entacapone and Parkinson-Disease

Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.

Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechols; Dopamine Agonists; Drug Combinations; Humans; Levodopa; Parkinson Disease

In advanced Parkinson's disease, oral medication can often no longer achieve sufficient therapeutic success. As one of the device aided therapies, the intrajejunal levo-dopa administration has been established as valuable treatment option. A modern form of the well-known intestinal levodopa pump offers the opportunity to continue the oral triple combination of levodopa, carbidopa and entacapone that many patients already use. Since February 2021 this modern option is available in Austria and Germany which also contains entacapone, whereby levo-dopa can be saved. In many other countries, including Hungary, approval is expected in the near future. The pump and cartridge are significantly smaller and lighter than in the LCIG pump which should improve the accep-tance of the therapy. The higher acceptance of the smaller pump and the improved user-friendliness has already been reported in an observational study from Sweden. The unwanted effects of entacapone have to be considered..

Előrehaladott Parkinson-kórban a szájon át adható gyógyszeres kezelés gyakran nem éri el a kellő terápiás hatást. Az eszköztámogatott terápiás módszerek egyike, a levodopa intrajejunalis adagolása, értékes alternatívának bizonyult. A jól ismert intestinalis levodopapumpa egy modern változata lehetővé teszi a levodopa, karbidopa és entakapon orális hármas kombinációjának további alkal­mazását, amellyel sok beteg már előzőleg kezelve volt. Ez, az entakapont is tartalmazó, modern kezelési lehetőség 2021. február óta érhető el Ausztriában és Német­ország­ban és a levodopadózis csökkentését is eredményezheti az intestinalis levodopadózishoz (LCIG) viszonyítva. A közel­jövőben számos más országban, köztük Magyarországon is egyedi támogatással igényelhető. A pumpa és az in­tes­tinalis gélt tartalmazó patron lényegesen kisebb és könnyebb, mint az LCIG-pumpa, ami javítja a terápia elfogadottságát. Egy Svédországban végzett tanulmány a kisebb pumpa magasabb elfogadottsági arányáról és felhasználóbarátabb kezelésről számolt be a betegek körében. Azonban az entakapon esetlegesen fellépő nem­kívánt mellékhatásait nem szabad figyelmen kívül hagyni.

Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Gels; Humans; Levodopa; Observational Studies as Topic; Parkinson Disease

Topics: Administration, Oral; Adult; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Humans; Nitriles; Oxadiazoles; Parkinson Disease

Treatment of Parkinson's disease with levodopa/carbidopa/entacapone (LCE) has been studied for a long time. However, the efficacy and safety of LCE in the treatment of early Parkinson's disease (PD) still need to be assessed. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy and safety of LCE for early PD. PubMed, Embase, the Cochrane Library, and the Web of Science were searched for RCTs with "levodopa/carbidopa/entacapone" and "Parkinson's disease" as keywords. The search period was from inception to October 2018. The quality of included studies was strictly evaluated. We evaluated the quality of included studies strictly and six studies met all inclusion criteria. The results showed that LCE could improve activities of daily living and motor function in PD patients. However, LCE therapy was associated with higher risks of total AEs and single AEs compared with traditional therapy.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Drug Combinations; Humans; Levodopa; Nitriles; Parkinson Disease

Motor fluctuations are frequently seen in Parkinson disease patients on chronic treatment with levodopa. Management of motor fluctuation includes the addition of catechol-O-methyl transferase (COMT) inhibitors. Opicapone is a recent and selective third-generation COMT inhibitor which achieves marked increase in the bioavailability of levodopa. We present a consensus of a group of Spanish neurologists with extensive experience in the clinical management of motor fluctuations. The clinical experience of this group of experts is in line with clinical trials and confirms that opicapone is an effective drug in the control of motor fluctuations, regardless of the daily levodopa dose, or the use of other antiparkinsonian drugs. However, in the opinion of these experts, the ideal patient with Parkinson's disease to initiate treatment with opicapone is the one with mild motor fluctuations, since the ratio between clinical efficacy and adverse effects is more favorable. In general, it is an easy-to-use drug both in those first treated with a COMT inhibitor or those already on entacapone. In any case, the secondary side effects are easily managed.. Optimización del manejo clínico de opicapona en la enfermedad de Parkinson. Recomendaciones de expertos españoles.. Las fluctuaciones motoras constituyen una importante complicación en los pacientes con enfermedad de Parkinson tratados con levodopa. Entre las opciones terapéuticas para el manejo de las fluctuaciones motoras se cuenta con los inhibidores de la catecol-O-metil-transferasa (COMT), incluyendo la opicapona. La opicapona muestra una elevada afinidad por la COMT y consigue un aumento marcado de la biodisponibilidad de la levodopa. Se presenta el consenso de un grupo de expertos españoles en la enfermedad de Parkinson con experiencia en el tratamiento clínico de fluctuaciones motoras y el empleo de opicapona. La experiencia de este grupo de expertos, en consonancia con los ensayos clínicos, confirma que la opicapona es un fármaco eficaz en el control de las fluctuaciones motoras de la enfermedad de Parkinson, con independencia de la dosis de levodopa recibida o de la utilización de otros fármacos antiparkinsonianos. No obstante, a juicio de estos expertos, el paciente ideal para iniciar el tratamiento con opicapona es el que presenta fluctuaciones motoras leves, ya que muestra una mejor relación entre eficacia clínica y efectos adversos. En general, la opicapona es un fármaco de fácil manejo, tanto en pacientes que requieren opicapona como primer inhibidor de la COMT como en los previamente tratados con entacapona, o en los que están en tratamiento concomitante con otros fármacos antiparkinsonianos. En cualquier caso, los efectos secundarios son fácilmente corregibles.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dopamine Agonists; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Oxadiazoles; Parkinson Disease; Patient Selection; Treatment Outcome

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.. 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.. 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.

Topics: Antiparkinson Agents; Catechols; Drug Combinations; Humans; Levodopa; Motor Activity; Nitriles; Parkinson Disease; Quality of Life; Randomized Controlled Trials as Topic; Tablets

Topics: Administration, Oral; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitriles; Oxadiazoles; Parkinson Disease

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.. 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.. 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.. Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review.. 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.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease; Tolcapone; Treatment Outcome

To assess the efficacy and safety of adjuvant treatment with entacapone in the treatment of later Parkinson's disease (PD) patients with motor fluctuation.. We conducted a systematic review of relevant studies from 8 databases to June 23, 2016.. Fourteen studies were included in this review (n = 2,804). The results showed that compared with placebo, adjuvant therapy with entacapone significantly increased on time (p < 0.01) and reduced off time (p < 0.01), the required levodopa (LD) dose (p < 0.01) and improved Parkinson's Disease Rating Scale (UPDRS) scores (activities of daily living score: p < 0.01; motor score: p < 0.01; UPDRS I-III score: p > 0.05). However, the withdrawal (OR 1.44, 95% CI 1.10-1.89, p < 0.01) due to adverse events and adverse events rates including nausea (OR 2.23, 95% CI 1.56-3.20, p < 0.01), urine discoloration (OR 14.99, 95% CI 7.63-29.44, p < 0.01), gastrointestinal disorder (OR 2.6, 95% CI 1.89-3.57, p < 0.01) and dyskinesia (OR 2.00, 95% CI 1.56-2.58, p < 0.01) increased in patients with entacapone compared with those given a placebo .. This meta-analysis suggests that the entacapone used as adjuvant therapy to LD is effective in the management of later PD with fluctuation. However, patients on entacapone had a higher frequency of adverse events than those on placebo but no occurrence of severe adverse reactions.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Dyskinesias; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Chemistry, Pharmaceutical; Drug Combinations; Humans; Levodopa; Nitriles; Parkinson Disease

Topics: Benserazide; Benzothiazoles; Catechols; Circadian Rhythm; Dementia; Dopamine Agonists; Drug Combinations; Drug Therapy, Combination; Drug Tolerance; Dyskinesias; Education, Medical, Continuing; Hallucinations; Humans; Levodopa; Nitriles; Parkinson Disease; Practice Guidelines as Topic; Pramipexole; Reference Standards; Referral and Consultation

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.

Topics: Amantadine; Antiparkinson Agents; Carbidopa; Catechols; Dopamine Agonists; Drug Administration Schedule; Drug Combinations; Hospitalization; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitriles; Nursing Care; Parkinson Disease

To investigate efficacy and safety of entacapone across phase III studies in Parkinson's disease (PD) with wearing-off symptoms.. Retrospective, pooled analysis of four phase 3 randomized, double-blind, placebo-controlled studies with entacapone.. 475 of 808 patients with PD received entacapone and 333 received placebo. Entacapone improved daily OFF- and ON-times (change from baseline) by 0.8 h compared with placebo (P < 0.0001 for both variables). Entacapone was also better in UPDRS II (P < 0.01) and III (P < 0.01) scores and global evaluation (P < 0.05). Similar benefits were seen in subgroups of patients with and without dopamine agonist (DA) or selegiline, but the subgroup results should be regarded as exploratory. Entacapone was generally well tolerated. Dyskinesia and nausea were more frequently reported by patients on entacapone (25.7% and 14.5% of patients, respectively) than those receiving placebo (15.6% and 6.0%, respectively). However, there was no difference in reports of hallucinations between entacapone (4.8%) and placebo (4.8%).. Entacapone improved daily OFF- and ON-times by a mean of 0.8 h compared with placebo across the four pooled efficacy studies and was generally well tolerated. The results of this pooled analysis potentially serve as a useful benchmarking data for new therapies (especially levodopa products) in advanced patients with PD.

Topics: Aged; Antiparkinson Agents; Catechols; Clinical Trials, Phase III as Topic; Dopamine Agonists; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nausea; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; Retrospective Studies; Selegiline

Oxidative stress reduction via monoamine oxidase-B (MAO-B) inhibition with rasagiline is under investigation to modify the course of Parkinson's disease (PD) progression. Rasagiline moderately improves motor symptoms and therefore reduces the predominant levodopa-associated wearing-off phenomena.. Following a PubMed database search with the terms rasagiline and selegiline, this review describes the role of rasagiline in the treatment of Parkinson's disease, within a critical discussion of current treatment guidelines. This so-called evidence based research suggests that rasagiline is an alternative to the catechol-O-methyltransferase-inhibitor entacapone, in the treatment of wearing-off phenomena. There is some recent evidence to suggest rasagiline also has monoamine oxidase-A (MAO-A) inhibiting properties, as well as different clinical and pharmacodynamic properties when compared with selegiline, and clinical benefits when used in combination with a dopamine agonist monotherapy.. Rasagiline is well tolerated and safe, however its use has not yet been fully exploited as an alternative to selegiline due to the availability of cheaper generics. When generic rasagiline is available in Europe, more widespread use should focus on the simultaneous administration with entacapone as an approach to delaying the onset of, and improving the severity of, motor complications in levodopa treated patients. The complimentary combination of the pharmacologic principles of rasagiline and entacapone may support the concept of continuous nigrostriatal dopaminergic stimulation.

Topics: Animals; Antiparkinson Agents; Catechols; Disease Progression; Humans; Indans; Monoamine Oxidase Inhibitors; Nitriles; Oxidative Stress; Parkinson Disease; Selegiline

The development of pharmacogenetic-based clinical practice guidelines for the use of anti-Parkinson's disease drugs requires, as a pre-requisite, the identification and validation of genetic biomarkers. These biomarkers are then used as surrogate endpoints. This review analyzes potential genetic biomarkers which can be used to improve anti-Parkinson's disease therapy.. The authors present an overview of current knowledge of pharmacogenetic implications of anti-Parkinson's disease drugs, including genes coding for the corresponding drug-metabolizing enzymes and drug targets. The gene/drug pairings with the strongest potential for pharmacogenetic recommendations include: CYP2C19/benztropine, COMT/levodopa and entacapone, CYP2B6/selegiline, UGT1A/entacapone, DRD2/ropinirole, pramipexole and cabergoline, and DRD3/ropinirole and pramipexole. Evidence supporting the effect of substrates, inhibitor or inducers for drug specific metabolizing enzymes in anti-Parkinson's disease drug response includes CYP1A2 in the response to ropinirole and rasagiline, and CYP3A4 in the response to bromocriptine, lisuride, pergolide and cabergoline. The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti-Parkinson's disease drugs. They also review and discuss the clinical implications of these variations.. The goal of pharmacogenomic testing for anti-Parkinson's disease drugs should be conservative and aimed at selecting determined drugs for determined patients. However, much additional research is still needed to obtain reliable pre-prescription tests.

Topics: Aryl Hydrocarbon Hydroxylases; Benzothiazoles; Benztropine; Bromocriptine; Cabergoline; Catechols; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Ergolines; Genetic Markers; Humans; Indans; Indoles; Levodopa; Lisuride; Nitriles; Parkinson Disease; Pergolide; Pharmacogenetics; Pramipexole; Receptors, Dopamine D2; Receptors, Dopamine D3; Reproducibility of Results; Selegiline

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.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Drug Administration Schedule; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of motor fluctuations and dyskinesia, complicating long-term levodopa therapy of Parkinson's disease (PD). Continuous dopamine stimulation (CDS) is a concept that refers to the hypothesis that more continuous dopamine-receptor stimulation will reduce the risk of motor complications, particularly dyskinesias, and may also treat established dyskinesias. In line with this hypothesis, the intermittent administration of dopaminergic agents with short half-lives induce motor complications in animal models, whilst the continuous administration of the same compounds via mini-pumps substantially reduces such symptoms. Continuous drug delivery (CDD) strategies are therefore explored in clinical trials to prevent or manage motor complications. The early use of a dopamine agonist reduces the risk of motor fluctuations compared with levodopa. Conversely, the early combination of the catechol-O-methyltransferase inhibitor entacapone with levodopa has failed to demonstrate a comparable advantage. Outcomes of uncontrolled long-term studies of PD patients with motor complications treated for several months with subcutaneous continuous infusion of apomorphine or intraduodenal levodopa are compatible with CDS. New once-daily prolonged-release formulations of dopamine agonists have demonstrated antiparkinsonian efficacy in randomized trials conducted in early as well as advanced patients with PD. Once-daily administration is convenient and may improve compliance. Other theoretical advantages in terms of efficacy or tolerability deserve further exploration.

Topics: Animals; Antiparkinson Agents; Benzothiazoles; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Dopamine Agonists; Drug Delivery Systems; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitriles; Parkinson Disease; Pramipexole

Levodopa (LD) is an efficient drug for patients with Parkinson's disease (PD). Its short half-life supports peaks and troughs. These plasma fluctuations support alternating stimulation of striatal postsynaptic dopamine receptors and thus onset of motor complications. They are significant components for the quality of treatment of PD patients.. This review discusses peripheral components of motor complication manifestation related to LD metabolism.. LD troughs are associated with wearing off, which is reappearance of motor symptoms with decreasing drug effect. The addition of the catechol-O-methyltransferase inhibitor entacapone (EN) to LD/carbidopa (CD) improves wearing off, as EN prolongs LD half-life and avoids troughs. LD peaks are mostly related to peak dose dyskinesia, which are involuntary movements due to a central overstimulation with dopamine. One time addition of EN to LD/CD showed no increase of maximum LD concentration, but repeat EN supplementation to LD/CD elevated LD bioavailability and peaks.. These pharmacokinetic data may explain the failure of the STRIDE-PD study, which aimed to show a delayed interval of dyskinesia onset with LD/CD/EN therapy. This study only allowed up titration with a fixed LD intake every 4 h. But dyskinesia occurrence may require down titration of LD dose or delay of next LD intake.

Topics: Animals; Antiparkinson Agents; Biological Availability; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitriles; Parkinson Disease

Entacapone and tolcapone are reversible COMT inhibitors which have been approved for clinical use in patients with Parkinson disease (PD). Nebicapone is a third COMT inhibitor which has been studied in humans. COMT inhibitors are used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor. Each of them has problems either in pharmacokinetics, pharmacodynamics, clinical efficacy, or in safety. All three inhibitors have short elimination half-lives, about 2-3h. Tolcapone is longer acting and more potent COMT inhibitor than entacapone; nebicapone lies in between. However, none of the present inhibitors cause a complete peripheral COMT inhibition. Tolcapone and nebicapone have increased more levodopa AUC than entacapone which is reflected also in their clinical efficacy. The most common adverse event with COMT inhibitors is dyskinesia which is usually managed by decreasing levodopa dose. The greatest problem with tolcapone and probably also with nebicapone is their liver toxicity which is not seen with entacapone. Tolcapone causes severe diarrhea more often than entacapone. Though the present COMT inhibitors have improved significantly the treatment of advanced PD patients, they still have several problems and weaknesses leaving room for developing better COMT inhibitors.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

The year of 2007 was a turning point of the treatment of Parkinson's disease (PD) in Japan. Severe adverse effects of dopamine agonists including valvular heart disease induced by ergots and sudden onset of sleep attacks induced by non-ergots, were disclosed, and treatments with agonists were reassessed. Good news were marketing of ropinirole, a new non-ergot agonist, in December 2006 and entacapone, the first catechol-O-methyl transferase (COMT) inhibitor in Japan in April 2007. Having faced these new situations, Japanese Neurological Association has started revising "the Guideline 2002 for the treatment of Parkinson's disease". Clinical trials of translational gene therapy for Parkinson's disease with adeno-associated virus (AAV) vector are now going on in four approaches: restoring dopamine synthetic capacity, protecting against cell death with trophic factors, interfering with the aberrant protein aggregation, and converting the subthalamic nucleus into an inhibitory, rather than an excitatory, structure. In Japan, gene delivery of the dopamine synthesizing enzyme aromatic amino acid decarboxylase (AADC) to the striatum of PD patients is going on in Jichi Medical University. New findings of the causative genes, environmental factors and molecular mechanism of PD have provided with new tools for developing new treatments. The big success of induction of induced pluripotent stem (iPS) cells from fibroblast has given an impact on cell therapy research of PD.

Topics: Antiparkinson Agents; Aromatic-L-Amino-Acid Decarboxylases; Catechol O-Methyltransferase Inhibitors; Catechols; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Dependovirus; Dopamine Agonists; Enzyme Inhibitors; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Indoles; Nitriles; Parkinson Disease; Pluripotent Stem Cells; Practice Guidelines as Topic

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.

