Drugs Helping People with Parkinson's Disease
by Evelyn Zamula

Walter is approaching 80, but his smooth, unlined face looks years younger.    
When he sits quietly in his chair, no one can tell he has Parkinson's          
disease. He has never had tremor, the trembling of the hand or foot that       
plagues the majority of people with this chronic neurological ailment.

But watch him try to get out of the chair. He grips the wooden arms, moves to  
the edge of the seat, and rocks back and forth a number of times to gain       
momentum. Using all his strength, he pushes down on his hands to propel        
himself upright. For a long time he stands as if rooted to the spot. Then he   
hurries forward, shoulders bent, walking in short, shuffling steps, looking    
every one of his 80 years.

For the most part, Walter (who asked that his last name not be used) has       
coped remarkably well with his illness, which began when he was 65. Until a    
few months ago, he drove his car around the rural area where he lives, doing   
his little errands. But lately he appears to be going downhill rapidly         
despite carefully regulated medication. Doing fine tasks with his hands, such  
as buttoning his shirt and handling eating utensils, has become more and more  
difficult, which depresses him. Slight drooling has also become a problem.     
But what bothers him most is that he has begun to hallucinate, a side effect   
of one of the drugs he is taking. He stands at the window and peers into the   
woods, seeing strange creatures that are not there, but appear only too real   
to him. His daughter reports that this retired policeman, once strong and      
confident, becomes anxious when left alone. Since it's not possible for her    
to be with him all the time, she is thinking, finally, of a nursing home.

Unlike Walter, Virginia "Jinny" Krohnfeldt's first symptom was a tremor that   
affected her writing hand. Her symptoms showed up much earlier, too, when she  
was in her mid-40s, 13 years ago. Presently a realtor in the Washington,       
D.C., area, Krohnfeldt had to resign her high level government job because it  
became difficult for her to sign checks, an essential part of her duties.      
Like Walter, Krohnfeldt also stoops and shuffles, symptoms that make her       
appear to many people as if she is a drug abuser. Once reluctant to tell       
people she had Parkinson's disease, Krohnfeldt is now outspoken about her      
condition: "Better to say you have Parkinson's than have people think you're   
on drugs."

Diagnosing the Disease

The chief or major signs of Parkinson's disease are slowness of movement       
(bradykinesia), tremor, and muscle stiffness or rigidity.

In addition to these, Parkinson patients may have minor signs, including a     
mask-like face (which accounts for Walter's deceptively youthful look),        
drooling, stooped posture, "freezing" (feet unable to move), difficulty        
swallowing, mumbly speech, sleep disturbances, a tendency to fall forward      
(propulsion) or backward (retropulsion), infrequent blinking, and bowel and    
bladder problems. Diagnosis is based on the presence of two major signs, or    
one major sign and at least two minor signs. Often, the disease progresses so  
slowly that it may take years before a doctor can make a firm diagnosis.

To rule out other brain disorders, doctors may also order tests, such as a     
computerized axial tomography ("CAT") scan, which produces images of "slices"  
of the brain, or an electroencephalogram (EEG), which measures electrical      
activity in the brain. These tests are usually normal in patients with         
Parkinson's disease.

Dopamine Key

Parkinson's disease results from a depletion of the chemical dopamine in the   
brain. Dopamine is produced and stored in a small, pigmented group of nerve    
cells in the upper brainstem called the substantia nigra. Long, thin fibers    
connect these pigmented cells to nerve cells in the corpus striatum, a part    
of the brain that controls movement, balance, walking, and posture. Dopamine   
aids the transmission of messages between the pigmented nerve cells and the    
striatal nerve cells.

If, for any reason, the substantia nigra's nerve cells are injured or          
destroyed, the corpus striatum does not receive enough dopamine to correctly   
program movement, and parkinsonian symptoms develop. Symptoms may not show up  
until more than 50 percent of the dark nerve cells are destroyed and the       
striatal dopamine content is reduced by 80 percent or more, a process that     
can take many years. During the course of the disease, the substantia nigra    
continues to degenerate.

Treatment with Levodopa

In 1817, the British physician James Parkinson described as the "shaking       
palsy" the disease that now bears his name. He had little at his disposal to   
relieve the disease's disturbing symptoms. Medical men of his time were great  
believers in keeping the bowels open and bloodletting; Dr. Parkinson approved  
of the former for palsy patients, but not the latter.

