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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: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations., Methods: This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h., Results: ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC 0-10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of -2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H 0 of μ 0 ≤-1.6)., Conclusion: Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone-carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients., Methods: In this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale., Results: Systemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P = 0.84)., Conclusions: Levodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

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.

Parkinson disease (PD) is a progressive, disabling, neurodegenerative disorder characterized by both motor and nonmotor symptoms. Monoamine oxidase B inhibitors, dopamine agonists, N-methyl-D-aspartate antagonists and levodopa (LD), with its various formulations and administration modes, mainly improve the motor symptoms in PD, which are thought to be related to decreased dopamine levels in the brain. Of these therapeutic drug options, LD represents the most effective and best tolerated compound when it is administered several times a day. Pharmacokinetic trials of oral LD/dopa decarboxylase inhibitor (DDCI) formulations with and without the catechol-O-methyltransferase inhibitor, entacapone, showed that repeated administration with entacapone causes an increase in both the maximum concentration (Cmax) and time to Cmax (Tmax) of LD. In addition, gastrointestinal motility may also impact plasma LD behavior. These peripheral components of LD metabolism contribute to the onset of motor complications, which are predominantly associated with LD/DDCI owing to its short plasma half-life. The increase in Tmax is related to a slower increase in plasma LD concentrations after repeated LD/DDCI intake, which may also increase the risk of wearing off. An elevation in Cmax after reiterated LD intake increases the risk of peak-dose dyskinesia. Therefore, it may be useful to start with higher doses of LD formulations in the morning and then to titrate with different LD doses during the day according to the individual patient's motor behavior, which is particularly characterized by the onset of motor complications, such as off periods and dyskinesia, in more advanced stages of PD.

Objectives: An oral dispersible microtablet formulation of levodopa/carbidopa 5/1.25 mg (LC-5) was developed for individualized repeated dosing. The aim was to compare pharmacokinetic profiles of LC-5 and levodopa/carbidopa/entacapone (LCE)., Materials and Methods: A randomized, crossover study was carried out in 11 healthy subjects. Plasma concentrations of levodopa, carbidopa and 3-O-methyldopa were determined after intake of 300 mg levodopa during the day, either as three intakes of 100/25/200 mg LCE or as a morning dose of 75/18.25 mg followed by five repeated doses of 45/11.25 mg LC-5., Results: Repeated dosing (2.4-hourly) with LC-5 microtablets compared to LCE (6-hourly) avoided long periods with low plasma levodopa levels. Time to maximum plasma concentrations was significantly shorter for LC-5. LC-5 showed lower fluctuation index (FI) in plasma compared to LCE (ANOVA P = 0.0028). FI for dose 2-5 was on average 1.26 for levodopa in LC-5, and 2.23 for dose 1-2 of LCE. The ratio between the two mean FI:s is 0.565; that is, LC-5 gave nearly half the FI as compared to LCE., Conclusions: Fractionation of levodopa with LC-5 into small, frequent administrations as compared to standard administrations of LCE decreased the FI in plasma for both levodopa and carbidopa by nearly half., (© 2012 John Wiley & Sons A/S.)

Background: Repeated dosing of levodopa/carbidopa/entacapone (LCE) has shown a favourable pharmacokinetic (PK) profile compared with levodopa/carbidopa (LC), but increases maximum plasma levodopa concentrations (C(max)) during the day. High levodopa concentrations are associated with peak-dose dyskinesias., Purpose: To determine whether administering LCE 75/18.5/200 and 125/31.5/200 mg (LCE 75 and LCE 125) following a morning dose of LCE 100/25/200 and 150/37.5/200 mg (LCE 100 and LCE 150), respectively, would avoid the increase in levodopa C(max) values observed during multiple dosing of LCE 100 and LCE 150., Methods: This was an open, randomized, three-period, crossover PK trial in healthy volunteers (n = 19). Subjects were randomized to Group 1 or 2. Group 1 received in random sequence: LCE 150 followed by LCE 125 three times daily (tid); LCE 150 four times daily (qid); LC 150 qid. Group 2 received in random sequence: LCE 100 followed by LCE 75 tid; LCE 100 qid; LC 100 qid. Levodopa C(max), minimum plasma concentration (C(min)), area under the curve (AUC(0-14)) and peak-trough fluctuation (PTF) were calculated up to 14 h after the first dose., Results: Levodopa C(max) was not increased when the LCE dose was decreased by 25 mg after the morning dose. In comparison to LC, levodopa C(min) levels and AUC(0-14) values for LCE were significantly higher, while the levodopa PTF was significantly smaller., Conclusions: Reducing the dose of LCE by 25 mg following the first morning dose results in a more consistent levodopa C(max) profile, avoiding levodopa accumulation while maintaining significantly higher C(min) levels and AUC(0-14) values compared with LC.

