The following was written by Dr. Matthias C. Kurth, one of the premier
movement disorders neurologists and researcher of many of the new drugs
mentioned in this article. The first hand knowledge of the effects
of these compounds on parkinsonians makes this information timely.
The Neurosciences Institute, which is associated with Good Samaritan
Hospital in Los Angeles, sponsored a symposium on Nov. 2-3, 1996
in Rancho Mirage, CA. Dr. Kurth made his presentation there.
I thank Carole Hilton for making this information available to the
Parkinsn archives.
Up And Coming Medical Therapies for Parkinson's Disease
by Matthias C. Kurth, MD, Ph.D., Medical Director and Advisor for
Young Parkinsonians and the US NPR YOPPERS FORUM
The coming year will bring new and exciting treatment
options for Parkinson's disease patients. Four new drugs, all shown
to improve patients' symptoms, are expected to be approved by the
Federal Drug Administration (FDA). Each drug offers unique
advantages that will greatly increase patient and physician choices
in developing a therapeutic program to minimize the impact of
Parkinson's disease throughout the day. These agents will be
particularly useful for young onset patients since two of
them may offer some element of neuroprotection and all four
agents will enhance patients' well-being by improving symptom
control. In preparation for the release of these agents, a review
of their properties, mechanisms of action and results of clinical
trials is in order. This knowledge will empower patients and
physicians to combine the appropriate medications for optimal
control of parkinsonian symptoms.
Catechol-O-Methyl Transferase Inhibitors
One new approach to treating Parkinson's disease involves
prolonging the action of levodopa by inhibiting the enzyme catechol-
o-methyltransferase (COMT) involved in the metabolism of levodopa
and dopamine. inhibition of this enzyme in the body decreases the
concentration of a levodopa metabolite, 3-0-methyldopa, which may
have a role in inducing or aggravating levodopa response
fluctuations. More importantly, blood levels of levodopa are
maintained for a longer time and patients experience a smoother,
more beneficial effect from each dose of levodopa.
Tolcapone (Tasmar(r), Hoffman-LaRoche)
Tolcapone is the most potent COMT inhibitor currently
in clinical development. Studies in patients with Parkinson's
disease in the United States and Europe are complete and have
been submitted to the FDA. Tolcapone prolongs the effects of
levodopa thereby decreasing motor response fluctuations in patients
and improving quality of life. Patients on levodopa that do not
experience motor fluctuations also benefited significantly through
improved quality of life and decreased symptoms.
Tolcapone is given three times daily in doses from 100 mg
to 200 mg in addition to the patient's levodopa medication schedule.
Peak effect of tolcapone is reached in about 1 - 2 hours and
maintained for the duration of the 6 hour dosing interval.
Patients experience better control of their Parkinsonian symptoms
while needing lower doses of levodopa. Side effects are few, but
include occasional mild headache, nausea, loose stools, change
in urine color, and in some patients a transient increase in
dyskinesia. Tolcapone is absorbed by the small intestine and
metabolized by the liver. Food delays the absorption of tolcapone
somewhat, but this does not appear to be clinically significant.
The ability of this compound to prolong blood and brain levels of
levodopa while reducing the levels of potentially toxic metabolites
should be an important development in the treatment of
Parkinson's disease.
Entacapone (no brandname available. Orion/Farmos and Sandoz)
Entacapone is another new catechol-o-methyltransferase
inhibitor. Like tolcapone, this compound improves the effectiveness
of levodopa by decreasing fluctuations in medication response
through inhibition of COMT.
Studies to determine long-term safety and benefits of
entacapone as a supplement to levodopa treatment in Parkinson's
disease patients with reduced benefits or complications from
levodopa have been completed in the United States and Europe.
Entacapone enhances the effects of levodopa and is safe. Occasional
mild side effects include headache, dizziness. nausea, loose stools,
increased dyskinesia and changes in the color of urine.
Entacapone is taken with each dose of levodopa. Peak effect
is within one hour and its duration of action closely matches that
of carbidopa/levodopa. These properties suggest that a combination
tablet containing levodopa, carbidopa and entacapone may be feasible
and desirable. Current plans include further studies to determine the
benefit of entacapone in patients taking levodopa, but not
experiencing motor fluctuations.
Both tolcapone and entacapone are potent COMT inhibitors
that prolong the duration of levodopa activity in patients with
Parkinson's disease. Differences in the side effect profile,
dosing schedule and potency will need to be addressed in comparative
studies. Both tolcapone and entacapone will be valuable adjuncts for
all patients using levodopa therapy.
New Dopamine Agonists
As soon as levodopa became available for the treatment of
Parkinson's disease, efforts to find medications that could mimic
it's dramatic effect on the symptoms of Parkinson's disease, but
with fewer side effects, were begun. The result of this search
yielded the well known dopamine agonists bromocriptine (Parlodel(r))
and pergolide (Permax(r)). Neither met the desired expectation of
fully replacing levodopa. Only the nonspecific dopamine agonist,
apomorphine, has the spectrum of efficacy needed to fully treat
patients in a manner similar to levodopa. Unfortunately, apomorphine
has significant side effects and is difficult to store and administer.
In a significant step towards achieving true levodopa replacement,
two new agents are currently under review by the FDA for use in
patients with early Parkinson's disease. In addition to having
sufficient potency to act as first line therapy, these two drugs
may also have neuroprotective effects that slow disease progression.