Topics: Aged; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Brain; Catechols; Clinical Trials, Phase III as Topic; Dopa Decarboxylase; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; Retrospective Studies; Time; Treatment Outcome

The relative efficacy has not been adequately established for the two catechol-O-methyltransferase (COMT) inhibitors that are currently available for adjunctive therapy in Parkinson's disease; tolcapone and entacapone. A recent Cochrane meta-analysis of 14 studies in 2566 patients, conducted to assess the efficacy and safety of tolcapone and entacapone, found both to be statistically superior to placebo in increasing ON time and decreasing OFF time. The meta-analysis also showed that the weighted mean difference from baseline to endpoint in tolcapone-treated patients was twice that in entacapone-treated patients for both placebo-corrected ON time and OFF time. Withdrawal rates were generally lower for tolcapone. Two additional studies have examined the switch between tolcapone and entacapone. In 40 Parkinson's disease patients with fluctuations who were switched from tolcapone to entacapone, improvements in ON time and reductions in OFF time were approximately twice the magnitude for tolcapone than for entacapone. In a second study examining the switch from entacapone to tolcapone, the results for several exploratory variables also suggested that tolcapone has greater efficacy than entacapone. These findings indicate that tolcapone should be considered in all patients with entacapone-refractory motor fluctuations.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechols; Dose-Response Relationship, Drug; Evidence-Based Medicine; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Treatment options for Parkinson's disease have greatly expanded in recent years. Pharmacological treatments, such as levodopa, dopamine receptor agonists, anticholinergic medications, monoamine oxidase B inhibitors, and the catechol-O-methyl transferase inhibitors, remain the mainstay of therapeutic intervention and are reviewed. Additionally, the traditional and new roles for amantadine are explained. Despite the great efficacy of levodopa, "levodopa-sparing strategies" in early Parkinson's disease are emphasized in order to delay the development of difficult-to-manage motor fluctuations and dyskinesias.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitriles; Parkinson Disease; Receptors, N-Methyl-D-Aspartate

To evaluate the role of the practicing pharmacist in the identification and current treatment of the levodopa wearing-off phenomenon experienced by patients with Parkinson's disease (PD) who are receiving chronic levodopa therapy.. Literature retrieval was accessed through MEDLINE (1967-June 2007) using the terms levodopa, wearing-off, and Parkinson's disease. In addition, reference citations from publications identified were reviewed.. All articles that were identified from the data sources and written in English were evaluated.. Levodopa is the most efficacious therapeutic agent in PD; however, the response of patients to levodopa changes over time. Eventually, the duration of response becomes shorter and more unpredictable, and complications emerge. One of the first complications observed with levodopa therapy is wearing-off, which can emerge within 1-3 years of initiation of levodopa treatment. Wearing-off is characterized by the predictable emergence of motor and nonmotor PD symptoms before the next scheduled dose of medication. Despite effective treatment options to tackle wearing-off, it remains underrecognized and under treated. With early identification and optimization of treatment, wearing-off can be managed effectively, resulting in improved quality of life for patients with PD.. Owing to their training and accessibility, pharmacists play an increasingly important role in the management of patients with PD. Pharmacists are uniquely placed to identify wearing-off, offer timely advice, and facilitate the optimization of treatment regimens to improve patients' quality of life and enhance long-term outcomes.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Dopamine Agonists; Drug Combinations; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitriles; Parkinson Disease; Patient Education as Topic; Pharmacists; Professional Role; Severity of Illness Index

Topics: Catechols; Deep Brain Stimulation; Disease Progression; Humans; Indans; Nitriles; Parkinson Disease

Levodopa is the most efficacious treatment in the management of Parkinson's disease. Unfortunately, chronic use of traditional levodopa/dopa decarboxylase inhibitor formulations is associated with the development of complications, such as wearing-off and dyskinesia. In an attempt to avoid these complications, some physicians delay the introduction of levodopa or employ levodopa-sparing strategies; however, these strategies are frequently suboptimal for patients. As most patients require the superior efficacy of levodopa during the course of their disease, an appreciation of the changing response to levodopa over time and an understanding of the pharmacokinetic principles underlying the development of complications such as wearing-off is essential in the long-term management of the patient.

Topics: Animals; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Delayed-Action Preparations; Dopa Decarboxylase; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease

Long-term care of elderly patients with Parkinson's disease (PD) is challenging for long-term care staff and physicians. Because the progression of PD varies among patients, an individualized treatment plan, updated as necessary based on disease progression, comorbid conditions, and side effects, is essential. Education regarding PD management is also needed to provide optimal care, and treatment guidelines from professional associations are available. Especially important is the management of motor complications, which usually emerge after treatment with antiparkinsonian medications, particularly levodopa/carbidopa. Current treatment strategies to avoid or treat motor complications aim at providing a more continuous (ie, physiologic) dopaminergic stimulation, rather than the pulsatile (intermittent) stimulation provided by traditional PD treatments. Catechol O-methyltransferase (COMT) inhibitors prolong the levodopa serum half-life and allow more levodopa to be delivered to the brain over a longer time, thereby smoothing dopaminergic stimulation. Dopamine agonists also provide more continuous dopaminergic stimulation but are associated with a greater likelihood of hallucinations and confusion, especially in the elderly. Treatments that reduce motor complications, allowing a higher level of functioning, lessen the burden of care in long-term care settings and increase quality of life for patients and their families.

Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Levodopa; Long-Term Care; Nitriles; Parkinson Disease

Diagnosis of PD can be difficult in elderly patients because some of the key PD symptoms also may be manifestations of normal aging. Asymmetrical symptom onset, resting tremor,and sustained response to levodopa are key features that suggest a diagnosis of PD. For most patients, PD progresses fairly slowly. The goal of treatment is to control symptoms, thereby allowing quality of life and functional ability to be maintained. Pharmacologic therapies are primarily targeted at stimulating dopaminergic receptors, either by increasing the levels of dopamine or by using dopamine agonists. Levodopa, the main therapy for PD and a precursor of dopamine, has a short half-life and is quickly metabolized.Accordingly, decarboxylase inhibitors, like carbidopa, are almost always administered with levodopa to prevent breakdown in the periphery. Catechol-O-methyltransferase (COMT)inhibitors, which increase dopamine levels by inhibiting the metabolism of levodopa and dopamine, recently have become available, including a tablet containing carbidopa, levodopa,and entacapone. Other pharmaceutical therapies for PD include dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, anticholinergic agents, and amantadine. Dopamine agonists, anticholinergic agents, and amantadine are associated with an increased risk of hallucinations or other adverse events in elderly patients; therefore, use of these should be avoided in this population. Surgical management, particularly deep brain stimulation(DBS), is an option for patients who are refractory to pharmaceutical therapy. Although patients may not need levodopa as an initial treatment, over time most patients will require this drug to control symptoms. With chronic levodopa therapy, patients ultimately experience a wearing off in levodopa response and other motor complications. Management of wearing off is a significant challenge in the treatment of patients with advanced PD.

Topics: Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Female; Humans; Levodopa; Male; Monoamine Oxidase Inhibitors; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Topics: Apomorphine; Benzophenones; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Ergolines; Humans; Levodopa; Movement Disorders; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

In advanced Parkinson's disease, the combination of disease progression and levodopa therapy leads to the development of motor problems complicating the therapeutic response, known as motor response complications. The nonphysiological, pulsatile stimulation produced by most currently available dopaminergic therapies triggers a complicated series of responses resulting in the dysregulation of glutamate receptors and many other neurotransmitter systems on striatal neurons. Although a number of novel compounds that provide a more continuous dopaminergic stimulation are becoming available, no practical way to accomplish this in a truly physiological manner currently exists. Novel strategies for pharmacological intervention with the use of nondopaminergic treatments, with drugs targeting selected transmitter receptors expressed on striatal neurons appear more promising. These include NMDA or AMPA antagonists, or drugs acting on 5-hydroxytryptamine subtype 2A, alpha2-adrenergic, adenosine A2A and cannabinoid CB1 receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern, like synaptic vesicle proteins, or nonsynaptic gap junction communication mechanisms, or drugs with actions at the signal transduction systems that modulate the phosphorylation state of NMDA receptors. These new therapeutic strategies, alone or in combination, hold the promise of providing effective control or reversal of motor response complications.

Topics: Administration, Cutaneous; Animals; Antiparkinson Agents; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dopamine Agonists; Drug Delivery Systems; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Indans; Levodopa; Liposomes; Monoamine Oxidase Inhibitors; Motor Neurons; Movement Disorders; Nitriles; Parkinson Disease; Receptors, Glutamate; Signal Transduction

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.

Topics: Akathisia, Drug-Induced; Animals; Antiparkinson Agents; Carbidopa; Catechols; Clinical Trials as Topic; Dopamine; Drug Therapy, Combination; Humans; Hyperhomocysteinemia; Levodopa; MPTP Poisoning; Neuroprotective Agents; Nitriles; Parkinson Disease; Parkinsonian Disorders; Rats; Treatment Outcome

The development of fluctuations in motor response and involuntary movements commonly complicate the treatment of Parkinson's disease (PD). Catechol-O-methyltransferase (COMT) inhibitors delay the breakdown of levodopa, which leads to an increase in levodopa bioavailability and more stable concentrations of plasma levodopa. The addition of a COMT inhibitor therefore combines the rapid onset of levodopa with prolonged efficacy, and theoretically provides a more continuous stimulation of dopamine receptors with reduced risk of motor complications. Randomised, controlled trials have shown that in patients with PD who have motor fluctuations, the addition of the COMT-inhibitor entacapone results in an improvement in motor fluctuations, particularly of the "wearing-off" type, with about 1.0-1.7 h more on-time and less off-time per day, reduced required levodopa dose, modest improvement in motor and disability scores (mean total unified PD rating scale [UPDRS] scores of about 4.5), and in some but not all studies improvement of health-related quality of life [HRQOL] scores.. Patients with stable PD, without motor fluctuations, also have improved HRQOL scores on treatment with entacapone in addition to levodopa with a dopa-decarboxylase inhibitor. However, in a recent large multicentre study, UPDRS motor and disability scores were not improved despite significant improvements in HRQOL scores. The disparity between results on clinical rating scales and HRQOL scores suggests that these scales give different and potentially complementary information on health status changes in PD, and that entacapone provides benefit that may not be captured with standard clinical rating scales. Whether entacapone combined with levodopa can delay dyskinesia or motor fluctuations in patients with untreated PD is unknown; however, in animal studies, a decrease in motor complications has been reported in drug-naive animals given frequent doses of levodopa combined with entacapone. WHERE NEXT?: Clinical studies are underway to address the hypothesis that motor complications in PD can be delayed if entacapone is given from the start of treatment. Until the results of these trials are available, entacapone is indicated as a useful adjunct to levodopa in the symptomatic treatment of patients with PD with and without motor fluctuations. In addition, future trials should specifically assess the effect of entacapone on HRQOL in PD.

Topics: Antiparkinson Agents; Catechols; Humans; Nitriles; Parkinson Disease

Several prospective double-blind, placebo-controlled trials have demonstrated that combining levodopa with the COMT inhibitor entacapone is efficacious in reducing motor fluctuations. Compared with levodopa alone, mean daily "on" time was increased by 1-1.7 hours, with a corresponding decrease in daily "off" time. In addition, some studies have shown that these benefits are associated with significant improvements in both UPDRS motor and ADL scores. These benefits have been shown to persist in long-term clinical trials with follow-up for up to 3 years. Recent studies have also examined the value of combining levodopa with entacapone in stable patients who do not experience motor response fluctuations. Here, too, benefits have been reported, especially in health-related quality of life measures. Studies to determine if administering levodopa in combination with entacapone will delay the development of dyskinesia and motor fluctuations are eagerly awaited.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Humans; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Treatment Outcome

Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Humans; Liver; Male; Nausea; Nitriles; Nitrophenols; Parkinson Disease; Safety; Tolcapone

Evidence from preclinical and clinical studies indicates that pulsatile stimulation of striatal dopamine receptors is a key factor in the development of levodopa-associated motor complications. Therefore, in the de novo patient it is believed that providing a more continuous dopaminergic stimulation from the start of antiparkinson therapy may prevent priming for motor fluctuations and dyskinesia. Conversely, in the more advanced patient who is already suffering from motor complications, it is believed that providing a more continuous stimulation may reverse the development of motor complications, enabling the patient to enjoy more stable benefits from therapy. All PD patients eventually require levodopa therapy during the course of their disease, and the benefits of providing continuous dopaminergic stimulation with levodopa have been clearly demonstrated in a number of studies. However, these studies have included the use of approaches such as SC infusion or intra-intestinal infusion. Because these are relatively difficult to handle and not very practical for the patient, compliance is generally low. Therefore, the development of a simple treatment regimen using an oral formulation of levodopa to provide a more continuous dopaminergic stimulation will represent a significant advance in antiparkinsonian pharmacotherapy.

Topics: Animals; Antiparkinson Agents; Catechols; Dopamine Agents; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease

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%. Based on studies with home diaries, entacapone increases the daily ON-time by an average of one to two hours, and reduces the daily OFF-time correspondingly in patients with PD with motor fluctuations. The daily LD dose has been reduced by 10 to 30%. These positive effects are sustained in long term use over several years. There is still scant information of the benefit of entacapone in patients without motor fluctuations. Entacapone can cause both dopaminergic and non-dopaminergic adverse events. Increased dyskinesias are most frequently recorded in patients with motor fluctuations. The dopaminergic adverse events can usually be diminished by reducing the LD dose. Non-dopaminergic adverse events are abdominal pain and diarrhea. Diarrhoea has led to discontinuation in 3 to 4% of the patients in clinical trials. Entacapone has not been connected to liver toxicity and there are no indications to follow laboratory safety during treatment. The benefit-risk ratio of entacapone is considered favorable.A triple LD/carbidopa/entacapone combination tablet has recently been developed. Three LD strengths (50, 100 and 150 mg) are available, each contains 200 mg of entacapone. The majority of the patients can be managed with these three LD strengths. Entacapone has today an established position in treatment of PD patients with motor fluctuations, either as a separate tablet or as the triple LD combination.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease; Quality of Life

As Parkinson's disease progresses the control of motor symptoms often requires the addition of other drugs to levodopa. The principle aim of COMT inhibitor therapy is to increase the duration of effect of each levodopa dose and thus reduce the time patients spend in the relatively immobile 'off' phase.. To compare the efficacy and safety of adjuvant COMT inhibitor therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications.. Electronic searches of the Cochrane Controlled Trials Register, (The Cochrane Library Issue 1, 2003), MEDLINE (1966-2003), EMBASE (1974-2003), were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of COMT inhibitors were contacted.. Randomised controlled trials of adjuvant COMT inhibitor therapy versus a placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy.. Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events.. Fourteen trials fulfilled the inclusion criteria. 2566 patients with Parkinson's disease and motor fluctuations were included in this review. Eight trials examined entacapone versus placebo in a total of 1560 patients. These trials were between two and twelve months in duration. Six trials examined tolcapone versus placebo in a total of 1006 patients. These trials were between six weeks and twelve months in duration. Both tolcapone and entacapone reduced 'off' time, reduced levodopa dose and modestly improved motor impairments and disability. This was at the expense of increased risk of dyskinesias, nausea, vomiting, and diarrhoea. A few participants taking tolcapone were found to have raised liver enzyme levels.. In the management of the motor complications seen in Parkinson's disease, tolcapone and entacapone can be used to reduce off time, reduce levodopa dose, and modestly improve motor impairment and disability. This is based on, at best, medium term evidence. However some participants on tolcapone had raised liver enzymes. This combined with three cases of fatal hepatic toxicity found during post-marketing surveillance has raised concerns over the safety of tolcapone.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Drug Combinations; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease

Topics: Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease; Risk Assessment

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

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Administration, Oral; Antiparkinson Agents; Carbidopa; Catechols; Clinical Trials as Topic; Drug Combinations; Humans; Levodopa; Movement Disorders; Nitriles; Parkinson Disease; Tablets

The diagnosis of Parkinson's disease (PD) is clinical and is based on the identification of a combination of the cardinal motor signs of bradykinesia plus at least one of the following: rigidity, tremor or postural instability. There are many causes of parkinsonism such as drug induced parkinsonism, subcortical vascular disease, and multisystem atrophy. PD is a well characterised syndrome which represents only a part of the various causes of parkinsonism. A good response to dopaminergics is an important diagnostic criteria for PD. Pharmacotherapy for PD relies primarily on levodopa and dopamine agonists. Deep brain stimulation is increasingly used in the management of patients with severe dopa fluctuations and dyskinesias. Cholinesterase inhibitors are introduced for dementia in parkinsonism. Neuroprotective compounds, nerve growth factors such as GDNF and the implantation of dopaminergic cells are studied in clinical trials.

Topics: Aged; Amantadine; Antiparkinson Agents; Apomorphine; Botulinum Toxins; Catechols; Cholinesterase Inhibitors; Clinical Trials as Topic; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Enzyme Inhibitors; Ergot Alkaloids; Family Practice; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Piperidines

Topics: Antiparkinson Agents; Benzophenones; Brain; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Disorders; Randomized Controlled Trials as Topic; Tolcapone

Entacapone is one of a new class of drugs, the catechol-O-methyltransferase (COMT) inhibitors, which expand the therapeutic options for Parkinson's disease by extending the action of levodopa. Entacapone is used in conjunction with levodopa and provides benefit to patients who suffer from motor fluctuations. Side effects include worsening of the dyskinesias associated with peak doses of levodopa, hypotension, constipation and urine discoloration. Unlike tolcapone, an earlier COMT inhibitor, entacapone does not require liver function monitoring.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catecholamines; Catechols; Clinical Trials as Topic; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease

Parkinson's disease is the most common neurodegenerative disease in which the chemical pathology is known and effective symptomatic treatment, levodopa, is available. Therapy in the initial years after initiation with dopa decarboxylase inhibitors, carbidopa or benserazide, combined with levodopa results in favorable, stable responses. However, by 5 years after the initiation of treatment, over two thirds of patients experience motor fluctuations beginning initially with a "wearing-off" effect followed by more complex fluctuations including dyskinesias and "on-off" responses. A number of strategies have been developed in an attempt to deal with these complications including changing doses and frequencies, adding agonist medications, adding or substituting controlled-release levodopa, and surgical therapies. A more recent strategy has centered on increasing the availability of intracellular levodopa and synaptic dopamine by inhibiting the peripheral and central metabolism of levodopa to 3-O-methyldopa with the use of a catechol-O-methyltransferase inhibitor. To date, two of these inhibitors, tolcapone and entacapone, are available to treat the wearing-off phase of levodopa therapy.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Dopamine Agents; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

When levodopa therapy is used in Parkinson's disease, degradation of the drug in the peripheral nervous system is associated with dyskinesias and motor fluctuations. Much of this degradation is produced by catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines and catechol compounds. Inhibition of COMT activity prolongs the action of levodopa and reduces fluctuations in response. Entacapone is a selective inhibitor of COMT whose activity is primarily in the peripheral nervous system, with little effect in the central nervous system.. This paper reviews the pharmacologic properties and clinical usefulness of entacapone in the treatment of Parkinson's disease.. Recent studies, abstracts, and reviews published in the English-language literature were identified through searches of MEDLINE (1966-September 2000), International Pharmaceutical Abstracts (1970-September 2000), and PharmaProjects (September 2000 version), and from the Web sites of Parkinson's disease conferences held from 1996 to September 2000. Relevant human studies provided further information on the pharmacologic properties and clinical usefulness of entacapone.. Entacapone is rapidly absorbed, with a time to maximum concentration of approximately 1 hour. Its plasma elimination half-life is 0.4 to 0.7 hour in the beta phase and 2.4 hours in the gamma phase, and it has 35% absolute bioavailability after oral administration, secondary to first-pass clearance. Entacapone is 98% protein bound; thus, it is not distributed widely in tissues and is almost completely metabolized before excretion (0.1%-0.2% of dose unchanged in urine). The drug inhibits erythrocyte-soluble COMT activity in a dose-dependent fashion (48% after a 400-mg dose, 82% after an 800-mg dose). The inhibitory effect is reversible, with recovery of soluble COMT activity within 4 to 8 hours. In levodopa-treated patients with Parkinson's disease who experience motor fluctuations, clinical trials have demonstrated entacapone's effectiveness in increasing "on" time (the period during which medications relieve the symptoms of Parkinson's disease) by up to 1.2 hours, decreasing "off" time (the period during which symptoms increase) by 0.9 to 1.3 hours, and producing overall total improvement in scores on the Unified Parkinson's Disease Rating Scale. The recommended dosage of entacapone is 200 mg administered orally with each dose of levodopa/carbidopa, up to 8 doses per day. The drug is generally well tolerated, with most adverse effects attributed to levodopa-related dopaminergic effects, including dyskinesias and nausea.. In clinical trials, adjuvant treatment with entacapone appeared to be an effective and well-tolerated therapeutic strategy in patients with Parkinson's disease who experience fluctuations in the response to levodopa therapy. The increased elimination half-life of levodopa with concomitant entacapone results in greater and more sustained plasma levodopa levels, with more constant dopaminergic stimulation in the brain and greater amelioration of parkinsonian symptoms.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Drug Interactions; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease

Registration of the inhibitor of the catechol-O-methyltransfersase (COMT) tolcapone has been stopped due to the possible relationship of tolcapone treatment to three cases of fatal hepatitis. As a result, strong uncertainty has emerged among neurologists about the principle of COMT inhibition itself. We review data, especially on the remaining COMT inhibitor, entacapone, with regard to pre-clinical and clinical efficacy and safety.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dopamine; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Catechol-O-methyltransferase (COMT) inhibitors are a new therapeutic option in the treatment of patients with Parkinson's disease. COMT inhibitors act by extending the duration of action of levodopa, thus improving the amount of time a patient can experience benefit from levodopa. COMT inhibitors are only used in conjunction with levodopa. They do have a propensity to augment dopaminergic effects, such that levodopa doses might need to be adjusted downward. Other side effects of COMT inhibitors include diarrhea and liver function abnormalities. Due to the latter, recent guidelines have been developed to monitor patients on tolcapone for this rare side effect, and these guidelines will be discussed. This article also provides representative case histories for the appropriate use of COMT inhibitors that illustrate how these drugs can be used to manage patients with a fluctuating response to levodopa.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Synergism; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Patient Selection; Tolcapone

Catechol-O-methyltransferase (COMT) inhibition is an important advance in the treatment of Parkinson's disease. This consensus statement provides guidelines for the optimal use of the only currently available COMT inhibitor, entacapone (Comtess, Orion Pharma (UK) Ltd, Newbury, Berkshire).