Levodopa has been the mainstay of Parkinson's disease (PD) therapy for over 40 years, with its efficacy surpassing that of other antiparkinsonian medications. As such, most PD patients eventually require levodopa-based therapy during the course of the disease. However, despite its proven efficacy, long-term levodopa therapy is associated with motor complications, with wearing-off being the most prevalent. Wearing-off occurs, in part, as a result of the short half-life of levodopa, which leads to fluctuations in plasma levodopa levels. A pharmacokinetic profile characterized by a higher trough value of levodopa can be achieved by combining levodopa/carbidopa with entacapone, which inhibits the peripheral breakdown of levodopa, resulting in higher plasma levodopa levels. Here, we review the limitations of conventional levodopa and the clinical data for levodopa/carbidopa/entacapone in treating patients with wearing-off.

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.

Nocturnal symptoms are integral part of the general clinical picture of Parkinson's disease (PD). They are subdivided into non-motor and motor symptoms, the latter included night akinesia, crampi, night akathisia, dystonia, restless leg syndrome (RLS), periodic movements of limbs (PML) and psychomotor agitation during sleep. We have studied 53 patients with PD and evaluated the frequency of these disturbances as follows: night akinesia (42.7%), crampi (31.1%), night akathisia (7.8%), RLS (5.8%), PML (3.8%). The symptoms were treated with the three-component drug stalevo in a single dose in the evening during 3 months. The dose was equivalent to that of levodopa prescribed to the patient earlier in the composition of a two-component drug. The significant reduction of nocturnal motor symptoms with the respective decrease in the frequency of emotional disorders, the improvement of daily activities and quality of life of patients were seen after the treatment.

In Stalevo tablets, used in the therapy of patients with Parkinson's disease, levodopa is combined with decarboxylase inhibitors and COMT inhibitors to provide a more steady plasma concentration of levodopa. Previously several study has shown, that the better pharmacokinetic profile decreases the fluctuation of motor and non-motor symptoms. Better control of symptoms improves quality of life. Ideal blood levels of levodopa however can only be achieved by multiple daily dosing. This may be uncomfortable, may decrease compliance, thereby influence quality of life. To evaluate this, an observational follow-up study was undertaken in Hungary in 2007, among patients who were given Stalevo - independently of this study - because of signs of decrease in the duration of drug effect (wearing off). Patients got Stalevo in three, four or five daily divided dosages, the results were assesed after three months. The study included 223 patients (ITT population), of whom 208 (PP population) responded regarding quality of life on both visits. Statistical analysis of the results showed that treatment significantly decreased symptoms of wearing off (wearing off card with 19 items) and improved quality of life (EQ-5D and VAS quality of life scale) regardless of the frequency of dosing.

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.

