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Age-related Neurodegenerative Disease Parkinson’s Disease
Evidence for the Use of Levodopa–Carbidopa–Entacapone (STALEVO) to
Improve Motor Fluctuations in Parkinson’s Disease
a report by
Philippe Damier
French National Institute for Health and Medical Research (INSERM), CIC0004, UMR 643, University Hospital Nantes, and
CIC0004, Pôle Neurosciences, University Hospital Nantes
Levodopa is the logical treatment in Parkinson’s disease (PD) as it of entacapone to the formulation increases the availability of levodopa in
replaces dopamine that is lost due to the neurodegenerative nature of the plasma (see Figure 1B).
the disease. It could be considered a natural agonist and remains the
most effective dopaminergic replacement therapy. However, in many Levodopa–Carbidopa–Entacapone Is an Effective and
patients the efficacy of long-term conventional levodopa therapy is Well-tolerated Treatment to Reduce Motor Fluctuations
hampered by its association with the progressive development of STALEVO has been shown to increase the bioavailability of levodopa by
motor fluctuations.
1
Initially, PD symptoms reoccur after prolonged 35–40% in plasma and prolongs its elimination half-life from 1.3 to 2.4
levodopa intake due to progressive shortening of the drug effect hours. The addition of entacapone to each dose of levodopa–
duration (the so-called ‘wearing-off’ phenomenon), resulting in the carbidopa given three to five times a day leads to a less pulsatile profile
reappearance of disabling PD symptoms, as well as dyskinesia. Motor of plasma levodopa levels by avoiding deep troughs (see Figure 1B).
6
fluctuations can become more difficult to manage with late (delayed- Four six-month prospective, randomised, double-blind, placebo-
‘on’ phenomenon) or even the absence (no-’on’ phenomenon) of controlled phase III efficacy studies involving over 1,000 patients
beneficial effects of levodopa intake. Problematic motor fluctuations worldwide have demonstrated that adding entacapone to conventional
can also result from a rapid and sudden reoccurrence of PD symptoms
during a successful ‘on’ that is induced by a single dose of levodopa
(‘on–off’ phenomenon).
Levodopa is the logical treatment in
The classic consensus is that about 50% of patients develop motor
Parkinson’s disease as it replaces
fluctuations after five years of levodopa treatment.
2
However, recent
studies have suggested that the frequency is even higher. In the
dopamine that is lost due to the
Deprenyl and Tocopherol Antioxidative Therapy for Parkinson’s
neurodegenerative nature of the disease.
Disease (DATATOP) study, 20% of the patients developed motor
fluctuations after six months of conventional levodopa treatment and
50% suffered from complications after 18 months.
3
Due to the
disability caused by the reappearance of motor PD symptoms, motor levodopa/DDCI significantly improves motor fluctuations.
7–10
The
fluctuations create a real burden for patients and have a negative severity of motor fluctuations was assessed through the home diaries of
impact on their quality of life;
4
accordingly, there is a real need for patients. Patients recorded ‘on’ and ‘off’ times and ‘on’ times with
physicians to take on the challenge of correcting motor fluctuations dyskinesia experienced every hour. The extent of therapeutic response
for the benefit of their patients. Moreover, evidence also suggests that was also determined by Unified Parkinson’s Disease Rating Scale
a non-optimised dopamine replacement strategy, reflected by the (UPDRS) scoring by an examiner. In NOMECOMT (the Nordic
presence of motor fluctuations, could be responsible for a deleterious Multicenter Study on Entacapone, the Catechol-O-Methyltransferase
brain plasticity that, with time, could reinforce the fluctuations and Inhibitor Trial),
8
the addition of entacapone to levodopa–carbidopa
contribute to the development of dyskinesia, another complication significantly increased the mean daily ‘on’ time by 1.2 hours compared
induced by conventional levodopa therapy.
5
with placebo (see Figure 2). In CELOMEN, a six-month randomised,
placebo-controlled, double-blind study conducted in Germany and
For decades, levodopa has been co-administered with a dopa Austria,
9
the addition of entacapone to each daily dose of standard
decarboxylase inhibitor (DDCI) – carbidopa or benserazide – which or controlled-release levodopa significantly decreased the ‘off’ time
prevents levodopa from being metabolised into dopamine before by 1.6 hours compared with 0.9 hours in the placebo-treated group
entering the brain. Peripheral dopamine does not cross the (see Figure 3).
blood–brain barrier and, moreover, is responsible for side effects such
as hypotension and nausea. More recently, the fixed combination The reduction of motor fluctuations leads to significant improvements in
levodopa–carbidopa–entacapone (STALEVO), a new formulation that patient function. In the NOMECOMT study, motor scores decreased (i.e.
combines levodopa, carbidopa and entacapone, an inhibitor of catechol- improved) in the patients treated with levodopa–DDCI and entacapone
O-methyl transferase (COMT), has been approved for the treatment of from 25.5 to 22.5 points. In comparison, conventional levodopa plus
adult patients with PD and end-of-dose motor fluctuations not stabilised placebo resulted in a decrease from 24.6 to 23.8 points; the difference
on levodopa/DDCI treatment. The enzyme COMT catabolises peripheral between the groups was statistically significant (p<0.05). In the CELOMEN
levodopa to 3-O-methyldopa (3-OMD) (see Figure 1A); thus, the addition study, activities of daily living (ADL) scores improved in fluctuating patients
© TOUCH BRIEFINGS 2008 37
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