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A. Gordin - One of the best experts on this subject based on the ideXlab platform.

  • clinical advantages of comt inhibition with Entacapone a review
    Journal of Neural Transmission, 2004
    Co-Authors: A. Gordin, Seppo Kaakkola, Heikki Teravainen
    Abstract:

    Two catechol-O-methyltransferase (COMT) inhibitors, Entacapone and tolcapone, were developed during the 1990’s to be used as adjuncts to levodopa (LD) – dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson’s disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and Entacapone are quite similar, and Entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first Entacapone dose. When LD is administered in several frequent daily doses, addition of Entacapone reduces the daily fluctuations of plasma LD by 30 to 40%.

  • the tolerability and efficacy of Entacapone over 3 years in patients with parkinson s disease
    European Journal of Neurology, 2003
    Co-Authors: Jan Petter Larsen, A. Gordin, Kari Reinikainen, J Wormpetersen, A Siden, M Leinonen
    Abstract:

    The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor Entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with Entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of Entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P < 0.05). The patients' global assessment indicated that 69% of patients improved when given Entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of Entacapone. In conclusion, Entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

  • efficacy and safety of Entacapone in parkinson s disease patients with suboptimal levodopa response a 6 month randomized placebo controlled double blind study in germany and austria celomen study
    Acta Neurologica Scandinavica, 2002
    Co-Authors: Werner Poewe, A. Gordin, E R Kultalahti, Gunther Deuschl, M Leinonen
    Abstract:

    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.

  • the catechol o methyltransferase comt inhibitor Entacapone enhances the pharmacokinetic and clinical response to sinemet cr in parkinson s disease
    Journal of Neurology Neurosurgery and Psychiatry, 2000
    Co-Authors: Paola Piccini, David J. Brooks, Kirsi Korpela, Nicola Pavese, Marianne Karlsson, A. Gordin
    Abstract:

    Objectives—Entacapone is a specific, potent, peripherally acting catechol-Omethyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical eVect when used as an adjunct to standard levodopa preparations, but there is little experience of the eVect 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 eVect 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 eYcacy 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 EntacaponeSinemet CR™ combination is, however, required to verify this viewpoint. (J Neurol Neurosurg Psychiatry 2000;68:589‐594)

  • Entacapone enhances levodopa induced reversal of motor disability in mptp treated common marmosets
    Movement Disorders, 1997
    Co-Authors: Lance A Smith, A. Gordin, P Jenner, C D Marsden
    Abstract:

    Oral administration of levodopa (L-dopa) (2.5–25.0 mg/kg) plus carbidopa (12.5 mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in locomotor activity and a corresponding decrease in motor disability. Pretreatment with the peripheral COMT inhibitor Entacapone (12.5 mg/kg p.o.) enhanced the intensity and duration of the increase in locomotor activity and the reversal of motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus carbidopa. By contrast, Entacapone pretreatment did not potentiate the increased locomotor activity or reversal of motor disability produced by a near-maximal dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of Entacapone (5.0–25.0 mg/kg p.o.) were dose related, with doses of >12.5 mg/kg tending to produce less potentiation of L-dopa's effects compared to lower doses. Pretreatment with Entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5 mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both carbidopa and Entacapone produced the greatest overall motor response. In conclusion, Entacapone enhances the motor response produced by a low threshold dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa and Entacapone appears necessary to obtain the maximal therapeutic response.

David J. Brooks - One of the best experts on this subject based on the ideXlab platform.

Mikko Kuoppamaki - One of the best experts on this subject based on the ideXlab platform.

  • increased dose of carbidopa with levodopa and Entacapone improves off time in a randomized trial
    Neurology, 2019
    Co-Authors: Claudia Trenkwalder, Thomas Müller, Mikko Kuoppamaki, Mikko Vahteristo, Juha Ellmen
    Abstract:

    Objective To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of Entacapone might improve “off” time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of Entacapone (LCE) during a 4-week treatment period. Methods This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD. Results One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily “off” time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline “off” times were during ODM-101/65, −1.53 hours (p = 0.02 vs LCE), during ODM-101/105, −1.57 hours (p = 0.01 vs LCE), and during LCE −0.91 hours. Changes in daily “on” time without dyskinesia were 1.54 hours (p = 0.005 vs LCE), 1.38 hours (p = 0.0214 vs LCE), and 0.69 hours, respectively. Changes in “on” time with troublesome dyskinesia were Conclusion Increasing the dose of carbidopa in combination with levodopa and Entacapone should be considered in the treatment of fluctuating PD to improve daily “off” times. Genotyping patients with PD according to COMT activity may improve individual treatment strategies. ClinicalTrials.gov identifier NCT01766258. Classification of evidence This study provides Class II evidence that an increased dose of carbidopa improves motor fluctuations when administered with levodopa and Entacapone.

