FDA Consumer magazine (July-August 1998)

Parkinson's Disease: New Treatments Slow Onslaught of Symptoms

Joe Dulaney calls himself the Backward Man.

Although the tag is lighthearted, the awkward and dangerous dilemma he often
faces as his lower limbs simply lock in mid-stride is not. At these moments,
his body halts abruptly like a movie freeze-frame, and the only way he can
walk is to step backward.

"I've gotten to where I can move pretty fast in reverse," says Illinois
resident Dulaney, 65, whose finessed footwork helps him cope with one of many
symptoms of Parkinson's disease.

Nationwide, as many as 1.5 million people suffer from Parkinson's, according
to the Parkinson's Disease Foundation.

A chronic and progressive disorder, Parkinson's strikes slightly more men than
women and more whites than blacks in the United States.

Though the disease is found most often in patients over 50, as many as 10
percent of patients--afflicted with the so-called "young-onset"
Parkinson's--are under 40. About 50,000 Americans are diagnosed with
Parkinson's yearly, according to the National Institute of Neurological
Disorders and Stroke, which estimates that the total cost of health care for
Parkinson's patients will exceed $5.6 billion this year.

The Food and Drug Administration has approved nearly a dozen drugs for
treating Parkinson's, three of which have been put on the market just in the
past year. Also approved in 1997 was a device that is surgically implanted in
the brain to lessen the violent shaking experienced by some Parkinson's
patients.

The 1996 discovery of a gene believed responsible for a form of Parkinson's
may result in future innovative treatments. Despite the range of therapies
available to ease the disease's debilitating symptoms, however, treatments now
on the market can neither replace the faulty nerve cells that cause the
disease nor stop Parkinson's from progressing.

Numerous public figures have acknowledged their battle with Parkinson's.
Attorney General Janet Reno, evangelist Billy Graham, former boxer Muhammad
Ali, and former Alabama governor George Wallace all are fighting the disease.
Chinese leader Deng Xiaoping was in the late stages of Parkinson's when he
died last year at age 92.

Parkinson's also gained attention last year with passage of the Morris K.
Udall Parkinson's Research Act, which authorized $100 million for Parkinson's
research. At press time, the funds had not yet been appropriated. Udall, who
has Parkinson's, served in the House of Representatives for 30 years.

What Is It?

Parkinson's disease is one of a larger group of neurological conditions called
motor system disorders. Historians have found evidence of the disease as far
back as 5000 B.C. It was first described as "the shaking palsy" in 1817 by
British doctor James Parkinson. Because of Parkinson's early work in
identifying symptoms, the disease came to bear his name.

In the normal brain, some nerve cells produce the chemical dopamine, which
transmits signals within the brain to produce smooth movement of muscles. In
Parkinson's patients, 80 percent or more of these dopamine-producing cells are
damaged, dead, or otherwise degenerated. This causes the nerve cells to fire
wildly, leaving patients unable to control their movements.

Symptoms usually show up in one or more of four ways:
1] tremor, or trembling in hands, arms, legs, jaw, and face
2] rigidity, or stiffness of limbs and trunk
3] bradykinesia, or slowness of movement
4] postural instability or impaired balance and coordination.

This diagram of the brain shows several structures related to Parkinson's
disease. Basal ganglia affect normal movement and walking; substantia nigra
are types of basal ganglia that produce the neurotransmitter dopamine, which
sends messages that control muscles.

The globus pallidus is part of a larger structure connected to the substantia
nigra affecting movement, balance and walking. The thalamus serves as a relay
station for brain impulses, and the cerebellum affects muscle coordination.

Though full-blown Parkinson's can be crippling or disabling, experts say early
symptoms of the disease may be so subtle and gradual that patients sometimes
ignore them or attribute them to the effects of aging.

At first, patients may feel overly tired, "down in the dumps," or a little
shaky. Their speech may become soft and they may become irritable for no
reason. Movements may be stiff, unsteady, or unusually slow.

Joe Dulaney says he was in "perfect health" nine years ago when his wife
noticed that he had stopped swinging his right arm when he walked. Soon,
simple tasks such as brushing his teeth and combing his hair became major
ordeals. His right hand was always ice cold and he produced small, jerky
letters when he wrote.

Dulaney's doctor diagnosed the problem as arthritis and prescribed drugs to
treat it. But symptoms worsened. Dulaney's voice dwindled to a slight whisper.
Leg cramps, dry mouth, severe constipation, itchy eyes, and trouble turning
over in bed tormented him.

"My wrists were rigid and my fingers were not flexible, so I couldn't even
button my shirt," he says.

Still another doctor seconded the arthritis diagnosis and prescribed different
drugs. Finally fed up because his deteriorating condition prevented him from
doing simple tasks such as turning newspaper pages, putting money in his
wallet, and replacing a light bulb, Dulaney checked himself into a local
hospital, arriving in such a weakened state he couldn't walk.

Though a Parkinson's diagnosis rarely comes quickly, the three doctors who
examined Dulaney at the hospital agreed within minutes that his classic
symptoms indicated Parkinson's. The doctors gave him the Parkinson's drug
levodopa, marketed as Larodopa and in generic forms, and the effect was nearly
immediate.