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Placebos

To introduce entacapone, a new catechol-O-methyltransferase inhibitor, and discuss its pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, drug interactions, adverse events, dosage guidelines, and therapeutic and formulary considerations.. A MEDLINE database search (1966-December 1999) was performed to identify relevant English-language articles including recent studies, abstracts, and reviews. Search terms included entacapone, OR-611, catechol-O-methyltransferase inhibitor, and Parkinson's disease.. Relevant published human studies were chosen to summarize the pharmacokinetics, clinical efficacy, adverse effects, and drug interactions.. All available human clinical trials were reviewed.. Entacapone is the second medication of a new class of drugs, the catechol-O-methyltransferase inhibitors, indicated for clinical use as an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson's disease who experience the signs and symptoms of end-of-dose wearing-off. Entacapone in combination with levodopa/dopa decarboxylase inhibitor has been shown to increase the AUC of levodopa, which leads to less fluctuation of levodopa plasma concentrations. Clinically, the duration of motor response to levodopa was prolonged as reflected by an increase in the mean on time. The addition of entacapone resulted in a decrease in the mean daily dosage of levodopa. The recommended dosage of entacapone is 200 mg administered orally with each dose of levodopa/carbidopa, up to a maximum of eight doses per day. Common adverse effects include dyskinesia, nausea, diarrhea, and urine discoloration.. Entacapone should be considered as add-on treatment to levodopa/carbidopa in Parkinson's disease patients with end-of-dose wearing-off effect.

Topics: Catechols; Clinical Trials as Topic; Drug Interactions; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease; Retrospective Studies

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.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Liver; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Two inhibitors of catechol-O-methyl transferase (COMT), tolcapone and entacapone, have recently been introduced as adjuncts to levodopa in the treatment of Parkinson's disease patients. Both have been shown to provide PD patients with increased "on" time, decreased "off" time, and improved motor scores. There are, however, a number of practical issues that must be considered in order to achieve maximal benefits with this class of agent. They include dosing and administration, efficacy, adverse events, and patient education. In general, these agents are easy to administer and well tolerated. Both the benefits and the principal side effects of treatment are related to increased dopaminergic activity. Patients must be advised of possible side effects so that they can be reported in a timely manner. Physicians must appreciate that dopaminergic side effects, such as dyskinesia, should be controlled by adjusting the dose of levodopa and not the COMT inhibitor. Explosive diarrhea has been reported with tolcapone and usually necessitates discontinuing the drug. Tolcapone must also be monitored for possible liver dysfunction. This has not been reported with entacapone, and no monitoring is required. Metabolites of tolcapone and entacapone may cause discoloration of the urine. This is harmless but patients should be advised that this may occur.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism of levodopa, increase its plasma half-life, and enhance its brain availability. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa. In PD patients with motor fluctuations, they have been shown to increase "on" time and reduce "off" time. In patients with more advanced disease, they provide similar benefits, but patients tend to experience less overall benefit and a greater likelihood of developing dopaminergic adverse events. Accordingly, closer monitoring is required. In stable patients who have not yet developed motor complications, there are preliminary data suggesting that they experience improvements in motor function and in activities of daily living. Finally, there are theoretical reasons to consider administering a COMT inhibitor to patients from the onset of levodopa therapy in order to reduce the likelihood that motor complications will develop. COMT inhibitors are easy to administer, do not require titration, and are generally well tolerated particularly in patients with relatively mild disease. Adverse events are primarily dopaminergic and can usually be controlled by levodopa dose adjustments. COMT inhibitors have thus proven to be a useful addition to the therapeutic armamentarium of PD.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Enzyme Inhibitors; Humans; Monoamine Oxidase Inhibitors; Nitriles; Nitrophenols; Parkinson Disease; Randomized Controlled Trials as Topic; Selegiline; Tolcapone

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease; Treatment Outcome

Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the 'wearing off' phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson's disease. In 2 well conducted trials of 6 months' duration and smaller short term studies, treatment with entacapone (200 mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily 'on' time and decreases in 'off' time. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores concurred with changes in 'on' and 'off' times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials. Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug's ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation.. The efficacy and tolerability of entacapone administered with levodopa/AADC inhibitor have not yet been compared with those of other strategies for the treatment of Parkinson's disease. However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson's disease and the 'wearing off' phenomenon.

Topics: Animals; Antiparkinson Agents; Catechols; Humans; Nitriles; Parkinson Disease

Movement disorders is a term applied for a heterogeneous group of diseases and syndromes sharing deficits of voluntary motor function or movement patterns. In clinical practice, the term movement disorders is usually employed to designate those syndromes and diseases that are linked to a pathology or dysfunction of cortico-basal ganglia circuits. The last years have witnessed a rapid expansion in our understanding of the etiological and pathophysiological factors underlying movement disorders such as Parkinson's disease or dystonia. The discovery of new gene mutations is bound to give rise to new insights into the molecular pathogenesis of movement disorders related to neurodegenerative processes. It is already becoming apparent that pathological protein aggregation may be a common link in the neuronal degeneration underlying such diverse entities as spinocerebellar ataxia, idiopathic torsion dystonia and Parkinson's disease. So far, these new findings have not been translated into new forms of symptomatic or preventive therapies. Nevertheless, symptomatic treatment of movement disorders, as evident in the field of Parkinson's disease, is one of the most rewarding and innovative areas of neurological therapy.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Therapy, Combination; Electric Stimulation Therapy; Enzyme Inhibitors; Globus Pallidus; Humans; Movement Disorders; Mutation; Nitriles; Nitrophenols; Parkinson Disease; Subthalamic Nucleus; Tolcapone

Variations in levodopa delivery and subsequent dopamine exposure may lead to motor fluctuations and dyskinesias in patients with Parkinson's disease, as the therapeutic window for levodopa narrows with disease progression. Long-term exposure to the oscillations in levodopa-derived dopamine also is suggested to cause postsynaptic changes within the dopaminergic system, leading to further reductions in the drug's efficacy. The need to extend the actions of levodopa led to the development of the catechol-O-methyltransferase (COMT) inhibitors, which are the newest agents introduced to manage the symptoms of Parkinson's disease. Entacapone and tolcapone are two potent, selective, and reversible COMT inhibitors that effectively augment levodopa's pharmacokinetics by increasing area under the plasma concentration versus time curve and plasma elimination half-life without significantly affecting peak levodopa concentrations. This enhanced pharmacokinetic effect results in marked improvements in patients' clinical response. In patients experiencing end-of-dose wearing-off, the addition of either entacapone or tolcapone led to improvements in "on" time, "off" time, and the Unified Parkinson's Disease Rating Scale scoring system, even though many patients already were receiving optimum dosages of various other antiparkinsonian drugs. In patients with stable responses to long-term levodopa, addition of tolcapone significantly reduced the onset of motor fluctuations. These data, combined with the potential for delaying the onset of motor fluctuations, suggest that COMT inhibition may enhance levodopa's short- and long-term efficacy.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Disease Progression; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease

During the initial stages of Parkinson's disease, treatment with levodopa plus a decarboxylase inhibitor (carbidopa or benserazide) provides adequate control of symptoms. However, as the disease progresses, the clinical response to treatment often begins to fluctuate, becoming increasingly correlated with fluctuations in plasma concentrations of levodopa-the "wearing-off" phenomenon. Many strategies have attempted, with various degrees of success, to increase the availability of levodopa and its active metabolites, thus reducing these fluctuations in response. This review focuses on the role of the new catechol O-methyltransferase (COMT) inhibitors tolcapone and entacapone as adjuncts to levodopa therapy. These agents act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Performance; Randomized Controlled Trials as Topic; Tolcapone

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.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Pentanones; Tolcapone

A new approach in the treatment of Parkinson's disease is the inhibition of catechol-O-methyltransferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyldopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the Cmax or tmax of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson's disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson's disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.

Topics: Benzophenones; Catechol O-Methyltransferase; Catechols; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

To summarize the development, pharmacology, pharmacokinetics, efficacy, and safety of five investigational antiparkinsonian drugs that are in or have recently completed Phase III trials: three dopamine agonists, pramipexole, ropinirole, and cabergoline; and two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone. The pathophysiology and the role of dopamine in Parkinson's disease are also reviewed.. A MEDLINE search of relevant English-language literature, clinical studies, abstracts, and review articles pertaining to Parkinson's disease was conducted. Manual searches of 1996/1997 meeting abstracts published by the American Academy of Neurology and the Movement Disorders Society were also performed. Manufacturers provided unpublished Phase III trial efficacy and pharmacokinetic data.. Clinical trial investigations selected for inclusion were limited to human subjects. Interim analyses after 6 months for long-term clinical studies in progress were included. Pharmacokinetic data from animals were cited if human data were unavailable. Statistical analyses for all studies were evaluated.. By selectivity targeting D2 receptors, the newer dopamine agonists (i.e., cabergoline, pramipexole, ropinirole) may delay the introduction of levodopa and thus the occurrence of levodopa-induced dyskinesias. In addition, they are efficacious as adjunctive therapies in patients with advanced Parkinson's disease. Unlike the currently available dopamine agonists, pramipexole and ropinirole are non-ergot derivatives and do not cause skin inflammation, paresthesias, pulmonary infiltrates, or pleural effusion. The COMT inhibitors, tolcapone and entacapone, improve the pharmacokinetics of levodopa by preventing its peripheral catabolism and increasing the concentration of brain dopamine; thus, these agents may reduce the incidence of "wearing-off" effects associated with the short half-life of levodopa and the progression of Parkinson's disease.. Interim 6-month analyses of pramipexole, ropinirole, and cabergoline for symptomatic treatment of early Parkinson's disease have shown these drugs to be efficacious and relatively well-tolerated when used as monotherapy. Their role in delaying the development of motor fluctuations and delaying the addition of levodopa is the subject of long-term clinical studies. In advanced stages of Parkinson's disease, these medications were also efficacious; however, the main adverse effects included dyskinesias, somnolence, and hallucinations. The COMT inhibitors, entacapone and tolcapone, have also demonstrated efficacy in improving on-time in patients with stable disease. Tolcapone has also demonstrated efficacy in patients with motor fluctuations. Both drugs are relatively well-tolerated, with the exception of dyskinesias that require reduction of the levodopa dosage and occasional diarrhea.

Topics: Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Enzyme Inhibitors; Ergolines; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Receptors, Dopamine D2; Thiazoles; Tolcapone

New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Ergolines; Guidelines as Topic; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone; Treatment Outcome

The treatment of Parkinson's disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100 mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200 mg entacapone.. A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa.. The effect of increased carbidopa doses 50 and 100 mg on the total exposure (AUC) of 100 mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa.. Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.

Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Healthy Volunteers; Humans; Levodopa; Parkinson Disease

ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.. 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.. 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. 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.

Topics: Administration, Oral; Aged; Antiparkinson Agents; Carbidopa; Catechols; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infusions, Subcutaneous; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Proof of Concept Study; Treatment Outcome

Previous studies have suggested a significant increase in plasma homocysteine (Hcy) levels in levodopa-treated Parkinson's disease (PD) patients, and vitamin B12 and folate supplementation may decrease Hcy levels. However, the effects of catechol-O-methyltransferase inhibitors on levodopa-induced increase in Hcy levels were conflicting. The aim of this study was to evaluate whether Hcy levels are increased in levodopa-treated PD patients and to evaluate the effects of vitamin B12 and folate or entacapone on Hcy levels in levodopa-treated PD patients.. We analyzed and compared plasma Hcy levels in 20 levodopa-naïve PD patients and 42 levodopa-treated PD patients, followed by randomized assignment of 42 levodopa-treated patients to treatment groups with either vitamin B12 and folate, entacapone, or no medication.. Plasma Hcy levels in levodopa-treated PD patients were higher than those in the control group, but the difference was not statistical significant (15.25 ± 6.70 and 13.13 ± 4.68, P = 0.216). Patients treated with vitamin B12 and folate had a significant decrease in plasma Hcy levels (P < 0.001). In the entacapone group, Hcy levels were mildly decreased, but the change did not reach statistical significance.. Levodopa-treated PD patients had higher plasma Hcy than levodopa-naive PD patients. Unlike entacapone, combination supplementation with vitamin B12 and folate was associated with significantly decreased plasma Hcy. We suggest that plasma Hcy levels should be monitored during levodopa treatment, and supplementation with inexpensive vitamin B12 and folate is beneficial for levodopa-treated patients.

Topics: Aged; Antiparkinson Agents; Catechols; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Research Design; Vitamin B 12

Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.

Topics: Carbidopa; Catechol O-Methyltransferase; Catechols; Cross-Over Studies; Dopa Decarboxylase; Double-Blind Method; Drug Combinations; Drug Delivery Systems; Female; Gels; Genotype; Humans; Levodopa; Male; Models, Biological; Nitriles; Parkinson Disease; Polymorphism, Genetic

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.. 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.. 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).. 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.

Topics: Aged; Antiparkinson Agents; Carbidopa; Catechols; Cross-Over Studies; Drug Combinations; Female; Humans; Infusions, Parenteral; Levodopa; Male; Nitriles; Parkinson Disease; Treatment Outcome

Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations.. We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073.. Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group.. The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit.. BIAL.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Europe; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Oxadiazoles; Parkinson Disease

Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia.

Topics: Adult; Aged; Aged, 80 and over; Catechol O-Methyltransferase; Catechols; Dopamine Agonists; Female; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Prospective Studies

Discuss the effect of rhythmic auditory stimulation with visual stimuli on motor and balance function in patients with Parkinson's disease (PD).. One hundred and sixteen patients with PD participated in this study. The control group used a routine drug treatment for eight weeks. The comprehensive treatment group used conventional drug treatment with sound rhythm metronome released as the rhythmical auditory stimulation, in accordance with the ground fixed ribbon rhythmic visual stimulation walking training for eight weeks. After four and eight weeks, the two groups of subjects took the walking parameters test, and used the disease Parkinson score scale to assess the damaged degree of motor function of PD patients. The Berg Balance Scale was used to evaluate the balance function of the PD patients. A six minute walk test was used to evaluate the walking motor function of the patients.. The comparison between the groups suggests that after treatment of rhythmic auditory stimulation with visual stimulation group, the step size increased, frequency decreased, pace increased, and PD score scale part II decreased. As well, the PD score scale part III reduced, the six minute walking distance increased, and the Berg Balance Scale score increased significantly. There were significant differences compared with the control group after the treatment (p < 0.01). Comparison of time points suggests that after rhythmic auditory stimulation with visual stimulation group trained for eight weeks, the step size increased, frequency decreased, pace increased, and PD score scale part II were reduced. As well the PD score scale part III reduced, six minute walking distance increased, Berg Balance Scale increased. There were significant differences compared with the parameters of training for four weeks (p < 0.01).. Rhythmic auditory stimulation with visual stimulation can improve motor and balance function of patients with PD.

Topics: Acoustic Stimulation; Aged; Benserazide; Benzothiazoles; Catechols; Dose-Response Relationship, Drug; Drug Combinations; Female; Gait; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Periodicity; Piribedil; Postural Balance; Pramipexole; Walking

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.

Topics: Antiparkinson Agents; Benserazide; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Data Interpretation, Statistical; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Retrospective Studies; Treatment Outcome

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.. 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.. 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.. 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.. 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.

Topics: Aged; Antiparkinson Agents; Carbidopa; Catechols; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Parkinson Disease; Treatment Outcome

To compare the efficacy and safety of levodopa/carbidopa/entacapone (LCE) with levodopa/carbidopa (LC) on Parkinson's disease (PD) patients with mild, or only minimally disabling motor complications. A prospective 3-month, multicentre, parallel-group, double-blind, and randomised phase IV study was performed. The primary endpoint was to assess the efficacy of LCE compared to LC on ADLs using the UPDRS part II. Secondary endpoints were assessed by the UPDRS (I, III and IV) scores, QUICK and PDQ-39 questionnaires, and patient and investigator clinical global impression (CGI). Ninety-five patients were randomly assigned to treatment with LCE (100/25/200 or 150/37.5/200 mg tablets, n = 46) or LC (100/25 mg tablets, n = 49), at the same levodopa dose that were administered before randomization. Treatment with LCE resulted in significantly greater improvement in UPDRS part II (ADLs) scores compared to treatment with LC (adjusted mean difference between groups of -1.5 points) (p = 0.0288). Amelioration was also observed in UPDRS part III scores (p = 0.010), and CGI (patient and investigator) scores (p = 0.015, and p = 0.028, respectively). LCE and LC were generally well tolerated with 78 % of subjects completing the study. Most AEs (50 % in LCE and 71.4 % in LC) were classified as mild. No serious AEs were related to the treatment. Treatment with LCE results in improved efficacy compared to LC in PD patients with mild, or minimally disabling motor fluctuations, maintaining a good safety and tolerability profile.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Catechols; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires

IPX066, an investigational extended-release carbidopa-levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E).. At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries).. Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E.. In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated.

Topics: Aged; Antiparkinson Agents; Carbidopa; Catechols; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Treatment Outcome; Walking

The controlled trial Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) reported an unexpected increase in acute myocardial infarction (AMI) with entacapone use in patients with Parkinson's disease (PD). The authors investigated whether entacapone increased cardiovascular and mortality risk compared with the use of a non-levodopa dopamine agonist (DA) or a selective monoamine oxidase type-B inhibitor (MAOBI). Using national Medicare data, a new-user cohort of elderly patients with PD treated with entacapone was propensity score (PS) matched with new users of either DA or MAOBI. The PS model included variables for sociodemographics, cardiovascular disease, medications, prior PD treatment, and comorbidities. Cox proportional hazards regression was used to compare on-therapy time to event for AMI, stroke, and death with DA-MAOBI as a reference. Study cohorts included 8681 entacapone-treated and 17,362 DA-MAOBI-treated initators who were followed for 2569 and 5385 person-years, respectively. Cohorts were closely balanced for all covariates. During follow-up, there were 106 AMIs, 89 strokes, and 201 deaths. The hazard ratio (HR) and 95% confidence interval (CI) associated with entacapone use was 0.86 (95% CI, 0.57-1.30) for AMI, 0.85 (95% CI, 0.54-1.35) for stroke, and 0.79 (95% CI, 0.58-1.07) for death. The risk was unchanged for treatment of ≤ 6 months' and>6 months' duration and was unaffected by adjustment for time-varying levodopa use during follow-up. The risk of each endpoint was not differentially affected by diabetes, ischemic heart disease, or kidney failure status. However, the risk of stroke was modified by the presence (HR, 2.09; 95% CI, 0.98-4.45) or absence (HR, 0.51; 95% CI, 0.27-0.95) of advanced PD-related morbidities (P value for interaction=0.004). Entacapone was not associated with an increased risk of AMI, stroke, or death in elderly patients with PD.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Cardiovascular Diseases; Catechols; Dopamine Agonists; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease; Risk; Treatment Outcome

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a variety of motor symptoms including freezing of gait (FOG), in which walking is transiently halted as if the patient's feet were 'glued to the ground'. Treatment of FOG is still challenging. Although L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline, has been on the market in Japan because of its beneficial effect for FOG, clinical use of L-DOPS has been far from satisfying. However, the fact that there were some responders to L-DOPS encouraged us to hypothesize that the enhancement of L-DOPS concentration in the brain by the co-administration of L-DOPS and a catechol-O-methyl transferase (COMT) inhibitor, which is expected to interrupt L-DOPS metabolism in the peripheral circulation, would be beneficial for FOG. Based on our hypothesis, we conducted a preliminary study with a small number of participants with FOG. Of the 16 PD patients with FOG who completed this study, group 1 (n=6) received L-DOPS co-administered with entacapone, which is a COMT inhibitor used worldwide as an anti-parkinson drug, group 2 (n=5) received entacapone alone, and group 3 (n=5) received L-DOPS alone. Only the patients in group 1 showed a significant improvement in FOG. Moreover, the beneficial effect was observed only in patients with levodopa-resistant FOG. This result supports our hypothesis, at least in patients with levodopa-resistant FOG, and shows that the co-administration of L-DOPS and entacapone could be a new strategy for FOG treatment.

