Long-term Levodopa Therapy Research Articles

Genetic, temporal and diurnal influences on L-dopa-induced dyskinesia in the 6-OHDA model

Current treatments for Parkinson's disease rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including the onset of abnormal movements (‘dyskinesia’). The neural mechanisms that underlie dyskinesia are far from clear but they have been associated with pulsatile stimulation of dopamine receptors, downstream changes in proteins and genes, and abnormalities in non-dopamine transmitter systems. However, there has been no pathophysiological explanation for the worsening motor symptoms in the afternoon and evening reported by Parkinsonian patients in long-term L-dopa therapy, and no direct relationship has been found with the pharmacokinetics of the drug. Moreover, there continues to be a debate about whether the development of dyskinesias in patients is dependent upon the duration of L-dopa treatment or on the degree of denervation/advanced stage of the disease, both factors that are difficult to resolve experimentally in the human disease. The objective of this study was to characterise, in an animal model, factors that predispose some individuals to develop dyskinesia after a prolonged treatment with L-dopa, whereas others continue to exhibit symptom alleviation without the side effects. We report that none of the parameters studied – genetic variation within and between strains, delay of treatment onset after lesion, or time of day of the drug treatment – were found to influence directly the formation of dyskinesias after L-dopa treatment. We conclude that a complex combination of individual factors are likely to interact to regulate the onset and development of abnormal movements in some animals but not others.

Rotigotine transdermal system for the treatment of Parkinson's disease

Background: Levodopa has been the cornerstone of the treatment of Parkinson's disease (PD) for >30 years, but long-term levodopa therapy is associated with development of such motor complications as motor fluctuations, dyskinesias, and drug-induced involuntary movements. Rotigotine is a dopamine agonist with high affinity for the D 2 receptor. Rotigotine transdermal system, the first such system approved by the US Food and Drug Administration for the management of PD, has been formulated to deliver a consistent concentration of drug to the bloodstream with the goal of minimizing the complications associated with pulsatile dosing. Objective: This article reviews the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and efficacy of rotigotine transdermal system in the treatment of PD. Methods: MEDLINE (1966-April 2008) and International Pharmaceutical Abstracts (1971-April 2008) were searched using the term rotigotine. All prospective, randomized clinical efficacy trials in humans were included. The reference lists of the identified articles were reviewed for additional publications. Results: In clinical trials, rotigotine transdermal system at doses ranging from 4.5 to 67 mg/d was associated with significant clinical benefit in patients with early and advanced PD. In 4 randomized, doubleblind, placebo-controlled trials of 6 months' duration, patients receiving rotigotine transdermal system had significant improvements on the Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) that ranged from -0.3 to -4.2, compared with +0.92 to -2 for placebo ( P < 0.001, rotigotine transdermal system vs placebo). In one trial that included pramipexole as an active comparator, the change in UPDRS II at 6 months was -4.2 in the rotigotine transdermal system group and -4.6 in the pramipexole group ( P = NS, rotigotine transdermal system vs pramipexole). Changes on the UPDRS III (motor examination) at 6 months ranged from -3.58 to -8.7 with rotigotine transdermal system, compared with +0.38 to -4.3 in the placebo group and -10.3 in the pramipexole group ( P < 0.001 vs placebo; P = NS vs pramipexole). The change in “off” time at 6 months ranged from -2.1 to -2.7 hours with rotigotine transdermal system, compared with -0.9 hour with placebo and -2.8 hours with pramipexole ( P < 0.001 vs placebo; P = NS vs pramipexole). The proportion of patients achieving a >30% reduction in “off” time ranged from 55.1% to 59.7% of patients receiving rotigotine transdermal system, compared with 34.5% to 35.0% of patients receiving placebo and 67.0% of patients receiving pramipexole (P<0.001 vs placebo; P = NS vs pramipexole). The most commonly reported adverse event was application-site reaction, occurring in 9% to 46% of patients receiving rotigotine transdermal system, compared with 5% to 13% of patients receiving placebo. Other adverse events occurring in >20% of patients receiving rotigotine transdermal systemweresomnolence(8%\\2-33%)and nausea(12%-49%). Less than 5% of patients assigned to rotigotine transdermal system discontinued study medication because of an adverse drug event. Conclusions: The available evidence suggests that rotigotine transdermal system was effective compared with placebo in decreasing morbidity in patients with early and advanced PD. The most commonly reported adverse events associated with rotigotine transdermal system were application-site reaction, nausea, and somnolence. Additional clinical trials are needed to determine the long-term tolerability profile of rotigotine transdermal system and its clinical efficacy and tolerability compared with oral dopamine agonists.

