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Background: Levodopa-entacapone-carbidopa intestinal gel (LECIG) was introduced on the Swedish market in 2019. The therapy is aimed at patients with Parkinson's disease (PD) with fluctuations and dyskinesias. Long-term efficacy and safety data are lacking., Objective: To investigate the efficacy, tolerability, and safety of LECIG in regular clinical practice for Parkinson's disease in Sweden., Methods: Real-world data were collected from the Swedish registry for Parkinson's disease (ParkReg) for all patients reported to receive LECIG during the period from 2019 until 31 August 2022., Results: A total of 150 patients were identified. Sixty-one (41%) of 150 patients were females. At the start of treatment, the median age was 73 years (range: 43-86). The median duration since motor symptoms onset was 17 years (IQR: 9). Fifty (33%) of 150 patients switched from another device-assisted therapy, mostly LCIG (39 patients). Reported complications were mainly related to PEG-J tube and stoma (30%). Twenty (13.3%) of 150 patients discontinued LECIG and 11 (7.3%) patients died while on LECIG. The Parkinson KinetiGraph scores for bradykinesia, dyskinesia, fluctuations, tremor, and immobility for 53 patients during LECIG showed good therapy control. The median (IQR) p-Hcy during LECIG was 12 (4.6) μmol/L (n = 44). The median (IQR) PDQ-8 summary index during LECIG was 31 (17) (n = 52). The median (IQR) EQ5D during LECIG was 0.62 (0.32) (n = 41)., Conclusions: Data from ParkReg covering 150 patients over 3 years show LECIG to be an effective and safe device-aided therapy for advanced PD. However, the long-term efficacy and tolerability of LECIG need to be further investigated., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is a recently developed device-aided therapy for advanced Parkinson disease (PD) patients. The aim of this study was to report real-world evidence about the effectiveness, tolerability, and safety of LECIG in PD patients., Methods: A multicenter observational retrospective study of the first patients who initiated LECIG in Spain was performed. All neurologists with an experience of at least two patients treated until 30 March 2024 were invited to participate. Data about effectiveness and safety from the medical records (V0, pre-LECIG; V1, initiation of LECIG; V2, post-LECIG follow-up) with a total of 246 variables were collected., Results: Seventy-three PD patients (61.6% males, 70.1 ± 9.1 years old) from 21 Spanish centers with a mean disease duration of 14.4 ± 6.3 years (range = 5-31) were included. Twenty-six patients (35.6%) were switched directly from levodopa-carbidopa intestinal gel. The mean exposure to LECIG was 177.3 ± 110.5 days (range = 7-476). The mean daily OFF time decreased from 5.2 ± 3 (pre-LECIG) to 1.9 ± 1.8 (post-LECIG; n = 66, p < 0.0001). Global improvement was observed in >85% of the patients. No significant change was detected in the levodopa equivalent daily dose from V0 to V2. Only 7% received 24-h infusion, and 24.7% required more than one cartridge per day at V2. Thirty-four patients (46.6%) had at least one adverse event related to LECIG and/or the device system. Five patients (6.8%) discontinued LECIG., Conclusions: LECIG was safe and effective in advanced PD patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021., Study Question: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD?, Study Design: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania., Measures and Outcomes: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted., Results: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications., Conclusions: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen., Competing Interests: J. A. Szász consultant and speaking honoraria: AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, and UCB. V. A. Constantin speaking honoraria: AbbVie, Bayer, UCB, Pfizer, Stada, Ewopharma, Lundbeck and Wörwag Pharma. A. O. Dulamea has served as a scientific advisor or speaker for Novartis, Merck, Roche, Sanofi Genzyme, Genesis Pharma, Krka, Gedeon Richter, Eli Lilly, Wörwag Pharma, Zentiva, Takeda, Janssen, AbbVie, and Stada. C. Tiu speaker's honoraria from Merck, Genzyme, Roche, Janssen, Novartis, Boehringer Ingelheim, and Pfizer. L. P. Dumbravă consultant and speaking honoraria: Sanofi, Roche, SC Bayer, UCB Pharma, Ipsen Pharma, Bristol Myers Squib, Pfizer, AbbVie, Stada M&D, and Vedra International. A. Ene speaker honoraria: AbbVie, Stada, Pfizer, Genesis, and Worwag. M. Lungu speaker honoraria from AbbVie, Boehringer-Ingelheim, Stada M&D, and Bayer. A. Axelerad speaker honoraria from AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, UCB, Wörwag Pharma, Sanofi, Krka, Gedeon Richter, Eli Lilly, Zentiva, Takeda, Janssen, Zentiva, Merck, Roche, and Ipsen Pharma. M. Simu honoraria for advisory boards and educational lectures from: AbbVie, Astra Zeneca, Biogen, Boehringer Ingelheim, Pfizer, UCB, Servier, Teva, Merck, Ever Pharma, Roche, and Novartis A. G. Danci speaker honoraria from Teva, Stada and Ipsen Pharma. Sabău Monica consultant and speaking honoraria: Bayer, AstraZeneca, Roche, AbbVie, Pfizer, Novartis, Sanofi, Johnson& Johnson, Merk, Stada, SunWave Pharma, Ewopharma, Krka, and Elly Lilly. C. Falup-Pecurariu received royalties from Elsevier and Springer Verlag honoraria from AbbVie and the International Parkinson's Disease and Movement Disorders Society, outside of the present work. Ş. Strilciuc discloses an academic grant from Pfizer Inc (Delaware, US), unrelated to this manuscript. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder. The main neuropathological cause of the disease is the death of dopaminergic neurons in the substantia nigra. Unfortunately, there is no curative treatment yet. The gold-standard of the treatment is levodopa (LD). During the course of the disease, motor complications develop, which postulates the addition of entacapone (ENT) to the dopaminergic medication. Previous studies have suggested that patients have a better quality of life when entacapone is added in a combination with LD., Areas Covered: A systematic literature search was performed. Articles were identified through PubMed (MEDLINE), Web of Science, Ovid, and ClinicalTrials.gov databases. The following search terms were used: 'Levodopa' AND 'Carbidopa' OR 'Benserazide' AND 'Entacapone'. The search period was between 2000 and 2020. Twenty randomized and 10 non-randomized clinical trials (12,893 subjects) were included in the qualitative analysis. The systematic review was written in line with the PRISMA guideline., Expert Opinion: ENT administered in combination with LD resulted in a better quality of life compared to separate tablets. Therefore, in PD patients where impaired motor performance develops and the application of entacapone is necessary, it is suggested to be administered in a single tablet form.

