Differential progression of motor impairment in levodopa-treated Parkinson's disease.

OBJECTIVE: To monitor comparative progression of clinical impairment over 4 years in patients with Parkinson's disease (PD) who present on levodopa at two different levels of Hoehn and Yahr (HY) stages, II and III. BACKGROUND: The rate of clinical impairment progression in patients with PD being treated with levodopa has not been studied in detail using current, standardized assessment tools. Sample size estimates for all levodopa adjunctive treatment studies and proper definition of study groups require a solid estimate of longitudinal motor impairment progression. DESIGN/METHODS: From our computer database, we identified two groups of patients with PD being treated with levodopa based on their initial HY stage at presentation to our center (II or III). Fifty randomly selected subjects in each stage were monitored in the ON state with annual Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, dyskinesia ratings, and antiparkinsonian medication doses using a repeated measures analysis of variance. RESULTS: The stage II and stage III subjects had similar disease duration. In stage II subjects, parkinsonian impairment was maintained without progression over 4 years, but in association with significantly higher dyskinesia scores and dopaminergic medication doses. In stage III subjects, UPDRS motor scores deteriorated despite more medication and increased dyskinesias. Of the established six factors comprising the UPDRS motor scale, bradykinesia accounted for the increased impairment. Initial UPDRS motor score and disease duration did not influence progression of motor impairment. CONCLUSION: In subjects with similar disease duration, progression of PD motor impairment differs significantly between stage II and stage III subjects over 4 years. Whereas in stage II subjects, parkinsonian impairment can be stabilized at the expense of increased dyskinesia and dopaminergic drugs, once subjects reach stage III, motor impairment progresses. Power estimates and sample size calculations for these groups of patients should be calculated separately.     

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.     

Parkinson’s disease: Is the initial treatment established?

Recent studies have suggested that initial dopamine agonist therapy with pramipexole or ropinirole may slow the progression of Parkinson’s disease (PD) and also reduce the subsequent risk of levodopa motor complications. This presumed effect on PD progression, however, could be artifactual, resulting from the influence of chronic drug treatment on regulation of dopamine system proteins. With respect to levodopa motor complications, there is no dispute that pramipexole and ropinirole are effective in reducing levodopa dyskinesias and motor fluctuations; however, it is not clear that they must be started early, as opposed to initiation only after the levodopa complications develop. Levodopa therapy has numerous advantages that include greater efficacy, much lesser expense, simpler administration, and a lower frequency of hallucinosis and somnolence. Carbidopa/levodopa, pramipexole, and ropinirole are all appropriate first choices in the treatment of PD.     

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.     

The evolution of pharmacological treatment for Parkinson's disease

Since the introduction of levodopa therapy in the 60's, there has yet to be a more efficacious drug identified for the symptomatic treatment of Parkinson's disease (PD). Perhaps more importantly, there has been little to no success finding agents that have proven effective in protecting against neurodegeneration. In fact, recent development efforts have been primarily directed at stabilizing the side effects (wearing off, drug-induced dyskinesias, motor fluctuations) that accompany prolonged levodopa therapy, such as catechol O-methyltransferase inhibiton to combat the side effects of levodopa therapy. This review also examines alternative strategies to levodopa therapy, including potential adjuncts therapies, recent patents and future directions to be evaluated for neuroprotection. While dopamine agonists are inferior to levodopa in controlling motor symptoms, potential benefits and drawbacks with this class of drugs are presented. Potential neuroprotective agents such as monoamine oxidase-B inhibitors are also examined for their therapeutic benefit as well as their potential to slow disease progression. Neuroprotection will continue to be an important area of research in CNS drug development.     

A new look at levodopa based on the ELLDOPA study

Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing oxidative stress and possibly enhance neurodegeneration of dopaminergic neurons. Though widely debated and without definite evidence, this possibility was sufficient to make some clinicians have further reason to delay the start of levodopa therapy. The ELLDOPA study was created to test this hypothesis. The clinical component of the study failed to find an enhancement of PD symptoms after levodopa was withdrawn following 40 weeks of levodopa therapy. Rather, the clinical results indicated that the symptoms had progressed much less than placebo, and in a dose-response manner. This suggests that levodopa may actually have neuroprotective properties. The uncertainty that a 2-week withdrawal of levodopa may not have entirely eliminated its symptomatic benefit and the discordant results of the neuroimaging component of the ELLDOPA study have created even more uncertainty that levodopa is neuroprotective. A survey of neurologists who treat PD patients showed that the vast majority of these clinicians do not believe levodopa is neuroprotective, and they remain concerned about the drug's likelihood of inducing motor complications. Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach.     