Until levodopa (or L-DOPA) was introduced in the 1960s, doctors relied mostly  
on botanical preparations, such as tincture of belladonna, to treat the        
disease. Then Arvid Carlsson, a Swedish professor, found in 1957 that the      
effects of reserpine, a drug that caused parkinsonism in laboratory animals,   
could be reversed by injections of levodopa. He proved that dopamine levels    
in the brain were reduced by reserpine and restored to normal by levodopa,     
and suggested that levodopa be tried in treating Parkinson's disease.

Doctors prescribed the drug timidly at first--either given by mouth or         
injected into a vein--fearing serious adverse reactions. The results were      
disappointing. But George Cotzias, M.D., of the Brookhaven National            
Laboratories, Upton, N.Y., daringly prescribed doses a thousand times greater  
than had ever been used. His patients improved dramatically. When Leonard L.,  
a postencephalitic Parkinson patient (and hero of the movie "Awakenings,"      
based on the book by Oliver Sacks, M.D.), heard about the drug, he spelled     
out on his letterboard, "Dopamine is Resurrectamine. Cotzias is the Chemical   
Messiah."

FDA approved levodopa in 1970. But there were problems. Curiously, levodopa    
can cross the blood-brain barrier--where it is converted in the brain to       
dopamine--but dopamine itself cannot. When taken orally, an enzyme in the      
blood and tissues converts levodopa to dopamine so rapidly that only a small   
part of a levodopa dose enters the brain unchanged. Consequently, large        
amounts of levodopa are needed to relieve neurological symptoms and replace    
the lost dopamine, causing unbearable nausea and other side effects.

Researchers found that when carbidopa was added to levodopa, it blocked the    
enzyme responsible for the breakdown of levodopa in the body, and allowed      
more levodopa to get to the brain. Carbidopa makes it possible to use about    
75 percent less levodopa, thereby reducing nausea and vomiting. This           
combination of levodopa and carbidopa is marketed as Sinemet.

Another problem with levodopa medications is that some patients develop        
complications with long-term use. This has made some doctors reluctant to      
prescribe them until symptoms interfere with the quality of life. (Recent      
studies have shown that it may make no difference to the eventual outcome      
when levodopa drugs are started, because no anti-parkinsonian agent can slow   
the natural progression of the underlying disease.) After about four or five   
years, sometimes sooner, the patient begins to respond less satisfactorily to  
levodopa. Dyskinesias, or involuntary movements (such as lip smacking or       
tongue thrusting), may develop. Reducing the dose helps reduce the             
dyskinesias, but results in a worsening of Parkinson symptoms.

Some Parkinson disease patients may have "on-off" effects, which means that    
their movements fluctuate from normal to abnormal in a random fashion, or as   
a "wearing off," when symptoms return as the blood level of levodopa           
decreases. The controlled-release form of Sinemet, Sinemet CR, which was       
approved for use by FDA in 1991, was formulated to help keep blood levels of   
levodopa more constant throughout the day, possibly preventing these           
fluctuations.

Modernizing Old Therapies

Anticholinergic drugs have been used to treat Parkinson's disease for almost   
a century. (Those old botanical preparations had anticholinergic properties.)  
Used along with levodopa, modern anticholinergic drugs are useful in reducing  
tremor. As decreased amounts of dopamine are produced in the brain, an         
imbalance with the neurotransmitter acetylcholine occurs, making symptoms      
worse. Anticholinergics work by partially blocking the action of               
acetylcholine. Examples of anticholinergic medications used to treat           
Parkinson's disease are Artane (trihexyphenidyl), Akineton (biperiden),        
Kemadrin (procyclidine), Pagitane (cycrimine), and Cogentin (benztropine).

Although used primarily in treating asthma and allergies, antihistamines are   
also effective against tremor because of their anticholinergic properties.     
Most frequently used antihistamines for this purpose are Benadryl              
(diphenhydramine) and Phenoxene (chlorphenoxamine).

Like antihistamines, Symmetrel (amantadine), an antiviral drug, was            
serendipitously discovered to benefit patients with Parkinson's disease.       
Prescribed for a woman to prevent flu, Symmetrel relieved some of her          
Parkinson symptoms and made her generally feel better. It is helpful both in   
the early and late stages. In addition to its anticholinergic properties,      
Symmetrel promotes the release of dopamine in the brain.

Other drugs, called dopamine agonists (activators), bypass the degenerating    
nerve cells in the substantia nigra and directly stimulate the striatal        
dopamine receptors. Though dopamine receptors are selective about which        
chemical messengers they'll receive, they can respond to synthetic compounds   
that aren't dopamine, but act like dopamine in the brain. Dopamine agonists    
can be used alone, but are more effective when used with Sinemet. They are     
usually added to the treatment when the patient is encountering too many side  
effects, such as dyskinesias, with Sinemet. Dopamine agonists available in     
the United States are Parlodel (bromocriptine) and Permax (pergolide). They    
don't necessarily have the same effects in all patients, so if one drug loses  
its efficacy or causes too many side effects, the physician may prescribe the  
other drug.

