Long-term effectiveness and quality of life improvement in entacapone-treated Parkinson's disease patients: the effects of an early therapeutic intervention

To evaluate the long-term effects of entacapone on both mean daily 'on' time and health-related quality of life (QoL) in patients with Parkinson's disease (PD) experiencing 'end-of-dose' motor fluctuations and the benefits of an early therapeutic intervention. A prospective, multicenter, observational, 12-month study was performed with an initial 3-month intervention phase, consisting of a phone call to half of the patients from randomly selected investigators to assess if dose adjustment was necessary. Effectiveness was determined by home diaries ('on' time), subscales II and III of the Unified Parkinson's Disease Rating Scale (UPDRS), and the Parkinson's Disease Questionnaire (PDQ-8). After 3 months of treatment, 4.0% of the intervention group patients discontinued the study, versus 18.4% in the control group ( P  < 0.01). The improvement in 'on' time was significantly increased since the 3-month visit (21%, P  < 0.0001) until the end of the study (23% at 12 months, P  < 0.0001). Entacapone also induced significant reductions in the UPDRS scores for subscales II and III and in the PDQ-8 score. 11.2% of patients experienced at least one adverse reaction. This study confirms the effectiveness of entacapone in reducing motor fluctuations by increasing 'on' time, and in improving QoL of PD patients. An early adjustment of entacapone and levodopa doses reduces the number of treatment discontinuations during the first months of treatment.     

Employment, medical absenteeism, and disability perception in Parkinson's disease: A pilot double-blind, randomized, placebo-controlled study of entacapone adjunctive therapy.

The objective of this study was to test the impact of entacapone (ENT) addition to levodopa with a decarboxylase inhibitor (LD) in full-time-employed patients with Parkinson's disease (PD), focusing on retirement rates, medical absenteeism, self-perception of disability, as well as motor assessments of parkinsonism, motor fluctuations, and dyskinesias. Thirty full-time-employed PD patients (disease onset before age 60 years) and on optimized monotherapy with LD exhibiting minor motor fluctuations or dyskinesias were entered into a 2-year randomized double-blind placebo-controlled study of ENT adjunctive therapy. The outcome measures were the number of full-time-employed patients at study end, cumulative days of medical absenteeism, patient-completed disability assessments, diary records, and the Unified Parkinson's Disease Rating Scale-based measures of motor fluctuations and dyskinesias. LD + ENT treatment was associated with a lower retirement rate (2 [17%] of 12 vs. 6 [50%] of 12; P = 0.12), lower absenteeism rate (21.5 vs. 43.5 days; P < 0.0001), improved self-perception of disability progression over 2 years (change score 1.0 vs. 4.5; P < 0.0001), and lower scores for both motor fluctuations and dyskinesia assessments compared to LD monotherapy. In this pilot study, LD with ENT adjunctive therapy positively influenced employment rate over 2 years; this effect was associated with reduced motor complications and patient perceptions of stabilized disability.     

Hepatotoxic profile of catecholOmethyltranferase inhibitors in Parkinson’s disease

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson’s disease (PD). They extend the duration of action of levodopa. As a result, they increase ‘on’ time, decrease ‘off’ time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.     

复方左旋多巴制剂的研究进展

左旋多巴治疗帕金森病有40多年的历史,一直是治疗帕金森病的主要药物。但长期应用左旋多巴后,会引起“开-关”现象和运动障碍等并发症,给患者带来极大的痛苦。提高临床疗效、减少并发症的发生,延缓帕金森病进程是治疗帕金森病的重点内容。现综述近年来复方左旋多巴制剂,包括目前临床使用中的药物和制药公司研发的药物的研究进展。     

恩他卡朋添加治疗症状波动的帕金森病的随机、双盲、安慰剂对照临床研究

目的:探讨添加恩他卡朋治疗PD患者剂末现象的疗效和安全性。方法:40例伴有剂末现象的PD患者进行随机、双盲、安慰剂、平行分组临床对照试验。根据患者日记记录的"开"、"关"期时间、UPDRS各部分评分、研究者总体评估变化量表和左旋多巴每日剂量来评定疗效。结果:恩他卡朋治疗12周时能显著延长"开"期时间、缩短"关"期时间,降低UPDRS评分,减少每日左旋多巴用量,研究者主观感觉65%的患者病情好转,与安慰剂组相比差异有显著意义。不良事件的发生率与安慰剂组相比差异无显著意义。结论:添加恩他卡朋治疗伴有剂末现象的PD患者安全、有效。     

Excessive daytime sleepiness and 'sleep attacks' induced by entacapone

Three patients with advanced Parkinson's disease, all of whom developed excessive daytime sleepiness and 'sleep attacks' after the administration of entacapone, are described. This is another demonstration that inappropriate daytime sleep episodes are not exclusive to dopamine agonists.     

