Claudine Brownfelt uncharacteristically tired. Shealso felt depressed and lethargic – like she was moving in slow motion. “I figured I was getting older. Still, friends my age didn't feel this way,” she says.
Brown, then 67, was experiencing the early effects of Parkinson's disease. Within four years, she was bent over and could not walk without dragging her left foot.
All this changed last year, when the homemaker from Kansas City, Mo., was first diagnosed with Parkinson's disease (PD), and in December started taking her first prescription – a new formulation of a standard PD drug that combined carbidopa-levodopa (Parcopa). After taking the pills for three days, her symptoms completely cleared up, so much so that her doctors were amazed.
Parkinson's disease is a movement disorder that results from a loss of dopamine, a chemical in the brain that helps control movement. Many PD drugs are made from levodopa, a compound that replaces dopamine. Although levodopa-based drugs are usually effective at first, they can become less effective with time and people who take them often develop jerky movements called dyskinesias.
The new formulation is one of several new therapies that are emerging from years of research, says Stewart Factor, D.O., a professor of neurology and director of the Movement Disorders Program at Emory School of Medicine in Atlanta, Ga.
Taking a medication that combines levodopa with carbidopa is a standard treatment for PD. Nerve cells use levodopa to make dopamine and replenish the brain's dwindling supply in people with PD. Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain, which reduces side effects. Unlike an earlier version of the carbidopa-levodopa drug (Sinemet), the new drug dissolves in the mouth and does not require water. The new drug is particularly beneficial for people with PD who may have swallowing problems, Dr. Factor notes.
New Drugs Offer Options
One of the new drugs in development is apomorphine (Apokyn). Sold in the United States since 2004, it's chemically similar to morphine, but it's not addictive. This is the first injectible PD drug. It is intended for use along with the levodopa medications, during periods when these drugs wear off, and the person is left “frozen,” or immobilized, the so-called “off-times.”
Apomorphine takes effect within 10 minutes, and lasts about an hour, enough time for the next dose of the lev-odopa-based drug to take effect. This drug is for people with an advanced stage of PD, who often experience the off-time problem. It's been available in Europe and Canada for 12 years.
Pending FDA Approval
Several promising therapies are under review by the US Food and Drug Administration (FDA). Rotigotine (Neupro), for example, is a patch worn on the skin that delivers a continuous supply of a dopamine agonist, a chemical mat stimulates production of dopamine by brain cells. It is used for people in all stages of PD. Trials of the drug have been completed, and Schwarz Pharma, the manufacturer, has applied for FDA approval.
“If a patient receives more constant levels of the medication through the patch, this could potentially further delay dyskinesias and off-times. New patients could be started on it, or it could be used in combination with levodopa in more advanced patients,” Dr. Factor says.
Rasagaline (Agilect) is also pending approval. This medication, a monoamine oxidase-B inhibitor, prevents dopamine from breaking down in the brain, enabling it to remain there longer. In people with advanced Parkinson's disease, it has reduced off-time by an hour each day.
Protecting Brain Cells
Researchers believe that there is more than one neurotransmitter involved in PD. They are studying medications that do not rely on dopamine, but which act in other ways to protect the brain's critical nerve cells, says Stanley Fahn, M.D., director of the Center for Parkinson's Disease and Other Movement Disorders at the Neurological Institute of New York at Columbia University He notes that trials are underway to investigate these compounds - coenzyme Q10, GPI 1485 and istradefylline. Study results are expected later this summer.
Coenzyme Q10 is found in every cell of the body. Cells use it to produce energy for cell growth and maintenance. It also functions as an antioxidant, which protects the body from damage caused by harmful molecules produced by the metabolic process. Studies are underway to test for side effects and early indications of any benefit, Dr. Fahn says.
Istradefylline acts on adenosine, which is another neurotransmitter. According to University of Washington researchers, when adenosine is blocked from binding with specialized adenosine receptors, dopamine levels increase.
One hypothesis is that caffeine, which is chemically related to adenosine, may also block those receptors. This would help to explain why the incidence of PD was lower in those who drank more coffee in a study of 8,000 Japanese-American men studied over a 30-year period. But, so far this theory remains to be confirmed.