  • efficacy and safety of Entacapone in levodopa carbidopa versus levodopa benserazide treated parkinson s disease patients with wearing off
    Journal of Neural Transmission, 2015
    Co-Authors: Mikko Kuoppamaki, Mika Leinonen, Werner Poewe
    Abstract:

    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.

  • the effect of different dosing regimens of levodopa carbidopa Entacapone on plasma levodopa concentrations
    European Journal of Clinical Pharmacology, 2012
    Co-Authors: Kimmo Ingman, Mikko Kuoppamaki, Mikko Vahteristo, Tarja Naukkarinen, Irja Korpela, Juha Ellmen
    Abstract:

    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 (Cmax) during the day. High levodopa concentrations are associated with peak-dose dyskinesias.

  • early versus delayed initiation of Entacapone in levodopa treated patients with parkinson s disease a long term retrospective analysis
    European Journal of Neurology, 2009
    Co-Authors: Helena Nissinen, M Leinonen, Mikko Kuoppamaki, Anthony H V Schapira
    Abstract:

    Background:  We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with Entacapone can lead to better long-term outcomes than delayed Entacapone treatment. Methods: Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to Entacapone (‘early-start’ group) or placebo (‘delayed-start’ group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and Entacapone treatment for up to 5 years. Results:  A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and Entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of −1.66 (95% confidence intervals [−3.01, −0.31]) points compared with the delayed-start treatment group (P < 0.05). Levodopa/DDCI and Entacapone therapy was well tolerated. There was no excess of dyskinesia in the early-start group. Conclusions:  These data suggest that early rather than delayed addition of Entacapone to levodopa/DDCI in PD patients with wearing-off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.

  • five year efficacy and safety of levodopa ddci and Entacapone in patients with parkinson s disease
    Journal of Neural Transmission, 2008
    Co-Authors: David J. Brooks, Mikko Kuoppamaki, Mika Leinonen, Helena Nissinen
    Abstract:

    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.

M Leinonen - One of the best experts on this subject based on the ideXlab platform.

  • early versus delayed initiation of Entacapone in levodopa treated patients with parkinson s disease a long term retrospective analysis
    European Journal of Neurology, 2009
    Co-Authors: Helena Nissinen, M Leinonen, Mikko Kuoppamaki, Anthony H V Schapira
    Abstract:

    Background:  We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with Entacapone can lead to better long-term outcomes than delayed Entacapone treatment. Methods: Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to Entacapone (‘early-start’ group) or placebo (‘delayed-start’ group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and Entacapone treatment for up to 5 years. Results:  A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and Entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of −1.66 (95% confidence intervals [−3.01, −0.31]) points compared with the delayed-start treatment group (P < 0.05). Levodopa/DDCI and Entacapone therapy was well tolerated. There was no excess of dyskinesia in the early-start group. Conclusions:  These data suggest that early rather than delayed addition of Entacapone to levodopa/DDCI in PD patients with wearing-off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.

  • the tolerability and efficacy of Entacapone over 3 years in patients with parkinson s disease
    European Journal of Neurology, 2003
    Co-Authors: Jan Petter Larsen, A. Gordin, Kari Reinikainen, J Wormpetersen, A Siden, M Leinonen
    Abstract:

    The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor Entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with Entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of Entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P < 0.05). The patients' global assessment indicated that 69% of patients improved when given Entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of Entacapone. In conclusion, Entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

  • efficacy and safety of Entacapone in parkinson s disease patients with suboptimal levodopa response a 6 month randomized placebo controlled double blind study in germany and austria celomen study
    Acta Neurologica Scandinavica, 2002
    Co-Authors: Werner Poewe, A. Gordin, E R Kultalahti, Gunther Deuschl, M Leinonen
    Abstract:

    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.

  • twelve month safety of Entacapone in patients with parkinson s disease
    European Journal of Neurology, 2001
    Co-Authors: V. V. Myllylä, E R Kultalahti, H M Haapaniemi, M Leinonen
    Abstract:

    The safety of Entacapone combined with levodopa and a dopadecarboxylase (DDC) inhibitor was tested in a 12-month double-blind study of 326 patients with idiopathic Parkinson's disease (PD). The study population represented 'typical' PD outpatients, including patients with varying disease severity and with various concomitant medications. Two-thirds of the patients were randomized to receive 200 mg of Entacapone with each of 2--10 daily levodopa doses, and one-third to receive placebo. All Entacapone patients were included in the safety evaluation of adverse events (AEs), vital signs, ECG, and laboratory parameters. Entacapone was well tolerated with a discontinuation rate due to AEs of 14% compared with 11% with placebo (NS). As expected, due to dopaminergic enhancement, dyskinesia was more frequent as an AE with Entacapone than with placebo. Dryness of mouth, urine discoloration and diarrhoea were more frequent non-dopaminergic AEs with Entacapone than with placebo. Entacapone had no adverse effects on hepatic enzyme activity, ECG or haemodynamic parameters, and there was no evidence of any toxicity. As an indication of levodopa enhancement with Entacapone, patients taking 5--10 doses of levodopa, most likely representing predominantly fluctuating patients, showed a significant decrease in their mean daily levodopa dose of 94 mg in the Entacapone group compared with a decrease of 39 mg in the placebo group (P < 0.01). The interval between the first two morning doses of levodopa increased by 17% with Entacapone, whereas with placebo no extension was observed (P < 0.05). Despite levodopa dose reduction, efficacy of Entacapone was maintained. As further evidence of efficacy, Parkinsonian symptoms markedly worsened in all patients after withdrawal of Entacapone. We conclude that Entacapone is safe in optimizing levodopa in long-term treatment of idiopathic Parkinson's disease. Monitoring of liver or other safety parameters during Entacapone treatment is not required.

