buscopan

[Guest guest]

hyoscine (scopolamine) n.

a drug that prevents muscle spasm (see parasympatholytic). It is used in

the treatment of gastric or duodenal ulcers, spasm in the digestive

system, and difficult or painful menstruation and also to relax the

uterus in labour. It can also be used to calm excitement in some

psychiatric conditions, for preoperative medication, for motion sickness,

and to dilate the pupil and paralyse the muscles of the eye for

examination. It is administered by mouth or injection.

Side-effects are rare but can include dry mouth, blurred vision,

difficulty in urination, and increased heart rate.

Trade names: Buscopan, Scopoderm.

Concise Medical Dictionary, Oxford University Press, © Market House Books

Ltd 1998

_____I've highlighted what I found relevant for me, but all of it

is well worth reading (figusre it was on Berkerley's site).____

PARKINSON'S DISEASE

Category: Neurochemistry

Term Paper Code: 572

Parkinson's Disease: Characteristics

Parkinson's Disease (or P.D.) refers to a well-recognized set of symptoms

that is a manifestation of a deficiency in brain

dopamine in the substantia nigra, or " black substance, " located

under (and connected to) the corpus striatum. The diagnosis is

made when three hallmark symptoms are present: tremor, rigidity, and

bradykinesia (Duvoisin 19). The tremor usually affects

the hands and feet and, unlike other tremors of other disorders, is a

resting tremor which disappears during a movement. The

muscular rigidity in the limbs is also unusual in that there is a

constant, uniform resistance in response to manipulation, as if the

muscles were unable to relax even at rest. Finally, bradykinesia (Greek

for " slow movement " ) is the third condition that involves

difficulty in initiating and sustaining movement as well as rapid

fatiguing. This not only affects conscious movements but also

automatic movements such as blinking, swinging the arms while walking,

swallowing saliva, and manipulation of facial

expressions. As a result, the affected person may seem more mechanical

than usual.

There are many secondary symptoms associated with Parkinson's Disease.

Changes in resting posture can result in backaches

and problems with balance. The tilting of the body can also result in

involuntary running to maintain balance when one's intention

was to walk (initially remedied by the aid of walking canes). The

bradykinesia can spontaneously interrupt walking so that one

has to be prepared for a loss of balance if a foot suddenly seems to

stick to the ground. People with P.D. tend to speak softly

without being aware of it, talk slowly and deliberately (monotone speech)

or, at the other extreme, quite rapidly. The halt of

automatic movements such as blinking or swallowing saliva can cause dry,

irritated eyes and drooling. Edema of the feet and

seborrhea (excessive oily secretions) are also secondary symptoms. Low

blood pressure while standing can be remedied by

putting on stockings, but this and other secondary symptoms usually

disappear upon treatment of P.D.

A Brief History

Parkinson's Disease was first described in 1817 by Parkinson in An

Essay on the Shaking Palsy. He opens up the piece

with a short but comprehensive definition of the condition he observed:

Involuntary tremulous motion, with lessened muscular power, in parts not

in action and even when supported; with a propensity

to bend the trunk forwards, and to pass from a walking to a running pace;

the senses and intellect being uninjured. "

Some of the symptoms mentioned here had been described by the ancient

Greeks, who wrote of tremors of the hand at rest,

and 18th century French physicians who described the " tendency to

pass from a walking to a running pace. " A sketch by

Rembrandt of " The Good Samaritan " portrays an innkeeper

stooping over with folded hands who seems to have Parkinson's

disease. Although these descriptions suggest that the disease had been

around long before Parkinson's time, there is no

conclusive evidence because no other symptoms had been simultaneously

mentioned. To this day, Parkinson's Disease retains

the name of its discoverer because no satisfactory descriptive term has

yet been found that encompasses the pathology or the

complex, characteristic pattern of symptoms of the disease.

Although Parkinson was the man who first recognized the symptoms of

P.D., many other physicians contributed greatly

to knowledge about the disease. A mid 19th-century medical teacher

named Jean Marie Charcot studied people with the

disease and added other descriptions, including muscular rigidity. In

1867 he introduced treatment with the alkaloid drug

hyoscine (or scopolamine) derived from the Datura plant, which was used

until the advent of levodopa (L-Dopa) a century

later. His work, along with that of other medical teachers, made P.D. a

well-recognized disorder during the later 1800s.