Pramipexole (Mirapex(r), Pharmacia & Upjohn
Pramipexole is a potent, non-ergot dopamine agonist used
alone in treating patients not yet taking levodopa and as an adjunct
to levodopa in treating advanced Parkinson's disease patients. While
stimulating the dopamine D2-receptor, pramipexole may be effective
in either blocking or selectively not stimulating the D1-receptor,
thereby preventing dyskinesia. More recently, a specific dopamine
D3 receptor activity has been identified and linked to a
neurotrophic effect. In tissue culture models of Parkinson's
disease, pramipexole protected neurons from specific dopaminergic
neurotoxins, while bromocriptine and pergolide had no such effect.
Pramipexole may also delay the need for levodopa and the development of
dyskinesla. End of dose wearing off is reduced in patients with more
advanced disease receiving pramipexole and levodopa.
Patients in the United States, Canada and Europe have been
treated with pramipexole in doses ranging from 0.1 mg to 5 mg daily.
No dose-limiting toxicity was identified. Tolerability and safety were
excellent with only occasional dizziness, nausea, vomiting, insomnia
or somnolence and visual hallucinations identified as primary side
effects. Symptomatic low blood pressure was not a significant side
effect. The half-life of pramipexole is about 9-12 hours, easily
allowing a three times a day schedule. The drug is excreted by the
kidneys so that patients with kidney problems may need to be
monitored closely for side effects.
Ropinirole (Requip(r), Smith, Kline and Beecham)
Ropinirole is a potent, highly selective, dopamine agonist,
not related to pramipexole or the ergot derived drugs, developed for
early therapy in Parkinson's disease patients not yet treated with
levodopa and as adjunct therapy in treating Parkinson's disease
patients not optimally controlled on levodopa. This potent D2-dopamine
agonist is active both centrally and peripherally with central
nervous system and cardiovascular activity seen. Antidepressant and
anxiolytic effects have also been noted in patients with
Parkinson's disease. Evidence of a possible neuroprotective effect
has been documented.
More than 300 patients with Parkinson's disease have
completed placebo-controlled studies of ropinirole, taking doses up
to 10 mg daily. Typical dopamineric side effects such as nausea,
vomiting and orthostatic hypotension may occur at doses above 0.5 mg.
Incremental dosage increases minimize these side effects, and the drug
is tolerated extremely well by the majority of patients. A three times
daily dosing schedule of lower doses given with meals allows for fewer
side effects and closer conformance to it's half-life of 3.5-5 hours.
Cabergoline (no brandname available, Pharmacia & Upjohn)
Cabergoline, an ergoline derivative related to bromocriptine
and pergolide, is a D2-specific dopaminergic agonist that is more
potent and longer-acting than other dopamine agonists currently used
to treat Parkinson's disease. In patients receiving levodopa, it
effectively decreases levodopa response fluctuations and allows for
lower levodopa doses. Plasma activity peaks between 0.5 and 4 hours
with a half-life of about 7.5 hours and a slower elimination of 68-72
hours.
Patients in Italy, the United States and Canada have been
treated with cabergoline once daily in dosages from 0.5 to 5.0 mg.
Side effects are typical for dopaminergic agents and can include
dizziness, nausea, dry mouth and orthostatic hypotension. Episodes
of visual hallucinations also occurred in a few patients. The once
daily schedule and long-acting effects offer greater compliance and
provide greater control of motor fluctuations than currently
available dopamine agonists. Unfortunately, this drug may not be
offered as an anti-parkinsonian agent, but instead may only be
marketed as a prolactin suppressing agent to stop lactation. At this
time, no efforts to market this drug for Parkinson's disease are
underway.
Two new dopamine agonists, chemically different than
currently used agents, are under review at the FDA for possible use
in the treatment of Parkinson's disease. Both agents have
demonstrated benefit in improving symptoms in patients with early
(untreated) and late (levodopa treated) Parkinson's disease.
Differences in benefit profiles, side effects and metabolism
of the drugs will allow patients to find the right medication for
their particular needs. If the potential of neuroprotection is born
out in future studies then these agents will truly be a major advance
in the treatment of Parkinson's disease. A third drug that offered
once a day dosing may never be released for Parkinson's disease
despite evidence of efficacy and safety.
The treatment options for patients diagnosed with
Parkinson's disease will be increased significantly with the
introduction of these new medications. Combining the right amount
and frequency of each medication in an individual will be more
complicated in some ways, yet simpler in other ways. One prediction
would be that newly diagnosed patients will begin therapy with
one of the new dopamine agonists. Later such patients might
consider adding one of the older drugs that offers additional hope
of neuroprotection, either amandatine or selegiline.
Another prediction Is that patients already taking levodopa,
either in the form of Sinemet(r) (primarily taken by US patients)
or Madopar(r) (used mainly in Europe), would want to consider addition
of a catechol-o-methyltransferase inhibitor, either tolcapone or
entacapone. Significant improvements in symptom control and reduced
wearing-off can be expected immediately. Both medications, work well
with either regular carbidopa/levodopa and the slow-release
formulation of Sinemet CR(r). Patients with a stable response to
levodopa should experience improvement without needing significant
adjustments in levodopa dosages. Some adjustments might be warranted
in patients with significant levodopa induced dyskinesia or other
dopaminergic side effects.
The introduction of these new medications will make 1997 one
of the most exciting years for advancements in the treatment of
Parkinson's disease. Patients, family members, caregivers, physicians
and health care systems all over the world will benefit, all because
of the diligent application of our rapidly growing understanding of
the functions of the human central nervous system. Given the pace of
progress over the last few years, a true understanding of the cause
and ultimate cure for Parkinson's disease should not be too far in
the future.
John Cottingham To search the Parkinsn archive, send search requests
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