Background: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response., Objective: The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone., Methods: Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined., Results: Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review., Conclusions: Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness.

Entacapone is frequently used together with levodopa/carbidopa (LC) and levodopa/benserazide (LB) in the treatment of Parkinson's disease (PD) patients with wearing-off symptoms. It is generally assumed that the effects of entacapone are independent of the type of decarboxylase inhibitor used, but there is very little published data available on the efficacy of entacapone administered with LB versus LC. We have performed a pooled analysis of three randomized, double-blind, 6-month, phase III studies to compare the treatment effects of entacapone (compared to placebo) in PD patients receiving LC or LB. A total of 551 PD patients experiencing wearing-off were included in the analysis. 300 patients were on LB and 251 on LC at baseline. At 6 months, entacapone (compared to placebo) improved mean daily OFF-time in patients on LB and LC by 0.76 (p = 0.016) and 0.95 (p = 0.011) hours, respectively. The corresponding improvements in ON-time were 0.97 (p = 0.002) and 0.83 h (p = 0.022), respectively. The treatment effects of entacapone both in LB and LC users were statistically significant (p < 0.05) also in UPDRS II and III scores, except in UPDRS II scores in patients receiving LC (p = 0.20). None of the treatment effects of entacapone were statistically significantly different between patients receiving LB or LC. Reported adverse events were comparable between LB and LC users. We conclude that entacapone provided comparable benefits in PD patients with wearing-off symptoms using either LB or LC.

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax ) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD---LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively., (© 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours., Objective: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting., Methods: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided., Results: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE., Conclusions: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Background and Objectives: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone., Methods: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose., Results: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments., Conclusion: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.

The unique needs of patients with Parkinson disease challenge staff when such patients are admitted to hospitals or nursing facilities. Prolongation of the hospital stay, falls with injuries, fainting, or declining motor function may result from therapeutic misadventures or failure to anticipate common problems. Staff familiarity with Parkinson disease, and especially carbidopa-levodopa dosing and dynamics, may prevent such problems and streamline hospital and nursing home care., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy and tolerability of the three component drug stalevo in the treatment of patients with Parkinson's disease (PD)., Material and Methods: We analyzed the experience of using the antiparkinsonian drug stalevo (levodopa/carbidopa/entacapone) in the treatment of acute stages of PD and elderly patients with restricted possibilities of using other antiparkinsonian drugs. The study included 47 patients. A clinical example is presented. RESULTS AND СONCLUSION: Stalevo increased motor and daily activities, reduced the severity of basic symptoms of PD and improved quality of life of the patients.

Levodopa remains a 'gold standard' for the treatment of patients with Parkinson's disease (PD), but its chronic use is accompanied by fluctuations of symptoms and dyskinesias related to unfavorable pharmacokinetics of levodopa and progressing loss of the nigrostriatal neurons. Prescribing inhibitors of catechol-O-methyl-transferase (enzyme of dopamine metabolism), entacapone or tolcapone, is a perspective approach to the correction of the above-mentioned complications. We followed up 402 patients with PD who received long-term therapy with a combined preparation Stalevo (levodopa/carbidopa/entacapone) for 2-5 years (2.9 ± 0.9 years). The high (92.8%) compliancy and good tolerance of the drug in patients with PD was shown. Stalevo leads to the stabilization of the response to levodopa, improvement of patients' functional capacities, increase in their everyday activity, and improvement of quality of life. Stalevo may be regarded as a preparation of choice in the treatment of motor complications in elderly patients, correction of night symptoms of PD and in a number of other clinical situations arising in hospital and outpatient practice.

