Evidence for the Use of Levodopa–Carbidopa–Entacapone (STALEVO) to Improve Motor Fluctuations in Parkinson’s Disease

Evidence for the Use of Levodopa–Carbidopa–Entacapone (STALEVO) to Improve Motor Fluctuations in Parkinson’s Disease

Damier Philippe
Published: European Neurology - Volume 3 Issue 2
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Levodopa is the logical treatment in Parkinson’s disease (PD) as it replaces dopamine that is lost due to the neurodegenerative nature of the disease. It could be considered a natural agonist and remains the most effective dopaminergic replacement therapy. However, in many patients the efficacy of long-term conventional levodopa therapy is hampered by its association with the progressive development of motor fluctuations.1 Initially, PD symptoms reoccur after prolonged levodopa intake due to progressive shortening of the drug effect duration (the so-called ‘wearing-off’ phenomenon), resulting in the reappearance of disabling PD symptoms, as well as dyskinesia. Motor fluctuations can become more difficult to manage with late (delayed- ‘on’ phenomenon) or even the absence (no-’on’ phenomenon) of beneficial effects of levodopa intake. Problematic motor fluctuations 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).

The classic consensus is that about 50% of patients develop motor fluctuations after five years of levodopa treatment.2 However, recent studies have suggested that the frequency is even higher. In the Deprenyl and Tocopherol Antioxidative Therapy for Parkinson’s 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 fluctuations create a real burden for patients and have a negative impact on their quality of life;4 accordingly, there is a real need for physicians to take on the challenge of correcting motor fluctuations for the benefit of their patients. Moreover, evidence also suggests that a non-optimised dopamine replacement strategy, reflected by the presence of motor fluctuations, could be responsible for a deleterious brain plasticity that, with time, could reinforce the fluctuations and contribute to the development of dyskinesia, another complication induced by conventional levodopa therapy.5

For decades, levodopa has been co-administered with a dopa decarboxylase inhibitor (DDCI) – carbidopa or benserazide – which prevents levodopa from being metabolised into dopamine before entering the brain. Peripheral dopamine does not cross the blood–brain barrier and, moreover, is responsible for side effects such as hypotension and nausea. More recently, the fixed combination levodopa–carbidopa–entacapone (STALEVO), a new formulation that combines levodopa, carbidopa and entacapone, an inhibitor of catechol- O-methyl transferase (COMT), has been approved for the treatment of adult patients with PD and end-of-dose motor fluctuations not stabilised on levodopa/DDCI treatment. The enzyme COMT catabolises peripheral levodopa to 3-O-methyldopa (3-OMD) (see Figure 1A); thus, the addition of entacapone to the formulation increases the availability of levodopa in the plasma (see Figure 1B).

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