From Medscape Neurology & Neurosurgery

Parkinson's Disease Expert Column

The Future of Levodopa Therapy for Parkinson's Disease
Posted 09/22/2003

Robert A. Hauser, MD, MBA, Kelly E. Lyons, PhD, Rajesh Pahwa, MD



Introduction
Levodopa, the chemical precursor of dopamine, has been used in the
treatment of Parkinson's disease (PD) for more than 30 years. Despite the
development of several new medications for controlling PD symptoms,
levodopa remains the most efficacious treatment. Levodopa has been
combined with peripheral decarboxylase inhibitors, such as carbidopa, to
reduce the incidence of nausea.

Compared with dopamine agonist medications, levodopa achieves therapeutic
dose levels in a relatively short time, with simple dosing and fewer short-term
adverse effects, such as hallucinations, somnolence, and pedal edema.[1] The
major disadvantage of long-term use of levodopa is that the patient may
develop motor fluctuations and dyskinesias.[2,3] Motor complications occur
in PD because of both disease progression and levodopa pharmacokinetics.
The half-life of levodopa, when administered with carbidopa, is
approximately 90 minutes.

Pathophysiology of Motor Fluctuations

Before individuals develop clinical symptoms of PD, they already will have
lost 50% to 60% of nigrostriatal dopamine neurons, with a corresponding
reduction of approximately 70% to 80% in striatal dopamine
concentration.[4] Normally, dopamine neurons release dopamine in a
relatively constant manner. In early disease, surviving neurons are still able to
take up levodopa, store it as dopamine, and slowly release it over time in a
continuous fashion. As the disease progresses, more dopamine neurons die
and this "buffering capacity" is lost.[5]

Clinically, patients begin to notice that the beneficial effects of levodopa last
a few hours and then diminish (wearing off motor fluctuations). As more
dopamine neurons are lost, a patient's clinical response more closely mirrors
fluctuations in blood levodopa concentrations. Ultimately, the beneficial
response to levodopa may last 1 or 2 hours and then wear off. In addition,
with the loss of the buffering capacity, postsynaptic dopamine receptors are
exposed to fluctuating dopamine concentrations. These fluctuations appear to
cause a receptor sensitivity that is expressed clinically as twisting, turning
movements called dyskinesias. When levodopa-derived brain dopamine is
"too high," the patient experiences dyskinesias, and when the brain dopamine
concentration is "too low," PD symptoms return. This creates a therapeutic
window that progressively narrows over time. Once a patient exhibits
dyskinesias and motor fluctuations, the addition of more dopamine
medication will increase dyskinesias; a reduction in dopamine medication will
increase "off" time, wherein PD symptoms return.




--------------------------------------------------------------------------------




Robert Hauser, MD, MBA, Director, Parkinson's Disease and Movement
Disorders Center; Departments of Neurology, Pharmacology, and
Experimental Therapeutics, University of South Florida and Tampa General
Healthcare, Tampa, Florida

Kelly Lyons, PhD, Research Associate Professor, Department of Neurology,
University of Kansas Medical Center, Kansas City

Rajesh Pahwa, MD, Associate Professor of Neurology; Director, Parkinson
Disease and Movement Disorder Center, University of Kansas Medical
Center, Kansas City


Disclosure: Dr. Hauser has disclosed that he has served on the advisory board
for Roche Laboratories, GlaxoSmithKline, Athena Neurosciences,
Pfizer/Pharmacia, Medtronics, Novartis, Teva Pharmaceuticals, Watson
Laboratories, and Somerset Pharmaceuticals. He has served as a consultant
for Roche, Somerset, Merck Germany, and Kyowa, and on the speaker's
bureaus of Roche, GSK, Athena Neurosciences, Pfizer/Pharmacia,
Medtronics, Teva, Novartis, and Somerset. Dr. Hauser has also served as an
investigator for Roche, GSK, Athena, Pfizer/Pharmacia, Medtronics,
Novartis, Teva, Somerset, and Kyowa. He has reported that he discusses the
unlabeled uses of levodopa/carbidopa/entacapone (Stalevo) and levodopa
plus entacapone as initial levodopa therapy in Parkinson's disease.

Disclosure: Dr. Lyons has disclosed that she has received grants for
educational activities from Medtronic.

Disclosure: Dr. Pahwa has disclosed that he has received grants for
educational activities and clinical research from, and has served as an advisor
or consultant for, Medtronic. He has had financial relationships with Glaxo,
Teva, Novartis, and Pharmacia.

Medscape Neurology & Neurosurgery 5(2), 2003. © 2003 Medscape


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Preventing Motor Fluctuations and Dyskinesias

Potential strategies to prevent the development of motor fluctuations and
dyskinesias in patients with PD include using medications that would slow or
stop the progression of the disease or using symptomatic medications that
have longer half-lives, thereby preventing pulsatile stimulation of
postsynaptic receptors. Another possibility would be to deliver levodopa to
the brain in a more continuous fashion. Thus far, no medication has
definitively slowed or stopped the progression of PD, although several
medications are under investigation.

Continuous Dopaminergic Stimulation (CDS)

The CDS hypothesis suggests that symptomatic treatment strategies that
provide more continuous dopaminergic stimulation can curtail the emergence
of motor fluctuations and dyskinesias. Studies have shown that initial use of
dopamine agonists with relatively long half-lives can delay the onset of motor
fluctuations and dyskinesias. Investigations have demonstrated that using
long-acting dopamine agonists to treat PD symptoms in 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP)-treated primates results in a lower
incidence of dyskinesias than using levodopa .[6,7] On the basis of these
primate studies, several clinical trials have been conducted to compare the
initial use of dopamine agonists with levodopa in patients with early PD.[2,3]

Dopamine Agonist Studies

Ropinirole is a long-acting dopamine agonist with a half-life of approximately
6 hours. In a 5-year study,[2] 268 de novo PD patients were randomized to
receive levodopa or ropinirole as initial therapy. Additional levodopa could
be administered for better symptomatic control in either group, as required.
PD symptoms improved in both groups, but the benefit was significantly
greater for patients in the levodopa group. However, significantly more
patients in the levodopa group developed dyskinesias (45%) than in the
ropinirole group (20%). Adverse effects, such as hallucinations, somnolence,
and peripheral edema, were more common in the ropinirole group.

