Current Therapy
Because of the idiopathic nature of Parkinson's
disease, current therapy is designed only to alleviate
symptoms and occasionally to try to slow clinical
progression of the disease (Calne 1993). The first, and
still most universally used, therapeutic agent is
levodopa (L-dopa), the precursor of dopamine. L-dopa,
biosynthesized from tyrosine, is converted to dopamine by
aromatic-L-amino acid decarboxylase (see Figure 7).=20
Because dopamine causes negative side effects outside the
blood-brain barrier it is administered with a
noncompetitive inhibitor of aromatic-L-amino acid
decarboxylase that is unable to cross the blood-brain
barrier. There are some side effects of L-dopa therapy
such as severe dyskinesia, sudden unpredictable loss of
mobility, confusion, and psychosis. If the free radical
hypothesis of neuronal degeneration is correct, the
administration of L-dopa (which can be metabolized to
form free radicals) could increase the rate of
progression of Parkinson's disease. However, because
L-dopa therapy adds an average of five years to a
parkinsonian patient's survival, most patients are
willing to endure the side effects and risk of disease
progression (Kurtzke and Murphy 1990).
The noted rise in acetylcholine activity in
Parkinson's disease led to the use of anticholinergic
drugs. Anticholinergic drugs are antagonists at
muscarinic receptors and they can increase dopamine in
the synaptic cleft. They reduce tremor but they usually
do not decrease rigidity or bradykinesia. The side
effects of anticholinergic drugs include the impairment
of memory, hallucinations, impaired ocular accommodation,
dryness of the mouth, constipation, urinary retention,
and vasodilation. A drug called amantadine (the mode of
action of which is unknown) reduces tremor like
anticholinergics and has similar side effects, but it
also often helps rigidity and bradykinesia. Amantadine
is used much more commonly than anticholinergic drugs.
Synthetic dopamine agonists act on the D2
receptors. Some classes of D2 agonists antagonize or
agonize D1 receptors. Because there is a great deal of
uncertainty about the mode of action of dopamine
receptors and the mesostriatal circuitry, the
agonist/antagonist combinations are varied. Certain
combinations work for some patients while other
combinations do not. These tetracyclic ergot derivatives
have some side effects such as pleuropulmonary fibrosis
and erythromelalgia.
Deprenyl is an inhibitor of the oxidant MAO-B.=20
It might decrease neuronal death by decreasing the
oxidative metabolism of dopamine, thereby inhibiting free
radical production. It could also increase dopaminergic
transmission by activating trophic mechanisms (Parkinson
Study Group 1993).
There are several drugs in the research stage.=20
Some experimental drugs include long-acting dopamine
agonists, non-ergot dopamine agonists, partial dopamine
agonists, and dopamine receptor antagonists (Calne 1993).=20
Extracellular metabolism of dopamine and L-dopa are the
processes that catechol-O-methyltransferase inhibitors
are hoped to inhibit. Glutamate-release inhibitors might
protect nigral neurons from the toxic overexcitatory
effects of glutamate. A trophic agonist, glial-derived
neurotrophic factor (GDNF), promotes axonal sprouting in
adult dopaminergic neurons. These and other drugs are
all in the testing stages.
Surgical techniques have had some positive
results in animal tests. Most commonly, fetal
mesencephalic tissue is grafted in the brain as tissue
masses or cell suspensions. It is not known if fetal
grafts allow circuit reconstruction or have trophic
effects. Bj=94rklund and Stenevi, the pioneers of fetal
grafts in parkinsonian therapy, believe that grafts could
cause catecholaminergic neurons to sprout additional
terminal processes (1979). Grafts could also act as
pumps to supply dopamine and other neurotransmitters
(Yurek and Sladek 1990). Long-term survival of fetal
grafts is still unclear. Other surgical techniques have
been explored also. Unilateral lesions of the
subthalamic nucleus in parkinsonian animals often
immediately ameliorates contralateral tremor, akinesia,
rigidity, and bradykinesia (DeLong 1990). Accidental
lesioning of the caudate nucleus has alleviated some
parkinsonian symptoms in animals. Other surgical
techniques are currently being explored but have as yet
had little success.
The future of research in Parkinson's disease
is multifaceted. Many recent advances have opened paths
of potential cures. From the field of genetics we might
see genetically modified neurons which can synthesize
neurotrophic factors or the missing neurotransmitters.=20
New advances in surgery such as selective lesioning could
produce favorable results. Definite implications of
endogenous neurotoxins central to Parkinson's disease
could lead to antioxidant therapy. Because so much about
Parkinson's disease remains a mystery it is possible that
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D
Barbara [log in to unmask]
HSC 2J22=09=09=09=09=09905-525-9140, ext. 22403
=09=09=09School of Nursing
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D
@ t8
