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Background: Levodopa-carbidopa intestinal gel (LCIG) is effective in the treatment of advanced Parkinson's disease (PD). However, the patients' profile that might benefit from treatment with LCIG has not been characterized., Objective: This retrospective study explored the influence of disease duration (DD) on the effectiveness of LCIG and identified factors associated with treatment discontinuation in a cohort of advanced PD patients., Methods: Patients initiating LCIG therapy between Jan-2006 and Dec-2011 in 18 Spanish centers were included. Effectiveness in treating motor symptoms (MSs), non-motor symptoms (NMSs), and adverse events (AEs) occurrence was compared in DD≥10 or <10 years and LCIG continuation/discontinuation groups. Factors associated with LCIG discontinuation were evaluated using univariate and multivariate analyses., Results: Overall, 177 PD patients were included (52.5% male; mean age 70.6±8.4 years; mean LCIG duration 35.6±18.6 months). Patients with DD≥10 years (n = 125) experienced less reduction in "off" time (-29%) than those with DD <10 years (-38%; n = 51; p = 0.021), and reported more severe AEs (32.8% vs. 17.6%; p = 0.043). DD did not significantly influence changes in NMSs or discontinuation rates. Fifty-four patients discontinued LCIG therapy, factors associated with discontinuation were higher percentages of waking day in the "off" state (OR, 1.028; 95% CI, 1.002-1.055; p = 0.0360) and in the "on" state with troublesome dyskinesia (OR, 1.032; 95% CI, 1.002-1.064; p = 0.0376) at baseline., Conclusions: Advanced PD patients with DD <10 years might benefit more from treatment with LCIG than patients with a longer DD. Although MSs severity at baseline was statistically associated with LCIG discontinuation, the probability was very low with little clinical significance.

Aim: To assess long-term effectiveness and tolerability of levodopa-carbidopa intestinal gel (LCIG) in Spanish patients with advanced Parkinson's disease., Patients & Methods: This was an observational, multicenter, cross-sectional, retrospective study., Results: Data of 177 patients were analyzed. LCIG treatment led to a reduction in the percentage of daily 'off' time (16.2 vs 47.6% before LCIG), an increase in the percentage of daily 'on' time without disabling dyskinesia (55.6 vs 21.6%). Most patients experienced improvements in freezing of gait, tremor, dizziness, fatigue or flat mood. Adverse events related to levodopa, gastrostomy and technical issues were reported in 36.2, 42.4 and 43.5% of patients, respectively., Conclusion: This study confirms the long-term effectiveness and safety profile of LCIG in patients with advanced Parkinson's disease.

Objective: To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease., Methods: The clinical response to a single oral dose of standard and controlled-release levodopa/carbidopa was assessed in 12 patients with Parkinson disease complicated with motor fluctuations and dyskinesias. Plasma concentrations of levodopa and large neutral amino acids were determined, and the theoretical central levodopa influx was calculated using a model based on competitive inhibition of substrates to cross the blood-brain barrier., Results: The mean (SD) central levodopa influxes at the onset of the antiparkinsonian clinical effect were 19.7 (10.9 x 10(-3) and 19.1 (7.4 x 10(-3) nmol min(-1) g(-)1 (P >0.1) for standard and controlled-release levodopa, respectively. The mean (SD) central levodopa influxes at the onset of choreic dyskinesias were 20.1 (8.2 x 10 (-3) and 19.9 (10.8 x 10(-3) nmol min (-1) g(-)1 (P 9 0.1) for standard and controlled-release levodopa, respectively. During the tests, choreic dyskinesias were associated with a central levodopa influx of 10 x 10(-3) nmol min(-1) g(-1) or greater, and foot dystonia occurred with a central levodopa influx less than 9 x 10(-3) nmol min(-1) g(-1)., Conclusions: The clinical response to levodopa in patients with advanced Parkinson disease may be related to central levodopa influx. We found no differences in the central levodopa influx threshold for clinical improvement with different levodopa formulations. The central levodopa influxes at the onset of choreic dyskinesias and antiparkinsonian effect were similar. Choreic dyskinesias and foot dystonia were associated with high and low central levodopa influx, respectively.

Levodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, alpha2 adrenergic, serotonergic (5HT1A, 5HT2A), opioid, histamine H3, adenosine A2A receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing., (Copyright 2007 Movement Disorder Society)

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

To assess the patterns of drug use in Parkinson's disease in Spain, information about the clinical characteristics and current treatment of 1803 parkinsonian patients was obtained from a nationwide survey, involving 241 physicians with practice based on the different assistance levels of the Spanish National Healthcare System. Approximately 90% of the patients were treated with levodopa, regardless of the characteristics of their physicians, but the use of the other available antiparkinsonian treatments was highly influenced by the medical specialty and interest in movement disorders of the prescribing doctors., (Copyright 2002 Movement Disorder Society)

To identify putative risk factors for levodopa-induced dyskinesias we studied the effect of several clinical variables on the occurrence of dyskinesias in a series of 168 consecutive patients with Parkinson's disease treated for at least 6 months with levodopa. Of these, 108 (64%) developed dyskinesias after a mean duration of levodopa treatment of 51.4 +/- 43.3 months. Patients tended to suffer dyskinesias on the side of the body first affected by Parkinson's disease. The overall probability of developing dyskinesias increased with levodopa treatment duration, about 10% per year during the first 7 years. Univariate and multivariate logistic regression analysis identified the age at onset of Parkinson's disease (OR 0.923; 95% CI 0.883-0.964) and the initial levodopa dose (mean dose of the first 6 months of treatment; OR 1.004; 95% CI 1.002-1.006) as the main independent predictors. Survival curves showed that onset of Parkinson's disease at age 50 years or before (logrank, P < 0.05) and initial levodopa treatment with more than 600 mg/day (logrank, P < 0.05) were associated with a higher risk for the appearance of dyskinesias.