Another study -- this one using the long-acting dopamine agonist pramipexole
-- produced similar results.[3] In this 2-year trial, 301 patients with early PD
who required dopaminergic therapy were randomized to receive either
pramipexole or levodopa, to which additional levodopa could be added, if
necessary. At 2 years, patients assigned to receive levodopa demonstrated
greater improvement in motor function than did patients assigned to receive
pramipexole. However, 51% of patients taking levodopa developed wearing
off, dyskinesias, or on-off motor fluctuations, compared with 28% of patients
taking pramipexole. Short-term adverse effects were higher in the
pramipexole group than in the levodopa group.

Both of the above-mentioned clinical trials demonstrated that initial use of a
long-acting dopamine agonist, to which levodopa could be added, caused
fewer motor fluctuations and dyskinesias. Furthermore, these studies showed
that the MPTP primate model of PD is predictive of what occurs in PD
patients, and the results are consistent with the CDS hypothesis.

Continuous Levodopa Administration

Another strategy for providing CDS is to administer levodopa in a more
continuous fashion. If this could be achieved, motor complications might be
avoided, while at the same time providing greater symptomatic benefit and
causing fewer short-term side effects than dopamine agonists. In patients with
motor fluctuations and dyskinesias, experience has demonstrated that
continuous enteral infusion of levodopa provides more continuous plasma
levels, compared with oral doses, and results in reductions in both off periods
and dyskinesias.[8] However, providing levodopa by continuous enteral
infusions is very impractical for PD patients, especially in early disease.

Other potential strategies involve administering smaller levodopa doses closer
together or using the controlled-release formulation. However, both of these
strategies have been found to be associated with high variability of levodopa
blood concentrations and do not seem to provide continuous dopamine
stimulation.[9]

Catechol-O-methyltransferase (COMT) Inhibitors

Another strategy for providing CDS is to prolong the half-life of levodopa
through the addition of a COMT inhibitor, such as entacapone. Entacapone is
a peripheral COMT inhibitor that reduces the peripheral catabolism of
levodopa, thereby increasing its half-life to approximately 2.25 hours.[10-12]
Thus, a greater amount of levodopa is delivered to the brain over a longer
time period. In PD patients with motor fluctuations, the addition of
entacapone to levodopa therapy results in reductions in off periods.[13,14] At
the same interdose interval, levodopa blood concentrations fluctuate less with
levodopa/carbidopa plus entacapone than with levodopa/carbidopa alone,
which raises the possibility that initiation of entacapone at the same time that
levodopa is introduced could provide CDS and reduce the development of
motor complications.

Using the MPTP primate model, Jenner and colleagues[15] compared
levodopa/carbidopa with levodopa/carbidopa plus entacapone.
Administration of levodopa/carbidopa on a 3-hour dosing schedule (4
administrations per day) resulted in rapid induction of severe dyskinesias.
However, when levodopa/carbidopa (at the same dose and on the same
schedule) was administered with entacapone, significantly less dyskinesia
occurred, with comparable improvement in parkinsonian signs.

The study by Jenner and colleagues provides strong support for the CDS
hypothesis because the same agent (levodopa) was demonstrated to cause
fewer dyskinesias when administered in a more continuous way (with
entacapone). In addition, the study suggests that use of entacapone starting at
the time levodopa is introduced should curtail the emergence of motor
complications in PD patients. Clinical trials to definitively evaluate this are
now in development. Important considerations include the optimal dose and
interdose interval required to achieve CDS.

-------------------------------------------------------------------

CDS in Clinical Practice

To maximize the use of CDS in clinical practice, young PD patients might be
treated initially with a dopamine agonist, and when the agonist alone is no
longer sufficient to control symptoms, levodopa/carbidopa plus entacapone
could be added. For patients who are not good candidates for dopamine
agonists (eg, older individuals and those with cognitive impairment),
levodopa/carbidopa could be used together with entacapone from the time
symptomatic treatment is first required.

The concurrent use of levodopa/carbidopa plus entacapone is now facilitated
by the availability of a levodopa/carbidopa/entacapone combination
product.[16] It is available in 3 dose combinations: 50 mg levodopa/12.5 mg
carbidopa/200 mg entacapone, 100 mg levodopa/25 mg carbidopa/200 mg
entacapone, and 150 mg levodopa/37.5 mg carbidopa /200 mg entacapone.
The combination product provides greater convenience than using separate
products because fewer pills are required. In addition, the 2 lower-dose
tablets are smaller than entacapone tablets, and the combination product is
less expensive than purchasing the products separately.

Thus, the levodopa/carbidopa/entacapone combination product can be used
when levodopa is first required to improve PD symptoms. Similar to
levodopa/carbidopa, the triple combination product should provide the
greatest symptomatic benefit with the fewest short-term side effects. In
addition, preclinical evidence suggests that this triple combination should
provide the additional benefit of causing fewer motor complications over the
long term.

=====================================

Best,

Bob

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Robert A. Fink, M. D., F.A.C.S., P. C.
2500 Milvia Street  Suite 222
Berkeley, California  94704-2636
Telephone:  510-849-2555   FAX:  510-849-2557
WWW:  http://www.rafink.com/

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