In the 19th century, medical technology was not yet advanced

enough to provide deeper insights to the disease. Parkinson's

hope that future anatomists would be able to ascertain the disease's real

nature began its fulfillment when Tretiakoff, a doctoral

student in Paris, published a controversial thesis in 1915 marking the

changes in the substantia nigra of postmortem patients

affected by P.D. Many were skeptical that damage to such a small part of

the brain could be manifested in such great physical

effects, and others believed that P.D. was rooted in other parts of the

brain. An epidemic of sleeping sickness (encephalitis

lethargica) during the years 1916-1926 brought a lot of confusion to the

subject because suddenly many young patients were coming down with

Parkinsonian symptoms, something that had previously only affected the

elderly. A German pathologist, Dr. R. Hassler, noted that the substantia

nigra of people with sleeping sickness was affected as well and he

published his work in 1939. (Only later was it realized that

post-sleeping sickness parkinsonism was different from the P.D. prevalent

today, cases of the former having virtually disappeared by this time).

However, much research was halted during the years of World War II, after

which it became accepted that the substantia nigra was the major site of

anatomical derangement in P.D., although no one really knew its purpose.

New microscopic technology advanced knowledge about P.D. when

scientists were able to trace compounds in the body with

UV light. They found dopamine highly concentrated in the substantia nigra

and corpus striatum, and nearly depleted in those

who had P.D. In 1957 the Swedish Professor Arvid Carlsson did an

experiment with reserpine, a tranquilizer that can produce

a Parkonsonian condition in man. He found that an injection of levodopa

(the generic name for the medical preparation of

L-DOPA, which also occurs naturally) reversed the effect of the

tranquilizer and that it restored dopamine levels back to

normal, suggesting a new treatment for parkinsonism. This levodopa was so

effective that it was approved by the Food and

Drug Administration for use in treating P.D. in 1970. The principle of

L-DOPA treatment --administering the metabolic

precursor of a substance deficient in the brain in a certain disease--

has since been extended to other disorders with some

success.

The " Cause " of P.D. Symptoms and its Drug Treatments

The effect of dopamine levels on fluidity of movement can be followed by

tracing the pathway " upstairs " from the substantia

nigra to the motor cortex. In the normal human brain, the substantia

nigra (via dopamine) stimulates the corpus striatum, to

which it is attached by many thin fibers. The corpus striatum inhibits

the globus pallidus which in turn inhibits the motor thalamus,

which finally stimulates the motor cortex (at the top of the brain) to

initiate muscle action. This delicate balance of excitatory and

inhibitory pathways is disrupted in the patient with a degenerating

substantia nigra. Diminished dopamine levels cause the corpus

striatum to be less inhibiting on the globus pallidus, which in turn

overinhibits the motor thalamus. This means that the motor

cortex is hardly stimulated at all, resulting in the bradykinesia

characteristic of Parkinson's Disease.

Clearly, treatment should either restore dopamine levels in the brain,

involve drugs that imitate dopamine, or modify the brain in

some way to compensate for the deficiency in dopamine. With the aim of

restoring brain dopamine levels, the administering of

levodopa is the prevalent form of treatment today. Levodopa is converted

to dopamine in the body via AADC (aromatic amino

acid decarboxylase). Levodopa taken orally is absorbed by the small

intestine and enters the circulation to all parts of the body,

peaking in blood around 2-3 hours after ingestion, and the effects slowly

wear off after 4-6 hours. These peaks and valleys in

levodopa effects are referred to as " on/off " periods. Only

about 10f the levodopa finally penetrates the brain (dopamine being

unable to cross the blood-brain barrier), implying that one must take

large as well as continuous doses of the drug for it to be

effective. Several months of continuous treatment are necessary to fill

up dopamine stores in the brain.

Unfortunately, a common side effect to levodopa treatment is nausea and

vomiting. Today, levodopa is administered in

conjunction with carbidopa (or another enzyme inhibitor) which prevents

levodopa from being converted to dopamine except in

the brain. This significantly reduces the side effects as well as

allowing levodopa to be administered in much lower doses,

eliminating the " dilution effect " caused by AADC's converting

L-DOPA to dopamine while it is still floating around in the body.

Another side effect of levodopa treatment is chorea, the neurological

term for a series of jerky, involuntary movements. The

severity of the chorea increases with levodopa levels, but cutting back

on the dosage results in the reappearance of parkinsonian

symptoms. A compromise must be made, which is a major drawback of

levodopa therapy.