Role of tolcapone in the treatment of Parkinson’s disease

For decades, the cornerstone of treatment for Parkinson’s disease (PD) has been levodopa, which provides a smooth clinical response early in the course of disease. However, many PD patients develop motor complications on long-term levodopa therapy. Catechol-O-methyltransferase (COMT) is a selective and widely distributed enzyme involved in the catabolism of levodopa. Tolcapone and entacapone are selective and potent COMT inhibitors that slow the metabolism of levodopa, thus prolonging its effects. While both drugs act peripherally, tolcapone also inhibits COMT in the CNS. Tolcapone has been shown to be an effective adjunct in the treatment of PD in Phase II and III clinical trials, improving motor fluctuations and reducing levodopa requirements. Rare reports of severe hepatotoxicity, however, limited tolcapone’s implementation in the treatment of PD. A reappraisal of the data for tolcapone treatment in PD has found that this risk is very small if proper hepatic monitoring guidelines are followed. This article reviews the pharmacology and clinical data on tolcapone, with particular focus on drug safety and the future role of tolcapone therapy in the treatment of PD.

Motor fluctuations in Parkinson's disease

Almost all patients with Parkinson's disease will eventually require levodopa during the course of their disease. The effectiveness of levodopa is evident, but earlier use and higher doses are causative of the emergence of motor fluctuations. About one half of patients develop motor fluctuations 4–6 years after starting levodopa therapy for parkinsonian symptoms. Peripheral and central pharmacokinetic mechanisms are related to motor fluctuations. It was reported that time to peak concentration (Tmax) and elimination half-life (T1/2) of levodopa decreased especially in patients with wearing-off (peripheral pharmacokinetics). On the other hand, there are several reports demonstrating no change in peripheral pharmacokinetics in patients on long-term levodopa therapy. The reduced capacity for presynaptic storage of dopamine by nigral neurons is believed to be another important factor responsible for motor fluctuations (central pharmacokinetics). In addition, a mathematical model that was recently established based on the hypothesis that dopamine release is subject to probabilistic variations in the quantity of dopamine has indicated that motor fluctuations might be explained by presynaptic mechanisms. On the other hand, several studies demonstrated that changes in postsynaptic mechanisms (pharmacodynamics) play an important role in shortening the duration of levodopa action in advanced stages. In clinical practice therapeutic strategies for motor fluctuations are focused on continuous dopaminergic stimulation at postsynaptic dopamine receptors. Once motor fluctuations appear, therapeutic regimens should be individualized to retain optimal control of the symptoms based on accurate assessment of each patient's levodopa cycle and responses to drugs. Symptom diaries kept by patients or caregivers are useful for this purpose.

Continuous dopaminergic stimulation: Is it the answer to the motor complications of Levodopa?

Continuous dopaminergic stimulation (CDS) is a treatment strategy hypothesized to avoid or reduce the motor complications of long-term levodopa therapy, motor fluctuations, and dyskinesia, by preventing or reversing sensitization induced by pulsatile dopaminergic stimulation. The CDS hypothesis is itself based on several hypotheses. First, tonic dopaminergic stimulation is physiological. Second, sensitization is undesirable and should be reversed. Third, reduction of off time and dyskinesia can be induced simultaneously. Finally, clinical studies substantiate the CDS hypothesis. The evidence for these hypotheses is reviewed, and the need for randomized clinical trials that rigorously test the CDS hypothesis is emphasized.

It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson’s disease

Neuroleptic malignant-like syndrome (NMLS) is a rare but life threatening and important complication because of the withdrawal of long-term l-Dopa therapy in Parkinson's disease patients. In this case report, we review the pathophysiology, clinical features and treatment of this curable condition.