Topics: Adult; Aged; Catechol O-Methyltransferase Inhibitors; Catechols; Droxidopa; Drug Therapy, Combination; Gait Ataxia; Humans; Japan; Middle Aged; Nitriles; Parkinson Disease; Treatment Outcome

Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.. A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.. Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.. According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechols; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Pilot Projects; Self Report; Single-Blind Method; Sweden; Tolcapone; Tyrosine

Several cases of syndrome of inappropriate antidiuresis induced by anti-Parkinson agents have been reported. Our previous study demonstrated that pergolide and pramipexole stimulated elevation of plasma arginine vasopressin (AVP) levels in some patients with Parkinson's disease (PD), but that levodopa/carbidopa (300/30 mg/day) did not affect plasma AVP levels in treatment-naïve PD patients. On the basis of the binding profile of ropinirole to monoamine receptors, we hypothesized that ropinirole does not stimulate AVP secretion. The aim of this study was to test this hypothesis.. Inclusion criteria were patients with probable PD suffering from a wearing-off phenomenon and who had been treated using levodopa/carbidopa with or without entacapone, but not with other classes of anti-Parkinson agents. Patients were excluded if they had at least one condition that could be associated with high AVP levels. Ropinirole was initiated at 0.5 mg 3 times daily, and daily dosages were increased by 1.5 mg/day on a biweekly basis up to 6 mg/day. Plasma AVP levels were determined every two weeks. Effects of escalating ropinirole dosage on plasma AVP levels were evaluated using a one-way analysis of variance for repeated measures, an a priori Dunnett multiple comparison test, and a regression analysis.. Of 16 patients enrolled, 11 patients (four males and seven females) completed the study. There was no statistically significant dose-response relationship between the ropinirole dosage and plasma AVP levels.. A minimal therapeutic dosage of ropinirole did not affect plasma AVP levels in patients with PD taking levodopa.

Topics: Aged; Arginine Vasopressin; Carbidopa; Catechols; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Humans; Inappropriate ADH Syndrome; Indoles; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic amino-acid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect.. Twelve patients with autonomic failure took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured.. L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15,000 th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS.. After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation.

Topics: Aged; Antiparkinson Agents; Blood Pressure; Carbidopa; Catechols; Double-Blind Method; Droxidopa; Drug Interactions; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Nitriles; Norepinephrine; Parkinson Disease; Prodrugs; Pure Autonomic Failure; Vasoconstriction

In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients.. Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells.. The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02).. The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined.

Topics: Aged; Antiparkinson Agents; Biological Availability; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Female; Genotype; Humans; Levodopa; Male; Methionine; Middle Aged; Nitriles; Parkinson Disease; Pharmacogenetics; Polymorphism, Genetic; Valine

Elevation of plasma total homocysteine concentrations were observed in levodopa/dopa decarboxylase inhibitor (DDI)-treated patients with Parkinson's disease (PD). Degradation of levodopa to 3-O-methyldopa via the enzyme catechol-O-methyltransferase (COMT) is a methyl group demanding reaction. It generates homocysteine from the methyl group donor methionine. But there are inconsistent outcomes, as most investigators determined homocysteine after an overnight washout of levodopa. They did not consider the acute effects of levodopa/DDI intake in relation with COMT inhibition on homocysteine bioavailability. The purpose of this study is to measure levels of homocysteine, levodopa, and its metabolite 3-O-methyldopa in plasma after reiterated oral levodopa/DDI administration with and without the COMT-inhibitor entacapone (EN). Sixteen PD patients received 100 mg levodopa/carbidopa three times on day 1 and with EN on day 2 under standardized conditions. Homocysteine concentrations increased on day 1 and generally over the whole interval. No significant ascent of homocysteine appeared on day 2 only. Levodopa bioavailability was higher on day 2 due to the COMT inhibition. No change of 3-O-methyldopa appeared between both days. The correlation coefficients between homocysteine, levodopa, and 3-O-methyldopa were higher on day 1 than on day 2. Rise of homocysteine does not only depend on the oral levodopa dose, but also on the acute intake of levodopa/DDI with or without COMT inhibition. Measurements of homocysteine should consider acute repeated levodopa/DDI applications, as homocysteine and metabolically related 3-O-methyldopa accumulate due to their long plasma half-life in contrast to short-living levodopa.

Topics: Aged; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Biological Availability; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Combinations; Drug Therapy, Combination; Female; Half-Life; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Tyrosine

To determine the efficacy of standard levodopa combined with controlled release levodopa and entacapone in controlling end-of-dose symptoms in Parkinson's disease.. A single-blind cross over design was used to compare the duration of action for three pharmacological combinations: standard levodopa (L/DDC); standard levodopa combined with entacapone (L/DDC/E); and standard levodopa combined with controlled release levodopa (CR) and entacapone (L/DDC/CR/E). Thirty two participants with wearing-off symptoms and inadequate symptom control with L/DDC/E had their optimum dose of L/DDC determined at base line. Entacapone was added to the optimal L/DDC dose and duration of action determined. Levodopa CR dosage was adjusted to match the optimal L/DDC dose for each participant. All participants were then trialed on L/DDC/CR/E and duration of response calculated. Timed Up and Go (TUG) times and magnitude of extra movements were recorded hourly throughout the day over several days to determine the optimum interval between doses for each combination. The UPDRS (Sections 2 and 3), PDQ39 and fatigue scale, the PDF-16, were recorded at base line and when dosage intervals had stabilized on L/DDC/CR/E.. Duration of response was greatest with L/DDC/CR/E compared to L/DDC/E (p < 0.001) and number of daily doses were less on L/DDC/CR/E compared to L/DDC/E (p < 0.001). UPDRS, PDQ39 and fatigue scores also improved on L/DDC/CR/E compared to L/DDC (p < 0.001). Dyskinesia increased on L/DDC/CR/E (p = 0.001) however magnitude was mild.. Combining standard levodopa and levodopa CR preparations with entacapone is an additional treatment strategy to manage motor fluctuations in advanced PD.

Topics: Aged; Antiparkinson Agents; Catechols; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesias; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Single-Blind Method

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).. LCE treatment improves motor function in PD patients with EODWO. Correlations with QoL have not been previously assessed.. 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.. 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%).. The IS provided greater motor improvement at week 4 and improved QoL at week 8.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Catechols; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Prospective Studies; Quality of Life; Single-Blind Method

The LARGO study demonstrated that rasagiline 1 mg/day as adjunct to levodopa significantly reduces OFF time to the same magnitude as adjunct entacapone. This substudy of LARGO aimed to assess the effect of rasagiline and entacapone on the motor symptoms of PD during the practically defined OFF state.. LARGO was a randomized, double-blind, multicenter trial that assessed the efficacy and safety of rasagiline (1 mg/day), entacapone (200 mg with each levodopa dose), and placebo in 687 levodopa-treated PD patients with motor fluctuations. A substudy of LARGO measured UPDRS motor scores in the practically defined OFF state in 32 rasagiline, 36 entacapone, and 37 placebo patients.. Treatment with rasagiline produced a significant improvement over placebo of 5.64 units in UPDRS motor OFF score (P = 0.013 vs. placebo). By contrast, the effect of adjunct entacapone was not significant (P = 0.14 vs. placebo). Whereas rasagiline also showed a trend in reducing the UPDRS-ADL OFF score (P = 0.058 vs. placebo), no such trend was noted for entacapone (P = 0.26 vs. placebo). Retrospective analysis, using the Bonferroni correction, of UPDRS motor subdomains further revealed that rasagiline, but not entacapone, significantly improved bradykinesia (P < 0.001) and showed trends for improvements in facial expression, speech, and axial impairment during OFF time.. This study provides the first objectively measured evidence that adjunct rasagiline 1 mg/day is effective in reducing the severity of motor symptoms in the OFF state. This suggests a continuous effect of rasagiline 1 mg/day throughout the day and night and is consistent with its extended duration of therapeutic action.

Topics: Aged; Antiparkinson Agents; Catechols; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Dysarthria; Facial Expression; Female; Humans; Hypokinesia; Indans; Levodopa; Male; Middle Aged; Monoamine Oxidase Inhibitors; Motor Activity; Muscle Rigidity; Nitriles; Parkinson Disease; Severity of Illness Index; Tremor

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.

Topics: Aged; Antiparkinson Agents; Benserazide; Carbidopa; Catechols; Drug-Related Side Effects and Adverse Reactions; Dyskinesias; Feasibility Studies; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

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.. 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.. 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).. 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.

Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Disease Progression; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Risk; Time Factors; Treatment Outcome

To determine the efficacy, safety and tolerability of nebicapone, a new catechol-O-methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8-week double-blind, placebo- and active-controlled, parallel-group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty-two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4-8 daily doses) were enrolled and 250 patients were eligible for intention-to-treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8-week change from baseline in absolute "Off" time duration noted in self-scoring diaries. At 8 weeks of treatment the mean daily "Off" time decreased significantly compared to placebo for nebicapone 150 mg (-106 min; 95%CI: -192; -21) and entacapone 200 mg (-81 min; 95%CI: -142; -19). The decrease in "Off" time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment-emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.

Topics: Acetophenones; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benserazide; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Endpoint Determination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Treatment Outcome

Levodopa (LD) provides the most effective symptomatic treatment for Parkinson's disease (PD). Long-term treatment with LD, however, is often associated with the development of response fluctuations. Previous evidence suggests that the short half-life of LD is a major contributor to the development of response fluctuations and the wearing-off phenomenon in particular. Entacapone, a peripheral catechol-O-methyltransferase inhibitor has been shown to reduce OFF time and increase ON time in several therapeutic trials on PD patients treated with LD experiencing motor fluctuations. However, data are missing on the tolerability and efficacy of entacapone in elderly PD patients. This is of particular relevance, as most PD patients develop LD-related motor fluctuations after several years of disease duration. Here we report that addition of entacapone in a group of 45 elderly PD patients with LD-related motor fluctuations is well tolerated and efficacious in reducing the time, frequency and severity of the OFF periods. These data suggest that the drug can be used safely and efficaciously in elderly PD patients.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Pilot Projects

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.

Topics: Aged; Antiparkinson Agents; Benserazide; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Gastrointestinal Diseases; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Quality of Life; Severity of Illness Index; Treatment Outcome

Topics: Aged; Antiparkinson Agents; Catechols; Female; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

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.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Catechols; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

We performed a 39-week, randomized, double-blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinson's disease (PD). Four hundred twenty-three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three-times daily. The adjusted mean difference in total Unified Parkinson's disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject-reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator-rated CGI scores. Wearing-off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Catechols; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Parkinson Disease; Severity of Illness Index

To revalidate the Freezing of Gait Questionnaire (FOG-Q), patients with Parkinson's disease (PD) were randomly assigned to receive rasagiline (1 mg/day) (n = 150), entacapone (200 mg with each dose of levodopa) (n = 150), or placebo (n = 154). Patients were assessed at baseline and after 10 weeks using the FOG-Q, Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Parkinson's Disease Questionnaire (PDQ-39). FOG-Q dimensionality, test-retest reliability, and internal reliability were examined. Convergent and divergent validities were assessed by correlating FOG-Q with UPDRS, BDI, and PDQ-39. Comparisons between FOG-Q item 3 and UPDRS item 14 were also made. Principal component analysis indicated that FOG-Q measures a single dimension. Test-retest reliability and internal reliability of FOG-Q score was high. FOG-Q was best correlated to items of the UPDRS relating to walking, general motor issues, and mobility. Correlations between baseline and endpoint suggested that FOG-Q item 3 is at least as reliable as UPDRS item 14. At baseline, 85.9% of patients were identified as "Freezers" using FOG-Q item 3 (> or =1) and 44.1% using UPDRS item 14 (> or =1) (P < 0.001). FOG-Q was a reliable tool for the assessment of treatment intervention. FOG-Q item 3 was effective as a screening question for the presence of FOG.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Catechols; Double-Blind Method; Female; Freezing Reaction, Cataleptic; Gait Disorders, Neurologic; Humans; Indans; Levodopa; Male; Middle Aged; Neuroprotective Agents; Nitriles; Parkinson Disease; Principal Component Analysis; Psychiatric Status Rating Scales; Reproducibility of Results; Severity of Illness Index; Statistics as Topic; Surveys and Questionnaires

Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Carbidopa; Catechols; Cross-Over Studies; Disability Evaluation; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Retrospective Studies; Severity of Illness Index; Time Factors

Entacapone (EN) improves the efficacy of levodopa/dopadecarboxylase inhibitor (LD/DDI) formulations by inhibition of the enzyme catechol-O-methyltransferase (COMT). COMT inhibition also promotes the synthesis of basic LD metabolites, whereas DDI support the composition of acidic LD derivatives. LD metabolism correlates to the one of (13)C-sodium-octanoate, which is employed in breath tests to measure gastric emptying velocity. Objectives were to investigate the impact of COMT inhibition on the recovery rate of (13)C-sodium-octanoate in parkinsonian patients, who received first 100 mg LD/Carbidopa (CD) and the next day 100 mg LD/CD/EN combined with (13)C-sodium-octanoate in each case. The recovery rate of (13)C-sodium-octanoate was significant higher during the LD/CD/EN-compared with the LD/CD condition. COMT inhibition combined with LD/DDI improves absorption of a co-administered salt probably due to a COMT inhibition induced basic environment in gastrointestinal membranes. This improves dissolution and absorption of acids and salts. Thus it may enhance absorption of LD itself.

Topics: Adult; Aged; Antiparkinson Agents; Breath Tests; Caprylates; Carbidopa; Carbon Isotopes; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gastric Emptying; Humans; Intestinal Absorption; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Solubility

To evaluate the effectiveness of entacapone in the management of levodopa wearing-off in Parkinson's disease (PD) in a naturalistic, real-life setting.. 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.. 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).. 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.. 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.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Canada; Catechols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Surveys and Questionnaires; Treatment Outcome

Catechol-O-methyl transferase (COMT) inhibition by entacapone enhances levodopa absorption and reduces 'off' time in Parkinson's disease (PD). We hypothesized that the administration of entacapone in a bimodal fashion (two doses 1 h apart) would enhance levodopa absorption and improve the motor symptoms of PD. Patients with PD (n = 17) were given immediate (IR)- or controlled (CR)-release levodopa each with either one or two doses of entacapone. Bimodal entacapone produced a significant increase in IR and CR levodopa half-life, 'area under the curve' (AUC), and C(max) with levodopa CR. For both IR and CR levodopa, bimodal entacapone resulted in a significant improvement in the Unified Parkinson's Disease Rating Scale part III (motor). Bimodal entacapone increased COMT inhibition, improved the pharmacokinetics of levodopa and improved motor scores for 6 to 8 h. Bimodal use of entacapone may be useful in selected patients to improve motor control and implies that controlled release COMT inhibition would be beneficial in PD patients.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Antiparkinson Agents; Area Under Curve; Catechol O-Methyltransferase; Catechols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Nitriles; Parkinson Disease; Severity of Illness Index

A possible strategy to prolong plasma metabolism of Levodopa/Carbidopa (LD/CD) is Entacapone addition (EN), which improves impaired motor behaviour in patients with Parkinson's disease (PD).. Objectives were to evaluate the clinical response to an increased dopaminergic substitution with EN by clinical rating and assessment of complex motions and to investigate the change of movement in PD patients during repeat drug administration during an eight hour interval.. We used peg insertion with a computer based device and clinical rating for assessment of motor function in 20 treated PD patients. They received LD/CD and then the same LD/CD dosage plus EN in a standardised, open label fashion.. Motor scores and performance of the instrumental task were significantly better and the fluctuation of movement was less intense during the LD/CD/EN condition according to the motor test outcomes.. EN supplementation improves motor symptoms and provides a more continuous movement behaviour in PD patients.

Topics: Adult; Aged; Analysis of Variance; Antiparkinson Agents; Catechols; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Nitriles; Parkinson Disease; Psychomotor Performance; Severity of Illness Index

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

Topics: Aged; Antiparkinson Agents; Benzophenones; Case-Control Studies; Catechols; Cross-Over Studies; Double-Blind Method; Drug Tolerance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Prospective Studies; Tolcapone; Treatment Outcome

We conducted a multicenter randomized, placebo-controlled double-blind parallel-group study in Japanese Parkinson's disease (PD) patients with wearing-off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100-mg and 200-mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing-off fluctuations, although the safety and tolerability profile appeared more favorable for the 100-mg dose.

Topics: Aged; Antiparkinson Agents; Catechols; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

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

Topics: Aged; Antiparkinson Agents; Catechols; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Early Diagnosis; Female; Humans; Interviews as Topic; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Patient Compliance; Patient Satisfaction; Prospective Studies; Quality of Life; Time; Time Factors; Treatment Outcome

In this 12-wk, multi-center, randomized, open-label, rater-blinded study, efficacy and tolerability of Entacapone (ENT) or Cabergoline (CBG) in conjunction with levodopa were compared in 161 older Parkinson's disease patients with wearing-off. Patients received either ENT, 3 to 5 times daily, or CBG, titrated according to requirements to a maximum of 6 mg/d. A significant decrease of nearly 2 hours in the daily OFF-time (primary efficacy variable) was recorded in both treatment groups. The non-inferiority test failed despite a trend in favor of ENT. Reduction in OFF-time occurred faster in the ENT compared to the CBG treated patients. A decrease of approximately 20% was detected in parts II and III of the UPDRS, with no differences between the groups. Forty-three percent of the patients in the ENT group reported dyskinesias at baseline, and 35% at the final visit. The corresponding figures in the CBG group were 46% and 43%. Quality of life, measured by PDQ-39, increased substantially with both ENT and CBG. The mean daily dosage at the final visit was 698 mg for ENT (plus 447 mg levodopa) and 3.45 mg for CBG (plus 475 mg levodopa). Adverse events (AE), leading to discontinuation, were reported in 8.5% of the ENT and 13.9% of the CBG treated patients. Nausea was the most common AE in each group, corresponding figures being 7.3% with ENT and 25.3% with CBG (P=0.0024). A probable or possible causal relationship with ENT was reported in 41% and with CBG in 64% of the AE. Among these, only one serious AE (dehydration) was recorded with each treatment group. ENT and CBG reduced the patient's motor complications effectively and to a similar degree. The clinical benefit was more quickly apparent with ENT, which also showed a more favorable AE profile than CBG.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Cabergoline; Catechols; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Dyskinesias; Ergolines; Female; Humans; Male; Medical Records; Middle Aged; Nitriles; Parkinson Disease; Psychiatric Status Rating Scales; Surveys and Questionnaires

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.

Topics: Adult; Aged; Antiparkinson Agents; Carbidopa; Catechols; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Tyrosine

Serum folate and vitamin B12 levels were measured in 67 consecutive Parkinson's disease patients treated either with levodopa + dopa decarboxylase inhibitor (DDC-i) plus catechol-O-methyltransferase inhibitors (COMT-i) or only with levodopa + DDC-i. The data were compared to 67 age-matched controls. Our findings show that levodopa-treated Parkinson's disease patients have low folate (p < 0.0007) and vitamin B12 levels (p < 0.0003). They also demonstrate that the addition of a COMT-i to levodopa + DDC-i treatment causes lower serum vitamin B12 (p < 0.03) and folate levels (p < 0.005) than levodopa + DDC-i treatment alone. We suggest supplementary treatment with vitamin B12 and folic acid in these situations.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Case-Control Studies; Catechols; Female; Folic Acid; Humans; Immunoassay; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Vitamin B 12

To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias.. Thirty-four PD patients had cabergoline up-titrated and their levodopa (L-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26).. Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean L-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious.. High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for L-dopa.