Depression is a commonly reported side effect of Parkinson's Disease

itself. Most anti-depressants (and other prescription

drugs in general) are safe and will not interact negatively with

levodopa. However, a group of antidepressants called

" monoamine oxidase inhibitors " (MAO inhibitors) must never be

administered with levodopa. Monoamine oxidase keeps

dopamine, norepinephrine, and epinephrine levels in the body in check;

levodopa will quickly be converted to these substances

in the presence of MAO inhibitors, leading to an " overdose " and

possibility of a heart attack or a cerebral hemorrhage.

The idea behind the second form of treatment is that administering drugs

that mimic dopamine will eliminate the possibility of

side effects caused by levodopa. The first dopamine receptor agonist to

be tested on P.D. patients was apomorphine, a drug

that was already used as an emetic (to induce vomiting). It had been

reported in the 1950s that apomorphine alleviated the

tremors of P.D. However, not only was it half as effective as levodopa,

it was also discovered to have a toxic effect on the

kidneys. Other drugs were tested but either did not improve the P.D. or

else were also toxic to the kidneys. Finally,

bromocriptine (or Pardolel) was found to have about the same potency as

apomorphine (half that of levodopa) but the main

advantage is that it lasts longer. Bromocriptine acts as a prolactin

suppresser and in the future may also be used to treat

premenstrual syndrome. It is usually co-administered with levodopa, has

the same side effects, and is expensive, being very

difficult to synthesize. Consequently, although it can help a select few,

it is not the treatment of choice. The search for dopamine

receptor agonists is exacerbated by the fact that there are several types

of dopamine receptors (D-1 and D-2 included here)

and drugs such as bromocriptine are agonists of one but antagonists of

the other. Drugs that imitate the natural effects of

dopamine through fine-tuned interactions with the receptors remain to be

found.

The third method of treatment focuses on compensating for reduced

brain dopamine levels. Acetylcholine is present in the brain in much

larger amounts than dopamine, and levels are normal even in people with

P.D. These two hormones have a reciprocal relationship; dopamine has a

restraining effect on acetylcholinergic nerve cells and when it is gone,

acetylcholine is no longer regulated, resulting in parkinsonian symptoms.

Anticholinergic drugs aim to alleviate this problem. The first

anticholinergics were derived from plants and used to treat P.D. at least

as far back as the 19th century when Jean Charcot prescribed

hyoscine/scopolamine to his P.D. patients. The closely-related atropine

(from the belladonna place) and hyoscyamine, both from the potato family,

have also been used medicinally since ancient times. However,

anticholinergics only reduce P.D. symptoms about 25% (compared to

levodopa). Interestingly, post-encephalitic P.D. patients respond to

anticholinergics much more positively than regular P.D. patients.

Maybe

MSA patients do too?

Surgical Treatments

Surgery to treat Parkinson's Disease was first used in the 1930s. The aim

was to destroy enough parts of the motor pathway to

diminish tremor and rigidity. The first procedures were crude and the

results were mediocre and unpredictable. In 1939, New

York doctor Russel Myers was performing brain surgery on a P.D. patient

when he accidentally discovered that cutting through

a part of the corpus striatum reduced tremor on the opposite side of the

body. The best results were pinned down to severing a

bundle of nerve fibers deep in the brain called the ansa lenticularis,

and the procedure was later dubbed an " ansotomy. "

However, this surgery proved difficult and delicate because the ansa

lenticularis was not easily accessible. The practice by many

neurosurgeons refined the technique to be most successful when aimed at

severing the fibers close to the terminus, or at the

thalamus, a procedure called " thalamotomy. "

Although this type of surgery received a lot of public enthusiasm,

especially from P.D. patients themselves who wanted the

surgery, they were to be disappointed because doctors turned away most

candidates in favor of healthy young adults whose

symptoms were mainly on one side. This is because operating on both sides

of the brain often resulted in unwanted side effects

like slurring of speech and difficulty in swallowing. Many young patients

who did have successful results because of the surgery

and thought they were " cured " were disappointed a few years

later when their parkinsonian symptoms would reappear. This

surgery is a remedy for symptoms but by no means a cure, and they were

largely discontinued when levodopa treatments were

introduced in 1967-1970.

