The following was written by Dr. Chase for the APDA, announcing
the commencement of a study on slowing or stopping the progression of PD.
Volunteers with Hoehn & Yahr state I & II progression are requested.
Thomas N. Chase, M.D.
Chief Experimental Therapeutic Branch
National Institute of Neurological
Disorders and Stroke, Bethesda, MD.
Parkinson's disease (PD) symptoms are due to the progressive
loss of dopamine containing neurons (nerve cells). The cause of
this degenerative process remains a mystery with both genetic and
environmental factors being implicated. Increasing evidence now
suggests that either or both of these factors might act by increasing
the formation of free radicals.
Until recently, free radicals were mainly a subject of interest in the
manufacture of plastics or the preservation of food. During the
past two decades, however, it has become increasingly apparent that
the human body constantly produces these substances. At times,
free radicals perform essential functions, such as fighting infection,
but excessive free radical production leads to oxidative stress,
which, in turn, can cause tissue damage. This process has been
implicated in a wide range of disorders involving the heart, kidney,
brain, and other organs, even though the body uses an elaborate
system of defenses to fight the excessive production of free radicals.
Just what are free radicals and how do they produce oxidative
stress? The answer requires some knowledge of simple chemistry.
Electrons which orbit the central nucleus of an atom normally occur
in pairs. A free radical is formed when one or more of these electrons
becomes unpaired. In this state atoms tend to be unstable and highly
reactive: when free radicals meet with non-radicals, new free radicals
are generated. Formation of these reactant species thus starts a
kind of chain reaction that can destroy cell membranes and ultimately
lead to cell death.
How does all this relate to PD? The brain is relatively vulnerable
to free radical damage since it is filled with fatty substances that are
a major component of cell membranes and are a perfect target for
free radicals. This possibility is further enhanced by the compensatory
increase in dopamine production that occurs in surviving neurons as PD
advances. Increasing evidence from studies carried out in Parkinson's
patients supports the theory that oxidative stress may play a role in
the disease. For example, alterations in iron levels and proteins that
serve as carriers for iron, in enzymes involved in the detoxification of
free radicals, and in levels of lipid peroxidation, which occur in the
brain of Parkinson patients, support this possibility, but they are
hardly conclusive. Direct measures of oxidative stress in the human
central nervous system are not yet possible. An alternative approach to
evaluating this possibility might be to test the ability of drugs that
act as free radical scavengers to slow disease progression. Unfortunately,
the DATATOP study failed to show any benefits associated with the use of
the free radical scavenger, Vitamin E. This negative result, however,
does not necessarily indicate that free radicals do not participate in
the degenerative process in PD since it is not known whether adequate
Vitamin E concentrations were attained in the brain of the DATATOP
study participants.
Recent laboratory studies indicate that a new drug (code number OPC 14117)
does possess free radical scavenging activity. This drug can be taken
by mouth and readily enters the brain. OPC 14117 has now been given to
over one thousand people in this country and abroad. Side effects were
limited to increased liver enzyme levels in some individuals. Biochemical
studies conducted at the NIH Clinical Center involving fourteen patients
with PD suggested that OPC 14117 may have significantly increased free
radical scavenging activity in the brain.
As a result of these promising preliminary results, additional patient
studies are now planned, in accordance with a protocol approved both by
the NIH and the FDA. Their purpose is to evaluate whether the long-term
administration of OPCI4II7, at doses that appear to influence oxidative
stress in the human brain, may have the ability to substantially retard
progression of Parkinson symptoms. Individuals newly diagnosed with PD
are being sought for the study, which will take place at the outpatient
clinic of the NIH Clinical Center located just outside of Washington, DC
and last up to two years. All participants must have relatively mild
symptoms, not require therapy with levodopa (Sinemet) or a dopamine agonist
(such as Parlodel or Permax,) and have no other serious medical condition.
Prior treatment with anticholinergics (such as Artane or Congentin), with
amantadine (Symmetrel), or with selegiline (Eldepryl) is allowable as long
as these drugs can be withdrawn at least two months prior to the beginning
of the study.
On the first visit to NIH, patients will receive a complete medical
evaluation and laboratory tests and Parkinson symptoms will be scored
using a standardized rating scale. Participants will be then randomly
assigned to one of two groups, one of which will receive the active drug
and the other a placebo in order to allow a comparison of the symptom
progressian between the two groups. Both groups will then take tablets at
home twice daily and blood and urine studies will also be performed
weekly at home. More extensive clinical and laboratory testing will be
carried out once a month with participants living outside the Washington
area having them done at a local clinic or a doctor's office. Examinations
at the NIH Outpatient Clinic will occur every three months, and like all
other medical evaluations. laboratory tests, and drug supplies. will
be free of charge. The study will be discontinued if at any time it is
felt that conventional therapy Is necessary to control the symptoms of
the disease. If OPC 14117 appears safe and beneficial, all participants
completing the study will be offered active drug on a long-term basis as
long as supplies are made available by the manufacturer.
Individuals desiring further information about this study or wishing to
be considered as participants are invited to call the Experimental
Therapeutics Branch at the NIH Clinical Center at 301-496-4604.
Alternatively, letters from patients or their referring physicians may be
addressed to Dr. Thomas N. Chase, NIH/NINDS, Building 10 / Room SC103, 10
Center Drive, MSC 1406, Bethesda, Maryland 20892-1406.
Editors note:
Some studies at NIH/ETB/NINDS have travel expenses available for those
not living in the Washington, DC area. To determine if this one has travel
expenses available, call Marge Gillespie, R.N. or Susan Kastris, R.N. at
1-800-362-3479.
Patient inclusion characteristics are as follows:
Mild symptoms
Aged 18-79
Generally healthy
Not taking antiparkinsonian medications for more than six months,
and able to discontinue current medications for the duration of the study.
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