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Movement Disorders, Parkinson's Disease
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Long-term Efficacy of Entacapone in Patients with Parkinson’s Disease and Motor Fluctuations – A Six-year Clinical Follow-up Study

Published Online: June 4th 2011
Authors: Angelo Antonini, Gianni Pezzoli, Ioannis U Isaias, Margherita Canesi, Roberto Cilia
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Abstract
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Abstract:
Overview

Introduction

Levodopa is the most effective drug in the treatment of Parkinson’s disease (PD) but its administration has been associated with the development of motor fluctuations (wearing off, ‘on-off ’ phenomenon, and dyskinesias) with a frequency of 5–10% per year. Under normal circumstances, dopamine neurons in the substantia nigra pars compacta (SNc) fire continuously at a relatively slow rate,1 resulting in striatal dopamine receptors being exposed to relatively constant levels of dopamine. In PD, due to the progressive degeneration of nigral dopaminergic neurons, striatal dopamine levels become increasingly dependent on the peripheral availability of exogenously administered levodopa. The presence of alternating high and low levels of dopamine results in “pulsatile stimulation of striatal dopamine receptors”.2 This abnormal and intermittent activation of denervated striatal dopamine receptors may induce plastic changes in striatal neurons,3 dysregulation of genes and proteins,4 and alterations in neuron firing patterns,5 ultimately leading to the emergence of motor complications.

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The additional administration of an aromatic amino acid decarboxylase inhibitor markedly reduces the rate of peripheral levodopa degradation, and the additional inhibition of the enzyme catechol-O-methyltransferase (COMT), which peripherally metabolizes levodopa to 3-O-methyldopa, further enhances the anti- Parkinsonian clinical effect by increasing levodopa bioavailability without altering the peak concentration.6 Drugs that inhibit COMT were developed as a means of blocking the peripheral metabolism of levodopa and thereby modifying levodopa pharmacokinetics to extend its half-life 7,8 and provide more continuous availability of levodopa to the brain, and more continuous dopaminergic stimulation (CDS) of brain dopamine receptors.9

The authors studied the clinical effects of long-term administration of the COMT inhibitor entacapone on motor performance and pharmacological compensation in advanced PD patients with motor fluctuations.

Table 1: Demographics at Baseline and History of Parkinson’s Disease
SD = standard deviation.

Methods

Forty-seven patients with advanced PD and motor fluctuations, whose demographics are detailed in Table 1, were followed for six years from the first prescription of entacapone (baseline visit). All patients had been followed at the authors’ Parkinson outpatient facility for many years; all of them were non-demented and fulfilled UK brain bank diagnostic criteria for PD.10

The authors analysed mean dopaminergic drug dosage variations (dopamine agonists in levodopa equivalents 11), mean daily ‘off ’ period duration (extrapolated from the number of levodopa intakes required to cover wearing-off periods), disease progression (Unified Parkinson’s Disease Rating Scale (UPDRS) part III; Hoehn and Yahr stage), disability score (UPDRS part II-activities of daily living (ADL)) and adverse events (AE). Entacapone was associated with each levodopa consumption during the day. Statistical analysis was by two-way analysis of variance (ANOVA) (repeated measures); significance was set at p<0.05 corrected.

Results

Motor fluctuations appeared after 6.8±3.4 years from disease onset and entacapone was introduced 4.9±3.5 years later (11.8±3.8 years from symptom onset). The clinical features at baseline and at one-year, three-year and six-year follow-up are summarized in Table 2.These included mean L-dopa and dopamine-agonist dosage, number of levodopa tablets consumed, UPDRS II and III, and Hoehn and Yahr stage. Statistical analysis did not show any significant change in either mean daily drug dosage and number of doses or in motor performance and disability scores during the six-year follow-up compared with baseline. However, mean total dopaminergic (levodopa + dopamine agonists) dose was reduced in 32% of cases (n=12); the decrease was in the range of 1.9% to 27%.

Table 2: Clinical Features at Baseline and Follow-up
Values are given as mean (standard deviation). ADL = activities of daily living, UPDRS = Unified Parkinson’s Disease Rating Scale.

Adverse events are detailed in Table 3. The most common of these dopaminergic side effects is increased dyskinesia (36.2%). Other side effects were insomnia (12%) and nausea and abdominal pain (6%). In the authors’ cohort, only one case of diarrhea was reported. No cases of hepatotoxicity and liver dysfunction were noted. Overall, all patients discontinued entacapone during the first three years of treatment and 12 patients did not reach the sixth year of follow-up. Only two patients sought to withdraw medication because of adverse events unresponsive to entacapone dosage reduction and the causes were abdominal pain in one case and dyskinesia in the other.Three patients dropped out at follow-up visits: two patients ceased entacapone intake because they underwent deep brain stimulation and one underwent subcutaneous apomorphine infusion. Five patients started entacapone in the three-year period from 2000 to 2002.

Table 3: Adverse Events

Discussion

The authors collected clinical data from 47 patients with advanced PD and motor fluctuations over a period of six years. The results confirm that treatment with entacapone improves the efficacy of levodopa in patients with advanced PD experiencing motor fluctuations and are consistent with several prospective, double-blind placebo-controlled trials.12,13 Indeed, during the six-year follow-up, the absence of an increase in the mean drug dosage and in the number of doses suggests that entacapone can maintain adequate inhibition of COMT over time, allowing better management of levodopa treatment.

The safety profile is substantially in accordance with reported results from other studies,12,14,15 although the authors found a lower incidence of diarrhea. The most common adverse event was increased dyskinesia (36.2%), reflecting greater bioavailability of levodopa; it was successfully managed with a reduction in levodopa dose rather than withdrawal of entacapone. Overall, it is concluded that the introduction of entacapone to the current treatment schedule of advanced PD patients allows a stabilization of motor conditions.

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