b)
  was found in patients with Alzheimer's disease as compared to normal age
  matched controls. A high level of antibodies to GM1 was also found in
  patients with multi-infarct dementia and Parkinson's disease with dementia
  but not in non-demented patients with other neurodegenerative diseases.
  These results may reflect a specific change in ganglioside metabolism
  which is associated with the neurodegenerative processes underlying
  Alzheimer's disease and other causes of dementia.

<3>
Authors
  Agnati LF.  Fuxe K.  Calza L.  Goldstein M.  Toffano G.  Giardino L.  Zoli
  M.
Title
  Further studies on the effects of the GM1 ganglioside on the degenerative
  and regenerative features of mesostriatal dopamine neurons.
Source
  Acta Physiologica Scandinavica. Supplementum.  532:37-44, 1984.
Abstract
  By means of computer assisted morphometry and microdensitometry the
  effects of chronic GM-1 ganglioside treatment have been further evaluated
  on the degenerative and regenerative features of mesostriatal DA neurons
  in the rat brain. In this study mainly a rostrocaudal morphometrical
  analysis was performed in the substantia nigra of the lesioned side. The
  specificity of the action of the GM-1 ganglioside on the substantia nigra
  DA cells was evaluated by a comparison with antiinflammatory drugs such as
  betametazon and acetylsalicylic acid. In the rostrocaudal analysis it was
  demonstrated that chronic GM-1 treatment preferentially protected the
  caudally located dopamine nerve cells from degeneration after partial
  hemitransection, while instead this chronic GM-1 treatment increased
  tyrosine hydroxylase immunoreactivity mainly within the rostrally located
  DA nerve cells present close to the site of the lesion. Furthermore, the
  specificity of the GM-1 action was demonstrated by the absence of
  protective effects of chronic treatment with betametazon and
  acetylsalicylic acid on the dopamine nerve cells of the lesioned side.
  These results open up the possibility that chronic GM-1 treatment, by
  exerting a stimulatory metabolic action on the DA nerve cells located
  close to the lesion, can enhance the production of neurotrophic factors in
  these cells, which in turn can diffuse out to increase the survival of the
  less severely lesioned DA nerve cells located in the caudal part of the
  substantia nigra. These results indicate that chronic GM-1 treatment may
  be beneficial in the treatment of neurons undergoing degeneration, which
  takes place e.g. in Parkinson's disease and after mechanical injury to the
  brain due to accidents or neurosurgical operations.

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