Background: Controlled-release levodopa-carbidopa (CRLC) improves some aspects of Parkinson's disease (PD) in patients previously treated with standard levodopa formulations (SL). However, little is known about the effect of this strategy on the health-related quality of life (QoL)., Objective: To assess the QoL and clinical changes due to the conversion of treatment from SL to CRLC in patients with mild to moderate PD., Patients and Methods: Through the Nottingham Health Profile (NHP), QoL was measured in 276 non-selected PD patients included in a multicenter, open study. Guidelines for switching to CRLC and optimization of treatment were given. Assessment of patients was carried out by means of the Hoehn & Yahr, UPDRS, and Schwab & England scales, and questionnaires for dyskinesias and sleep. Examination of the NHP-Spanish Version-scaling properties by fitting data to the Rasch model, disclosed that 3 NHP scales (Emotional reactions, Pain, and Physical mobility) and the NHP distress index (NHPD) were suitable for efficacy analysis., Results: Comparison of scores at baseline and at the end of the study showed significant improvement (paired Student t-test, p < 0.0001) in all these four scales associated with the change to CRLC. Responsiveness to change of the NHP was high. In the present study, changes in QoL were not contingent to baseline factors such as age, gender, stage of disease or ADL capabilities., Conclusion: Conversion to CRLC significantly improves the QoL of patients with mild to moderate PD.

Entacapone (Comtan) is a potent, selective inhibitor of peripheral catechol-O-methyltransferase (COMT) with therapeutic potential as an adjuvant to levodopa therapy in patients with Parkinson's disease. Entacapone decreases peripheral conversion of levodopa to 3-O-methyldopa increasing central extracellular levodopa and consequently striatal dopamine concentrations. At doses of 200 mg 2 to 10 times daily coadministered with levodopa/carbidopa or levodopa/benserazide entacapone may increase the duration of clinical response both after the first single dose and after repeated dosing in patients with end-of-dose fluctuations. At this dosage, it has a time to peak-plasma concentration of 1.2 hours and an elimination half life of 3.4 hours. In two multicentric, long-term (approximately 6 month), randomized and placebo-controlled studies, the duration of 'on' time was increased and the duration of 'off time' was decreased in patients who received adjunctive entacapone therapy. Moreover, patients randomized to entacapone reduced their levodopa requirements. In these and other phase III studies, entacapone was generally well tolerated, with few reported adverse events, mainly dyskinesias and gastrointestinal disorders. The dyskinesias were generally well controlled by decreasing the mean daily levodopa dose. Entacapone appears as a clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations.

We present the results of an open, prospective, multicentric study including 450 patients with mild to moderate Parkinson's disease (PD) converted from standard Sinemet to Sinemet CR (controlled release; Dupont Pharma, Pavia, Italy). Patients with complex fluctuations and diphasic dyskinesias were excluded and the conversion was made after some recommendations, depending on the clinical problems and the daily dosage and administration schedule of standard (STD) Sinemet. The condition of more than 60% of the patients improved after the change and 80% of them preferred the CR formulation by the end of the study. We found a moderate, but significant, improvement in most of the efficacy parameters used, such as the Unified Parkinson's Disease Rating Scale (UPDRS), the Schawb and England scale, and dyskinesias and sleep questionnaires. Forty-five patients (10%) discontinued the study due to adverse effects (mainly gastrointestinal disturbances, functional deterioration, and dyskinesias). We conclude that Sinemet CR is a useful and safe therapeutic option in patients with mild and moderate PD. Selection of the patients is the most important outcome factor.

Conversion from standard levodopa to Sinemet CR was performed in a series of 450 patients with Parkinson's disease. Of these, 299 experienced motor complications (group A) and 151 showed stable motor response (group B). There was significant improvement in various parameters of efficacy (Unified Parkinson's Disease Rating Scale, Hoehn-Yahr staging, Schwab-England scale) particularly in those related to functional aspects such as activities of daily living of the Unified Parkinson's Disease Rating Scale, sleep questionnaires and the Nottingham Health Profile. Adverse effects were usually mild or moderate, and only 10% of patients discontinued Sinemet CR due to side effects. Sinemet CR treatment was preferred by 81% of patients in group A and by 73.8% of patients in group B.

Dyskinesias are one of most frequent motor complications of parkinsonian patients on chronic levodopa treatment. This article reviews their clinical characteristics, risk factors, pathophysiology and possible therapeutical approaches.

We studied the histories of 173 patients with Parkinson's disease (1985-1987) chronically treated with levodopa + dopa decarboxylase inhibitor. Ninety four patients had daily motor fluctuations and 79 showed stable motor response. The most significant differences between fluctuating and stable patients were given by age at disease onset and duration of levodopa therapy. Patient with disease onset before 60 had a greater risk (p less than 0.001) of developing fluctuations. Delaying the initiation of levodopa treatment was not associated with a smaller incidence of fluctuations.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.