Objective: Assess motor function and quality of life (QoL) in Parkinson's disease (PD) subjects with end-of-dose wearing off (EODWO), comparing immediate and delayed switch (IS, DEL) to levodopa/carbidopa/entacapone (LCE)., Background: LCE treatment improves motor function in PD patients with EODWO. Correlations with QoL have not been previously assessed., Methods: A 16-week, prospective, randomized, multicenter, open-label study in PD subjects on stable levodopa/carbidopa (LC) doses with EODWO. The IS subjects switched to LCE at baseline; DEL subjects at week 4. The primary efficacy variable was UPDRS III score (baseline to week 4). QoL measurements (PDQUALIF, PDQ-39) were assessed at baseline, weeks 4, 8, and study endpoint., Results: The intent-to-treat population comprised 350/359 patients (IS, n = 177; DEL, n = 173). A significant decrease in UPDRS III scores at week 4 was observed (IS, 3.7U, p < .0001; DEL, 1.8U, p = .0018). Group differences favored IS (1.9U, p = .0148). At week 8, IS subjects had significant total score decreases in PDQUALIF (2.5U, p = .0133) and PDQ-39 (5.8U, p = .0001). In the mobility and activities of daily living PDQ-39 subdomains, IS subjects had significantly larger week 4 decreases (versus DEL p = .0331 and p = .0125, respectively). Adverse events included diarrhea (14.5%), nausea (12.3%), and dizziness (8.4%)., Conclusion: The IS provided greater motor improvement at week 4 and improved QoL at week 8.

Objective: L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life., Methods: We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4x daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia., Results: In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001)., Interpretation: Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group.

Background: Observational studies suggest that single-tablet formulations are associated with improved adherence versus the same components taken as separate tablets. The objective of this study was to compare adherence in patients with Parkinson's disease (PD) receiving levodopa therapy as levodopa/carbidopa/entacapone tablets (LCE) versus levodopa/carbidopa (LC) tablets and entacapone (E) as separate tablets (LC and E)., Methods: This was a retrospective, observational cohort study using a large health insurance claims database. Subjects included persons with a PD diagnosis who were receiving LC without E and then received either an add-on therapy with E as a separate tablet (LC and E) or LCE as one tablet (LCE). The primary study outcome was treatment adherence, estimated from pharmacy refills based on the 'percent of days covered' (PDC) with LCE or LC and E during follow-up and compared for patients receiving LCE and LC and E using multivariate regression analyses., Results: In multivariate analyses controlling for differences between groups in baseline characteristics, including pre-index dosage of and adherence with LC, receipt of LCE (n = 388) was associated with 79% lower mean non-adherence during follow-up (95% CI: 73-83%; p < 0.001) versus LC and E (n = 823), 86% lower odds of unsatisfactory adherence (95% CI: 80-91%; p < 0.001), and a 26% lower risk of discontinuation (95% CI: 6-42%; p < 0.013)., Limitations: This was an observational study with the inherent potential for selection bias. Pharmacy claims may not provide an accurate estimate of adherence. Requiring subjects to have a certain number of prescriptions before and after the index date may yield a sample that is not representative of all patients initiating levodopa therapy in typical clinical practice., Conclusions: Better adherence with LCE may have important implications for maintaining function in patients receiving chronic oral levodopa therapy. Further research is needed to confirm these results and examine the association between improved adherence and clinical and economic outcomes.

The study objective was to assess the efficacy, safety and feasibility of switching from levodopa/benserazide (LB) or levodopa/carbidopa (LC) to levodopa/carbidopa/entacapone (LCE) in Parkinson's disease (PD) patients with wearing-off. This was a multicenter, open-label, 6-week study; the primary outcome was success rate based on the patient-assessed Clinical Global Impression of Change (P-CGI-C). Secondary outcomes included investigator-assessed CGI-C (I-CGI-C), change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS), motor/non-motor wearing-off symptoms and quality of life-visual analog scale (QoL-VAS). After switching to LCE, 77% of patients reported an 'improvement' (p < 0.0001 vs. patients reporting 'no change or worsening'). Significant improvements were seen in I-CGI-C, UPDRS and QoL-VAS, regardless of prior therapy. Oral levodopa dosing was increased in 28% of patients; the primary outcome remained significant when these patients were excluded. The data suggest that switching from LB/LC to LCE provided a significant benefit in PD patients with wearing-off.

Accumulating data on experience of long therapy with levodopa revealed the pathomorphosis of clinical presentations of Parkinson's disease during its progression, in particular, described, the occurrence of motor fluctuations and levodopa-induced dyskinesias. In later stages of the illness, these disturbances attracted special attention of both the patient, and the attending, worsening quality of a life of patients. The article describes the main issues of the pathogenesis of this type of disorders and the currently available strategies for its treatment. We present our own experience of treatment motor fluctuations by means of the combined three-component medical product stalevo containing levodopa, carbidopa and entacapone.