MAO-B inhibitors block the MAO-B enzyme in the brain that helps break down     
and metabolize dopamine. When the enzyme's action is slowed down, more         
dopamine may be available to relieve symptoms and improve motor performance,   
allowing Parkinson patients to move about more freely. Eldepryl (deprenyl) is  
the only MAO-B inhibitor to be approved for use in treating Parkinson's        
disease in this country. It is useful for patients with advanced disease who   
are having problems with Sinemet. In a large clinical trial in 1989, Eldepryl  
showed a possible neuroprotective effect by prolonging the time before the     
patient needed levodopa treatment.

Many Parkinson's disease patients suffer from profound depression, as well as  
insomnia. Doctors may prescribe tricyclic antidepressants (such as Elavil,     
Endep and Tofranil) that have both anticholinergic and sedative properties.    
Medications that relieve symptoms of depression, such as Prozac and Desyrel,   
are also used.

Many doctors say that levodopa preparations will probably continue to be the   
most useful drugs in treating Parkinson's disease for a long time.             
Researchers are studying newer drugs that will enhance levodopa's              
effectiveness by slowing down the rate at which the body breaks it down. They  
have also found that medications approved for other uses (such as Clozaril)    
can reduce side effects. Other substances (such as Eldepryl and vitamins C     
and E) are under study to see if they can reduce the rate of disease           
progression.

It's unlikely that results will be available soon enough to benefit Walter,    
who now lives in a nursing home in the small Midwestern town where he grew up  
and served on the police force. In general, he is doing fairly well, but no    
sooner is his medication adjusted to get rid of one troublesome side effect    
than a different one appears in its place. The usual infirmities of old age    
have added to his problems.

Krohnfeldt's symptoms are under control, except that her hand still trembles   
and she is suffering from dyskinesia--her right foot sometimes moves           
spastically back and forth and she is unable to stop it. But Krohnfeldt        
retains her good spirits. "I've always said it's my cross to bear. If I can    
stick with it, I'll hang in there. It's better than a lot of other diseases I  
wouldn't care to have. I started an exercise program about six weeks ago and   
it's doing me a world of good. I play golf occasionally and work out for two   
hours a day three times a week, and I feel just great. I get a lot of support  
from my family. My kids are behind me and that helps." n

Evelyn Zamula is a freelance writer who lives in Potomac, Md.
Trying to Find the Cause

Parkinson's disease affects slightly more men than women and more whites than  
blacks in the United States. About three-quarters of all patients develop the  
disease between 50 and 65, though one person in seven develops it earlier, in  
the 30s or 40s. An estimated 1.5 million Americans have the disorder,          
according to the Parkinson's Disease Foundation.

The question of whether the disease has a genetic factor has been debated for  
years. Studies of both identical and fraternal twins, in which one twin had    
Parkinson's disease, showed that the unaffected twin had about the same        
frequency of the disorder as found in the general population.

"There is no definitive data to support whether Parkinson's is or is not       
hereditary," says Thomas Chase, M.D., chief, experimental therapeutics         
branch, National Institute of Neurological Disorders and Stroke, Bethesda,     
Md. "The mainstream thinking is that most Parkinson disease cases look as      
though they do not have any hereditary component whatsoever, on the face of    
it. The twin studies support that view ....

"But one can't be absolutely sure that there is no hereditary component in     
ordinary [idiopathic] Parkinson's disease, because there are two or three      
families around the world where Parkinson's is clearly hereditary."

A recent study of two large families from the same small town in southern      
Italy revealed that 41 family members in four generations, including members   
who emigrated to the United States, have had a particularly serious form of    
the disease. Genealogical studies of the two families showed a common          
ancestor dating to the early 1700s.

"Fortunately, these cases are exceedingly rare," says Chase. "So when a        
patient asks if Parkinson's can be inherited, the answer is the chance is one  
in a million."

Other experts debate whether Parkinson's disease has an environmental cause.   
The occurrence of the condition in couples married for many years, presumably  
eating the same diet in the same environment--in many cases in                 
institutions--is exceptionally low. However, one researcher found that         
residents of three adjacent kibbutzim (community settlements) in Israel have   
five times the incidence of Parkinson's disease found in neighboring areas.    
Until recently, all three kibbutzim used drinking water from the same well,    
possibly contaminated by a nearby junkyard with rusting automobiles and        
tractor parts. Other researchers have also noted a higher risk of Parkinson's  
disease among rural populations who use well water.