Pharmacokinetics of L-dopa

According to our data in rats, peripheral 3.4-dihydroxyphenylalanine (DOPA) kinetics are similar to striatal DOPA and dopamine kinetics. The measurement of plasma l-3.4-dihydroxyphenylalanine (L-dopa) concentration is thus useful to predict dopamine kinetics in the striatum and to treat the motor fluctuations of parkinsonian patients. In patients with Parkinson’s disease (PD), long-term L-dopa therapy accelerated DOPA absorption and steepened features of L-dopa pharmacokinetics. In the senile-onset group, the pharmacokinetic pattern did not change even after long-term L-dopa therapy. The frequency of motor fluctuations is much lower in senile-onset patients with PD than in middle-onset patients. Differences in the pattern of L-dopa pharmacokinetics in the two groups may explain why the senile-onset group rarely develops ‘wearing-off’, even after long-term L-dopa therapy. L-dopa is transported by a saturable active transporter system, called the LNAA (large neutral amino acid) system, in the gut and blood brain barrier. L-dopa absorption is thus affected by food intake, especially a proteinrich diet. The slope of the time-concentration curve for L-dopa administered before a meal is steeper than if it is administered after a meal. Considering that pulsative stimulation of L-dopa may cause motor fluctuations, L-dopa should be given after meals whenever possible, even if it necessitates a higher L-dopa dose.

Cabergoline scavenges peroxynitrite enhanced by l‐DOPA therapy in patients with Parkinson's disease

Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

Acute intranigral homocysteine administration produces stereotypic behavioral changes and striatal dopamine depletion in Sprague–Dawley rats

Homocysteine has been considered a major risk factor for cardiovascular diseases, and patients with hyperhomocystinemia exhibit neurological and psychological abnormalities. Elevated level of this molecule in the blood of Parkinson's disease patients receiving long-term l-DOPA therapy prompted us to investigate whether homocysteine is neurotoxic to the nigrostriatal dopaminergic system in Sprague–Dawley rats. Animals infused unilaterally with different doses of homocysteine (0.25–1 μmol in 1 μl) intranigrally exhibited significant and dose-dependent decrease in dopamine levels in the ipsilateral striatum as assayed employing an HPLC coupled with electrochemical detector, 19 days post-infusion. While 3,4-dihydroxyphenylacetic acid level in the striatum showed a dose-dependent decrease, homovanillic acid was found to be inhibited only for the highest dose. Amphetamine administration in these animals on the 14th day caused stereotypic turning behavior ipsilateral to the side of infusion. Apomorphine challenge on the 16th day elicited stereotypic contralateral circling behavior. Neurotransmitter levels in the serotonergic perikarya or terminals were unaltered 19 days following intraraphe infusion of homocysteine, which suggested the specificity of its action to dopaminergic neurons. These results indicate nigrostriatal lesions similar to that observed following intranigral infusion of the dopaminergic neurotoxin, 6-hydroxydopamine and suggest its closeness to the parkinsonian animal model. Furthermore, these findings provide evidence for the neurotoxic nature of homocysteine to dopaminergic neurons and suggest that elevated level of this molecule in parkinsonian patients may be conducive to accelerate the progression of the disease.

A Randomized Controlled Trial of Etilevodopa in Patients With Parkinson Disease Who Have Motor Fluctuations

Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. A double-blind, randomized, comparative clinical trial. Forty-four sites in the United States and Canada. Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. Change from baseline in total daily TTON as measured using home diaries. The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.

Pharmacokinetic and Pharmacodynamic Changes During the First Four Years of Levodopa Treatment in Parkinson’s Disease

The purpose of this analysis is to describe how levodopa pharmacokinetic and pharmacodynamic parameters change over the first 4 years of long-term levodopa treatment in patients with Parkinson's disease. Twenty previously untreated Parkinsonian patients were admitted to the general clinical research center (GCRC) for 4 days at the beginning of long-term levodopa therapy and 6, 12, 24 and 48 months later. On each GCRC admission, patients received a 2 hr IV infusion of levodopa on day 1 and day 4 with no oral levodopa between the infusions. After the first GCRC admission patients were treated with oral levodopa dosed for optimal control of Parkinsonism. Motor function was measured by finger tapping rate. A pharmacokinetic-pharmacodynamic model incorporating 3 effect compartments was used to fit the individual plasma levodopa concentrations and tapping rates. Motor function before the first levodopa infusion (E0(1)) improved over the first 20 months and subsequently returned to the initial baseline at the start of the study. A similar pattern was seen in motor function before the second infusion (E0(2)) after the 3 days levodopa withdrawal, with a decline predicted to fall below the initial baseline at the start of the study by 6 years. Eight patients showed an increase in maximum tapping rate with levodopa (E(max)) approaching a steady state after 16 months. Ten patients showed an increase in E(max) with a peak at 31 months. One patient showed a linear decrease and another patient did not change over the 48 months. Longitudinal progress models were used to describe the time course of pharmacokinetic and pharmacodynamic parameters over 4 years. Peak treatment benefit, defined as the difference between E(max) and E0(1) or E0(2) (D(max)1 or D(max)2), increased with time particularly after the 3-day levodopa withdrawal. Deterioration of pre-dose motor function (E0) as disease progresses coupled with a greater amplitude of response due to levodopa (D(max)) could be a key factor contributing to motor fluctuations associated with long-term levodopa treatment.