Objectives: To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC)., Methods: Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included Cmin, Cmax, Cmax - Cmin, AUC, t(1/2), and tmax., Results: In healthy volunteers and PD patients, mean trough levels (Cmin), Cmax, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to Cmin, Cmax, and AUC, differences between the treatments in variability of levodopa concentrations (Cmax - Cmin) were less consistent., Conclusions: The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

A simple, precise, and accurate high-performance liquid chromatographic method was developed and validated to determine percent drug release of levodopa (LEV), carbidopa (CAR), and entacapone (ENT) from its combination dosage form. A mixture of acetonitrile and buffer was used as the mobile phase for reversed-phase liquid chromatographic separation for determination of the in vitro drug release of LEV, CAR, and ENT. A dissolution test was conducted at 75 rpm with United States Pharmacopeia (USP) apparatus-II (paddle) by using pH 5.5 phosphate buffer as a dissolution medium. Three formulations, differing in strength, were evaluated. The developed method was validated for specificity, linearity, precision, accuracy, and solution stability. The specificity of the method was determined in the presence of placebo interference. The method was linear over the drug concentration ranges of 4-210 microg/mL for LEV, 1-52 microg/mL for CAR, and 6-280 microg/mL for ENT. Precision was established by determination of system precision, method precision, and intermediate precision. Accuracy values for the method ranged from 96.8 to 104.3% for LEV, from 97.2 to 101.3% for CAR, and from 99.5 to 102.8% for ENT. The developed method was suitable for estimating percent drug release of LEV, CAR, and ENT in terms of the dissolution test.

We aimed to investigate whether treatment with levodopa/carbidopa/entacapone when compared with levodopa/carbidopa improves quality of life in Parkinson's disease (PD) patients with no or minimal, nondisabling motor fluctuations. This is a multicenter, randomized, double-blind study. One hundred eighty-four patients on 3 to 4 equal doses of 100/25 to 200/50 mg levodopa/carbidopa or levodopa/benserazide, 0 to 3 hours of nondisabling OFF time over a 48 hour period and no dyskinesia were randomized to levodopa/carbidopa/entacapone or levodopa/carbidopa treatment for 12 weeks. The primary outcome measure was quality of life as assessed by the PDQ-8. Secondary outcome measures were the UPDRS parts I-IV, and the Wearing Off Card. Treatment with levodopa/carbidopa/entacapone resulted in significantly greater improvements in PDQ-8 scores compared to treatment with levodopa/carbidopa (mean difference 1.4 points, P = 0.021). Statistically significant improvements were seen predominantly in nonmotor domains (depression, personal relationships, communication, stigma, all P < 0.05; dressing P = 0.056). Patients who were randomly assigned to levodopa/carbidopa/entacapone also showed significantly greater improvement in UPDRS part II scores (P = 0.032) with UPDRS part III scores showing borderline significance. Differences in UPDRS parts I and IV and Wearing Off Card scores were not significant. Treatment with levodopa/carbidopa/entacapone results in improved quality of life compared with levodopa/carbidopa in PD patients with mild or minimal, nondisabling motor fluctuations.

Unlabelled: The most effective symptomatic treatment for Parkinson's disease (PD) is levodopa/dopa decarboxylase (DDC)-inhibitor or conventional levodopa. However, after a few years of treatment, motor complications may develop, such as <> and dyskinesias. Symptoms of <> can be both motor symptoms, e.g. tremor and bradykinesia, as well as non-motor symptoms (pain, mood changes and anxiety). The development of these complications may affect the patients quality of life (QOL). To investigate the efficacy and safety direct switch from conventional levodopa to stalevo(levodopa/carbidopa/entacapone) in PD patients with fluctuations and dyskinesias., Methods/patients: Thirty four patients with PD were recruited in the study. The mean age (+/-SD) of the patients was 64,5+/-8,3 years, the mean duration of PD (+/-SD) was 5,9+/-3,1 years, the mean H&Y was 2,5+/-0,5. All patients experienced fluctuations and six had dyskinesias (one patient had biphasic dyskinesias with painful dystonia). The mean baseline levodopa dose was 785,8+/-150,2 mg per day taking in three to six doses. Assessments were performed before, end of 1, 4 and 12 weeks of treatment period and consisted of Hoen/Yahr stages (H&Y), II and III parts of the Unified Parkinson's Disease Rating Scale (UPDRS), patients diaries with registration <> periods, scale EQ-5D, WOQ-9. While switching from conventional levodopa to stalevo taking single levodopa doses were equivalent or less. Maximum allowed doses of stalevo were four times per day., Results: Direct switch to stalevo results in improvement of motor and non-motor symptoms (pain and anxiety) in fluctuating patients and significant prolongation of <> periods (p<0.01). We observed dramatic improvement biphasic dyskinesias with painful dystonia and reducing severity of dyskinesias in others patients. Improvement was seen in QOL by scale EQ-5D from 10,7+/-1,9 to 8,6+/-2,1 points (p<0,05). Conclusions. Switching from conventional levodopa to stalevo is efficacy and safety and can significantly improve QOL PD patients with fluctuations and dyskinesias.

