Talampanel in Parkinson Disease: Why the Excitement?

PARKINSON DISEASE

Parkinson disease is a chronic, progressive, disorder. It is characterized by problems with movement , problems with
thinking, and problems with behavior. Levodopa (combined with carbidopa) which restores dopamine levels in the brain
and dopamine agonists which mimic the actions of dopamine are the mainstay of treatment. Levodopa and the dopamine
agonists are helpful in restoring movement. However, their use is complicated by the appearance of extra, unwanted,
involuntary movements, called dyskinesia in 50% or more of patients. In addition the drugs cause abnormal behavior:
agitation, delusions, and hallucinations in 30% patients (especially patients 70 years and older). The current drugs do
not stop the progression of PD nor do they prevent the dementia of PD. It is recognized that more than dopamine is
involved in PD. However, until recently there were no drugs other than dopamine drugs for PD.

THE SUBSTANTIA NIGRA AND DOPAMINE

In PD there is a loss of nerve cells in a region of the brain called the SUBSTANTIA NIGRA. There are 400,000 nerve
cells in the substantia nigra, 200,000 on each side of the brain. The substantia nigra nerve cells make dopamine and
transport it to another region of the brain called the STRIATUM. The substantia nigra nerves cells connect with nerve
cells in a part of the striatum called the PUTAMEN. There are 20,000,000 nerve cells in the putamen, 10,000,000 on each
side of the brain. Thus each substantia nigra nerve cell connects with and regulates 50 nerve cells in the putamen.
This means the activity of a single substantia nigra nerve cell must be amplified 50 times in the putamen.

THE PUTAMEN AND GLUTAMATE

The nerve cells in the putamen use two chemicals: GLUTAMATE and gamma amino butyric acid (which is identified by its
acronym GABA). While dopamine is confined to a relatively few regions of the brain, GLUTAMATE and GABA are found in
many regions of the brain. The role of GLUTAMATE is to excite, stimulate nerve cells, the role of GABA is to inhibit,
dampen, nerve cells. GLUTAMATE and GABA are more important, overall, for brain function than dopamine and GLUTAMATE is
thought to be more important than GABA. In PD, for reasons that are as yet unknown, the substantia nigra dopamine cells
die. It is thought, by some, that one reason they die is from excessive excitation, stimulation of their nerve endings
in the putamen by GLUTAMATE. First the nerve endings die, then by a dying back processes, the dopamine nerve cells in
the substantia nigra die. All of us lose 2,000 substantia nigra nerve cells each year. GLUTAMATE may play a role in
this “normal” process. In PD, the rate of dopamine cell lose increases to 5,000 to 20,000 cells per year. GLUTAMATE
probably plays a role in this abnormal process. When we lose 60% of the dopamine cells in the substantia nigra, 120,000
cells on each side of the brain, the symptoms of PD appear. While the dopamine cells in substantia nigra die, the cells
in the putamen do not. This means the remaining 160,000 cells of the substantia nigra, 80,000 on each side must work
harder to regulate the nerve cells in the putamen. This means the activity of a single substantia nigra nerve cell must
be amplified 125 times in the putamen. The “harder” the cell must work, the sooner it may become “exhausted” and die.

EXCITATORY AND INHIBITORY CURRENTS

Dopamine has both an excitatory or stimulant effect and an inhibitory or dampening effect. Dopamine is transported from
the body of the nerve cell in the substantia nigra and is released from nerve endings onto nerve cells in the putamen.
The interaction takes place on a specialized part of the putamen nerve cell called the RECEPTOR. There are at least
five receptors for dopamine. The two that are important in PD are called the D (for dopamine)-1 receptor and the D-2
receptor. When dopamine is released on a D-1 receptor it generates an excitatory current in the nerve cell. When
dopamine is released on a D-2 receptor it generates an inhibitory or dampening current. It is through a combination of
excitatory and inhibitory (or dampening currents) that normal movement is achieved. In PD the loss of dopamine in the
substantia nigra results in a relative lack of movement or slowness of movement. This probably results from an excess
of inhibitory or dampening currents in the brain. But in PD in addition to the relative lack of movement there is often
an excess of movement, tremor. The probably results from an excess of excitatory currents in the brain. Here is the
paradox of PD: a person can, simultaneously be unable to move one part of his body, while another part is
trembling—moving too much. This implies that in some regions of the brain inhibitory or dampening currents predominate
while in other regions of the brain excitatory currents predominate. It is recognized that more than dopamine is
involved in generating these inhibitory and excitatory currents. Increasing attention is focused on the regulatory
roles of GLUTAMATE and GABA, with more attention, for a number of reasons, being focused on GLUTAMATE.