Two strategies to manage symptom re-emergence due to wearing-off with conventional levodopa/dopa-decarboxylase inhibitor (DDCI) therapy were compared in patients with Parkinson's disease (PD) in this randomized, open-label trial. PD patients receiving 3 daily doses of levodopa/DDCI were randomized to either levodopa/DDCI and entacapone or an increased dose frequency of levodopa/DDCI with or without an increased total daily dose (dose fractionation). After 1 month of treatment, patients were followed up for 1 year. A greater proportion of levodopa/DDCI and entacapone-treated patients had treatment success compared with dose-fractionated patients, according to investigator Clinical Global Impression of Change scores at 1 month (68 vs. 59%, respectively) and 1 year (60 vs. 51%, respectively). Mean 'off' time (time with symptoms) was improved in both groups at 1 month and 1 year, despite a reduction in the mean daily levodopa dose in the levodopa/DDCI and entacapone group at 1 month. The mean daily levodopa dose was increased in the dose fractionation group. At 1 month, there was a 4% reduction in patients experiencing dyskinesia with levodopa/DDCI and entacapone and a 3% increase with dose fractionation. These data suggest that levodopa/DDCI and entacapone reduces time with symptoms, the rate of motor complications and the daily levodopa dose compared with dose fractionation. However, as the observed differences were not statistically significant, further studies are required to confirm these results., (2008 S. Karger AG, Basel.)

Despite the significant symptomatic effects of levodopa, stable 24-h treatment responses are in the vast majority of patients replaced 2-3 years from the start of treatment by oscillations in motor symptoms (fluctuation, dyskinesia), amelioration of which requires addition of constant (physiological) stimulation of postsynaptic dopamine receptors. To some extent this is provided by Stalevo, which contains levodopa and two enzyme inhibitors: the DDC inhibitor carbidopa and the COMT inhibitor entacapone. The results obtained in the present study demonstrated the advantages of Stalevo over traditional agents in patients with the "wearing off" and "on-off" phenomena.

Objective: To evaluate the effectiveness of entacapone in the management of levodopa wearing-off in Parkinson's disease (PD) in a naturalistic, real-life setting., Research Design and Methods: This prospective, open-label, observational study included patients with idiopathic PD. Patients were eligible for inclusion if they had been taking 3-5 doses of levodopa per day for ≥2 months and had shown signs of levodopa wearing-off for ≥1 month. Subjects received entacapone (recommended dose: 1 × 200 mg tablet with each levodopa dose) for 28 days. Patients were asked to complete a wearing-off questionnaire and the eight-question Parkinson's Disease Questionnaire Quality of Life assessment (PDQ-8). Activities of daily living (both in the on and off states) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part II. Clinical Global Impression (CGI) of severity of PD-related symptoms was assessed using a modified CGI tool. Patient global assessment of severity of PD symptoms was also obtained., Results: A total of 341 patients were enrolled by 68 physicians across Canada. At Day 28, 56.9% of the subjects indicated improvement compared to baseline on the modified CGI of change (CGI-C); 21.4% reported no change. Improvements were also observed on the UPDRS II and the PDQ-8. Benefit from entacapone appeared to be relatively uniform across subgroups (e.g., number of daily levodopa doses, use of other anti-PD medications)., Study Limitations: The results of this study may be biased due to factors inherent in open-label, community-based trials (e.g., compliance). This is, however, reflective of everyday clinical practice., Conclusions: In this naturalistic, real-life study, the addition of entacapone to levodopa therapy provided benefits in quality of life and activities of daily living for a substantial proportion of PD patients experiencing wearing-off.

This was a retrospective pooled analysis of data from four comparably designed, double-blind, placebo-controlled, Phase III studies and their long-term open-label extensions. Patients on levodopa and a dopa decarboxylase inhibitor (DDCI) were randomized to entacapone or to placebo in the 6-month, double-blind phase, with all patients subsequently receiving entacapone in the extension phase. UPDRS III motor scores improved by -2.1 points during the first 6 months of levodopa/DDCI and entacapone therapy, and remained below baseline for up to 2 years. Increased daily 'ON' time, together with response duration to a single morning dose of levodopa and clinical global evaluation, also supported the long-term efficacy of levodopa/DDCI and entacapone. The mean daily dose of levodopa did not increase over the 5-year follow-up period. Long-term therapy with levodopa/DDCI and entacapone was well-tolerated.