Topics: Adolescent; Adult; Aged; Amantadine; Antiparkinson Agents; Cabergoline; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Humans; Levodopa; Middle Aged; Nitriles; Parkinson Disease; Piperidines; Prospective Studies; Quality of Life; Selegiline; Severity of Illness Index; Treatment Outcome

Parkinson's disease (PD) patients can perform many daily activities, but movement deficits are evident. Those deficits may be increased when the required movement is constrained in accuracy. Variable improvements in performance with PD medication have been demonstrated, and sensitivity to task constraint has been evident in some studies. The authors quantified both specific movement deficits and improvements for PD patients in a reaching task. PD patients (N=8) both on and off medication showed a need for greater ongoing control in movements with higher task-accuracy constraints. Increased task-accuracy constraints further compromised movement timing and structure among PD patients who were off medication, suggesting that unmedicated PD patients may typically compensate by using more conscious control of movement, resulting in increased slowing and segmentation of components when higher task accuracy is required.

Topics: Activities of Daily Living; Aged; Amantadine; Antiparkinson Agents; Arm; Benzothiazoles; Biomechanical Phenomena; Carbidopa; Catechols; Dopamine Agents; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Motor Skills; Movement; Nitriles; Parkinson Disease; Pramipexole; Thiazoles

Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson's disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [C(max)] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to C(max) of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.

Topics: Adult; Aged; Antiparkinson Agents; Area Under Curve; Carbidopa; Catechols; Chromatography, High Pressure Liquid; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Tyrosine

Elevated homocysteine is associated with increased risk of heart disease, stroke, and dementia. Therapy of Parkinson disease (PD) with levodopa elevates homocysteine. The authors conducted a 6-week, multicenter, randomized, double-blind, placebo-controlled trial to test whether folate 1 mg/vitamin B(12) 500 microg or entacapone reduced serum homocysteine in 35 levodopa-treated PD patients. Levodopa initiation caused a small elevation in homocysteine. Vitamin therapy, but not entacapone, resulted in a decrease in homocysteine compared to placebo.

Topics: Aged; Antiparkinson Agents; Canada; Catechols; Double-Blind Method; Drug Combinations; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Placebo Effect; Treatment Outcome; United States; Vitamin B 12; Vitamins

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).. 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.. 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.

Topics: Adult; Aged; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa; Catechols; Cross-Over Studies; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Patient Satisfaction; Treatment Outcome

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

Topics: Absenteeism; Antiparkinson Agents; Catechols; Disability Evaluation; Double-Blind Method; Drug Therapy, Combination; Employment; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Parkinson Disease; Self Concept

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinson's disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O-methylation of levodopa catalyzed by catechol-O-methyltransferase (COMT) that produces S-adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT-I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT-I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT-I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa-treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT-I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT-I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT-I effectively reduces HHcy.

Topics: Aged; Antiparkinson Agents; Case-Control Studies; Catechols; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; Folic Acid; Homocysteine; Humans; Levodopa; Linear Models; Male; Middle Aged; Nitriles; Parkinson Disease; Vitamin B 12

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.. 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.. 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.. 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.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Quality of Life

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo (levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

Topics: Aged; Antiparkinson Agents; Carbidopa; Catechols; Disability Evaluation; Drug Combinations; Drug Evaluation; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Pain Measurement; Parkinson Disease; Quality of Life; Severity of Illness Index; Single-Blind Method; Surveys and Questionnaires; Treatment Outcome

The aim of this trial was to evaluate the effects of the COMT inhibitor entacapone on both the pharmacokinetic profile and clinical efficacy of controlled release levodopa in Parkinson's disease (PD) patients. Twelve PD patients experiencing "end-of-dose" type motor fluctuations were evaluated in this single-blind, randomized cross-over study. A single dose of either entacapone (200 mg) or placebo was co-administered with controlled release levodopa. Blood samples were taken every 30 minutes for 3 hours, and in 6 patients, sampling was continued for a further 3 hours. The clinical response to treatment was evaluated using the Unified Parkinson's Disease Rating Scale motor score. Addition of entacapone to levodopa treatment prolonged the "on" phase of the PD patients by 37% (p<0.05). This increased duration of 'on' time was concomitant with a significant increase in levodopa bioavailability (AUC). These data confirm the ability of entacapone to enhance the clinical efficacy of controlled release levodopa formulations, and provide further evidence that entacapone is of value in extending the benefits of levodopa in PD patients experiencing motor fluctuations.

Topics: Aged; Area Under Curve; Carbidopa; Catechols; Cross-Over Studies; Delayed-Action Preparations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Single-Blind Method

Dopamine receptors agonists and catechol-O-methyltransferase (COMT) inhibitors are the novel classes of the drugs for Parkinson's disease (PD) treatment in both early and late stages. In the latter one, there is an increase of substantia nigra neurons degeneration, striatum denervation, changes of dopamine receptors state, dysregulation of Levadopa uptake, dopamine synthesis and storage, decrease of dopamine receptors density in striatum that results in clinical picture alteration and development of pharmaco-therapeutic side-effects, as well as motor fluctuations and drug diskinesias. The use of dopamine receptors agonists and COMT inhibitors at the late PD stages in combination with other antiparkinsonian medications allows improving pharmaco-therapeutic efficacy, along with patient's daily activity and quality of life.

Topics: Activities of Daily Living; Benzophenones; Benzothiazoles; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Pergolide; Pramipexole; Quality of Life; Thiazoles; Tolcapone; Treatment Outcome

Entacapone is a specific, peripherally acting catechol- O-methyltransferase (COMT) inhibitor that prevents peripheral degradation of L-dopa, thus improving its bioavailability. Entacapone is known to have pharmacokinetics similar to standard L-dopa but not to that of controlled-release (CR) L-dopa. The aim was to determine whether delayed entacapone administration may prolong CR L-dopa half-life in comparison to the co-administration modality. We compared plasma L-dopa concentrations after co-administration of CR L-dopa and entacapone or after administration of CR and a delayed (30 and 90 minutes) entacapone dose in 10 parkinsonian patients. The area under the concentration-time curve and other pharmacokinetic parameters were not changed by the delayed administration of entacapone. Different temporal modalities of entacapone administration had similar effects on CR L-dopa pharmacokinetics and on L-dopa-induced clinical improvement.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Area Under Curve; Biological Availability; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Delayed-Action Preparations; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Single-Blind Method; Treatment Outcome

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.

Topics: Antiparkinson Agents; Apomorphine; Catechols; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Parkinson Disease

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

Topics: Aged; Antiparkinson Agents; Area Under Curve; Biological Availability; Carbidopa; Catechols; Chromatography, High Pressure Liquid; Double-Blind Method; Drug Interactions; Drug Resistance; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations.. To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications.. Prospective, double-blind, placebo-controlled trial.. Outpatient multicenter study.. Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study.. Parkinsonian function and quality of life.. The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population.. The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Prospective Studies; Treatment Outcome

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.

Topics: Aged; Catechols; Dopamine Agonists; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Prospective Studies

To study the effect of entacapone, a specific peripherally acting catechol-O-methyltransferase (COMT) inhibitor used in combination with levodopa treatment, in cases of Parkinson's disease with both fluctuating and non-fluctuating response to treatment.. A randomised, placebo controlled, double blind, six month study was undertaken in 172 fluctuating and 128 non-fluctuating patients. The clinical efficacy and safety of 200 mg entacapone given with each daily levodopa dose was studied. Efficacy was examined using home diaries, the unified Parkinson disease rating scale (UPDRS), and recording of daily levodopa dose.. The primary efficacy variable for fluctuating patients-the proportion of daily ON time-showed a significant increase compared with placebo (p < 0.05). The absolute ON time (mean (SD)) increased from 9.5 (2.5) to 10.8 (2.4) hours (p < 0.01), and the daily OFF time was correspondingly reduced from 7.0 (2.6) to 5.9 (2.5) hours (p < 0.05 v placebo). This improvement was achieved despite a reduction in daily levodopa requirements. The effect was rapidly lost on withdrawal of entacapone. In non-fluctuating patients, the primary efficacy measure was part II of the UPDRS (activities of daily living; ADL). In this group of patients, ADL scores improved in the entacapone group (p < 0.01 v placebo), and there was also a 40 mg reduction in levodopa requirement (p < 0.01 v placebo). Entacapone was well tolerated by both fluctuating and non-fluctuating patients.. The ability of entacapone to provide additional benefits to levodopa treatment in increasing ON time in fluctuating Parkinson's disease patients was confirmed. A novel finding was that patients without fluctuations also obtained benefit from the addition of entacapone to their levodopa treatment, as evidenced by improved ADL scores and a relatively reduced levodopa requirement.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Motor Skills; Neurologic Examination; Nitriles; Parkinson Disease

To determine the cost effectiveness of adjunctive therapy with entacapone versus standard treatment (levodopa) without entacapone for patients in the US with Parkinson's disease (PD) who experience 'off-time' (re-emergence of the symptoms of PD) while receiving levodopa.. A Markov model was used to estimate 5-year costs and effectiveness of standard treatment with and without entacapone.. Probabilities, unit costs, resource utilisation data and utilities were obtained from published literature, clinical trial reports, a national database, and clinical experts. PD disability was measured using the daily proportion of off-time and Hoehn and Yahr scale scores. The analysis measured costs from a societal and third-party payer perspective, and effectiveness as gains in quality-adjusted life-years (QALYs) and years without progression to >25% off-time.. From a societal perspective, entacapone therapy resulted in an incremental cost of US dollars 9327 per QALY gained compared with standard treatment. Treatment with entacapone also provided an additional 7.6 months with < or =25% off-time/day compared with standard treatment. Sensitivity analyses indicated that the model is sensitive to changes in rates of improvement/deterioration of off-time, and to the number of doses per day of levodopa with adjunctive entacapone.. The addition of entacapone to standard treatment for patients receiving levodopa who experience off-time provides additional QALYs and gain in time with minimal fluctuations. Results of this modelling exercise suggest that therapy with entacapone may be cost effective when compared with standard treatment for PD.

Topics: Aged; Antiparkinson Agents; Catechols; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Health Care Costs; Humans; Levodopa; Markov Chains; Nitriles; Parkinson Disease; Patient Satisfaction; Quality-Adjusted Life Years; Treatment Outcome; United States

The inhibition of catechol-O-methyltransferase (COMT) may impair catecholamine clearance resulting in unwanted cardiac and hemodynamic events. We therefore studied the effects of entacapone, an inhibitor of peripheral COMT, on cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on respiratory muscle strength in l-dopa treated patients with Parkinson's disease (PD). A randomized, double-blind, cross-over study with two 1week treatment periods was performed in 15 PD patients. The test battery included analysis of hemodynamics, gas exchange parameters and plasma NA during a maximal exercise test, assessment of maximal static airway pressures and pre- and post-exercise motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). The first test was done after withholding l-dopa overnight ('run-in' test, off-phase). The second and third tests were done in on-phase after 1week treatment with either entacapone 200mg or placebo given with each dose of l-dopa. No differences in maximal work load, plasma NA, or in cardiorespiratory responses to either maximal or work rate standardized submaximal exercise were observed between entacapone and placebo, except for O(2) pulse, which was slightly lower (p < 0.05) after entacapone at submaximal exercise level. Maximal airway pressures were similar between the study treatments and run-in. Exercise had no effect on motor UPDRS after either study treatment or during the run-in test. No serious adverse events were observed. The results of this study suggest that entacapone does not change the work capacity, work efficiency or respiratory muscle strength in l-dopa treated PD patients with mild to moderate disease severity, and that its use with l-dopa seems to be safe in conditions of maximal physical effort. However, data from the long-term use of COMT inhibitors are needed to confirm these findings.

Topics: Adult; Aged; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Female; Hemodynamics; Humans; Levodopa; Male; Middle Aged; Nitriles; Norepinephrine; Oxygen Consumption; Parkinson Disease; Pulmonary Gas Exchange; Respiratory Mechanics

To investigate the relationship between the catechol-O-methyltransferase (COMT) genotype and the therapeutic efficacy of entacapone.. The efficacy of 2 months of entacapone treatment in 65 patients with PD with end-of-dose deterioration was studied. The efficacy of entacapone was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) score, the daily levodopa dosage, and the patients' diary card.. Thirty-six patients (55.4%) had a high-activity COMT gene (COMT(HH)), 22 (33.8%) had an intermediate-activity COMT gene (COMT(HL)), and 7 patients (10.8%) had a low-activity COMT gene (COMT(LL)). Two months of entacapone treatment resulted in a significant increase in "on" time, a reduction in "off" time, and a reduction in the total UPDRS score, but these results were independent of the COMT genotype of the patient. There was no significant difference in the frequency or severity of dyskinesias between the patients with different COMT genotypes.. The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration.

Topics: Aged; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chi-Square Distribution; Double-Blind Method; Enzyme Inhibitors; Female; Genotype; Humans; Male; Middle Aged; Nitriles; Parkinson Disease

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.. 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.. 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.. Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

Topics: Aged; Antiparkinson Agents; Austria; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Germany; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Treatment Outcome

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.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Neurologic Examination; Nitriles; Parkinson Disease; Prospective Studies; Treatment Outcome

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.

Topics: Aged; Antiparkinson Agents; Catechols; Disability Evaluation; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Safety; Time Factors

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.. 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).. 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.. 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.

Topics: Adult; Aged; Antiparkinson Agents; Biological Availability; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone.. Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program.. A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated.. A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.

Topics: Aged; Antiparkinson Agents; Catechols; Cross-Over Studies; Double-Blind Method; Drug Interactions; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

To study the effect and safety of entacapone as an adjunct to levodopa treatment in patients with PD with wearing-off motor fluctuations.. 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.. 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).. 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.. 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.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease

The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study. An L-Dopa test was performed on 3 study days. The first study day was with L-Dopa/benserazide only (control), the second after 14 days of treatment with 200 mg entacapone taken concomitantly with L-Dopa/benserazide in combination with either selegiline (10 mg daily) or placebo. After a 2-week washout period, selegiline and placebo treatments were switched, and the third study day was after 14 days of treatment. During the study days, clinical response was evaluated at 30-min intervals for 6 h, by using the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). In addition, repeated blood pressure measurements were made, and plasma samples were taken for analysis of L-Dopa, 3-O-methyldopa (3-OMD), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), dopamine, noradrenaline, and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Monoamine oxidase B (MAO-B) and COMT enzyme activities were measured from platelets and erythrocytes, respectively. Entacapone improved the clinical response to L-Dopa during both selegiline and placebo (p < 0.001) treatments. The improvement was more marked during combined selegiline and entacapone treatment than with entacapone alone (p < 0.01). Entacapone significantly increased plasma L-Dopa and DOPAC levels and decreased plasma 3-OMD and MHPG levels both with selegiline and placebo. Selegiline partially inhibited the entacapone-induced increase of plasma DOPAC. Plasma dopamine and noradrenaline levels did not change. Entacapone decreased erythrocyte COMT activity by > 35% (p < 0.001), and platelet MAO-B activity was almost completely inhibited by selegiline (p < 0.001). One patient withdrew because of diarrhea, dizziness, and loss of sleep when receiving selegiline treatment. Otherwise no differences in adverse events, mean daily blood pressures, or other safety parameters were observed between selegiline and placebo treatments. Our results suggest that entacapone can be safely administered together with L-Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Benserazide; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Over Studies; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Monoamine Oxidase Inhibitors; Motor Activity; Nitriles; Parkinson Disease; Selegiline

Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows the elimination of levodopa in humans by reducing the formation of 3-O-methyldopa. We conducted a placebo-controlled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of "on" time (relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At baseline, patients averaged approximately 10 hours of "on" time per day while awake (60.5% "on" time), and entacapone treatment increased the percent "on" time by 5.0 percentage points. The effect of entacapone was more prominent in patients with a smaller percent "on" time (<55%) at baseline, and increased as the day wore on. Entacapone is effective at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor fluctuations and was well tolerated during the 24 weeks of treatment.

Topics: Aged; Antiparkinson Agents; Catechols; Double-Blind Method; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Movement; Nitriles; Parkinson Disease; Patient Compliance; Substance Withdrawal Syndrome; Treatment Outcome

To establish, in a double blind manner, the antiparkinsonian effects of repeated dosing with entacapone, a peripheral COMT inhibitor.. 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.. 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.. The efficacy of repeated entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson's disease with levodopa related fluctuations is verified.

Topics: Aged; Antiparkinson Agents; Biological Availability; Catechols; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Middle Aged; Motor Activity; Nitriles; Parkinson Disease

To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise.. Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide.. This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise.. Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone.. The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG.

Topics: Administration, Oral; Adult; Analysis of Variance; Antidepressive Agents; Antiparkinson Agents; Benzamides; Catechol O-Methyltransferase Inhibitors; Catecholamines; Catechols; Cross-Over Studies; Depressive Disorder; Double-Blind Method; Exercise; Hemodynamics; Humans; Male; Moclobemide; Monoamine Oxidase Inhibitors; Nitriles; Parkinson Disease; Reference Values; Rest

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.

Topics: Aged; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agents; Double-Blind Method; Enzyme Inhibitors; Female; Homovanillic Acid; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Tyrosine

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 five 1-day treatment periods each 1 week apart was used. Entacapone (50, 100, 200, or 400 mg) or placebo was given at 8 a.m. with the patient's individual dose of levodopa/dopa decarboxylase inhibitor. The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) and plasma concentrations of levodopa, its metabolites, and entacapone were measured and motor responses were quantified at 30min intervals using the motor part of the Unified Parkinson's Disease Rating Scale. Entacapone brought about a dose-dependent decrease in S-COMT activity in the RBCs, maximally by 48% at 400 mg. With a 200-mg dose of entacapone, the area under the plasma concentration-time curve (AUC) and half-life of levodopa increased (p < 0.001); the AUCs of 3-O-methyldopa and homovanillic acid decreased (p = 0.01 and p < 0.001, respectively) and that of 3,4-dihydroxyphenylacetic acid increased (p < 0.001). Entacapone prolonged the duration of the motor response to levodopa by 33 min (p = 0.04) and dyskinesias by 45 min (p = 0.003) without affecting their magnitude; the highest increase in duration of these responses occurred with 200 mg of entacapone. Thus, on pharmacokinetic and clinical grounds, the 200-mg dose of entacapone was the most effective. Dose-related responses to entacapone demonstrated its value in the treatment of parkinsonian patients with levodopa-related fluctuations by prolonging the antiparkinsonian response to the levodopa dose.

Topics: Aged; Catechols; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

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 (k3R0), 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 (Ki) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the Ki 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.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Catechol O-Methyltransferase Inhibitors; Catechols; Corpus Striatum; Dihydroxyphenylalanine; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Nitriles; Parkinson Disease; Tomography, Emission-Computed

We used PET and [18F]-6-L-fluorodopa ([18F]dopa) to measure the effect of a peripheral COMT inhibitor, entacapone, on the extracerebral metabolism and subsequent striatal uptake of [18F]dopa. Four parkinsonian patients and six age-matched normal controls were each scanned twice, once after carbidopa (150 mg) plus placebo and once after carbidopa (150 mg) plus entacapone (400 mg or 800 mg). Without entacapone premedication, by 90 minutes from injection, only 22% of the [18F] signal in plasma represented unmetabolized [18F]dopa (the balance being 3-O-methyl[18F]dopa). After entacapone medication, this fraction increased to 56% of the [18F] signal (p < 0.0001). We did not find any significant differences between the changes observed in patients versus controls or between those subjects who received 400 mg entacapone versus 800 mg in either this or any of the other reported measures. PET image contrast increased in all cases, reflecting an increase in the specific striatal signal ([striatum-occipital]:occipital ratio increased 38% [p < 0.0001]). Entacapone did not alter the rate of striatal uptake and decarboxylation of [18F]dopa as estimated using a graphic approach with metabolite-corrected plasma as input function to calculate the influx constant, Ki(p) (p = NS). This confirms that such an analytic approach adequately corrects for the effect of extracerebral [18F]dopa methylation. In contrast, the influx constant Ki(o) (calculated using occipital counts as the input function) increased 45% after entacapone (p < 0.0001). This demonstrates the sensitivity of this analytic approach to the presence of peripheral 3-O-methyl[18F]dopa and provides an estimate of the percentage increase in brain free [18F]dopa resulting from entacapone premedication.