DYSKINESIA: DOPAMINE AND GLUTAMATE

In PD the main treatments are levodopa (combined with carbidopa) and the dopamine agonists. Their use compensates for
the loss of dopamine related to PD and restores, in part, a balance between inhibitory and excitatory currents.
However, the balance is uneven because while “normal” movement is restored initially, in time, after 2 or more years of
treatment, superimposed on normal movement are extra, unwanted, involuntary movements—dyskinesia. Dyskinesia occur in
50% or more of all PD patients treated with levodopa or a dopamine agonist. Dyskinesia can be disabling limiting normal
activity. Sometimes the dyskinesia are more disabling than the underlying PD. Dyskinesia are thought of as resulting
from a relative dopamine excess. Treatment consists of lowering the dose of levodopa or the dopamine agonists. However,
this results, usually, in slowness of movement or an inability to move that in most patients is as disabling or more
disabling than dyskinesia. The “trick” is to decrease or dampen dyskinesia without causing the patient to be unable to
move. It is known that amantadine (Symmetrel) can, in some patients, decrease or dampen dyskinesia without causing the
patient to be unable to move. It is thought that amantadine works by blocking, in part, the actions of GLUTAMATE.
GLUTAMATE is made in nerve cells in the cerebral cortex. Some regions of the cortex regulate movement, some regulate
thinking, some regulate behavior, some regulate memory, some regulate perception. GLUTAMATE may be involved in all of
these processes.

GLUTAMATE RECEPTORS: NMDA & AMPA

GLUTAMATE from nerve cells in the cortex that regulate movement is transported to the putamen where it is released onto
nerve cells in the putamen. The interaction takes place on a specialized part of the putamen nerve called the receptor.
There are two receptors for GLUTAMATE. One receptor is called the NMDA receptor the other receptor is called the AMPA
receptor. (NMDA and AMPA are acronyms for two complex chemicals). The AMPA receptor may be the more important of the
two receptors. Until recently there were only drugs that blocked the action of NMDA receptor, the less important
receptor. Amantadine (Symmetrel) which can partially decrease or dampen dyskinesia blocks the NMDA receptor. Memantine,
a cousin of amantadine, which can partially improve thinking, behavior, and memory, in Alzheimer disease, blocks the
NMDA receptor. TALAMPANEL is the first drug to be used in people that blocks the AMPA receptor.

DEEP BRAIN STIMULATION

At present for people with disabling dyskinesia the best treatment is deep brain stimulation (DBS). This is a surgical
procedure, with all the risks of a surgical procedure. In DBS an electrode is implanted into a region of the brain. The
electrode may be implanted into a region called the globus pallidus or a region called the subthalamic nucleus. The
reasons for implanting the electrode in one region over the other have not been defined. Most surgeons implant the
electrode into the subthalamic nucleus, some implant it into the globus pallidus. Nerve cells from the putamen, through
GLUTAMATE and GABA, regulate nerve cells in the subthalamic nucleus and the globus pallidus. It’s thought GLUTAMATE is
more important than GABA. DBS decreases or abolishes dyskinesia without slowing normal movement by restoring a balance
between excitatory and inhibitory currents between the putamen, the subthalamic nucleus and the globus pallidus. Such a
balance probably involves GLUTAMATE. It’s possible that TALAMPANEL a drug that by blocks GLUTAMATE at the AMPA receptor
may be as effective as DBS in decreasing or abolishing dyskinesia.

PARKINSON DEMENTIA, ALZHEIMER DISEASE

The dementia of PD results from a loss of dopamine and other nerve cells outside the substantia nigra. Approximately
30% of all PD patients develop a dementia. The dementia usually appears after age 70. The initial symptoms of the
dementia are agitation, delusions, and hallucinations while the patient is on levodopa or a dopamine agonists. These
symptoms markedly limit the use of levodopa and the agonists and are usually the reason patients go to nursing homes.
While the symptoms result from the drugs for PD the reason they occur is because the patient is developing a dementia.
There are reasons to believe that the actions of GLUTAMATE may be responsible, in part for the loss of these cells.
There are reasons to believe that blocking GLUTAMATE at the AMPA receptors may slow the progression of the dementia of
PD. Memantine an NMDA receptor blocking drug improves behavior, memory, and thinking in Alzheimer disease. It’s
possible that a drug such as TALAMPANEL which blocks the AMPA receptors may be more effective and may even slow the
progression of Alzheimer disease.

