entacapone and Dyskinesia--Drug-Induced

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

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

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

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

Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Catechols; Disease Models, Animal; Dopamine Agonists; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Levodopa; Nitriles; Parkinson Disease, Secondary; Primates; Rats

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

Parkinson disease progression is associated with the development of levodopa short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose adjustment and adjunctive treatment with dopamine agonists form the major therapeutic strategies. Catechol O-methyltransferase inhibitors are also appropriate considerations, whereas other drugs, including selegiline, amantadine, anticholinergic agents, and propranolol, have a more minor role.

Topics: Amantadine; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Combinations; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease, Secondary; Propranolol; Randomized Controlled Trials as Topic; Selegiline; 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

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

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

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

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

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

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

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

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L-DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low-dose L-DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol-O-methyltransferase (COMT) inhibition, as an add-on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Dyskinesia was established by chronic treatment with L-DOPA. Two doses of L-DOPA were identified - high-dose L-DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub-threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON-time), parkinsonism and dyskinesia were determined. The ON-time after LDh was ∼170 min and the ON-time after LDl alone (∼98 min) was not significantly different to vehicle (∼37 min). In combination with LDl, entacapone significantly increased the ON-time (5, 15 and 45 mg/kg being ∼123, ∼148 and ∼180 min, respectively). The ON-time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON-time that was compromised by disabling dyskinesia was ∼56% with LDh, it was only ∼31% with LDl/entacapone 45 mg/kg. In addition to the well-recognized action of COMT inhibition to reduce wearing-OFF, the data presented suggest that COMT inhibition in combination with low doses of L-DOPA has potential as a strategy to alleviate dyskinesia.

Topics: Animals; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Male; MPTP Poisoning; Nitriles

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; Catechols; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitriles; Parkinson Disease

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

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

More continuous delivery of l-3,4-dihydroxyphenylalanine (l-dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l-dopa regimens. We now investigate whether l-dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed motor disability and increased locomotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l-dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l-dopa BID or QID without entacapone produced only a minor further reversal of motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l-dopa BID or QID with entacapone also produced some further improvement in motor function with the combination of entacapone and l-dopa BID significantly improving motor disability compared to l-dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l-dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Catechols; Dopamine Agents; Dopamine Agonists; Drug Administration Schedule; Drug Synergism; Dyskinesia, Drug-Induced; Female; Indoles; Levodopa; Male; Motor Activity; Nitriles

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

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Carbidopa; Catechols; Dopamine Agents; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Injections, Subcutaneous; Levodopa; Locomotion; Male; MPTP Poisoning; Nitriles; Severity of Illness Index; Substantia Nigra; Time Factors

The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of "wearing-off" phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines "wearing-off" motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.

Topics: Animals; Benserazide; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Levodopa; Male; Nitriles; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Treatment Outcome

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

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

Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0-7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Carbidopa; Catechols; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Levodopa; Locomotion; Male; Nitriles; Parkinsonian Disorders; Pulse Therapy, Drug; Substantia Nigra; Time Factors

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

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agents; Dyskinesia, Drug-Induced; Enkephalins; Female; In Situ Hybridization; Levodopa; Macaca fascicularis; Male; Nitriles; Oligonucleotide Probes; Protein Precursors; Receptors, Purinergic P1; RNA, Messenger; Tachykinins