Effects of Homocysteine on the Dopaminergic System and Behavior in Rodents

Long-term treatment of levodopa for Parkinson's disease (PD) patients is known to elevate homocysteine level in their plasma. The present study was designed to examine the possible neurotoxic effects of the increased homocysteine level on the dopaminergic system. Homocysteine was administered into Sprague–Dawley male rats intracerebroventricularly or C57BL/6 mice intraperitoneally. Following homocysteine injection the locomotor activities, the levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and immunohistochemistry of dopaminergic neurons were examined. The results obtained indicate that homocysteine administration (1 or 2 μmol, i.c.v.) into the rat brains for 5 days significantly decreased the locomotor activities and dopamine as well as its metabolites, DOPAC and HVA, in the rat striatal regions. Two different doses of homocysteine (50 and 100 mg/100 g, i.p. daily) were administered into mice for 36 days to evaluate the effect of systemic treatment of homocysteine on the dopaminergic neurons of the brain. The intraperitoneal injections of two doses of homocysteine significantly increased homocysteine levels in the striatal regions of mouse brains by 21.5 and 39.2%, while reducing dopamine turnover rates in the striatal regions by decreasing (DOPAC + HVA)/DA, 23.7 and 51.6%, respectively. Accordingly, homocysteine decreased locomotor activities significantly by decreasing movement time by 29 and 38%, total distance by 32 and 42%, and numbers of movement by 28 and 41%, respectively. Moreover, homocysteine decreased tyrosine hydroxylase immunoreactivity in substantia nigra of mouse brain. The data obtained indicate that the potential of homocysteine to be toxic to the dopaminergic system. Consequently, long-term levodopa therapy for PD may accelerate the progression of PD, at least in part by elevated homocysteine.

Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias.

Brain adenosine A2A receptors have recently attracted considerable attention because of their interaction with the dopaminergic system and as potential targets for Parkinson's disease pharmacotherapy. Post mortem adenosine A2A receptor mRNA and [3H]SCH 58261- specific binding to adenosine A2A receptor were studied in the brain of Parkinson's disease patients using in situ hybridization and receptor binding autoradiography, respectively. Fourteen levodopa-treated Parkinson's disease patients, of which seven developed dyskinesias and seven did not, were compared with nine controls. Nigrostriatal denervation was similar between dyskinetic and non-dyskinetic Parkinson's disease patients, as assessed with catecholamine concentrations and [125I]RTI-121-specific binding to dopamine transporters. A2A receptor mRNA levels (+129%; P < 0.01) and [3H]SCH 58261-specific binding (+32%, P < 0.01) were increased in the putamen (lateral and medial) of dyskinetic patients compared with controls. The increase of adenosine A2A receptor mRNA in dyskinetic Parkinson's disease patients was also significant compared with non-dyskinetic Parkinson's disease patients (+60%; P < 0.05) in the lateral putamen. Moreover, [3H]SCH 58261-specific binding to adenosine A2A receptors was increased in the external globus pallidus (+24%; P < 0.001) of Parkinson's disease patients compared with controls, regardless of the dyskinesigenic response to levodopa. No change of adenosine A2A receptors was observed in the caudate nucleus, whereas adenosine A2A receptor protein and mRNA levels in the internal globus pallidus were not different from background. These findings suggest that increased synthesis of adenosine A2A receptors in striatopallidal pathway neurons is associated with the development of dyskinesias following long-term levodopa therapy in Parkinson's disease.

Cabergoline : a review of its use in the treatment of Parkinson's disease.

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for dopamine D2 receptors and a long elimination half-life. This agent provides continuous dopaminergic stimulation with once-daily administration. Adjuvant oral cabergoline is usually well tolerated and effective in controlling symptoms in patients with advanced Parkinson's disease experiencing response fluctuations to long-term levodopa therapy. In patients with early Parkinson's disease, cabergoline (with or without levodopa) is well tolerated and effective in controlling disease symptoms, and may reduce the risk of developing drug-induced motor complications. Data from two pharmacoeconomic analyses suggest that cabergoline may be a cost-effective treatment option versus levodopa in patients with early Parkinson's disease, and highlight the need for further evaluation of the drug in this indication.

Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease

Glutamate receptors were studied in the brains of controls and Parkinson's disease (PD) patients, of which 10 of 14 developed motor complications (dyskinesias and/or wearing-off) following levodopa therapy. 125I-RTI binding to the dopamine transporter and dopamine concentrations show comparable nigrostriatal denervation between the subgroups of PD patients. 3H-Ro 25-6981 binding to the NR1/NR2B NMDA receptor was increased in the putamen of PD patients experiencing motor complications compared to those who did not (+53%) and compared to controls (+18%) whereas binding remained unchanged in the caudate nucleus. 3H-AMPA binding was increased in the lateral putamen (+23%) of PD patients with motor complications compared to those without whereas it was decreased in the caudate nucleus of the PD patients (−16%) compared to controls. Caudate and putamen 3H-CGP39653 binding to NR1/NR2A NMDA receptor and NR1 subunit mRNA levels measured by in situ hybridization were unchanged in subgroups of PD patients compared to controls. These findings suggest that glutamate receptor supersensitivity in the putamen plays a role in the development of motor complications (both wearing-Off and dyskinesias) following long-term levodopa therapy in PD.

Long-term l-DOPA therapy: challenges to our understanding and for the care of people with Parkinson's disease

Long-term l-DOPA therapy: challenges to our understanding and for the care of people with Parkinson's disease

Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease.

Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.

Evolution of the response to levodopa during the first 4 years of therapy.

The short-duration response, long-duration response, and dyskinetic response to levodopa change during long-term levodopa therapy. How these responses evolve, and which changes contribute to the emergence of motor fluctuations, remain unclear. We studied 18 subjects with Parkinson's disease before they began levodopa therapy and after 6, 12, 24, and 48 months of long-term levodopa therapy. The responses to 2-hour levodopa infusions after overnight and after 3 days of levodopa withdrawal were studied from 6 months onward. The mean magnitude of the short-duration response and the long-duration response measured after overnight without antiparkinsonian medications did not change during the 4 years. However, after 3 days without levodopa, it was apparent that the short-duration-response magnitude was progressively increasing (p < 0.0001) and that the long-duration response was decaying more rapidly (p = 0.0004). The short-duration-response magnitude at 4 years was inversely related to the long-duration-response magnitude (p = 0.022), suggesting that the long-duration response was one determinant of the short-duration-response magnitude. Dyskinesia increased progressively in severity during the study (p = 0.013). The duration of the short-duration response and dyskinesia did not change during the 4 years. Subject reports of motor fluctuations tended to be associated with a large short-duration response (p = 0.054). We suggest that a larger long-duration response, rather than a shortened one, is more important to the development of fluctuations. Improving the baseline or practical-off motor function to reduce the magnitude of the short-duration response may be a strategy to treat fluctuations.

Long-term studies of dopamine agonists

Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

Increase of preproenkephalin mRNA levels in the putamen of Parkinson disease patients with levodopa-induced dyskinesias.

The expression of preproenkephalin messenger RNA was studied in the brain of Parkinson disease (PD) patients using in situ hybridization. All these patients were treated with levodopa (LD) and the development of motor complications was recorded. Eleven normal controls and 14 PD patients were used, of which 4 developed dyskinesias, 3 developed wearing-off, 3 developed both dyskinesias and wearing-off, and 4 developed no adverse effect following dopaminomimetic therapy. Nigrostriatal denervation was similar between the subgroups of PD patients as assessed using 125I-RTI-specific binding to the dopamine transporter and measures of catecholamine concentrations by HPLC. A significant increase of preproenkephalin messenger RNA levels was observed in the lateral putamen of dyskinetic patients in comparison to controls (+210%; p < 0.01) and in comparison to nondyskinetic patients (+112%; p < 0.05). No change was observed in medial parts of the putamen or in the caudate nucleus. No relationship between preproenkephalin messenger RNA levels and other clinical variables such as development of wearing-off, age of death, duration of disease, or duration of LD therapy was found. These findings suggest that increase synthesis of preproenkephalin in the medium spiny output neurons of the striatopallidal pathway play a role in the development of dyskinesias following long-term LD therapy in Parkinson disease.