Topics: Aged; Brain; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Corpus Striatum; Dihydroxyphenylalanine; Drug Synergism; Female; Fluorine Radioisotopes; Humans; Levodopa; Male; Middle Aged; Nitriles; Occipital Lobe; Parkinson Disease; Tomography, Emission-Computed

Catechol-O-methyltransferase (COMT) inhibitors may be useful in the treatment of Parkinson's disease by improving the bioavailability of levodopa and by prolonging its effects. Entacapone (OR-611), a novel COMT inhibitor, which does not cross the blood brain barrier, was assessed in 12 patients with Parkinson's disease and motor fluctuations in a randomised, double-blind, cross-over, single dose study. The magnitude and duration of the therapeutic response to a single dose of 200 mg levodopa/50 mg carbidopa was evaluated after concomitant placebo, or 200 or 800 mg entacapone. A significant increase in the duration of the motor response to levodopa was seen when 200 mg entacapone was given with levodopa/carbidopa. Plasma levodopa concentrations were increased with both doses of the COMT inhibitor. The latency to onset of motor response did not differ significantly between active drug and placebo. Entacapone may prove useful in prolonging the duration of the benefit obtained from individual doses of levodopa.

Topics: Aged; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Psychomotor Performance; Treatment Outcome

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

Topics: Aged; Catechol O-Methyltransferase Inhibitors; Catechols; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

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)

Topics: Adult; Aged; Biological Availability; Catechol O-Methyltransferase Inhibitors; Catechols; Disability Evaluation; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian patients. Entacapone significantly increased the mean area under the plasma concentration curve (AUC) of levodopa by 46%, from 3620 to 5280 h.ng.ml-1 and prolonged its elimination half-life (t1/2el) from 1.5 h to 2.0 h. The mean AUC of 3,4-dihydroxyphenylacetic acid (DOPAC), the monoamine oxidase-dependent metabolite of levodopa, was significantly increased from 122 to 343 h.micrograms.ml-1 by entacapone. A small decrease in the AUC of homovanillic acid (HVA), the COMT dependent metabolite of levodopa, was observed (from 455 to 303 h.ng.ml-1). Entacapone also decreased the excretion of HVA but not that of 3-methoxytyramine in the urine. Cardiovascular autonomic responses to sympathetic and parasympathetic stimuli were not changed by entacapone. We conclude that a single dose of entacapone moderately increases the AUC and prolongs the t1/2el of levodopa in man and that that does not affect cardiovascular autonomic regulation.

Topics: Aged; Blood Pressure; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Hemodynamics; Homovanillic Acid; Humans; Levodopa; Middle Aged; Nitriles; Parkinson Disease; Pulse; Respiration

In Parkinson's disease, oral medication often fails to achieve sufficient therapeutic success in an advanced stage. At this point, non-oral, device-aided therapies such as the apomorphine pump, the intrajejunal levodopa pump, and deep brain stimulation are discussed.. The purpose of this manuscript is to highlight a modern form of the well-known intestinal levodopa pump that allows for the continuation of the oral triple combination of levodopa, carbidopa and entacapone, a combination already used by many patients. This new form of pump has been available in both Austria and Germany since 2021, with entacapone being added to the combination to 'save' levodopa. The pump and cartridge are significantly smaller and lighter than the LCIG pump which should benefit therapeutic adherence.. Intrajejunal administration of levodopa is a useful treatment option for advanced Parkinson's disease. The higher acceptance of the smaller pump and the improved user-friendliness have already been reported in an observational study from Sweden. Clinical experience in Germany confirms this too and in addition to motor symptoms, even non-motor ones are influenced positively, and in this respect sleep and pain can be especially emphasized.

Topics: Antiparkinson Agents; Drug Combinations; Gels; Humans; Levodopa; Parkinson Disease

To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP).. A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span.. Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05).. Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease; Retrospective Studies

Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol-O-methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head-to-head data comparing the two COMT inhibitors in real-world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone.. In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0-6 months, 7-12 months and 13-18 months. Opicapone-treated pwPD were algorithm-matched (1:4) to entacapone-treated pwPD.. By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow-up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone-treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use.. This head-to-head study is the first to demonstrate, using 'real-world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post-treatment HCRU versus initiation of COMT inhibition with entacapone.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Humans; Levodopa; Oxadiazoles; Parkinson Disease; Patient Acceptance of Health Care; Retrospective Studies

Topics: Aged; Antiparkinson Agents; Catechols; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Nitriles; Parkinson Disease; Urine

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the "wearing-off" phenomenon). The drug indication is for Parkinson's disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature.

Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechols; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease; United States; United States Food and Drug Administration

Entacapone, one of the most common drugs distributed among patients with Parkinson's disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa.. The population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database.. Results of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare.. Our findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

Topics: Adenosine Deaminase; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Gastrointestinal Microbiome; Humans; Intercellular Signaling Peptides and Proteins; Levodopa; Nitriles; Parkinson Disease; Pilot Projects; RNA, Ribosomal, 16S

The catechol-O-methyltransferase inhibitors entacapone and opicapone prolong the efficacy of conventional oral levodopa/dopa decarboxylase inhibitor formulations through an increase in levodopa plasma bioavailability. Catechol-O-methyltransferase inhibitors influence the homocysteine metabolism associated with levodopa/dopa decarboxylase application. The objectives of this study were to compare the impact of additional single-day entacapone or opicapone intake on the pharmacokinetic plasma behaviour of levodopa, 3-O-methyldopa and total homocysteine in 15 Parkinson's disease patients, with concomitant scoring of motor symptoms, under standardized conditions. The patients received opicapone plus two doses of 100 mg levodopa/carbidopa and, one week later, two doses of levodopa/carbidopa/entacapone or vice versa. Levodopa, 3-O-methyldopa and total homocysteine were determined with reversed-phase high-performance liquid chromatography. Levodopa bioavailability and its maximum concentration were higher with opicapone. The computed peak-to-trough difference was lower after the second levodopa administration with entacapone. The fluctuation index of levodopa did not differ between both conditions. 3-O-methyldopa decreased on both days. Homocysteine levels did not significantly vary between both conditions. A significant homocysteine decrease occurred with entacapone, but not with opicapone. Motor behaviour improved with entacapone, but not with opicapone. Opicapone baseline scores were significantly better, and thus the potential for the improvement in motor symptoms was lower compared with the entacapone condition. The higher levodopa bioavailability with opicapone suggests that it is more efficacious than entacapone for the amelioration of "off" phenomena in fluctuating patients when co-administered with a levodopa/dopa decarboxylase inhibitor regimen. Both compounds prevented an increase in homocysteine, which is a metabolic marker for an impaired capacity in the performance of methylation processes.

Topics: Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Homocysteine; Humans; Levodopa; Nitriles; Oxadiazoles; Parkinson Disease

In response to the report of Ong and colleagues of a series of patients with levodopa/dopa decarboxylase inhibitor associated microscopic colitis, we report a case of entacapone associated microscopic colitis. We agree that chronic diarrhoea in patients with Parkinson's disease should prompt consideration of drug-induced microscopic colitis as the cause.

Topics: Antiparkinson Agents; Catechols; Colitis, Lymphocytic; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Oxadiazoles; Parkinson Disease

A wide variety of conversion factors for a levodopa-equivalent-dose (LED) have been proposed for each Parkinson's disease (PD) medication. The currently-used set of conversion factors is based on studies that relied on subjective experience or theoretical assumptions. This set was never validated in patients receiving polytherapy.. To use real-life data to identify an optimal set of conversion factors independent of prior assumptions regarding clinical efficacy of different medications.. Retrospective analysis of data from 206 cognitively-preserved patients with advanced PD receiving polytherapy before deep brain stimulation (DBS) surgery. A nonlinear automated problem solver was used to find a set of conversion factors that, when applied, minimized the coefficient of variation of LEDs in a relatively homogenous cohort of patients.. Independent and model-free evaluation of a wide range of possible sets of conversion factors to LED suggested a set of normalized conversion factors for immediate release levodopa (1.00), controlled release levodopa (0.88), and amantadine (1.23). A minimal clinical benefit of entacapone was observed for patients with motor fluctuations. Our analysis could not detect conversion factors for dopamine agonists and MAO-B inhibitors, possibly because their clinical contribution when added to levodopa is limited.. Independent from previous studies and prior assumptions we show that the currently-used LED conversion factors for immediate release levodopa, controlled release levodopa and amantadine are largely correct and that dopamine agonists, MAO-B inhibitors and entacapone, given in addition to levodopa, have little additional clinical value for PD patients with motor fluctuations.

Topics: Aged; Amantadine; Antiparkinson Agents; Catechols; Dopamine Agonists; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Monoamine Oxidase Inhibitors; Nitriles; Outcome Assessment, Health Care; Parkinson Disease; Retrospective Studies

Currently, peripheral COMT inhibitors have an important role in the treatment of Parkinson's disease, and central COMT inhibitors have a potential role in the treatment of various neuropsychiatric disorders, such as attention deficit hyperactivity disorder. Adverse reactions, low bioavailability and short elimination half-lives have prompted the development of new selective COMT inhibitors. The objective of this study was to evaluate the pharmacodynamic properties of novel tight-binding COMT inhibitors (NC, NE, NDE, NCAPE, CNCAFBn, CNCAPE, NCAFBn, CNCAPA, CNCABA and CNCAHA) and compared to standard inhibitors tolcapone and entacapone. The activity of soluble (S) and membrane bound (MB) COMT from rat liver and brain was assessed in the presence of varying concentrations of each inhibitor. NE and NC behaved most potently against liver S-COMT, and CNCAPE was the most potent inhibitor against brain MB-COMT. The cytotoxicity of tolcapone and CNCAPE in human neuroblastoma SK-N-SH cells and human liver adenocarcinoma SK-HEP-1 cells was also assessed. At lower concentrations, CNCAPE did not reduce cell viability, suggesting that CNCAPE may have a potential therapeutic role as a centrally active COMT inhibitor.

Topics: Animals; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cell Line, Tumor; Cell Survival; Enzyme Inhibitors; Humans; Liver; Liver Neoplasms; Neuroblastoma; Nitriles; Parkinson Disease; Rats; Tolcapone

Topics: Carbidopa; Catechols; Humans; Levodopa; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Carbidopa; Catechols; Combined Modality Therapy; Deep Brain Stimulation; Drug Combinations; Drug Therapy, Combination; Fever; Humans; Hyperkinesis; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

Parkinson's disease (PD) is a multisystem disorder that affects 2-3% of the population ≥ 65 years of age. The main pharmacologic agent use in the treatment of clinical symptoms of PD is levodopa (L-DOPA). However, the chronic use of L-DOPA might result in the emergence of motor complications such as motor fluctuation and dyskinesia. Previous studies have shown that the inter-individual variability and pharmacogenetic profile of PD patients seem to influence the occurrence of motor complications. For these reasons, the purpose of this study was to evaluate a possible relationship between DRD1 A48G and DRD3 Ser9Gly genetic variants with the occurrence of motor complications in PD patients in a Brazilian population. A total of 228 patients with idiopathic PD were enrolled. Patients were genotyped for DRD1 A48G and DRD3 Ser9Gly polymorphisms using PCR-RFLP. The univariate and multivariate analyses were performed to assess the association of these polymorphisms with the occurrence of motor fluctuation and dyskinesia in PD patients. Multiple Poisson regression analyses showed a protector effect to the occurrence of dyskinesia for individuals carrying of the DRD1 G/G genotype (PR 0.294; CI 0.09-0.87; p ≤ 0.020) after the threshold Bonferroni's. Besides, we verified risk increased to the occurrence of motor complications with daily L-DOPA dosage, disease duration, and users of rasagiline, selegiline, or entacapone (p < 0.05 for all). Our results suggest that the DRD1 A48G polymorphism and the presence of extrinsic and intrinsic factors may role an effect in the occurrence of dyskinesia in PD patients.

Topics: Antiparkinson Agents; Catechols; Cross-Sectional Studies; Dopamine; Dopamine Agonists; Genotype; Humans; Indans; Levodopa; Motor Activity; Nitriles; Parkinson Disease; Polymorphism, Single Nucleotide; Receptors, Dopamine D1; Receptors, Dopamine D3; Selegiline

To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease.. After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale-based assessments, and standard safety assessments.. One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone 50 mg in the double-blind phase maintained their efficacy, switching treatments led to further decreases in "off" time (-64.9, -39.3, -27.5, and -23.0 minutes for switching from placebo, entacapone, and opicapone 5 and 25 mg, respectively). Dyskinesia was the most frequently reported adverse event (14.5%) and was managed by adjustment of dopaminergic therapy. No new safety concerns were observed with long-term opicapone administration.. Long-term use of opicapone provided sustained efficacy over 1 year. Switching from entacapone to opicapone led to enhanced efficacy under the conditions of the study.. This study provides Class III evidence that for patients with Parkinson disease and end-of-dose motor fluctuations, long-term use (52 weeks) of opicapone is well tolerated and reduces "off" time.

Topics: Aged; Antiparkinson Agents; Catechols; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Oxadiazoles; Parkinson Disease; Treatment Outcome

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

Topics: Administration, Oral; Animals; Antiparkinson Agents; Biological Availability; Brain Chemistry; Capsules; Carbidopa; Catechols; Dopamine; Drug Compounding; Female; Hydrophobic and Hydrophilic Interactions; Levodopa; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Nitriles; Parkinson Disease

An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting.. To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis.. Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry.. Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts.. Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechols; Databases, Factual; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Nitriles; Parkinson Disease; Prostatic Neoplasms; Registries; Retrospective Studies; Risk; Severity of Illness Index; United States; United States Department of Veterans Affairs; Veterans

Impulse control behaviors (ICBs) are impulsive-compulsive behaviors often associated with dopamine replacement therapy in Parkinson's disease (PD). Although remission can occur in ICB, only four reports on the ratio of remission and the persistence of ICB have been published, and the associated factors with ICB remission or persistence have been little known. Therefore, we conducted a longitudinal assessment of the remission, persistence, and development of ICB and those associated factors in patients with PD.. We retrospectively investigated a PD database at Aomori Prefectural Central Hospital, Japan. One hundred and forty-eight patients with PD who could be followed up for 2 years were enrolled. ICB was assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease. Motor severity (Hoehn and Yahr scale and United Parkinson's Disease Rating Scale), cognitive function (Mini-Mental State Examination), and other clinical variables (sex, age, onset age, disease duration, olfactory dysfunction, and dyskinesia) and medications used to treat PD were assessed. Univariate analyses were performed.. Seven patients were excluded because of the exclusion criteria, and 141 patients were analyzed. Thirty patients (21.3%) had ICB at baseline, and these patients also had significantly higher use of pergolide. The ICB remission rate was 60%, the ICB persistence ratio was 40%, and the ICB development ratio was 12.6% over 2 years. Statistically, younger age and pergolide use were associated with ICB persistence. Being male, having dyskinesia, and rotigotine, entacapone, zonisamide, and istradefylline use were associated with ICB development.. This study suggests that younger age and pergolide use may be the new associated factors with ICB persistence and that entacapone, zonisamide, and istradefylline use may be associated with the development of ICB. Drug profiles and medication practices in Japan may explain the association of these factors with ICB.

Topics: Adenosine A2 Receptor Antagonists; Age Factors; Aged; Antiparkinson Agents; Calcium Channel Blockers; Case-Control Studies; Catechols; Cohort Studies; Disruptive, Impulse Control, and Conduct Disorders; Dopamine Agonists; Female; Humans; Impulsive Behavior; Japan; Longitudinal Studies; Male; Nitriles; Parkinson Disease; Pergolide; Purines; Retrospective Studies; Surveys and Questionnaires; Zonisamide

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Case-Control Studies; Catechols; Female; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Polyneuropathies; Statistics, Nonparametric

Topics: Adult; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cesarean Section; Female; Gestational Age; Humans; Infant, Newborn; Levodopa; Nitriles; Parkinson Disease; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Parkinson's disease (PD) is a progressive disease of the nervous system, and is currently managed through commercial tablets that do not sufficiently enable controlled, sustained release capabilities. It is hypothesized that a drug delivery system that provides controlled and sustained release of PD drugs would afford better management of PD. Hollow microcapsules composed of poly-l-lactide (PLLA) and poly (caprolactone) (PCL) are prepared through a modified double-emulsion technique. They are loaded with three PD drugs, i.e., levodopa (LD), carbidopa (CD), and entacapone (ENT), at a ratio of 4:1:8, similar to commercial PD tablets. LD and CD are localized in both the hollow cavity and PLLA/PCL shell, while ENT is localized in the PLLA/PCL shell. Release kinetics of hydrophobic ENT is observed to be relatively slow as compared to the other hydrophilic drugs. It is further hypothesized that encapsulating ENT into PCL as a surface coating onto these microcapsules can aid in accelerating its release. Now, these spray-coated hollow microcapsules exhibit similar release kinetics, according to Higuchi's rate, for all three drugs. The results suggest that multiple drug encapsulation of LD, CD, and ENT in gastric floating microcapsules could be further developed for in vivo evaluation for the management of PD.

Topics: Animals; Caproates; Capsules; Carbidopa; Catechols; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Humans; Hydrophobic and Hydrophilic Interactions; Lactones; Levodopa; Microscopy, Confocal; Nitriles; Parkinson Disease; Polyesters

The association between Parkinson's disease (PD) and prostate cancer, both common in elderly men, is disputable. In the STRIDE-PD study, prostate cancer developed in 9 patients (3.7%) receiving levodopa/carbidopa with entacapone, a catechol-O-methyltransferase inhibitor, versus 2 cases (0.9%) without entacapone. The current pharmacoepidemiological study aimed to determine whether entacapone increases prostate cancer incidence or mortality in PD patients and whether cumulative exposure affects these rates.. We performed a retrospective cohort study using population-wide health care registers with patient-level linkage. Prostate cancer incidence and mortality were modeled by Cox's proportional hazards models.. Use of entacapone with l-dopa/dopa decarboxylase inhibitor caused no increased risk of prostate cancer incidence (hazard ratio [HR]: 1.05; 95% confidence interval: 0.76-1.44) or mortality (0.93; 0.43-1.98). The HR for cumulative entacapone use of >360 days versus never-use was 0.82 (0.56-1.18) for prostate cancer incidence and 1.27 (0.60-2.72) for prostate cancer mortality.

Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Cohort Studies; Drug Therapy, Combination; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Prostatic Neoplasms; Registries; Risk; Time Factors

The comorbidity of schizophrenia and idiopathic Parkinson's disease (IPD) is illustrated by a case description of a schizophrenic patient who develops motor symptoms finally diagnosed and treated as comorbid IPD. Several aspects of the clinical challenges of this comorbidity are discussed and an overview of earlier reported cases is presented. IPD must be distinguished from neuroleptic-induced parkinsonism by clinical course and characteristics. A SPECT scan is helpful for diagnosis. We recommend antiparkinsonian treatment to be prescribed only with the protection of antipsychotic agents, of which clozapine and quetiapine are the best choices.

Topics: Antiparkinson Agents; Antipsychotic Agents; Brain; Carbidopa; Catechols; Clozapine; Diagnosis, Differential; Fluphenazine; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Schizophrenia; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Several therapeutic options are available for the symptomatic treatment of Parkinson's disease (PD).There is no reliable information about which factors are involved in the choice of treatment.. To identify factors contributing to the decision to start treatment with levodopa/carbidopa/entacapone (LCE) in patients with PD.. We completed a descriptive cross-sectional retrospective multicentre study of patients with idiopathic PD receiving LCE. Clinical data were collected with special attention to factors that could potentially determine when to initiate treatment with LCE in normal clinical practice.. We studied 1050 patients with a mean age of 71.3±8.7 years (58.2% men). Average time from onset of symptoms to diagnosis was 13.8±12.9 months, with a latency time of 74.5±53.6 months before starting LCE treatment. The most common initial symptoms were tremor (70.6%), reduced dexterity (43.2%) and slowness of movement (41.5%). At the start of LCE treatment, most patients were in Hoehn and Yahr stage 2 (57.5%), with an average rating of 73.4% on the Schwab & England scale. Eight hundred twenty two patients (78.3%) received treatment with other drugs before starting LCE (mean time between starting any PD treatment and starting LCE was 40.5±47.2 months). Clinical factors with a moderate, marked, or crucial effect on the decision to start LCE treatment were bradykinesia (84.7%), daytime rigidity (72.2%), general decline (72.2%), difficulty walking (66.4%), tremor (62.7%), nocturnal rigidity (56.1%), and postural instability (53%). Difficulty performing activities of daily living was the only psychosocial factor identified as having an influence on the decision (84.3%).. The decision to start patients with idiopathic PD on LCE treatment is mainly determined by motor deficits and disabilities associated with disease progression.