Objectives: This study was performed to determine if conversion from sustained release carbidopa/levodopa (SR-CL) with or without entacapone to carbidopa/levodopa/entacapone (CLE; Stalevo) improves motor functioning and quality of life in Parkinson disease (PD) patients and to assess patient tolerance and drug preference., Methods: PD patients reporting suboptimal symptom control with SR-CL were converted to CLE. The basic conversion was 1 SR-CL 25/100 to 1 25/100/200 CLE and 1 SR-CL 50/200 to 1 37.5/150/200 CLE with additional changes as necessary., Results: There were 62 patients with an average age of 68 years and an average disease duration of 11 years. CLE was preferred by 42 patients and SR-CL was preferred by 20 patients. In those that preferred CLE, Unified Parkinson Disease Rating Scale (UPDRS) mentation and motor subscores, Parkinson Disease Questionnaire-39 (PDQ-39) quality-of-life activities of daily living (ADL) and bodily discomfort subscores, and Epworth Sleepiness Scale (ESS) scores were significantly improved. There were no significant changes in any measures in the group that preferred SR-CL. Common adverse effects in the group that preferred CLE included nausea, vomiting, increased dyskinesia or off time, dizziness, and somnolence. The most common adverse events in the group preferring SR-CL were increased off time or dyskinesia, nausea, and vomiting., Conclusions: A majority of patients suboptimally controlled on SR-CL can be successfully converted to CLE with improvements in motor function, quality of life, and sleepiness. Older patients, with longer disease duration not previously exposed to entacapone, may better tolerate CLE after the addition of entacapone.

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.

Background: Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations., Methods: In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat., Findings: 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments., Interpretation: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.

Objectives: To evaluate the tolerability, safety and efficacy of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease (PD)., Background: Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound., Design Methods: An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments., Results: 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments., Conclusions: Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.

Objectives: To compare the efficacy of levodopa/dopa decarboxylase inhibitor (DDCI) plus entacapone with levodopa/DDCI plus placebo on measures of parkinsonian disability and health-related quality of life (QoL) in subjects with Parkinson's disease (PD) experiencing motor fluctuations., Materials and Methods: A double-blind, placebo-controlled phase IV study was performed in 270 PD patients randomized to receive either entacapone 200 mg or placebo with each dose of their current levodopa regimen. The primary variables were the Unified Parkinson's Disease Rating Scale (UPDRS) part II activities of daily living (ADL) and the Parkinson's Disease Questionnaire (PDQ)-39 summary index. UPDRS parts I, III-VI, Global Assessment of Change, PDQ-39 subscores, and the Short-Form (SF)-36 and the European Quality of Life five-dimension questionnaire (EQ-5D) were included as secondary variables., Results: There was a significant improvement in ADL scores with levodopa/DDCI/entacapone compared with levodopa/DDCI/placebo at 5 and 13 weeks (-2.3 vs -0.7, respectively; P = 0.0001). However, no significant differences were observed between treatments using the PDQ-39 summary index. UPDRS part III (motor) scores significantly decreased in the levodopa/DDCI/entacapone group compared with the levodopa/DDCI/placebo group (-5.0 vs -2.9, respectively; P = 0.03). Similarly, the change in the investigators Global Assessment was significantly greater (P = 0.004) in the levodopa/DDCI/entacapone group. There were no significant differences between treatments for any of the PDQ-39 subscores, the SF-36 variables or the EQ-5D utility score., Conclusions: Levodopa combined with entacapone demonstrated good efficacy in terms of ADL, global function, motor performance and was well tolerated. However, this short-term study did not generate significant improvements in QoL., (Blackwell Munksgaard 2004)

We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

The efficacy of entacapone and its impact on patient quality of life (QOL) was investigated in an open-label study of 899 patients with idiopathic Parkinson's Disease (PD) experiencing wearing-off fluctuations. Patients were divided into 3 groups (3, 4 or 5 doses daily) based on their current levodopa dosage frequency. Patients received 200 mg entacapone with each levodopa/dopa-decarboxylase inhibitor (DDCI) dose, while continuing their same levodopa/DDCI dosage regimen for 4 weeks. Primary efficacy measure was the Investigators' Clinical Global Impression of Change (CGIC). Patient QoL was assessed using the validated 8-item Parkinson's Disease Questionnaire (PDQ-8). Investigators' CGIC revealed that 76.5% of entacapone treated patients experienced an improvement in global status after 4 weeks. Treatment with entacapone was also associated with improvement in patient QoL, with a mean reduction (improvement) in PDQ-8 score of 1.8 from baseline. This study confirms and extends the results of earlier studies demonstrating that, independent of dosing frequency, completing levodopa/DDCI therapy with entacapone provides clinically relevant improvements in global status and QoL in PD patients experiencing wearing-off on their current levodopa dosing frequency.

Levodopa is the main pharmacologic treatment for Parkinson's disease. However, the long-term administration of levodopa is associated with the development of motor complications which can seriously compromise patient function. Increasing evidence indicates that such problems are related to abnormal pulsatile stimulation of striatal dopamine receptors and that treatments providing more continuous stimulation reduce the risk of motor complications. It is possible that administering levodopa with a reversible catechol-O-methyl transferase inhibitor at frequent intervals might reduce the risk of these complications. Stalevo (Orion) combines levodopa, the dopa-decarboxylase inhibitor carbidopa and the catechol-O-methyl transferase inhibitor entacapone in a single tablet. This review provides an overview of the initial clinical experience gained with Stalevo during clinical trials, including several case studies.