Levodopa "drug holiday" with amantadine infusions as a treatment of complications in Parkinson's disease.

The loss of beneficial effect of levodopa due to progression of the disease and alteration of receptor sensitivity makes the treatment of the advanced stadium of Parkinson's disease (PD) very difficult. In the past "drug holidays" was used in attempt to resensitize dopamine receptors in the striatum to make the treatment easier. However possible serious complications like neuroleptical malignant-like syndrome discouraged the use of this procedure. Intravenous administration of amantadine, another antiparkinsonian medication during "drug holidays," procedure could be a solution for this problem. We studied 12 patients with PD suffering from complication of the therapy. Daily dose of Levodopa used as monotherapy before amantadine infusions ranged between 700 and 2,000 mg. Levodopa was discontinued for 3 days and during that time amantadine sulfate intravenous was administrated. After "drug holidays" levodopa in the same dose as before treatment was resumed. An assessment of the parkinsonian condition was performed with Unified Parkinson's Disease Rating Scale before "drug holidays" 2 days after and 1, 2, 3, 4, 5, 6 months later. The follow-up study demonstrated a significant improvement both in the motor condition and complication of therapy. The improvement after therapy was maintained up to 4 month. The levodopa "drug holidays" with amantadine infusion is a valuable option in the therapy of advanced stages of PD.     

Ciągła stymulacja dopaminergiczna – doświadczenia kliniczne

Both disease progression and pulsatile stimulation of dopaminergic receptors are responsible for development of fluctuations and dyskinesia in about 50% of patients with Parkinson disease (PD) after 4-6 years of therapy with levodopa. In order to prevent motor complications, the ideal therapy should secure continuous dopaminergic stimulation (CDS). The concept of CDS is supported by the results of both experimental and clinical studies. Several treatment options are available to achieve CDS. Dopamine agonists have a longer half-life than levodopa and the development of dyskinesia is delayed when they are used as monotherapy in early PD. Continuous delivery of agonists can be improved with prolonged-release oral preparations, a transdermal delivery system or continuous subcutaneous infusion. Continuous enteral infusion of levodopa is another way to achieve CDS and it is very effective in reducing motor complications in advanced PD.     

Dopamine agonists: the treatment for Parkinson's disease in the XXI century?

Levodopa combined with a peripheral dopa-decarboxylase inhibitor (DCI) has been considered the therapy of choice for Parkinson's disease (PD). Levodopa is nearly always effective, but has a high incidence of adverse effects with long term use, including response fluctuations (on/off phenomena) and dyskinesias. Dopaminergic agonists, acting directly at the receptor level, would be able to decrease the incidence of these motor complications.In progressive neurodegenerative diseases, such as PD, modification of the rate of disease progression (often referred to as neuroprotection) is currently a highly debated topic. Increased oxidative stress is thought to be involved in nigral cell death, that is characteristic of PD. This oxidative stress may be further exacerbated by levodopa therapy. These mechanisms have been proven in vitro and animal models, but it's relevance in humans remains speculative.Based on the considerations above, the emerging therapeutic strategies for PD advocate early use of dopamine agonists in the treatment of PD. A number of recent well-controlled studies have proven the efficacy of dopamine agonists used as monotherapy. Moreover, as predicted by animal studies, on the long term, dopaminergic agonists induce significantly less motor complications than levodopa.In the last 2years, three new dopamine agonists have been launched, including ropinirole, pramipexole and cabergoline. These new agonists have been added, as therapeutical options to well-established drugs, like pergolide, bromocriptine or talipexole. The recently launched compounds have proven efficacy in monotherapy and as adjunctive therapy to levodopa. Unfortunately, only a very limited amount of comparative data among the different agonists is available. Pergolide has proven to be a superior drug to bromocriptine as adjunctive therapy to levodopa in a significant number of studies and is considered the gold standard dopamine agonist. Nevertheless, none of the recently launched compounds has compared itself against pergolide.A comparison of monotherapy trials is difficult, because of differences in design and populations. In a recently completed trial pergolide was statistically significantly better than placebo in all the efficacy parameters tested, with 57% of pergolide treated patients improving over 30% in the motor section of the UPDRS, as compared to 17% in the placebo arm. Interestingly, these results were obtained in the absence of any other antiparkinsonian drug during the trial. Recent monotherapy trials done with ropinirole and pramipexole achieved also significant improvements as monotherapy, but in these cases selegeline, a drug that causes a symptomatic improvement in PD, was allowed as co-medications during the trial. Not all trials used the same efficacy measures, i.e. monotherapy trials with pergolide and ropinirole used a "responder" based analysis (responder were all patients that improved 30% or more on the motor section of UPDRS), as well as a baseline to endpoint improvement in motor scores. Pramipexole monotherapy trials used only the latter approach, which is clinically less powerful than a responder analysis.Even with the difficulties mentioned above, all the recent trials with dopamine agonists have proven that these drugs are a useful symptomatic long term treatment for PD with or without levodopa and that the early use of dopamine agonists reduces the incidence of motor complications as compared to levodopa.     