Topics: Aged; Antiparkinson Agents; Carbidopa; Catechols; Cross-Sectional Studies; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Retrospective Studies; Socioeconomic Factors; Spain

Oxidative stress is influenced by the thiol homeostasis, which regulates the redox milieu via glutathione. Components of glutathione metabolism are cysteine and cysteinyl-glycine. Both substrates decay following levodopa application or dopamine-related oxidative stress. Objective was to investigate the impact of an acute levodopa application with and without catechol-O-methyltransferase inhibitor on cysteine- and cysteinyl-glycine plasma levels. On two investigation days, 13 patients with Parkinson's disease took one retarded release 200-mg levodopa/50 mg carbidopa-containing tablet or one 150-mg levodopa/50-mg carbidopa/200-mg entacapone formulation under standardized conditions. Levodopa, 3-O-methyldopa, cysteine and cysteinyl-glycine were measured at baseline, 80 and 140 min following levodopa administration. Cysteine and cysteinyl-glycine similarly decreased, levodopa was nearly equal during both conditions. Entacapone lowered 3-O-methyldopa. Cysteine decay may be due to an elevated glutathione generation, which consumes cysteine. Cysteinyl-glycine decrease results from the alternative glutathione transformation to its oxidized form glutathione dissulfide after free radical scavenging.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechols; Chromatography, Reverse-Phase; Cysteine; Dipeptides; Drug Delivery Systems; Female; Humans; Levodopa; Male; Methyldopa; Middle Aged; Nitriles; Parkinson Disease; Time Factors

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.

Topics: Aged; Antiparkinson Agents; Area Under Curve; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Performance; Statistics, Nonparametric; Tolcapone; Treatment Outcome

Wearing-off is one of the most frequent problems encountered by levodopa-treated patients. Entacapone, a peripheral inhibitor of catechol-O-methyltransferase (COMT), reduces this motor complication by prolonging the effect of levodopa. We sought to understand the impact of COMT-inhibition on movement execution in PD patients with wearing-off by comparing functional magnetic resonance imaging (f-MRI) activation patterns prior to and during entacapone treatment. Our hypothesis was to determine whether changes in cortical activation are associated to COMT-inhibitor treatment.. Nine levodopa-treated non-demented PD patients with wearing-off were prospectively studied in two f-MRI session, prior to and during entacapone treatment. A group of control subjects were also studied for comparison.. The patients significantly improved under COMT-inhibitor treatment based on home diaries. F-MRI results showed that at baseline the patients presented a bilateral activation of the primary motor, controlateral premotor cortex and supplementary motor area, as well as ipsilateral cerebellum. During treatment with entacapone, PD patients showed reductions in the activations of these cortical areas and a decreased activation in the ipsilateral cerebellum.. Our preliminary findings indicate that f-MRI is able to detect cortical activation changes during long-term modulation of dopaminergic treatment in PD patients with wearing-off, and thus, this technique could be further investigated in advanced PD patients.

Topics: Aged; Antiparkinson Agents; Case-Control Studies; Catechol O-Methyltransferase Inhibitors; Catechols; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Motor Skills; Nitriles; Parkinson Disease; Prospective Studies; Treatment Outcome

Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.

Topics: Acetophenones; Animals; Catalysis; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Levodopa; Male; Models, Molecular; Nitriles; Oxadiazoles; Parkinson Disease; Prodrugs; Rats

Levodopa (l-dopa) therapy in Parkinson's disease (PD) increases serum homocysteine levels because of its metabolism via catechol O-methyltransferase, which may lead to endothelial dysfunction.. We enrolled 40 PD patients treated with l-dopa, 33 PD patients treated with l-dopa/entacapone, 22 untreated PD and 30 controls, and compared the flow-mediated dilation in these subjects.. The flow-mediated dilation was significantly lower in PD patients with l-dopa (6.0 ± 1.8%) than in those with l-dopa/entacapone (7.2 ± 1.1%, P = 0.03), untreated PD patients (7.8 ± 1.2%, P < 0.05), and controls (8.5 ± 2.9%, P < 0.05). The homocysteine level was significantly higher in PD patients with l-dopa than in other groups. In a multivariate logistic regression model, the uppermost homocysteine quartile was an independent predictor of the lowest tertile of flow-mediated dilation (odds ratio, 6.33; 95% confidence interval, 1.61-26.65; P = 0.012).. Our findings indicate that endothelial dysfunction may be associated with chronic l-dopa treatment in patients with PD.

Topics: Aged; Antiparkinson Agents; Brachial Artery; Catechols; Dilatation; Endothelium; Female; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Logistic Models; Male; Middle Aged; Nitriles; Parkinson Disease; Statistics, Nonparametric

Topics: Aged; Antiparkinson Agents; Catechols; Echocardiography; Female; Humans; Nitriles; Parkinson Disease; Takotsubo Cardiomyopathy; Treatment Outcome

To explore the effects of entacapone on the plasma level of homocysteine (Hcy) in Parkinson's disease (PD) patients on levodopa.. This cross-sectional study was made up of 4 groups, i.e. 'L + E' group (primary PD patients on levodopa and entacapone), 'L' group (primary PD patients on levodopa alone), 'L(-)' group (primary PD patients never on levodopa) and control group (people without PD or any other nervous system diseases). They were randomly selected from the PD patient database of our department in September 2012. At the beginning, 60 cases were selected for each group. The C677T genotypes of methylenetetrahydrofolate reductase (MTHFR) were identified and the plasma concentrations of Hcy, folic acid and vitamin B12 detected in each subject. Then group t test, single factor analysis of variance and χ(2) test were used for statistical analysis by SPSS 11.5 software.. Among 240 early subjects, 98 cases with CC genotype at 677 site of MTHFR gene were finally recruited. Statistical analysis revealed no differences in age, gender, plasma concentrations of folic acid and vitamin B12 among the groups. The PD duration of 'L + E' group (96 ± 21 months) were the longest among 3 groups, followed by those of 'L' group (51 ± 17 months) and 'L(-)' group (21 ± 6 months). The treatment duration and daily dose of levodopa in 'L + E' group (77 ± 22 months, 765 ± 110 mg) were all higher than those in 'L' group (42 ± 14 months, 673 ± 73 mg). The plasma Hcy concentrations of 'L + E' group (15.1 ± 3.1 µmol/L) were lower than those of 'L' group (20.4 ± 4.7 µmol/L), but still higher than those of 'L(-)' group (12.2 ± 2.4 µmol/L) and control group (9.1 ± 2.2 µmol/L). The Hcy concentrations of 'L(-)' group were also higher than those of control group.. Entacapone increases the bioavailability of levodopa and simultaneously alleviates partially its resulting hyperhomocysteinemia.

Topics: Aged; Catechols; Cross-Sectional Studies; Female; Homocysteine; Humans; Levodopa; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Carbidopa; Catechols; Dyskinesia, Drug-Induced; Dystonia; Female; Foot Diseases; Humans; Levodopa; Middle Aged; Neurologic Examination; Nitriles; Parkinson Disease

Topics: 5-alpha Reductase Inhibitors; Aged; Antiparkinson Agents; Benzothiazoles; Cabergoline; Carbidopa; Catechols; Drug Combinations; Drug Monitoring; Drug Therapy, Combination; Ergolines; Finasteride; Gambling; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Pramipexole; Treatment Outcome; Video Games

In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically.

Topics: Amantadine; Antiparasitic Agents; Carbidopa; Catechols; Decision Making; Deep Brain Stimulation; Disease Progression; Dyskinesia, Drug-Induced; Gait Disorders, Neurologic; Globus Pallidus; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Quality of Life; Subthalamus

Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Catechols; Drug Combinations; Drugs, Generic; Humans; Indans; Levodopa; Nitriles; Parkinson Disease

Suboptimal adherence to long-term therapies is common and may potentially have adverse consequences on patient outcomes and healthcare costs.. To assess the association between adherence to levodopa/carbidopa/entacapone therapy and healthcare utilization and costs in patients with Parkinson's disease.. A retrospective historical cohort study, conducted in the US, using a health insurance claims database, with data spanning from 1 January 2000 to 31 December 2005. Subjects included patients with Parkinson's disease who were treated with levodopa (L), carbidopa (C) and entacapone (E) either as separate tablets (LC + E) or as a single-tablet formulation (LCE). The association between satisfactory adherence (defined as 'proportion of days covered' for LCE or LC + E during 1-year follow-up ≥80%) and healthcare utilization and costs was examined using multivariate regression to control for pretreatment adherence to LC and other patient characteristics.. Compared with unsatisfactory adherence (n = 598), satisfactory adherence (n = 617) was associated with 39% fewer Parkinson's disease-related hospitalizations (95% CI 20, 54; p < 0.001), 47% lower all-cause inpatient costs (95% CI 18, 65; p = 0.004) and 18% lower all-cause total costs (95% CI 11, 24; p < 0.001). On an adjusted basis, all-cause total costs were $US3508 less for those with satisfactory versus unsatisfactory adherence. In both the LC + E and LCE groups, satisfactory adherence was associated with significant reductions in all-cause hospitalizations (39% and 46%, respectively), and all-cause total costs (10% and 31%, respectively). The association between adherence and total healthcare costs was stronger for patients receiving LCE.. Better adherence to levodopa/carbidopa/entacapone therapy is associated with lower healthcare utilization and costs. Non-adherence to LCE is associated with a greater increase in costs than non-adherence to LC + E. Efforts should be made to ensure adherence to both therapies.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Cohort Studies; Delivery of Health Care; Health Care Costs; Humans; Levodopa; Nitriles; Parkinson Disease; Patient Compliance; Retrospective Studies

Topics: Antiparkinson Agents; Catechols; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitriles; Parkinson Disease

The aim of this study is to clarify the relationship between serum 3-O-methyldopa (3-OMD) and the clinical effects of entacapone. The 3-OMD and maximum serum concentration (Cmax) of levodopa were measured in 21 Parkinson's Disease patients who took 100 mg levodopa / dopa decarboxylase inhibitor. After the administration of entacapone, the 3-OMD concentration and percentage of "on" time during waking hours (% of "on" time) were studied for 8 weeks. The 3-OMD concentration was reduced by 34%, and the increase in % of "on" time was 28% at the 8th week compared with baseline. We defined the COMT-index as [baseline 3-OMD concentration] / [levodopa Cmax when 100 mg levodopa was administered alone]. The COMT-index was significantly correlated with the increase in % of "on" time at the 8th week. In conclusion, the measurement of baseline 3-OMD and levodopa pharmacokinetics is useful for predicting the clinical effects of entacapone.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Benserazide; Biomarkers; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Disease Progression; Dopa Decarboxylase; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Japan; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Parkinson Disease; Prospective Studies; Treatment Outcome; Tyrosine

Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C(max) of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C(max) in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antiparkinson Agents; Area Under Curve; Catechols; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Mepivacaine; Microdialysis; Middle Aged; Nitriles; Parkinson Disease; Time Factors

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).. 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.. 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).. 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.. 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.

Topics: Aged; Aged, 80 and over; Algorithms; Antiparkinson Agents; Carbidopa; Catechols; Cohort Studies; Dosage Forms; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Patient Compliance; Retrospective Studies; Tablets

Peripheral metabolism of L-DOPA via enzyme catechol-O-methyltransferase (COMT) is one of the possible sources of homocysteine (HCY). The aim of this study was to assess plasma HCY levels in L-DOPA-treated Parkinson's disease (PD) patients and its influence by adding the inhibitor COMT (entacapone). Patients were divided into two groups: (1) patients long term treated with L-DOPA but were naïve to entacapone, (2) L-DOPA naïve patients, in whom a combined treatment with L-DOPA and entacapone was started. The HCY levels were higher in Group 1 than in Group 2. No statistically significant changes of HCY concentrations were found in both patient groups after adding entacapone to their L-DOPA treatments. Results of this study confirm that patients treated with L-DOPA for a long term have increased plasma HCY concentrations. We believe combined L-DOPA and entacapone therapy could be a possible protective mechanism against hyperhomocysteinemia in early PD.

Topics: Aged; Antiparkinson Agents; Catechols; Female; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Time Factors

Topics: Animals; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agents; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Male; Nitriles; Parkinson Disease; Prostatic Neoplasms; Time Factors

Psychotic features in patients with Parkinson's Disease usually present as visual hallucinations against a background of cognitive deterioration and dopaminomimetic therapy. Isolated delusions are rare. We report here 4 patients with Parkinson's Disease who developed a delusional syndrome resembling schizophreniform psychosis in the absence of changes in alertness, visual hallucinations or dementia. We suggest that this syndrome may be more common than previously recognized, and that it may be related to the use of dopaminergic medications and environmental triggers on a background of a susceptible individual. This syndrome suggests interesting parallels with the pathophysiology of amphetamine-induced psychosis and schizophrenia.

Topics: Aged; Amantadine; Antiparkinson Agents; Benserazide; Benzothiazoles; Catechols; Clonazepam; Female; Humans; Indans; Indoles; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Pramipexole; Schizophrenia, Paranoid; Syndrome

As Parkinson's disease (PD) progresses, patients and their families experience substantial health and economic burdens. Because motor fluctuations (also called 'off-time') are linked to poor quality of life and higher healthcare costs, minimizing off-time is an effective strategy for reducing costs associated with PD.. To assess the cost utility of rasagiline or entacapone as adjunctive therapies to levodopa versus levodopa/carbidopa/entacapone (LCE) versus standard levodopa monotherapy in patients with advanced PD and motor fluctuations in the US.. A 2-year stochastic Markov model was utilized to examine the cost effectiveness of treatments of advanced PD. The model assumed that patients transition health status every 4 months. Transition probabilities, including uncertainties, were estimated from clinical trial data. Medical costs, daily drug costs and utility weights were obtained from published literature.. Over 2 years, all therapy options showed greater effectiveness than levodopa alone. Rasagiline+levodopa and LCE were cost saving from a payor perspective, while entacapone+levodopa was cost saving from a societal perspective. Mean benefits over 2 years were 0.12 (90% credibility interval [CI] 0.07, 0.18) additional quality-adjusted life-years (QALYs) for rasagiline+levodopa, entacapone+levodopa and LCE, 5.08 (90% CI 3.87, 6.28) additional months with

Topics: Antiparkinson Agents; Carbidopa; Catechols; Cost Savings; Cost-Benefit Analysis; Disease Progression; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Humans; Indans; Levodopa; Markov Chains; Models, Economic; Nitriles; Parkinson Disease; Quality of Life; Quality-Adjusted Life Years; Stochastic Processes; Time Factors; Treatment Outcome; United States

Topics: Adult; Antiparkinson Agents; Area Under Curve; Catechols; Drug Therapy, Combination; Humans; Levodopa; Male; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Carbidopa; Catechols; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Levodopa; Neurologic Examination; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; Receptors, Dopamine

Topics: Aged; Antiparkinson Agents; Azepines; Benzothiazoles; Cabergoline; Carbidopa; Catatonia; Catechols; Drug Therapy, Combination; Electroconvulsive Therapy; Ergolines; Female; Humans; Levodopa; Nitriles; Parkinson Disease; Pramipexole

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechols; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; Retrospective Studies

Levodopa is the most efficacious agent for the treatment of motor features of Parkinson's disease but its chronic use is associated with the development of motor complications. Mounting evidence indicates the short half-life of levodopa and resultant pulsatile stimulation of striatal dopamine receptors leads to wearing off, motor fluctuations and dyskinesias. Longer acting dopaminergic agents, such as dopamine agonists, are less likely to cause motor fluctuations and dyskinesias but are not as efficacious for control of motor symptoms. Therefore, there is interest in exploring ways to deliver levodopa in a more continuous fashion, in an effort to maintain benefit through the day and reduce the development of motor fluctuations and dyskinesias. A dopa decarboxylase inhibitor (DDCI), such as carbidopa or benserazide, is administered with levodopa to attenuate its peripheral conversion to dopamine, reduce nausea and increase central bioavailability. When levodopa is administered with a DDCI, its main route of peripheral metabolism is via catechol-O-methyl transferase (COMT). A COMT inhibitor can be added to the combination of levodopa and a DDCI to further extend the levodopa peripheral half-life and increase central bioavailability. Stalevo is a combination tablet comprised of levodopa, carbidopa, and the COMT inhibitor entacapone. It is available in fixed-dose combinations of levodopa/carbidopa/entacapone, 50/12.5/200, 75/18.75/200, 100/25/200, 125/31.25/200, 150/37.5/200 and 200/50/200 mg. Stalevo is currently approved for use in Parkinson's disease patients with end-of-dose wearing off.

Topics: Antiparkinson Agents; Biological Availability; Carbidopa; Catechols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson Disease

Chronic levodopa (LD)/dopadecarboxylase inhibitor (DDI) increases homocysteine generation as side reaction of O-methylation. Aim was to investigate the impact of the peripheral COMT inhibitor entacapone (EN) on plasma concentrations of homocysteine, LD and 3-O-methyl-dopa (3-OMD). Patients with Parkinson's disease (PD) received on two consecutive days in a standardised fashion one single dose of 200 mg retarded release LD/carbidopa (CD) or of 150 mg LD/CD/EN, since both were shown to have simultaneous pharmacokinetic LD behaviour. Homocysteine increased after retarded release LD/CD application, but not following LD/CD/EN intake. Homocysteine was lower during the LD/CD/EN condition 80 min after baseline when compared with its levels after LD/CD administration. LD levels simultaneously rose on both days. 3-OMD concentrations did not change. Acute LD/CD application caused a rise of homocysteine levels, which was prevented by LD/CD/EN intake. Therefore, peripheral COMT inhibition may have a beneficial effect on putative, controversially debated components of homocysteine-related progression of PD.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Delayed-Action Preparations; Dihydroxyphenylalanine; Enzyme Inhibitors; Female; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Time Factors; Tyrosine

Although levodopa is considered the gold standard for Parkinson's disease therapy, prolonged use of this drug can result in motor complications such as a 'wearing-off' phenomenon. This outcome is seen in a significant number of patients with Parkinson's disease taking levodopa and, in some cases, is observed only a few hours after intake of the last dose of levodopa. Patients experiencing the wearing-off period may present with sensory, autonomic, psychiatric and motor fluctuations. Although infrequent, shortness of breath is an important non-motor wearing-off symptom experienced by patients with Parkinson's disease. In addition to being a symptom induced by wearing off, other causes of shortness of breath include pulmonary diseases, coronary artery disease and anxiety. Thus, it is important to identify the cause of shortness of breath to ensure that the appropriate treatment is initiated. We report here on a patient with Parkinson's disease who was taking levodopa and developed both shortness of breath and hyperventilation during wearing-off periods. He underwent extensive pulmonary and cardiac investigations that were unremarkable. His shortness of breath was determined to be a wearing-off phenomenon and his condition improved with the addition of a catechol-O-methyltransferase inhibitor (entacapone).

Topics: Antiparkinson Agents; Catechols; Drug Resistance; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Respiratory Mechanics; Respiratory Tract Diseases

Topics: Aged; Antiparkinson Agents; Catechols; Encephalitis; Female; Humans; Levodopa; Nitriles; Parkinson Disease; Peripheral Nervous System Diseases

Levodopa is the gold standard drug for the symptomatic control of Parkinson's disease (PD). However, long-term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re-emergence of symptoms because of wearing-off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half-life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open-label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose-fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa-modification strategies for the effective treatment of PD motor fluctuations in clinical practice.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Catechols; Dopa Decarboxylase; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; France; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Practice Patterns, Physicians'; Retrospective Studies

Pisa syndrome (PS) is a dystonic lateroflexion of the trunk with a postural disturbance resembling the leaning tower of Pisa. Initially reported as a side effect related to antipsychotic therapy, this original dystonic posture is also manifested in neurodegenerative disorders such as Alzheimer's disease and multiple system atrophy, or in rare idiopathic cases. Recent observations have described the onset of PS with subchronic course in patients affected by Parkinson's disease (PD). Here, we report on the acute development of PS in a parkinsonian patient during treatment with entacapone/levodopa/carbidopa combination. This case illustrates how, in contrast to previously well-known chronic/subchronic forms, this axial dystonic posture may occur in PD as an acute onset reversible type, related to levodopa treatment.

