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Unfortunately, cholinergic receptors are involved in many
of the body’s functions and anticholinergics may bring about
unwanted side effects (blurred vision, dry mouth, constipation,
and urinary problems in men). A serious but less common
drawback is a tendency to cause problems such as confusion,
memory lapses and even hallucinations. Because of these
difficulties, they are now regarded as a form of therapy
reserved only for specific uses such as the control of severe
shaking or in the early stages to delay the need to commence
levodopa treatment.
In 1958, the link between Parkinson’s and brain dopamine
deficiency was discovered, but administering dopamine directly
to people with Parkinson’s was not practical, because it
was broken down by the body’s chemistry before it could
reach the brain. A related substance, levodopa, which
the body converts to dopamine, was tried in the mid 1960s.
This did enter the brain, albeit in small amounts, and was
introduced as therapy in 1970. Levodopa can have quite dramatic
and immediate effects, for example the reversal of the very
small handwriting typical of Parkinson’s.
However, it soon became apparent that levodopa was also
largely broken down before reaching the brain and pharmaceutical
companies began searching for substances to prevent this.
Two of these are now used in combination with levodopa –
carbidopa, from Du Pont, and benserazide from
Roche. By using such combinations, a larger fraction of
the given dose reaches the brain (50 per cent, compared
with just 10 per cent for levodopa alone).
Further studies of levodopa in the brain led to the discovery
of yet another pathway for its breakdown – monoamine
oxidase B. One compound, selegiline, originally
discovered in the 1960s, was shown to block this step. It
is available for the treatment of Parkinson’s both alone
and in combination with products containing levodopa. Selegiline
is available from ASTA Medica and Orion. Athena Neurosciences
has licensed a fast-dissolving form (developed by Scherer
DDS) which may permit a reduced dosage.
Despite these successes, it became clear that levodopa
breakdown by other enzymes such as COMT was still reducing
its effectiveness. Two inhibitors of this further process
have proved clinically useful and tolcapone from
Roche reached the market in 1997 as an add-on to levodopa
therapy, while entacapone, from Orion, is expected
to be launched during 1998.
Despite this great effort, levodopa therapy, alone or in
combination, has one major problem – loss of efficacy in
most people after a few years’ use. Responses become unpredictable,
rapid swings from rigidity to over-activity occur (the ‘on-off’
state), and Parkinsonian symptoms may reappear after years
of control. To try to solve this problem, much effort has
been devoted to the search for alternative molecules with
dopamine-like effects (called dopamine agonists).
Apomorphine, discovered in the 1950s, is one such
medicine, but it is broken down so rapidly in the liver
when given by mouth that it has to be injected. Apomorphine
is effective at rapidly restoring mobility in people who
are experiencing ‘on-off’ phenomena. Technology has now
largely overcome this problem and special self-inject ‘pens’
are marketed by Britannia. Many people with Parkinson’s
are able to learn self-injection and can use apomorphine
to ‘get themselves going’. A few patients have to inject
their medicine so often that they benefit from specially
developed continuous infusion pumps. A special form of apomorphine
that dissolves in seconds in the mouth is being investigated
by Scherer DDS. It has entered Phase II clinical trials,
where it appears to be well absorbed through the lining
of the mouth. This would be a particular advantage for people
with swallowing difficulties or for those who cannot master
self-injection. (It is important to note that, despite the
similar names, apomorphine does not contain morphine,
a powerful pain reliever).
Other dopamine agonists have been discovered. Earlier ones
include bromocriptine from Novartis, lysuride
from Cambridge Laboratories, and pergolide from Lilly.
Two medicines of this class that have reached the market
recently are ropinirole from SmithKline Beecham and
cabergoline from Pharmacia & Upjohn, launched in
1996 and 1997 respectively. Pramipexole, also from
Pharmacia & Upjohn, is expected to be licensed during 1998.
The final agent which should be mentioned is amantadine,
from Novartis. This was originally made as an anti-viral
agent but was found to increase dopamine release and act
as a dopamine re-uptake inhibitor – both actions which lead
to modest anti-Parkinson’s activity.
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