Levodopa response in dementia with lewy bodies: A 1-year follow-up study

PurposeTo evaluate levodopa responsiveness in patients with probable dementia with Lewy bodies (DLB) compared to early Parkinson’s disease (PD) patients.MethodsTwenty four cases with DLB and 21 with PD underwent a baseline assessment with UPDRS (sub-item II and III) and an acute levodopa challenge test. Positive response to acute levodopa test was defined as an improvement of at least 15% in the tapping test, and at least 25% in the walking test and rigidity or tremor score. Subsequently, all patients were treated continuously with levodopa and evaluated after 6 and 12 months by means of UPDRS II/III.ResultsPositive response to the acute levodopa test was observed in 55% of DLB patients (acute DLB responders), and in 90% of PD patients (acute PD responders). Acute DLB responders showed increased latency, and reduction of both duration and amplitude of response to acute levodopa in comparison with acute PD responders. At the 6-month follow-up visit, acute DLB responders showed a greater motor benefit compared with acute DLB non-responders. This improvement was similar to that observed in PD patients. However, at 1-year follow-up acute DLB responders showed a faster worsening of UPDRS III scores compared with acute PD responders, implying a reduction of levodopa efficacy.ConclusionsPositive response to acute levodopa test can occur in DLB patients and may be predictive of long-term benefit of chronic levodopa therapy, although the motor improvement is less impressive than in PD patients.     

Therapeutic prospects for Parkinson disease

Dopaminergic therapies such as levodopa have provided benefit for millions of patients with Parkinson's disease (PD) and revolutionized the treatment of this disorder. However patients continue to experience disability despite the best of modern treatment. Dopaminergic and surgical therapies are associated with potentially serious side effects. Non‐motor and non‐dopaminergic features such as freezing, falling, and dementia are not adequately controlled with available medications and represent the major source of disability for advanced patients. And, the disease continues to relentlessly progress. Major therapeutic unmet needs include a dopaminergic therapy that is not associated with serious side effects, a therapy that addresses the non‐motor and non‐dopaminergic features of the disease, and a disease‐modifying therapy that slows or stops disease progression. This review will consider current attempts to address these issues and the obstacles that must be overcome in order to develop more effective therapies for PD. Ann Neurol 2013;74:337–347     

Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up

BACKGROUND: The short term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced levodopa responsive Parkinson's disease (PD) are well documented, but long term benefits are still uncertain. OBJECTIVES: This study provides a 5 year follow up of PD patients treated with stimulation of the STN. METHODS: Thirty seven consecutive patients with PD treated with bilateral STN stimulation were assessed prospectively 6, 24, and 60 months after neurosurgery. Parkinsonian motor disability was evaluated with and without levodopa treatment, with and without bilateral STN stimulation. Neuropsychological and mood assessments included the Mattis Dementia Rating Scale, the frontal score, and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: No severe peri- or immediate postoperative side effects were observed. Six patients died and one was lost to follow up. Five years after neurosurgery: (i) activity of daily living (Unified Parkinson Disease Rating Scale (UPDRS) II) was improved by stimulation of the STN by 40% ("off" drug) and 60% ("on" drug); (ii) parkinsonian motor disability (UPDRS III) was improved by 54% ("off" drug) and 73% ("on" drug); (iii) the severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%. The MADRS was unchanged, but cognitive performance declined significantly. Persisting adverse effects included eyelid opening apraxia, weight gain, addiction to levodopa treatment, hypomania and disinhibition, depression, dysarthria, dyskinesias, and apathy. CONCLUSIONS: Despite moderate motor and cognitive decline, probably due to disease progression, the marked improvement in motor function observed postoperatively was sustained 5 years after neurosurgery.     