Some, such as Donald M. Calne, D.M., University of British Columbia, argue     
that Parkinson's disease is not a specific disease entity, but rather a        
syndrome that may have either a genetic or environmental cause, depending on   
the particular case. Professor C.D. Marsden of the National Hospital for       
Nervous Diseases, London, U.K., writes in The Lancet (April 21, 1990): "A      
more complex theory is that the development of Parkinson's disease may be due  
to a combination of exposure to an environmental toxin with an inherited       
inability to adequately dispose of such a toxin."

The possibility that a virus or other infectious agent is responsible has      
been proposed, but sophisticated techniques have so far been unsuccessful in   
finding any such agent.

About 85 percent of patients who develop tremor, rigidity, slowness of         
movement, and minor signs have ordinary (or idiopathic--of no known cause)     
Parkinson's disease. Other patients with the same symptoms for which the       
cause is known have symptomatic or secondary parkinsonism. Parkinsonism can    
be induced by a variety of causes. One type is caused by drugs that block the  
dopamine receptors in the brain. The chief offenders are the antipsychotic     
drugs, such as Haldol, Thorazine, Loxitane, Stelazine, Mellaril, Prolixin,     
Compazine, Orap, and others of this class. Fortunately, these symptoms         
disappear when the drugs are withdrawn or the dose is lowered.                 
(Benzodiazepine, or minor, tranquilizers such as Valium and Librium do not     
cause parkinsonism.) 

The drug reserpine is prescribed in low doses to combat high blood pressure;   
in high doses, however, reserpine depletes dopamine in the brain and causes    
parkinsonism. Its effects are also reversible when use is discontinued.

Other chemicals are also implicated. In 1977, a young chemist in California    
synthesized a street narcotic that was contaminated with a byproduct known as  
MPTP. After several injections, he developed a tremor and was unable to move   
or speak. When he died in 1978 of a drug overdose, the autopsy showed          
irreversible damage to the brain's dopamine-producing systems.

In a study conducted in the province of Quebec, Canada, researchers found a    
strong correlation between the use of herbicides chemically related to MPTP,   
such as paraquat, and the development of Parkinson's disease. In one area      
where these types of herbicides were heavily used, the incidence of            
parkinsonism was seven times higher than in neighboring areas with low         
herbicide use.

Certain occupations are associated with the destruction of the                 
dopamine-producing cells of the brain. Mechanics exposed to carbon monoxide,   
welders and miners exposed to manganese, and people in contact with mercury    
or carbon disulfide in rubber manufacture, for example, may have symptoms      
resembling those of parkinsonism.

Brain tumors, head injuries, strokes, tuberculosis, syphilis, subdural         
hematoma, degenerative diseases such as Alzheimer's, hereditary diseases       
(Huntington's chorea and Wilson's disease), or any other condition that        
damages the cells of the substantia nigra, may cause some degree of            
parkinsonism, but these cases are rare. n

--E.Z.
Some Drugs Used to Treat Parkinson's Disease

Drug
Use
Main Side Effects

Anticholinergics
relieves rigidity,
dry mouth, blurred
Artane
tremor and drooling
vision, mental changes,
Akineton

difficulty in voiding,
Cogentin

constipation
Kemadrin
Pagitane

Antidepressants with
relieves depression
same as anticholinergics
anticholinergic activity
and sleep (may also 

Elavil
relieve anxiety)
Endep
Tofranil

Antidepressants without
relieves depression 
mental changes
anticholinergic activity
(may also decrease anxiety
Desyrel
and improve sleep)
Prozac

Antihistamines        reduces tremor and    drowsiness
Benedryl              can be sedating
Phenoxine

Anti-psychotomimetics may lessen            mental changes
Mellaril              hallucinations and
Clozaril              delusions

Antiviral             improves all          mottling of skin,
Symmetrel             symptoms              swelling of feet,
                                            confusion, 
                                            hallucinations

Dopa decarboxylase    improves all          involuntary
inhibitor combined    symptoms              movements, mental
with levodopa                               changes, dizziness
Sinemet
Sinemet (controlled-
release)

Dopamine agonists     improves all          nausea, dizziness
Parlodel              symptoms              on standing, mental
Permax                                      changes

MAO-B Inhibitor       may slow progression  dizziness, nausea,
Eldepryl              of the disease and    insomnia
                      increases the effectiveness
                      of levodopa