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in l-DOPA/carbidopa treated rats

Summary. Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with l-DOPA (l-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of l-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with l-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. l-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 μl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with l-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation. Received June 30, 2000; accepted August 17, 2000     

Comparison of 200 mg retarded release levodopa/carbidopa – with 150 mg levodopa/carbidopa/entacapone application: pharmacokinetics and efficacy in patients with Parkinson’s disease

Summary. The interval of line tracing performance is more associated to basal ganglia function due to the dependence on bradykinesia and rigidity. The other component of this task, the precision of execution of complex movement sequences, is more related to attention. We compared the motor response after once dosing of 200 mg retarded release LD (levodopa)/CD (carbidopa) and of 150 mg LD/CD/EN (entacapone) by rating of motor symptoms, by measurement of LD- and 3-O-methyldopa (3-OMD) plasma concentrations and by the outcomes of a line tracing task. Thirteen treated patients with Parkinson’s disease (PD) took one of the two tested LD formulations on two consecutive days under randomised, double blind, identical standardised conditions. No significant differences appeared regarding rated motor response and LD plasma concentrations, but 3-OMD only significantly went up after LD/CD intake. LD/CD/EN was superior to LD/CD regarding the attention related components of line tracing probably due to a hypothetically increased dopamine occurrence at the prefrontal cortex, which guides human behaviour.     

Entacapone to tolcapone switch: Multicenter double‐blind,randomized, active‐controlled trial in advanced Parkinson's disease

This double‐blind study examined the efficacy and safety of replacing entacapone with tolcapone in fluctuating Parkinson's disease (PD) patients. Patients receiving entacapone for ≥15 days were randomly assigned to continue entacapone (n = 75) or switch to tolcapone (n = 75) and were followed up for 3 weeks. Efficacy measures included changes in on time (without disabling dyskinesia) and an investigator's global assessment (IGA). The on time increased by ≥1 hour/day (primary efficacy measure) in 43% of entacapone‐treated patients and 53% of tolcapone‐treated patients, and by ≥3 hours/day in 13% and 25%, respectively. The IGA indicated moderate/marked improvements in 25% of entacapone patients and 39% receiving tolcapone. Response rates (the proportion of patients with ≥1 hour/day increase in on time and improvements on IGA) were 17% with entacapone and 32% with tolcapone. Dyskinesia was the most common adverse event affecting 29% of entacapone and 31% of tolcapone recipients. One patient in each group had elevated liver enzymes, resulting in treatment withdrawal (levels returned to normal thereafter in both cases). In conclusion, within the limits of the protocol, there was a tendency for tolcapone to offer enhanced efficacy in patients with fluctuating PD, despite optimized entacapone therapy. Tolcapone can be considered, therefore, for patients whose motor fluctuations are inadequately controlled by their existing regimen. © 2006 Movement Disorder Society     

Delayed administration may improve entacapone effects in parkinsonian patients non-responding to the drug

BACKGROUND: Entacapone is a COMT inhibitor used in Parkinson's disease (PD) patients, as an adjunctive therapy to L-dopa in order to prolong its bioavailability and thus its clinical effect. However, previous studies reported entacapone-induced L-dopa to have lower C(max) and delayed t(max) values, coupled with a delayed onset of the clinical effect, possibly suggesting an interference between the two drugs. The aim of our study was to evaluate whether a delayed entacapone administration in association with standard L-dopa/carbidopa, may in some subjects improve the entacapone effects on L-dopa AUC and thus on the clinical 'on time' duration. METHODS: Twenty-eight idiopathic advanced PD patients were blindly evaluated in three different test days, following administration of carbidopa/L-dopa or carbidopa/L-dopa plus co-administered entacapone or plus entacapone administered with 30 min of delay. RESULTS: The AUC, the 'on time' and UPDRS score of the whole group were improved by both modalities of entacapone administration. An ex post analysis showed that the delayed entacapone administration produced a significant improvement in a subgroup of 10 non-responding patients to the co-administration. CONCLUSION: We suggest that the delayed administration should be attempted in the subjects not improved by entacapone co-administration.