A levodopa/carbidopa/entacapone combination product (Stalevo) was recently approved to treat patients with idiopathic Parkinson's disease (PD) who experience end-of-dose "wearing-off." Stalevo is available in dose combinations of levodopa/carbidopa/entacapone 50/12.5/200 mg (Stalevo 50), 100/25/200 mg (Stalevo 100), and 150/37.5/200 mg (Stalevo 150). A series of pharmacokinetic studies demonstrated bioequivalence between Stalevo and corresponding dosages of levodopa/carbidopa plus entacapone. A clinical advantage of Stalevo is that patients can take one pill rather than two (or more) separate tablets. In addition, Stalevo 50 and 100 tablets are smaller than entacapone tablets. These advantages may be particularly beneficial for patients taking many pills, those who have difficulty following complex medication regimens, and those with swallowing difficulty. Most PD patients taking levodopa/carbidopa immediate-release (IR) plus entacapone can be directly switched to the corresponding dose Stalevo product. For fluctuating PD patients taking levodopa/carbidopa IR without entacapone, switching to the corresponding Stalevo tablet is analogous to adding entacapone. In switching patients who are receiving levodopa/carbidopa controlled-release (CR), it should be noted that the bioavailability of levodopa from levodopa/carbidopa CR is approximately 70-75% that of levodopa/carbidopa IR products, including Stalevo.

The catechol-O-methyl transferase inhibitor entacapone is given in combination with levodopa/dopa decarboxylase inhibitor for Parkinson's disease (PD) patients experiencing end-of-dose wearing-off. This 4-week post-marketing surveillance study was undertaken to assess patients' responses to levodopa combined with entacapone in a real clinical practice setting. Overall, 466 patients with idiopathic PD treated with levodopa and experiencing symptoms of wearing-off were recruited. Both physicians and patients recorded the response to therapy, including improvements and side-effects. Following initiation of entacapone treatment, the average daily levodopa dose was reduced from 510 to 453 mg. Physician assessment of entacapone efficacy was judged to be "very good" or "good" in 77.6% of the patients, and tolerability was considered to be "very good" or "good" in 92.4% of patients, with only 12 patients (2.6%) withdrawing from the study. Compared with baseline, there was a decrease in the mean duration of daily 'off' time from 3.0 to 1.3 h per day during the treatment period. Adverse events were in line with those previously reported, with diarrhoea being the most frequent event. The percentage of patients suffering from dyskinesia decreased from 46 to 34%, and of those patients still suffering from dyskinesia, the average daily duration of dyskinesia was reduced from 2.2 to 1.7 h. The use of adjunct dopamine agonists decreased from 67 to 59%. At study end, the percentage of patients who rated their quality of life (QoL) as "very good" or "good" increased from 12.1 to 51.7% and the percentage of patients who rated their QoL as "bad" or "very bad" decreased from 40 to 10.7%. In summary, the results of this survey conducted in real clinical practice support the findings of previous clinical trials demonstrating the efficacy and tolerability of entacapone, as well as the benefits of improved QoL, for patients achieved with entacapone.

The combination of entacapone with levodopa is effective in the treatment of Parkinson's disease (PD), providing significant improvements in 'on' time and Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL scores in controlled clinical trials. This multicentre, open-label study was designed to further evaluate the effectiveness of levodopa combined with entacapone 200 mg in routine clinical practice. Patients experiencing end-of-dose wearing-off were treated for 8 weeks (treatment phase), with an optional extension phase up to 20 weeks. The primary efficacy parameter was the Investigators' Global Assessment of Change; secondary efficacy parameters included UPDRS, 'off' time (from patient diaries), Patients' Global Assessment of Change, quality of life (QoL), SF-36 Health Assessment Questionnaire and Parkinson's Disease Questionnaire 39 (PDQ-39). Of the 479 patients who entered this study, 427 (89.1%) completed the treatment phase and 374 (78.1%) continued into the extension phase. Based on the Investigators' Assessment of Change, 380 (79.7%) patients showed an improvement with entacapone during the treatment phase. This improvement was maintained into the extension phase, and at Week 20, 301 (82.2%) patients continued to show an improvement. A positive treatment effect with entacapone was also seen with all secondary efficacy parameters, including QoL. Mean change in the total PDQ-39 scores showed improvements from baseline of -4.0 score points to the end of the treatment phase (n=182) and -3.1 score points at the end of the extension phase (n=152). Entacapone in combination with levodopa was generally well tolerated: 40 patients (8.4%) discontinued treatment due to adverse events (AEs) by the end of the extension phase. This study in a daily clinical practice setting confirmed the efficacy of coadministering entacapone with levodopa shown in controlled clinical trials and suggests that the combination is useful in improving the disability and QoL in patients with PD.