Pergolide in the treatment of patients with early and advanced Parkinson's disease

Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.     

Entacapone in the treatment of Parkinson's disease

BACKGROUND: 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. RECENT DEVELOPMENTS: 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.     

Levodopa normalizes exercise related cortico-motoneuron excitability abnormalities in Parkinson's disease.

OBJECTIVES: To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa. METHODS: Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability. RESULTS: PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa. CONCLUSIONS: Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise. SIGNIFICANCE: This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.     

Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications?

Levodopa-carbidopa (LD) in low dosages adequately controls symptoms in most patients with Parkinson's disease and delays the appearance of fluctuations and dyskinesias. It has been suggested that early combination therapy with bromocriptine and levodopa delays or prevents the onset of late treatment complication associated with LD monotherapy in Parkinson's disease. We have conducted this study to assess the possible benefit of combined therapy compared with levodopa monotherapy. Seventy-eight previously untreated patients with Parkinson's disease were recruited over a period of 54 months and randomly allocated to either a levodopa-carbidopa (LD) Group or a levodopa-carbidopa in combination with low-dose bromocriptine (LD-Br) Group. The appearance of motor complications determined the end point of the study. We gradually increased the doses of bromocriptine (2.5–15 mg/d) or levodopa (125–500 mg/d) until the maximum "on" time was reached. In six patients, the doses of levodopa had to be increased up to the optimal dose (625–1000 mg/day). In the last evaluation the on-time and parkinsonian disability were similar in both treatment groups. We did not find statistically significant differences in the frequency of motor complications when comparing the two groups of treatment. Our study suggests that early combination of levodopa and bromocriptine does not confer any clinical benefit over levodopa alone in treating early Parkinson's disease, nor will it influence the evolution of the disease.     

Effect of late initiation of levodopa treatment in patients with long-standing Parkinson's disease

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.     

Evidence-based initiation of dopaminergic therapy in Parkinson's disease

The mainstay of Parkinson's disease (PD) therapy is levodopa. The crucial question is when should levodopa be initiated? Levodopa provides the most potent motor benefit for PD, but longer term use is marked by the development of motor complications such as fluctuations in response and involuntary motor movements. Dopamine agonists reduce the risk of development of motor complications in the 5-year term. However, side effects may change the risk-benefit of dopamine agonist first strategies. In the following, the evidence for levodopa and dopamine agonists as initial monotherapy for PD is examined.

     

Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease

The objective of this study was to compare the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease (PD). Tolcapone and entacapone are two currently available catechol- O -methyltransferase inhibitors that have demonstrated efficacy in the treatment of advanced PD. There are little published data on long-term experience and no direct comparisons. We compared the results of two separate, simultaneous, long-term open label extensions, one for tolcapone and the other for entacapone. The inclusion/exclusion criteria were similar. Data were collected prospectively at 6, 12, 24, and 36 months. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS) total score, subscores, items 32 (duration of dyskinesia) and 39 (duration of "off" time), and levodopa dose. The two groups were compared using a Mann-Whitney U test for change from baseline and analysis of variance. Tolerability was defined as the ability of patients to maintain therapy and was compared using a Kaplan-Meier analysis. Eleven patients enrolled in the entacapone study and 14 in the tolcapone study. The tolcapone group had more severe disease with significantly higher UPDRS motor score, duration of "off," and levodopa dose requirement. Tolcapone was more effective in lowering UPDRS motor and complication subscores, duration of "off" time, and levodopa doses. UPDRS motor scores and change in levodopa dose in the tolcapone group remained below baseline level for 36 months; however, they were above baseline in the entacapone group from 6 months on. Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.     

Optimising levodopa therapy for the management of Parkinson's disease

Levodopa remains unrivalled in providing symptomatic benefit for the treatment of Parkinson's disease (PD). However, wearing-off and dyskinesia have been associated with chronic therapy using traditional levodopa formulations. The onset of these motor complications arises, in part, due to the limited pharmacokinetic profile of traditional levodopa and not as a direct consequence of levodopa per se. Clinical trials addressing these issues have suggested that providing less pulsatile and more continuous dopaminergic stimulation by improving the pharmacokinetic profile of levodopa may overcome the onset of these motor complications. It can, therefore, be suggested that the onset of dyskinesia may be prolonged if levodopa is administered in a more continuous manner by administering it as a combination of levodopa/DDCI and COMT inhibitor.