Topics: Antiparkinson Agents; Carbidopa; Catechols; Dystonic Disorders; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Tomography, Emission-Computed, Single-Photon; Tropanes

Total plasma homocysteine (tHcy) may be a risk factor for vascular diseases and is associated with renal failure or deficiency of vitamin B12 or folate. Recently, elevated tHcy concentrations were observed in patients with Parkinson's disease (PD), particularly those under levodopa treatment. Our objective was to determine whether changes in tHcy are also found in patients with restless legs syndrome (RLS) in relation to levodopa treatment and whether folate and vitamins B6 and B12 play a role in RLS.. In a total of 228 subjects, tHcy and B vitamin status (vitamins B6 and B12, folate) were studied: 97 patients with idiopathic RLS (40 under levodopa therapy), 39 with PD (25 under levodopa therapy), and 92 healthy controls adjusted for age and gender.. No significant differences were observed in tHcy levels between RLS patients and controls or between the RLS groups without treatment or with levodopa or dopamine agonist treatment. Mean tHcy was significantly higher in PD patients (13.8 micromol/l) than in either RLS patients (11.7 micromol/l) or controls (11.0 micromol/l; p<0.001). There was an inverse association between tHcy and vitamin B12 in each group.. RLS and, in particular, levodopa treatment in RLS are not associated with hyperhomocysteinemia. Elevated tHcy could, however, be confirmed in PD patients.

Topics: Aged; Antiparkinson Agents; Catechols; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Reference Values; Restless Legs Syndrome; Vitamin B 12; Vitamin B 6

To assess the role of age in the results of bilateral deep brain stimulation in the subthalamic nucleus (DBS-STN), we carried out a study of two groups of patients regarding age at time of surgery.. We compared, up to 2 years after surgery, the clinical effects, safety, and quality of life in parkinsonian patients younger than 65 years old (young patients) vs parkinsonian patients 65 years old or older (old patients).. The mean age was 57.4 +/- 4.9 years (n = 53) in young patients and 68.8 +/- 2.8 years (n = 34) in old patients. A dramatic improvement in motor complications was equally observed in both groups of patients. There was no significant difference between the groups regarding acute effects of DBS-STN on the motor score of the Unified Parkinson's Disease Rating Scale part III (UPDRS III). Time course evolution of UPDRS the motor score (p < 0.0001) and axial score (p = 0.0001) assessed postoperatively in "on" medication and "on" stimulation conditions appeared worse in old patients as compared to young patients. Improvement in the Schwab and England Scale score was better in young patients in "on" (p < 0.0003) and "off" state (p < 0.001). Quality of life assessed with the 39-item Parkinson's Disease Questionnaire showed an improvement in subscales evaluating mobility (p < 0.0001), activities of daily life (p < 0.0001), emotion and stigma (p = 0.0004), cognition (p < 0.0074), and communication (p = 0.0029) in young patients as compared to old patients. Side effects were similar in the two groups.. Although deep brain stimulation in the subthalamic nucleus reduces motor complications equally in both groups of patients, postoperative quality of life improved only in young patients.

Topics: Activities of Daily Living; Age Factors; Aged; Antiparkinson Agents; Bipolar Disorder; Catechols; Cognition; Combined Modality Therapy; Communication; Deep Brain Stimulation; Dysarthria; Electrodes, Implanted; Emotions; Female; Humans; Levodopa; Male; Middle Aged; Movement; Neuropsychological Tests; Nitriles; Parkinson Disease; Pergolide; Prejudice; Quality of Life; Severity of Illness Index; Subthalamic Nucleus; Treatment Outcome; Weight Gain

Topics: Antiparkinson Agents; Carbon; Catechol O-Methyltransferase Inhibitors; Catechols; Folic Acid; Humans; Hyperhomocysteinemia; Levodopa; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; S-Adenosylmethionine; Time Factors; Vitamin B 12; Vitamin B 6

Topics: Adolescent; Antiparkinson Agents; Bromocriptine; Catechols; Drug Therapy, Combination; Epilepsy; Female; Humans; Levodopa; Nitriles; Parkinson Disease; Pregnancy; Prenatal Exposure Delayed Effects

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.

Topics: Adult; Aged; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Combinations; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

Topics: Aged; Antiparkinson Agents; Catechols; Drug Synergism; Humans; Levodopa; Nitriles; Parkinson Disease; Quality of Life

Topics: Aged; Amantadine; Benzothiazoles; Catechols; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Humans; Iatrogenic Disease; Indoles; Levodopa; Male; Middle Aged; Neurology; Neuropharmacology; Neurotoxicity Syndromes; Nitriles; Parkinson Disease; Pramipexole; Selegiline; Thiazoles; Treatment Outcome

Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol-O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone (P=0.001) or in the control group (P=0.0001). Concentrations of serum vitamin B12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Sectional Studies; Drug Therapy, Combination; Enzyme Inhibitors; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Vitamin B 12

Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

Topics: Adult; Aged; Antiparkinson Agents; Benzothiazoles; Catechols; Databases, Factual; Dopamine Agonists; Humans; Indoles; Levodopa; Male; Mental Disorders; Middle Aged; Multiple System Atrophy; Nitriles; Parkinson Disease; Pramipexole; Sexual Dysfunctions, Psychological; Thiazoles

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.

Topics: Apomorphine; Catechol O-Methyltransferase Inhibitors; Catechols; Gas Chromatography-Mass Spectrometry; Humans; Nitriles; Parkinson Disease; Reproducibility of Results

The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomatic hepatic dysfunction in women with Parkinson disease. The patients were genotyped for the UDP-glucuronosyltransferase (UGT) 1A9 gene (which encodes the main COMT inhibitor-metabolizing enzyme), and found to carry mutations leading to defective glucuronidation activity. This suggests that UGT1A9 poor metabolizer genotype(s) may be a predisposing factor for COMT inhibitor-induced hepatotoxicity.

Topics: Adult; Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chemical and Drug Induced Liver Injury; DNA Mutational Analysis; Enzyme Inhibitors; Female; Genotype; Glucuronates; Glucuronosyltransferase; Humans; Liver; Liver Diseases; Middle Aged; Mutation; Nitriles; Nitrophenols; Parkinson Disease; Polymorphism, Genetic; Tolcapone; UDP-Glucuronosyltransferase 1A9

Topics: Catechols; Humans; Levodopa; Nitriles; Parkinson Disease; Product Surveillance, Postmarketing

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.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Patient Satisfaction; Product Surveillance, Postmarketing; Quality of Life; Treatment Outcome

Topics: Carbidopa; Catechols; Diarrhea; Dose-Response Relationship, Drug; Drug Combinations; Humans; Levodopa; Nausea; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Blister; Catechols; Diagnosis, Differential; Drug Eruptions; Humans; Male; Middle Aged; Nitriles; Parkinson Disease

Topics: Amantadine; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Catechols; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Levodopa; Nitriles; Parkinson 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.

Topics: Aged; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Catechols; Disability Evaluation; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Quality of Life; Surveys and Questionnaires

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

Topics: Aged; Antiparkinson Agents; Catechols; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Nitriles; Parkinson Disease; Sleep Disorders, Circadian Rhythm

We present a patient who suffered from sleep attacks after starting entacapone in addition to levodopa. Entacapone, a catechol-O-methyl transferase inhibitor, alters the pharmacokinetics of levodopa, leading to increase of levodopa concentration in plasma and brain. This mechanism is suspected to be involved in the pathophysiology of sleep attacks in this case.

Topics: Aged; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Disorders of Excessive Somnolence; Humans; Male; Nitriles; Parkinson Disease; Sleep Disorders, Circadian Rhythm

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.

Topics: Aged; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Time Factors; Treatment Outcome

As well as the significant clinical effects of Parkinson's disease (PD), the disease places a high economic burden on society. Given the scarcity of health care resources, it is becoming increasingly necessary to demonstrate that new therapies for PD provide value for money in comparison with other potential interventions. This paper outlines the basic techniques of cost-effectiveness analysis and its application to PD. These techniques are illustrated by a recent economic evaluation of entacapone for use in Canada.

Topics: Antiparkinson Agents; Canada; Catechols; Cost-Benefit Analysis; Drug Costs; Humans; Nitriles; Parkinson Disease

We compared--retrospectively--the effects of a 3-month therapy with catechol- O-methyltransferase (COMT) inhibitors tolcapone (100 mg, t.i.d.) and entacapone (200 mg, t.i.d.), on L-DOPA metabolism in two groups of parkinsonian patients with motor fluctuations. Plasma and platelets concentrations of L-DOPA and its direct metabolites, dopamine and 3- O-methyldopa (3-OMD), were measured before starting treatment, after two weeks and at the end of treatment. Patients treated with tolcapone showed significant increases in plasma and platelet L-DOPA levels and marked reduction of plasma and platelet 3-OMD levels, both at short- and long-term. Entacapone did not modify L-DOPA levels, while inducing a less marked reduction of plasma and platelet 3-OMD concentrations, with respect to tolcapone, at both time points. Both drugs were similarly effective in increasing plasma and platelet levels of dopamine. These results confirm the different profiles of activity of the two drugs, with tolcapone proving more effective on both the intra- and extra-cellular levels of L-DOPA and 3-OMD.

Topics: Age Factors; Age of Onset; Aged; Antiparkinson Agents; Benzophenones; Blood Platelets; Catechols; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Retrospective Studies; Sex Characteristics; Tolcapone; Tyrosine; Up-Regulation

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.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Catechols; Confidence Intervals; Drug Therapy, Combination; Female; Humans; Internationality; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Prospective Studies

Since January 2000 we have administered entacapone (200 mg) to 75 patients with severe Parkinson's disease in combination with their routine levodopa dose. At baseline the mean UPDRS (item III) score was 38+/-6. After 3 months of entacapone therapy the patients presented a significant improvement of motor fluctuations; the mean UPDRS score (item III) was 20+/-4. This improvement was also statistically significant after 2 years of entacapone therapy.

Topics: Antiparkinson Agents; Catechols; Drug Therapy, Combination; Follow-Up Studies; Humans; Levodopa; Motor Activity; Neurologic Examination; Nitriles; Parkinson Disease; Prospective Studies; Time Factors

Topics: Catechols; Dopamine Agents; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitriles; Parkinson Disease; Time Factors

The treatment of idiopathic Parkinson's disease becomes rather difficult if levodopa-induced late complications such as motor fluctuations or dyskinesias occur. This prospective and open study shows that an add-on therapy with entacapone can significantly lower wearing-off and end-of-dose akinesia. This treatment is well tolerated and easy to perform.

Topics: Aged; Antiparkinson Agents; Catechols; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Motor Skills; Neurologic Examination; Nitriles; Parkinson Disease; Prospective Studies

We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports.

Topics: Aged; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Female; Humans; Liver Function Tests; Nitriles; Parkinson Disease

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.

Topics: Aged; Antiparkinson Agents; Brain; Catechol O-Methyltransferase; Catechols; Dihydroxyphenylalanine; Female; Humans; Levodopa; Male; Middle Aged; Movement; Nitriles; Parkinson Disease; Time Factors; Tomography, Emission-Computed

[corrected] Entacapone was given to try to improve the motor complications in eight patients with Parkinson's disease (PD) treated chronically with levodopa, with daily severe motor fluctuations and dyskinesias.. We introduced entacapone (200 mg added to every dose of levodopa) to 8 parkinsonian patients (mean age: 68.25 +/- 2.3; range: 68-72; mean PD duration: 10.4 +/- 2.7 years) treated with oral levodopa, plus a dopa-decarboxylase inhibitor (mean dose: 706.25 +/- 2.3 mg/day; mean period of levodopa-treatment; 9 +/- 2.3 years). Dyskinesias were present in all patients (chorea: 8 patients; "off"--dystonia: 4; byphasic dyskinesias: 3). The type and duration (time "on" and "off") of fluctuations was categorized on the "on-off" charts drawn up by the patients or their relatives, and observation by the investigators after the introduction of entacapone. One patient, with severe impairment with entacapone, was evaluated (motor response) during i.v. apomorphine infusion (40 mg, during 3 hours).. The combination of levodopa and entacapone was associated with a net increase in "off" time in all patients (from 5.8 +/- 1.2 h to 12.4 +/- 4.4 h) without change in the URPD. In the patient studied with i.v. apomorphine, "off" periods appeared during the infusion.. These findings suggest that increased daily levodopa consumption may reduce striatal responsiveness to dopaminergic stimulation in severe parkinsonian patients. These data should be considered when planning the treatment strategy of complex parkinsonian patients.

Topics: Aged; Antiparkinson Agents; Apomorphine; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Drug Therapy, Combination; Dyskinesias; Humans; Levodopa; Nitriles; Parkinson Disease

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Topics: Animals; Antiparkinson Agents; Benzophenones; Body Temperature; Catechols; Dose-Response Relationship, Drug; Drug Administration Routes; Enzymes; Liver; Male; Nitriles; Nitrophenols; Parkinson Disease; Rats; Rats, Sprague-Dawley; Survival Rate; Tolcapone

Topics: Adult; Age Factors; Aged; Antiparkinson Agents; Catechols; Depressive Disorder; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Follow-Up Studies; Humans; Indoles; Levodopa; Lewy Body Disease; Neuroprotective Agents; Nitriles; Parkinson Disease; Parkinsonian Disorders; Pergolide; Psychiatric Status Rating Scales; Psychotic Disorders; Time Factors

Topics: Antiparkinson Agents; Catechols; Double-Blind Method; Humans; Multicenter Studies as Topic; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic

Forty patients affected by severe Parkinson's disease (PD) were treated with tolcapone as an adjunctive therapy to L-DOPA, for 3-7 months, until this drug was discontinued because of side-effects (2 diarrhoea, one of them with orthostatic hypotension, 2 increments of liver enzymes) or because of mandatory indications of the European drugs authority. All patients, after 3-6 months of L-DOPA therapy adjustments, received entacapone for 3 months again followed by withdrawal. L-DOPA daily dosage was significantly reduced by tolcapone and entacapone (p = 0.01 and 0.05). "On" time was increased by 15% during tolcapone treatment (p < 0.05), and by 8% during entacapone treatment. "Off" time was decreased by 16% during tolcapone and by 7% during entacapone treatment. Entacapone was withdrawn in the same patient who experienced diarrhoea and orthostatic hypotension during tolcapone because of recurrence of side-effects, in 6 patients because of increment of dyskinesias (with hallucinations) and in 1 patients because of rhythmic, jerking myoclonus.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Substance Withdrawal Syndrome; Tolcapone

Topics: Antidepressive Agents; Antiparkinson Agents; Benzothiazoles; Brain Stem; Catechols; Depression; Dopamine Agonists; Humans; Levodopa; Nitriles; Parkinson Disease; Pramipexole; Selegiline; Thiazoles

Topics: Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Fees, Pharmaceutical; Humans; Nitriles; Parkinson Disease

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

After levodopa, dopaminergic agonists are the most powerful agents in idiopathic Parkinson's disease treatment. Used in monotherapy or rather in early combination with levodopa, they allow a dramatic reduction of long-term motor side effects of the latter: onset and peak-dose dyskinesias, early morning dystonias. Their gastro-intestinal (nauseas) and moreover psychiatric (confusion and hallucinations) side effects limit their use, notably in geriatric populations. Superiority of so-called "second generation" agonists (ropinirole, pramipexole) on "first generation" agonists (bromocriptine, pergolide) remains to be proved.

Topics: Aged; Antiparkinson Agents; Apomorphine; Benzothiazoles; Biological Availability; Bromocriptine; Catechols; Dopamine Agonists; Drug Combinations; Drug Hypersensitivity; Humans; Hypotension, Orthostatic; Indoles; Levodopa; Metabolic Clearance Rate; Nitriles; Parkinson Disease; Pergolide; Pramipexole; Selegiline; Thiazoles

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Catechols; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease; Tomography, Emission-Computed

Topics: Antiparkinson Agents; Benzothiazoles; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Enzyme Inhibitors; Humans; Indoles; Levodopa; Nitriles; Parkinson Disease; Pramipexole; Thiazoles

Topics: Amidines; Animals; Antiparkinson Agents; Benzophenones; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Female; Levodopa; Macaca mulatta; Motor Activity; Nitriles; Nitrophenols; Parkinson Disease; Pregnancy; Pyridones; Rats; Tolcapone

Topics: Animals; Blood-Brain Barrier; Catechol O-Methyltransferase; Catechols; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors; Humans; Nitriles; Parkinson Disease; Protein Folding; Protein Structure, Secondary

Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Brain; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Intestinal Absorption; Levodopa; Nitriles; Parkinson Disease; Tissue Distribution

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Catechol O-Methyltransferase Inhibitors; Catechols; Drug Administration Schedule; Humans; Nitriles; Parkinson Disease; Psychomotor Performance

The multistep assay of specific catechol-O-methyltransferase (COMT) activity in human erythrocytes was validated. Enzyme preparations from lysed erythrocytes were incubated with a substrate (3,4-dihydroxybenzoic acid) in the presence of Mg2+ and S-adenosylmethionine. The reaction products (vanillic acid and isovanillic acid) were analyzable by HPLC with electrochemical detection directly in the incubation medium after protein precipitation. The precision was calculated in order to define the random variability associated with the method by intra-assay and inter-assay relative standard deviations (RSDs) for the assays of both reaction products and protein. The intra-assay RDSs for the specific activities were between 4.8 and 11.9% (n = 5-6) at two levels of COMT activity. The inter-assay RSDs were between 6.4 and 14.2% (n = 5-6), respectively. The total variation was mostly caused by the protein assay and the HPLC assay, and contributions from the sample preparation and incubation steps were minor. Some results from the clinical application of the erythrocyte COMT assay are also reported. For both normal volunteers and patients having Parkinson's disease, a single 400 mg dose of entacapone, a peripherally acting COMT inhibitor, decreased the erythrocyte COMT activity. The application demonstrates that the assay was able to detect differences between the subjects and the effect of COMT inhibition in the clinical study.

Topics: Blood Proteins; Catechol O-Methyltransferase; Catechols; Chromatography, High Pressure Liquid; Electrochemistry; Enzyme Inhibitors; Enzyme Stability; Erythrocytes; Humans; Methylation; Nitriles; Parkinson Disease; Reproducibility of Results; Sensitivity and Specificity

Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.

Topics: Adult; Aged; Catechol O-Methyltransferase Inhibitors; Catechols; Chromatography, High Pressure Liquid; Corpus Striatum; Dihydroxyphenylalanine; Enzyme Inhibitors; Female; Fluorine Radioisotopes; Humans; Kinetics; Male; Middle Aged; Nitriles; Occipital Lobe; Parkinson Disease; Quality Control; Sensitivity and Specificity; Tomography, Emission-Computed; Tyrosine

L-Dopa is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.

Topics: Animals; Catechols; Corpus Striatum; Dihydroxyphenylalanine; Fluorine Radioisotopes; Levodopa; Macaca fascicularis; Magnetic Resonance Imaging; Male; Nitriles; Parkinson Disease; Tomography, Emission-Computed

We studied the effectiveness of OR-611 and OR-462, two novel inhibitors of the enzyme catechol-O-methyltransferase (COMT), on 3-O-methyldopa (OMD) formation in cynomolgus monkeys following intravenous levodopa administration. OR-611 dose-dependently reduced the area under the OMD concentration-vs-time curve, reduced maximum plasma OMD concentrations, delayed the time to peak OMD levels, reduced systemic levodopa clearance, and prolonged the elimination half-life of levodopa. Similar effects on peripheral levodopa metabolism were seen with doses of 15 mg/kg of OR-611 and OR-462, its sister compound, which lacks the ability to penetrate the central nervous system (CNS).

Topics: Animals; Catechol O-Methyltransferase Inhibitors; Catechols; Levodopa; Macaca fascicularis; Male; Nitriles; Parkinson Disease; Pentanones; Tyrosine