Another surgical procedure involves making a lesion in the globus

pallidus internus, part of the basal ganglia deep within the

brain. This procedure would result in less inhibition on the motor cortex

and more muscle action. This is called a " Posteroventral

Pallidotomy " (or PVP) and it successfully relieves symptoms in many

patients. The pallidotomy was first developed in the 1950s

by Dr. Leksell but it was abandoned after a decade because of the success

of levodopa (WWW3). However, interest in the

technique was renewed with the publication of an article by Dr. Laitenen

of Sweden in 1992 that described patients who were

currently benefiting, and advances in the technique along with modern

technology have made it more popular today. The ideal

candidates are those people who currently respond to medication (PVP

rarely eliminates the need for medication), have

problems mainly on one side, and whose symptoms are primarily

tremors/muscular rigidity and not axial/autonomic problems

such as difficulty in swallowing and incontinence. These candidates

should be people whose quality of life is poor despite the

best medical management and who are relatively young and strong enough to

recover from surgery.

Causes and Epidemiology of P.D.

There are many ways that the substantia nigra can be damaged to result in

parkinsonian symptoms, but no one knows to this

day exactly what causes Parkinson's Disease to occur in some people and

not others. There are three main categories of P.D.

The first is " ideopathic P.D. " which basically means that the

cause is unknown; this is the largest group. Parkinson's Disease

affects about 10f the general population (over one million in the U.S.

alone), including 20f people over age seventy (Duvoisin

1984). Although this percentage has been steady for decades, it may

increase due to the increasing life expectancy and

prevalence of elderly in the population. The average onset is after the

age of fifty although younger people have been diagnosed.

It is a disease that affects both men and women all over the world. The

second category is post-encephalitic P.D., which was

common after this century's sleeping sickness epidemic; this population

has largely dwindled. The third group is parkinsonism

caused by head trauma and tends to afflict boxers and steeple chase

jockeys but can also affect victims of automobile accidents.

Attorney General Janet Reno and actor J. Fox have been diagnosed

with Parkinson's (the latter having recently

undergone a thalamotomy himself), as well as boxer Muhammed Ali.

Animals (humans and mice included) can be induced chemically to exhibit

parkinsonism. Reserpine, used in 1957 by Dr.

Carlsson, is commonly used today to cause parkinsonism in mice for

experimental purposes, and additionally, used in small

amounts to treat high blood pressure. Reserpine and other major

tranquilizers that induce parkinsonism are at the same time the

most effective treatment for schizophrenia. This is because these

treatments work as antagonists of dopamine receptors, which

is the antithesis of P.D. treatment. Drug-induced parkinsonism is almost

as common as ideopathic parkinsonism; however, most

of the people affected are psychiatric patients. Drug-induced

parkinsonism differs from ideopathic P.D. in that it is usually

entirely reversible.

There is currently much research being done to identify possible causes

of Parkinson's Disease including inheritance of genetic

mutations as well as environmental toxins. There is a strong concordance

of P.D. in identical twins only when they are diagnosed

in young-to-middle adulthood; there is no concrete evidence that

late-onset P.D. has a genetic component. Scientists are still

trying to find genetic mutations that are responsible for P.D. In a study

done on Italians with affected family members in 1997,

Mihael Polymeropoulous claimed to find such a mutation on chromosome #4

in the alpha-synuclein gene, which is a presynaptic

nerve terminal protein (Polymeropoulous 1997). An incorrect amino acid

was assumed to disrupt the secondary structure of the

protein. Alpha-synuclein is a component of Lewy bodies, a pathological

feature of Parkinson's Disease. (Even on this point

there is controversy-- some believe that alpha-synuclein is definitely

not involved in P.D. and others believe that its presence in

Lewy bodies is also insignificant). However, other studies done on P.D.

patients find no alpha-synuclein mutations so

Polymeropoulous' results were regarded at best as a sign of a rare

autosomal dominant inheritance and more significant genetic

sources of P.D. remain to be found (French PDGSG 1998).

Because late-onset Parkinson's Disease does not yet have an identified

genetic cause, there is speculation that it may be due to

long-term exposure to environmental toxins. Studies indicate that

pesticide exposure is a risk factor for the development of

Parkinson's Disease, especially in women (Chan et al. 1998). According to

the same source, cigarette smoking seems to

decrease the risk for P.D. A study shows that GDNF (Glial cell

line-derived neurotrophic factor) supports growth of dopamine neurons and

may protect them from degeneration when mediated by gene therapy

(Choi-Lundberg 1997). Many other studies have been done to show that

certain chemicals may have neuroprotective effects when cells are exposed

to induced toxins, implying that P.D. or its symptoms may be delayed or

prevented altogether. Research is being done on these lines to use

buckyballs as a preventative measure or form of treatment because they

soak up free radicals and nerve-destroying chemicals, being an effective

antioxidant (Unknown 1997).

