Long-term Efficacy of Entacapone in Patients with Parkinson's Disease and Motor Fluctuations - A Six-year Clinical Follow-up Study
Long-term Efficacy of Entacapone in Patients with Parkinson's Disease and Motor Fluctuations - A Six-year Clinical Follow-up Study
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.
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.
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.
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