The efficacy and tolerability of entacapone was investigated in a randomized, double-blind, placebo-controlled, 3-month study of 162 patients with Parkinson's disease (PD) treated with levodopa and a dopamine agonist and experiencing wearing-off motor fluctuations. Patients were randomized in a 3 : 2 ratio to entacapone 200 mg or placebo, administered with each dose of levodopa. Efficacy was judged on the improvement of "on" and "off" time while awake (Patient Diary and UPDRS part IV Item 39), Investigators' Global Assessment, the SF-36 Health Survey, and changes in levodopa dosages. Patients were monitored for adverse events, laboratory safety and vital signs throughout the study. Improvements in "on" time as assessed using patient diary data showed a trend in favour of entacapone, however these did not reach statistical significance. "Off" time while awake (UPDRS part IV Item 39) showed an improvement of at least one category in 36% of entacapone-treated patients, compared with 22% in the control group (p = 0.0038). The proportion of patients showing an improvement at the Investigators' Global Assessment was significantly higher (p = 0.0006) in the entacapone-treated group of patients. Also, the proportion of patients with a reduction in their daily levodopa dose was significantly higher (p = 0.02) in the entacapone group (28%) compared with placebo (13%). As expected, the most frequent adverse events were dopamine-mediated (dyskinesia: entacapone 31% versus placebo 13%), and harmless urinary discoloration. The modest increase in dyskinesias could be readily managed by levodopa down-adjustment, and, at study end there was no significant difference for the UPDRS "overall dyskinesia score" between entacapone and placebo. In conclusion, although the primary efficacy variable did not reach statistical significance, the present results demonstrate that entacapone provides additional antiparkinsonian benefits to levodopa therapy and is well tolerated in levodopa-treated PD patients experiencing wearing-off motor fluctuations despite adjunct dopamine agonist therapy.

Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.

Objectives: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients., Patients and Methods: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests., Results: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results., Conclusion: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Entacapone is a potent, reversible and orally active inhibitor of catechol-O-methyltransferase. This open multicenter study evaluated the efficacy, safety and tolerability of entacapone as adjunct therapy to levodopa/dopa decarboxylase inhibitor (> or = 3 daily doses) in patients with idiopathic Parkinson's disease and end-of-dose motor fluctuations. The 8-week study included 489 patients under conditions of typical daily medical practice. Patients were treated with a 200-mg fixed dose of entacapone administered with each scheduled dose of levodopa to a maximum of 10 doses per day. Other antiparkinsonian medication should have been stable for at least 1 month. The primary efficacy criteria were: (1) Part II (activities of daily living, ADL) of the Unified Parkinson's Disease Rating Scale (UPDRS), (2) the reduction of 'off' time during the daily waking period as assessed by the percentage of patients improving by at least one category at Item 39 of Part IV of the UPDRS. Secondary outcome measures included: (1) the investigator's global assessment of change, (2) quality of life (QoL) was assessed using the Parkinson's Disease Questionnaire (PDQ-39). Adverse events, vital signs and liver enzymes were monitored at weeks 2 and 8. The baseline mean score for ADL was 10.5 (+/-7.04), which decreased to 8.5 (+/-6.37) at the end of the study (p < 0.0001). Compared to baseline, 40.8% of patients experienced a reduction in 'off' time during the waking period; this improvement was highly significant (p < 0.0001). A reduction in the daily dose of levodopa was observed in 35.8% of patients (mean decrease 209 +/- 149 mg). QoL was improved by a mean of 10% in all categories of the PDQ-39 (p < 0.001), except social support and cognition. This improvement was statistically significant (p < 0.001). The dyskinesia score (UPDRS Item 32) was decreased significantly from 2.3 to 2.1 from baseline to end of study (p < 0.001), although 52.7% of patients reported levodopa-induced dyskinesia as an adverse event. There was no case of increased liver enzymes. The study results confirm that the excellent risk/benefit ratio seen in phase III controlled studies can be seen in daily neurological practice. Moreover, the study suggests that the benefits of entacapone are associated with a significant improvement in QoL., (Copyright 2001 S. Karger AG, Basel)

Levodopa is the most efficacious drug in the symptomatic treatment of Parkinson's disease. However, exogenously administered levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) so that only 1% of an administered dose gains access to the brain. Even when levodopa is co-administered with an inhibitor of AAAD such as benserazide or carbidopa, the bulk (90%) of levodopa is converted by COMT to the therapeutically inactive 3-O-methyldopa. Two COMT inhibitors, tolcapone and entacapone, have recently been introduced as adjuncts to levodopa to further inhibit peripheral levodopa metabolism and thereby enhance brain levodopa availability. This paper reviews the pharmacokinetics, dosing schedule, peripheral and central effects, and safety profile of these agents.