"In one hour or so I was walking the halls. I took a shower by myself and did
one push-up to show off," says Dulaney. It was, for the moment, as if the
disease had somehow vanished. But Dulaney says he soon became "fully aware"
that because Parkinson's is progressive, he could manage some symptoms with
drugs, but the disease wasn't about to go away.

Treating the Disease

The drug Dulaney took at the hospital, levodopa, is what doctors call the
"gold standard" of Parkinson's therapy, because it is often the first-line
treatment for the disease. Approved in 1970, levodopa helps restore muscle
control when it is converted to dopamine in the brain.

Why not give a patient dopamine directly?

The reason is that dopamine cannot get through the body's blood-brain barrier,
which screens out certain substances. But, although levodopa can pass through
the barrier, it changes to dopamine so quickly only a small amount actually
makes it into the brain. So to relieve symptoms, many patients need to take
fairly large doses, which can cause side effects such as nausea and
dyskinesias (involuntary movements).

To reduce these drawbacks, doctors often prescribe levodopa mixed with
carbidopa, a drug that is marketed as Sinemet or in generic versions. About 80
percent of Parkinson's patients take this drug, according to drug industry
estimates. Carbidopa delays the conversion of levodopa to dopamine until it
reaches the brain, often lessening or even preventing levodopa side effects.
Carbidopa also decreases the amount of levodopa needed. Because each
Parkinson's patient reacts differently to treatment, doctors and patients must
work closely to find a tolerable balance between the drug's benefits and side
effects.

Though the levodopa-carbidopa combination can be so effective that some
patients forget for a while that they have Parkinson's, the drug is far from
perfect. Side effects aside, doses typically must be increased over time, and
the disease often manifests an "on-off" syndrome in advanced patients in which
the drug simply doesn't work for unpredictable durations. Fortunately,
alternatives are available.

Parkinson's experts are enthusiastic about the three new drugs FDA approved in
1997: Mirapex (pramipexole dihydrochloride), Requip (ropinirole
hydrochloride), and Tasmar (tolcapone).

Enrico Fazzini, M.D., who runs a neurology clinic in New York City, says the
three new drugs are "really helping me to treat my Parkinson's patients more
effectively."

Mirapex and Requip, which mimic dopamine's role in the brain, allow patients
to regain some of their lost muscle control. Both are approved for use alone
or with levodopa drugs. In clinical trials, patients taking Mirapex alone saw
as much as a 30 percent improvement in symptoms. Combining Mirapex with
levodopa drugs allowed advanced patients to reduce those doses by up to 25
percent. Requip trials showed similar benefits, allowing patients to reduce
levodopa doses by an average of 31 percent.

Tasmar is a new kind of drug called a COMT inhibitor. It also is indicated for
use with levodopa drugs. Researchers believe that Tasmar blocks a key enzyme
responsible for breaking down levodopa before it reaches the brain. In trials,
patients with a stable response to levodopa drugs who took Tasmar experienced
significant improvements in daily activities such as talking, writing,
walking, and dressing.

"Although we are still looking for a cure, COMT inhibitors represent an
entirely new class of therapy that will help many Parkinson's patients attain
better symptom control," says Emilio Alonso-Mendoza, executive director of the
National Parkinson Foundation.

Parkinson's drug therapy also can include:

Parlodel (bromocriptine) and Permax (pergolide), which mimic dopamine's role
in the brain. They are sometimes given with levodopa drugs to improve
response.

Eldepryl (selegiline hydrochloride), also called deprenyl and available in
generic versions, which can enhance and prolong levodopa response by delaying
the breakdown of naturally occurring and levodopa-formed dopamine, allowing
accumulation in surviving nerve cells.

A Brain "Pacemaker"

FDA approved an important tool for controlling Parkinson's tremors last
August. The Activa Tremor Control Therapy consists of a wire surgically
implanted deep within the brain and connected to a pulse generator, similar to
a cardiac pacemaker, implanted near the collarbone. Whenever a tremor begins,
patients can activate the device by passing a hand-held magnet over the
generator.

The system delivers a mild electrical stimulation that blocks the
dysfunctional brain signals that cause tremor. Effects are often dramatic.

"Before the implant, patients can't raise a glass of water or a spoonful of
food to their mouths without spilling it or striking themselves in the face,"
says William Koller, M.D., neurology chairman at Kansas University Medical
Center.

"Within hours, these same patients are sipping tea from a cup and eating peas
with a fork, with no signs of their disability."

Surgery Options

A brain operation shown to be helpful for many Parkinson's patients,
especially those in late stages of the disease, is called pallidotomy. Doctors
are not sure why the procedure works, but an October 1997 report in the New
England Journal of Medicine stated that half of the patients in a pallidotomy
study at Toronto Hospital, who before the surgery needed help in eating,
dressing, and personal hygiene, were able to resume these activities
independently. The study cautioned, however, that some of the surgery's
effects diminished after two years and that the long-term effectiveness of the
procedure still is unknown.