EPILEPSY & BRAIN TUMORS

GLUTAMATE is involved in triggering epileptic seizures. Drugs that block GLUTAMATE may be useful in treating epilepsy.
A study, under the sponsorship of the National Institutes of Neurological Disease and Stroke (Bethesda, Maryland), is
underway looking at TALAMPANEL as a drug to treat epileptic seizures. Initial results are promising GLUTAMATE excites
glial or support cells. These cells are also called astrocytes. The glial or support cells play a major role in
nourishing nerve cells. The glial or support cells import nutrients from the blood stream to the nerve cells and export
waste products from the nerve cells to the spinal fluid. The common form of primary brain tumor is called an
astrocytoma. A primary brain tumor is one that arises in the brain rather than a tumor that arises outside the brain
and then secondarily seeds or metastasizes to the brain. A malignant astrocytoma is called a glioblastoma. This tumor
kills 100% of patients within 2 years of diagnosis. It’s thought GLUTAMATE may play a role in stimulating the growth of
astrocytomas. A study, under the sponsorship of the National Cancer Institute (Bethesda, Maryland), is underway looking
at TALAMPANEL as a drug to treat astrocytomas.

TALAMPANEL , PARKINSON DISEASE, DYSKINESIA

Inappropriate or uncontrolled excitation or stimulation, with GLUTAMATE may be responsible, in part, for the
progression of PD, for the progression of the dementia of PD, and for the occurrence of agitation, delusions, and
hallucinations (collectively called psychosis) in PD. Inappropriate or uncontrolled stimulation with GLUTAMATE may be
responsible, in part, for the freezing phenomena that occurs in PD. Inappropriate or uncontrolled stimulation with
GLUTAMATE is probably responsible in large part for the dyskinesia of PD. Animal studies both in the United States and
Europe have shown that TALAMPANEL which blocks the actions of GLUTAMATE can decrease or abolish levodopa caused
dyskinesia. A pilot study of 30 PD patients conducted in 6 United States Parkinson centers and a smaller study
conducted in Europe indicates that TALAMPANEL may have a major role in decreasing or abolishing levodopa caused
dyskinesia.

The Parkinson Center of the Department of Neurology of the University of Miami is now conducing a study on TALAMPANEL
as a treatment for dyskinesia.

To qualify for the study you must: 1. Have had PD for at least 5 years. 2. Have dyskinesia that are sufficiently
disabling that you have considered DBS.

If you are interested contact Dr. Lieberman [log in to unmask]

SOURCE: The National Parkinson Foundation, Fl
http://www.parkinson.org/talampanel_pd.htm

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Effect of Talampanel (an AMPA Receptor Blocker) on Dyskenesia
To assess the effects of talampanel on patients with advanced Parkinson's disease who have been on sinimet for more
than 5 years and have dyskinesia (abnormal involuntary movements)
This study is currently recruiting patients.
http://clinicaltrials.gov/show/NCT00036296
http://www.clinicaltrials.gov/ct/gui/show/NCT00036296?order=7
http://www.wehealnewyork.org/studies/ivax.html
http://www.clinicaltrials.gov/ct/gui/show/NCT00036296?order=4

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Background on Talampanel...

1999  Eli Lilly & Co. discontinued development on a drug called Talampanel, which did not show any benefit over a
placebo (ALS)
http://www.lougehrigsdisease.net/als_news/991222area_firm_dropping_once.htm

Outlook for Neurodegenerative Disease Therapy Markets (2000)
http://www.mindbranch.com/catalog/print_product_page.jsp?code=R55-067

talampanel
An AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor antagonist being investigated in phase III
trials as a treatment for epilepsy. Partners in development and marketing: IVAX Corporation and Eli Lilly. Source:
Business Wire - 02/07/01.

8 Feb 2001
IVAX Corporation has entered into an exclusive agreement with Eli Lilly and Company to develop and market the AMPA
receptor antagonist, talampanel, worldwide.
http://atlas.pharmalicensing.com/news/adisp/981586676_3a81d2f4bdb1a

IVAX is developing new drugs to treat diseases of the brain and spinal cord.
Talampanel, an AMPA antagonist, is currently in expanded multi-center Phase II trials for epilepsy in more than 260
patients. Talampanel is also in Phase II trials to treat the dyskinesia associated with Parkinson's disease. Clinical
trials of Talampanel for multiple sclerosis are also planned.
http://www.ivax.com/jsps/research/cns.jsp

IVAX Initiates Phase II Clinical Trial of Talampanel for Brain Cancer
http://biz.yahoo.com/bw/030710/105471_1.html

Talampanel, a New Antiepileptic Drug:
Single and Multiple-dose Pharmacokinetics and Initial 1-Week Experience in Patients with Chronic Intractable Epilepsy.
http://tinyurl.com/lbqf

Effect of Talampanel (an AMPA Receptor Blocker) on Brain Activity
This study is currently recruiting patients.
http://www.clinicaltrials.gov/ct/gui/show/NCT00057460?order=33

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