The triple combination of levodopa, DDCI and entacapone (Stalevo) is used to treat motor complication in Parkinsonian patients with fluctuation. An observational investigation has been conducted in Hungary to study the effects of Stalevo on the "wearing off" phenomenon and on the quality of life in patients, who are to be treated with. The introduction of Stalevo to the treatment resulted in no changes in the number of patients taking selegiline, amantadine and dopamine agonists, while the number of patients taking anticholinergic drugs were slightly increased. This treatment significantly decreased the average Hoehn-Yahr stadium, as well as the non-motor symptoms, without any remarkable side effect. Stalevo also improved the quality of life, detected by the EQ-5D questionnaire and the visual analogue scale.

Despite significant symptomatic effect of levodopa, in most patients the stable 24 hour's effect changed for alterations of movement symptoms (fluctuations, dyskinesia) after 2-3 years of the therapy. These complications may be reduced due to the constant (physiologic) stimulation of post-synaptic dopamine receptors that, to a certain degree, provides the drug stalevo, which contains levodopa and 2 enzyme inhibitors, dopa decarboxylase (carbidopa) and catechol-O-methyltransferase (entacapone). The results of the study demonstrated beneficial effects of stalevo as compared to traditional therapy in patients with "wearing off" and "on-off" phenomena.

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.

Objectives and Methods: This study investigated the ease with which 52 Parkinson's disease patients already receiving adjunct entacapone to traditional levodopa were switched to Stalevo (levodopa/carbidopa/entacapone)., Results: The switch to Stalevo was straightforward for most patients taking standard-release levodopa with 86% of these patients being able to replace their entire regimen without having to change the amount of levodopa taken. The majority of patients (54%, P = 0.162) preferred Stalevo; 31% preferred their prior treatment regimen; 15% had no preference. Patients found Stalevo more simple to dose (94%), more convenient to use (84%), easier to handle (84%), easier to remember (67%) and easier to swallow (59%), compared with their previous medication., Conclusions: Stalevo was well tolerated, with a low incidence of adverse events. The study shows that Stalevo is an effective, preferred and well-tolerated means of delivering levodopa/carbidopa/entacapone in one easy-to-use tablet.

The short plasma half-life limits the antiparkinsonian efficacy of levodopa/carbidopa (LD/CD). Administration of LD/CD with the catechol-O-methyltransferase inhibitor entacapone in one tablet (LCE) may extend plasma half-life of LD and thus its effect on motor symptoms in patients with Parkinson's disease (PD). The objectives of this study were to monitor the motor response to a switch from LD/CD to LCE by a simultaneous performance of an instrumental motor test and rating of motor symptoms and to compare the LD plasma behavior between both conditions in terms of stability. Twenty-one treated PD patients received LD/CD and then the identical oral LD dosage of LCE within a standardized setting on 2 consecutive days. Rating better reflected the motor improvement after LD application than the instrumental test. Motor symptoms of PD patients decreased significantly more during the LCE than the LD/CD condition, probably due to significantly higher LD plasma levels and a significantly less pronounced fall of the LD concentrations following the second LD intake. Our study shows a more stable LD plasma behavior during LCE intake and accordingly a better effect on motor symptoms according to rating outcomes and motor test results to a lesser extent., ((c) 2005 Movement Disorder Society.)

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.

(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.