U K Rinne - One of the best experts on this subject based on the ideXlab platform.

  • Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations
    Neurology, 1998
    Co-Authors: U K Rinne, Jan Petter Larsen, A Siden, J Wormpetersen
    Abstract:

    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 Parkinson9s 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: Patients9 home diaries indicated that Entacapone increased the mean (± SD) "on" time significantly (9.3 ± 2.2 to 10.7 ± 2.2 hours; p p p p 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.

  • striatal 6 18f fluorodopa accumulation after combined inhibition of peripheral catechol o methyltransferase and monoamine oxidase type b differing response in relation to presynaptic dopaminergic dysfunction
    Synapse, 1997
    Co-Authors: H M Ruottinen, Juha O Rinne, Vesa Oikonen, Jorgen Bergman, Merja Haaparanta, Olof Solin, Ulla Ruotsalainen, U K Rinne
    Abstract:

    The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with Entacapone and MAO-B with selegiline on striatal 6-[18F]fluorodopa (FDOPA) accumulation, and whether the effect of Entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the Entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of Entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k3R0), increased significantly after Entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (Ki) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after Entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K1D) or the relative dopadecarboxylase activity (k3D). The changes in the studied parameters after Entacapone + selegiline administration probably reflect the effects of Entacapone, since Entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to Entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by Entacapone.

  • a double blind pharmacokinetic and clinical dose response study of Entacapone as an adjuvant to levodopa therapy in advanced parkinson s disease
    Clinical Neuropharmacology, 1996
    Co-Authors: H M Ruottinen, U K Rinne
    Abstract:

    Summary:A dose-response study of the effects of Entacapone on the pharmacokinetics and metabolism of levodopa and on the clinical response to levodopa was carried out in 20 parkinsonian patients with levodopa-related fluctuations. A randomized, double-blind, single-graded-dose, crossover design of f

  • Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations
    Journal of Neurology Neurosurgery and Psychiatry, 1996
    Co-Authors: H M Ruottinen, U K Rinne
    Abstract:

    OBJECTIVES--To establish, in a double blind manner, the antiparkinsonian effects of repeated dosing with Entacapone, a peripheral COMT inhibitor. METHODS--A one month, cross over study was conducted. During the two four-week treatment periods, Entacapone (200 mg) or placebo was given with each levodopa dose four to 10 times daily. Motor responses were repeatedly quantified using the motor part of UPDRS. Plasma levodopa and its metabolites were measured. RESULTS--Entacapone prolonged the availability of levodopa in the plasma and thus to the brain by decreasing its peripheral O-methylation and slowing its elimination rate, without affecting the maximum plasma levodopa concentration or the time to maximum concentration. Corresponding with the pharmacokinetic findings, Entacapone prolonged the duration of motor response to an individual levodopa/DDC inhibitor dose by 34 minutes (24%, P = 0.001) and dyskinesiae by 39 minutes (37%, P = 0.002) compared with placebo, without affecting their magnitude or starting time. Entacapone treatment resulted in a reduction of 16% in the mean total daily levodopa dose due to dyskinesiae. Also, according to the home diaries, the mean daily "on" time increased by 2.1 hours compared with placebo, despite the lowered mean levodopa intake. CONCLUSION--The efficacy of repeated Entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson's disease with levodopa related fluctuations is verified.

  • Striatal [^18F]fluorodopa utilization after COMT inhibition with Entacapone studied with PET in advanced Parkinson's disease
    Journal of Neural Transmission - Parkinson's Disease and Dementia Section, 1995
    Co-Authors: H M Ruottinen, Vesa Oikonen, Merja Haaparanta, J. O. Rinne, U. H. Ruotsalainen, J. R. Bergman, O. H. Solin, A. O. Laihinen, U K Rinne
    Abstract:

    The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with Entacapone on striatal uptake of 6-[^18F]fluoro-L-dopa (FDOPA) was studied with PET both without and with Entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k_3R_0), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (K_i) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the K_i remained virtually unchanged. Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.