Objective: To study the effect and safety of entacapone as an adjunct to levodopa treatment in patients with PD with wearing-off motor fluctuations., Background: Entacapone is a catechol-O-methyltransferase (COMT) inhibitor that has been shown to increase the area under the concentration-time curve of plasma levodopa by decreasing its systemic elimination, thereby promoting and improving therapeutic response to it., Methods: A total of 171 parkinsonian patients with wearing-off-type motor fluctuations participated in a 6-month randomized, placebo-controlled, double-blind, parallel-group study. The extent of therapeutic response was elicited in the first hand with home diary recordings of "on" and "off" times by the patient and with Unified Parkinson's Disease Rating Scale scoring by the examiner. The patients took either 200 mg entacapone or identical placebos concomitantly with each daily levodopa dose (four to 10 times a day)., Results: Patients' home diaries indicated that entacapone increased the mean (+/- SD) "on" time significantly (9.3 +/- 2.2 to 10.7 +/- 2.2 hours; p < 0.01) and correspondingly decreased the "off" time significantly (5.3 +/- 2.2 to 4.2 +/- 2.2 hours; p < 0.001). The average benefit derived from a daily levodopa dose as related by the patients was increased significantly (p < 0.01). The daily levodopa dose was reduced significantly in the entacapone group, the difference between the groups being 102 mg (p < 0.01). The entacapone-derived increase in the benefit from levodopa was lost almost completely following its withdrawal. Entacapone was well tolerated. Dopaminergic adverse events, which increased, were ameliorated by reducing the levodopa dose. Diarrhea was the most common nondopaminergic adverse event., Conclusions: Long-term entacapone treatment effectively prolonged the beneficial response to levodopa in parkinsonian patients with the wearing-off phenomenon. The improvement occurred irrespective of the reduction of the levodopa dose.

Degradation of levodopa in the periphery is known to be associated with motor fluctuations and dyskinesia in Parkinson's disease (PD) patients. The enzyme catechol-O-methyltransferase (COMT) is responsible for much of this degradation. Therefore, inhibiting COMT activity is one method of extending the action of levodopa. The new nitrocatechol-type COMT inhibitors entacapone, nitecapone, and tolcapone inhibit COMT in the periphery; tolcapone also inhibits COMT activity centrally. COMT inhibitors increase patients' duration of response to levodopa and reduce response fluctuations. Administration may prolong levodopa-induced dyskinesia, but peak-dose dyskinesia does not appear to increase. To reduce dyskinesia, the total daily dose of levodopa can be reduced.

Twelve parkinsonian patients with levodopa-related end-of-dose fluctuations in disability were studied in an open-label trial to examine the effects of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on pharmacokinetics and metabolism of levodopa and on clinical response to levodopa after a single dose and after 4 weeks' medication with entacapone. The clinical response was assessed with continuous monitoring using the motor part of Unified Parkinson's Disease Rating Scale. Entacapone increased statistically significantly the mean area under the plasma concentration-time curve (AUC) of levodopa by 29% after a single dose and by 21% after 4 weeks' administration, without affecting other pharmacokinetic parameters of levodopa. The AUC of 3-O-methyldopa decreased by 45% and AUC of homovanillic acid by 21% after 4 weeks' dosing with entacapone. The duration of motor response to levodopa increased significantly from 2.3 h to 3.2 h (i.e., by 39%) after a single dose and to 3.4 h (i.e., by 48%) after 4 weeks' medication with entacapone. The magnitude of clinical response remained unchanged, but peak latency of motor response was prolonged after 4 weeks' medication. The duration and magnitude of dyskinesias also increased. Peripheral COMT inhibition with entacapone increased significantly the bioavailability of levodopa and prolonged its antiparkinsonian effect after a single dose and after repeated dosing for 4 weeks. Thus entacapone seems to be a valuable adjuvant to levodopa treatment in parkinsonian patients with end-of-dose failure.

We studied the effect of entacapone, a selective catechol-O-methyltransferase inhibitor, on the bioavailability and clinical effect of levodopa in Parkinson's disease (PD). On day 1 (control day), nine patients received their own levodopa (plus benserazide) medication only; for the next 7 days they received 200 mg of entacapone with each dose of levodopa (tid or qid). We evaluated disability in the morning (8 AM) before drug administration and then at 1-hour intervals until 6 PM on days 1, 2, and 8, using a modified motor part of the Unified Parkinson's Disease Rating Scale. Repeated blood samples were taken before and during the 4 hours after the morning drugs for pharmacokinetic evaluation of entacapone and of levodopa and its metabolites. Added to the levodopa treatment, entacapone decreased clinical disability by about 16% (p < 0.05) from day 1 to day 8. The area under the curve (AUC) of levodopa increased by 38% (p < 0.01) after administration of a single dose of entacapone and by 40% (p < 0.05) after 7 days of multiple dosing with entacapone. Entacapone did not change the Tmax and Cmax values of levodopa. After 7 days of treatment with entacapone, the AUC of 3-O-methyldopa had decreased by 44% (p < 0.01) and of homovanillic acid by 26% (p < 0.05) as compared with treatment with levodopa alone. Four patients became slightly more dyskinetic during entacapone treatment than before it. The combination of entacapone and levodopa was well tolerated, judged by the lack of significant changes in hemodynamic and safety variables.(ABSTRACT TRUNCATED AT 250 WORDS)