Long-acting dopamine agonist drugs induce a lower incidence of dyskinesia in MPTP-treated primates and patients with Parkinson's disease compared to pulsatile treatment with levodopa, supporting the concept of continuous dopaminergic stimulation as a means of dyskinesia avoidance. We examined the effects of L-dopa administered with or without the COMT inhibitor entacapone on dyskinesia induction in previously untreated MPTP-treated common marmosets. Administration of L-dopa (12.5 mg/kg p.o.) plus carbidopa twice daily produced fluctuating improvement in motor behavior coupled with dyskinesia. Coadministration with entacapone produced similar patterns of motor improvement and dyskinesia that were not different from that produced by L-dopa alone. Treatment with L-dopa (6.25 mg/kg p.o.) plus carbidopa four times daily reversed motor disability and induced dyskinesia in a manner that was not different from the twice-daily treatment regimens. However, coadministration with entacapone produced more continuous improvement in locomotor activity with less dyskinesia than animals treated with L-dopa four times daily alone. These data support the notion that pulsatile stimulation contributes to the development of dyskinesia and suggests that more frequent dosing of L-dopa plus entacapone may be a useful treatment strategy for patients in the early stages of Parkinson's disease., (2004 Movement Disorder Society.)

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.

Objectives: Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an adjunct to standard levodopa preparations, but there is little experience of the effect of entacapone on controlled release levodopa preparations., Methods: A double blind, placebo controlled, single dose, randomised, cross over trial was performed in 14 patients with Parkinson's disease with motor fluctuations to investigate the clinical effect of a single dose of entacapone (200 mg) when administered with either standard levodopa-carbidopa (Sinemet) or controlled release levodopa-carbidopa preparations (Sinemet CR)., Results: When entacapone was administered with standard Sinemet the duration of the clinical response to standard Sinemet was longer in comparison with the response after placebo (p=0.02). Moreover, in the same patients, entacapone significantly increased the duration of the clinical response to Sinemet CR (p=0.05) without prolonging the latency of response or enhancing dyskinesias., Conclusions: These data confirm the clinical efficacy of entacapone-standard Sinemet combination. They also indicate that adding entacapone to controlled release levodopa preparations might provide a useful treatment option in patients with Parkinson's disease with motor fluctuations. A double blind clinical trial with a chronically administered entacapone-Sinemet CR combination is, however, required to verify this viewpoint.

The effects of carbidopa and entacapone pretreatment on the pharmacokinetics and metabolism of i.v. administered L-3,4-dihydroxyphenylalanine (L-dopa) have been examined in vivo in blood plasma and skeletal muscle extracellular fluid (ECF), in beagle dog, by microdialysis. Both with or without carbidopa, blood plasma L-dopa levels declined biexponentially after the i.v. administration of L-dopa. In contrast to blood plasma, a monoexponential decline was observed in muscle ECF in both these pharmacological conditions. Pretreatment with carbidopa had no significant effect on the pharmacokinetic parameters of L-dopa in blood plasma, but resulted in an increase in the area under the concentration versus time curve (AUC) and elimination half-life (t1/2) of L-dopa in muscle ECF (0.61 hr), compared with values achieved after L-dopa alone. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa (3-OMD) and dopamine (DA) in muscle ECF but decreased that of L-3,4-dihydroxyphenylacetic acid (DOPAC) in both blood plasma and muscle ECF. Entacapone had a pronounced inhibitory effect on the formation of 3-OMD, resulting in a reduction of the AUC for 3-OMD by 98% and 85% in blood plasma and muscle ECF, respectively. Pretreatment with carbidopa plus entacapone enhanced the Tmax of L-dopa in muscle ECF compared with the values achieved after pretreatment with carbidopa alone. In addition, the elimination half-life (2.66 hr) and volume of distribution by area of L-dopa in blood plasma and its AUC and t1/2 in muscle ECF (1.80 hr) were enhanced substantially. No DA was detected, but DOPAC levels were enhanced in both blood plasma and muscle ECF. These results suggested that carbidopa has a L-dopa-sparing effect in skeletal muscle, which is further enhanced by entacapone.