In pallidotomy, a surgeon makes a tiny hole in the skull and uses a tiny
electric probe to destroy a small portion of the globus pallidus, which
experts believe is overactive in Parkinson's patients.

Before operating, the surgeon has "mapped" the patient's brain with imaging
techniques such as magnetic resonance and knows precisely where the probe
should go. The patient is kept awake, but under sedation, so the surgeon can
note responses to stimuli. Though both sides of the brain have a globus
pallidus, pallidotomies typically are performed on one side at a time. After
the patient has recuperated, a second procedure is done if needed.

For Tom Riess, who has undergone the procedure four times over the last six
years, the surgery helped reduce his Parkinson's symptoms, especially the
violent shaking, "which was literally killing me," he says.

"Unfortunately, it left me with severely impaired speech, which is a fairly
common consequence," says the 51-year-old Californian, a Parkinson's patient
for 17 years. "Still, the tradeoff is worthwhile."

Thalamotomy, a surgical procedure that destroys a specific group of cells in
the thalamus, the brain's communications center, is aimed at the 5 to 10
percent of Parkinson's patients with disabling tremor in the hand or arm. It
reduces or eliminates tremor in as many as 90 percent of patients.

On the Horizon

A number of potential Parkinson's treatments in research laboratories now show
much promise.

They include:

Neurotrophic proteins--These appear to protect nerve cells from the premature
death that prompts Parkinson's. One hurdle is getting the proteins past the
blood-brain barrier.

Neuroprotective agents--Researchers are examining naturally occurring enzymes
that appear to deactivate "free radicals," chemicals some scientists think may
be linked to the damage done to nerve cells in Parkinson's and other
neurological disorders.

Neural tissue transplants--Researchers are studying ways to implant neural
tissues from fetal pigs into the brain to restore the degenerate area. In a
clinical trial conducted in part at Boston University School of Medicine,
three patients out of 12 implanted with the pig tissues showed significant
reduction in symptoms.

Genetic engineering--Scientists are modifying the genetic code of individual
cells to create dopamine-producing cells from other cells, such as those from
the skin.

Experts say some of these new treatments are still far off. Others say they
are hopeful that with bolstered research efforts, such as those earmarked in
last year's Udall Act, innovative new therapies will be available in the near
future.

"I'm optimistic," says Perry Cohen, 52, a Washington, D.C., Parkinson's
activist and patient for two years. "I think we are on the verge of an
important development. I'm confident that I won't have to go through the agony
I've seen others go through."


A Social Net

For Parkinson's disease patients, both updated information and social
interactions are key factors in battling the disease. Though patients seek
these through traditional means such as their doctors, families and friends,
many are turning to the Internet.

Patients can compare notes on Parkinson's issues and stay in touch with others
with the disease by subscribing to an Internet Parkinson's mailing list. Some
of these lists deal with Parkinson's as one of a number of neurological
disorders. Others focus on caregiving. One list that is an open forum just for
Parkinson's patients is called "PARKINSN."

Maintained at the University of Toronto, PARKINSN gives patients a place to
pose questions or just let off some steam. A recent scan of the list revealed
messages about exercises that can relieve some Parkinson's discomfort, surgery
success stories, reviews of books about the disease, poems, even some
Parkinson's jokes. One list member announced that he is marrying his doctor,
and he invited everyone on the list to his wedding.

To join PARKINSN, send an e-mail message to [log in to unmask] In
the body of the note, write: subscribe PARKINSN (your first name) (your last
name).


For More Information

Contact any of the following organizations to learn more about Parkinson's
disease and support groups:

American Parkinson's Disease Association (APDA)
1250 Hylan Blvd.
Staten Island, NY 10305
1-800-223-APDA (2732)
www.apdaparkinson.com

National Institute of Neurological Disorders and Stroke (NINDS)
P.O. Box 5801
Bethesda, MD 20824
1-800-352-9424
www.ninds.nih.gov

National Parkinson Foundation Inc. (NPF)
1501 N.W. 9th Ave. (Bob Hope Road)
Miami, FL 33136-1494
1-800-327-4545
in Florida: 1-800-433-7022
www.parkinson.org

Parkinson's Disease Foundation, Inc. (PDF)
650 W. 168th St.
New York, NY 10032
1-800-457-6676

Parkinson's Institute
1170 Morse Ave.
Sunnyvale, CA 94089-1605
(408) 734-2800

Parkinson's Support Groups of America
11376 Cherry Hill Road, No. 204
Beltsville, MD 20705
301-937-1545

United Parkinson Foundation (UPF)
833 W. Washington Blvd.
Chicago, IL 60607
(312) 733-1893
e-mail: [log in to unmask]

FDA Consumer magazine (July-August 1998)
by John Henkel
John Henkel is a staff writer for FDA Consumer.

U. S. Food and Drug Administration
http://www.fda.gov/fdac/features/1998/498_pd.html

janet paterson - 51 now / 41 dx / 37 onset - almonte/ontario/canada
http://www.newcountry.nu/pd/members/janet/
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