In several studies, istradefyline reduced off-times in patients with advanced PD. But researchers also want to study it in patients in an early stage of the disease to determine if it may be protective. “This would be interesting because some studies have shown that caffeine may be preventative,” Dr. Factor says.
Alternative Approaches to Dopamine Replacement
Researchers have also sought alternatives to dopamine replacement and other PD drugs to manage its symptoms. (See “Deep Brain Stimulation: New Safety Data is In.”) They also have been exploring the use of fetal cell implants, stem cells and retinal cells to replace the dopamine that the brain needs, to cure – or at least better manage – this disease.
One trial, now in an early stage, is testing the potential benefits of implanting cells from the external layer of the retina of the human eye into the brain. The cells are contained in a product called Spheramine. It is hoped that these implanted cells, which secrete dopamine, will take hold permanently, enhancing levels of dopamine in the brain.
The STEPS trial (Spheramine in advanced Parkinson's disease) will test the procedure on 68 people who are in an advanced stage of the disease. The cells are implanted surgically. One group will receive the implants and another will undergo a sham surgical procedure to make sure that there is no “placebo” effect (in which patients believe they are improving because they underwent the procedure). If the treatment proves safe and beneficial, the group, which received the placebo, will be offered the experimental drug. Participants are still being enrolled in this trial; call (866) 783-7703 or click on http://clinicaltrials.gov/show/NCT00059007 for more information.
Stem Cell Implants
Stem cells, which are taken from embryos that are a few days old, are immature cells that can mature into any type of cell the body needs. Once implanted in the brain, researchers hope they will mature into dopamine-producing cells, and replenish the needed neurotransmitter, thereby treating, or even curing, PD.
In the past, researchers used fetal tissue transplants to replace dopamine cells, but the results were mixed and a serious side effect surfaced. Although patients under 60 years old benefited, they eventually developed dyskinesias, probably because the implanted cells were producing too much dopamine. Subsequently, all fetal tissue trials on PD patients were stopped. Researchers contend that stem cells may produce better results, because they are purer than fetal tissue and the cells will not produce too much dopamine.
Experts are cautiously optimistic about the direction of this research. “Although nothing is proven yet,” says Dr. Fahn, “there's lots of research aimed at finding a way to slow the progression of the disease down.” And that, he says, is reason to be hopeful. NN
What is Parkinson's disease?
Parkinson's disease (PD) is a movement disorder that affects how messages travel from the brain to the body. Early symptoms are subtle and occur gradually. As the disease progresses, people may experience tremors, lack of balance and coordination, difficulty walking and emotional changes, such as depression, poor memory and sleep problems. The cause of Parkinson's disease remains unknown, although genetic and environmental influences have been implicated.
Clinical Trial Watch
The National Institutes of Health (NIH) lists 80 trials involving Parkinson's disease, about 40 of which are looking for volunteers. For information, click on http://www.clinicaltrials.gov.
For information on The Steps Trial, call (866) 783-7703 or click on http://clinicaltrials.gov/show/NCT00059007
The National Institute of Neurological Disorders and Stroke, an NIH agency, is looking for volunteers for Neuroprotection Exploratory Trials in Parkinson's Disease: Net-PD. Call (800) 352-9424, or visit http://www.parkinsontrial.org.
For More Information in Patient Pages:
An article entitled “Vitamins and the Risk for Parkinson's Disease,” can be found in the American Academy of Neurology's journal, Neurology, at www.neurology.org. Click on “Patients Pages” and scroll down to October 2002.
For More information on Parkinson's disease:
American Academy of Neurology Foundation The Brain Matters
National Institute of Neurological Disorders and Stroke (800) 352-9424 TTY: (301) 468-5981 http://www.ninds.nih.gov
American Parkinson Disease Association
(800) 223-2732, in California: (800) 908-2732 http://www.apdaparkinson.org
Michael J. Fox Foundation for Parkinson's Research
(800) 708-7644 http://www.michaeljfox.org
Muhammad Ali Parkinson Research Center
(602) 406-4931 http://www.maprc.com
National Parkinson Foundation
(305) 243-6666 or (800) 327-4545 http://www.parkinson.org
Parkinson's Disease Foundation
(212) 923-4700 or (800) 457-6676 http://www.pdf.org
(800) 579-8440 http://www.parkinsonalliance.org