Current Advances in Treatment of P.D.

Leaving the arena of drug treatment and surgery, there is a lot of

research being done to promote dopamine-producing cell

growth in the brains of patients with Parkinson's Disease. Although it

has been accepted for a long time that brain cells do not

divide after birth, there is evidence via a cancer study that cells in

the hippocampus's " dentate gyrus " show cell division

(Barinaga 1998). This evidence may provide hope for research for the

cures of other diseases as well.

The controversial issue of using fetal brain cells for research into

cures may be eliminate by another method involving the use of

carotid bodies instead (Barinaga 1998). Located in the neck region, not

only do the glomus cells in the carotid bodies have very

high dopamine output in experiments, they are readily available parts of

everyone's anatomy that are not really known for other

functions. To reverse parkinsonian symptoms, two hundred thousand to

three hundred thousand fetal neurons are necessary, but

each carotid body provides one hundred thousand glomus cells, and because

of the high dopamine output, one should be

sufficient.

There is even new technology that may help in the administration of

dopamine to P.D. patients by eliminating the need for oral

levodopa treatment. Tiny silicon chips have been designed that have many

tiny wells that can be filled with hormones or other

concentrated substances to be released in a timely manner (Service 1999).

Experiments have been done to show that individual

wells can be broken open by a trigger and that this could be implanted in

the brain and used as a mechanism for treatment of

hormones and painkillers. Other creative uses for these chips include

using them in television commercials to release fragrances

when certain products are being advertised.

Conclusion

Although Parkinson's Disease may have been around to afflict people since

the time of the ancient Greeks, recent developments in research and

technology have allowed vast improvements in pinpointing the mechanism

and various treatments of the disease. However, complications arise when

trying to find the exact cause of P.D.

Because symptoms do not manifest themselves

externally until at least seventy percent of the substantia nigra has

deteriorated, and because the brain is very plastic and helps to

compensate for injured areas by rerouting messages, it is difficult to

discover exactly where the problems begin and what areas are affected.

Hopefully the discovery of the cause will be as timely as

the current research into treatments and will soon result in a cure for

this elusive disease.

Use

it or lose it!

Bibliography

Barinaga, Marcia. New Leads to Brain Neuron Regeneration. Science 282:

1018b-1019b (1998).

Barinaga, Marcia. Unusual Cells May Help Treat Parkinson's Disease.

Science 279: 1113-1117 (1998).

Chan, D.K.Y., Woo, J., Ho, S.C., Pang, C.P., Law, L.K., Ng, P.W., Hung,

W.T., Kwok, T., Hui, E., Orr K., Leung, M.F.,

Kay, R. Genetic and Environmental Risk Factors for Parkinson's Disease in

a Chinese Population. Journal of Neurology,

Neurosurgery, and Psychiatry 65: 781-784 (1998).

Choi-Lundberg, L. Dopaminergic Neurons Protected from Degeneration

by GDNF Gene Therapy. Science 275:

838-841 (1997).

Duvoisin, C. Parkinson's Disease: A Guide for Patient and

Family. Raven Press (1984).

The French Parkinson's Disease Genetic Study Group. Alpha-synuclein Gene

and Parkinson's Disease. Science 279:

1113-1117 (1998).

, A.D. Parkinson: His Life and Times. Birkhauser Boston

(1989).

Parkinson, . An Essay on the Shaking Palsy. Whitingham and Rowland

(1817).

Polymeropoulous, Mihael H. Mutation in the Alpha-synuclein Gene

Identified in Families with Parkinson's Disease. Science

276: 2045-2047 (1997).

Service, F. Silicone Chips Find Role As InVivo Pharmacist. Science

283: 619 (1999).

Unknown. Buckyballs Save Nerves. Science 277: 1207b (1997).

WWW1. Movement Disorders: Marshfield Clinic Offers Pallidotomy and Deep

Brain Stimulation.

WWW2. Pallidotomy.com.

WWW3. History of the Pallidotomy Procedure.

WWW4. Basic Information About Parkinson's Disease.

WWW5. Bromocriptine.

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