Related Articles

Objectives

Parkinson’s disease (PD) is associated with motor fluctuations that have been shown to improve when stable plasma levodopa levels are achieved with continuous levodopa infusions. Many patients also develop mood fluctuations. In this pilot study, we gathered preliminary information about the relationship between changing mood states and plasma levodopa levels.

Methods

Six patients with idiopathic PD and histories of motor and mood fluctuations participated in a double-blind levodopa infusion study. Subjects received active oral carbidopa/levodopa and a placebo levodopa infusion on one day and placebo oral carbidopa/levodopa and an active levodopa infusion on the other day, in a randomly determined order. Evaluations included serial plasma levodopa levels and assessments of mood and motor states.

Results

Only 4 of the 6 subjects demonstrated mood fluctuations on at least one of the treatment days. All subjects achieved more stable plasma levodopa levels on the active infusion day. Two subjects experienced fewer mood fluctuations on the active infusion day and two experienced fewer on the oral day.

Conclusions The results of this pilot study suggest that the relationship between mood state and plasma levodopa level may vary among PD patients.

Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson’s disease (PD). In a randomized, double-blind, placebo-controlled clinical trial we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP-101,606, on the response to two-hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP-101,606 reduced the maximum severity of levodopa-induced dyskinesia approximately 30% but neither dose improved parkinsonism. CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.

Objective:

To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops.

Methods:

Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on long-term levodopa with dyskinesia and motor fluctuations.

Results:

The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa.

Conclusions:

The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered.

GLOSSARY

= General Clinical Research Center;

= Oregon Health & Science University;

= Parkinson disease.

This article reviews the role of an extended-release formulation of pramipexole in the treatment of Parkinson’s disease at an early stage. Pramipexole is a nonergot D2/D3 synthetic aminobenzothiazole derivative that is effective as monotherapy in early disease and as an adjunct to levodopa in patients with motor fluctuations. Although levodopa is the current “gold standard” for treatment of Parkinson’s disease, its effectiveness fades rapidly and its use results in serious motor fluctuations (on-off, wearing-off, freezing, involuntary movements) for most patients with the disease. Pramipexole has selective actions at dopamine receptors belonging to the D2 subfamily, where it possesses full activity similar to dopamine itself. Its preferential affinity for the D3 receptor subtype could contribute to its efficacy in the treatment of both the motor and psychiatric symptoms of Parkinson’s disease. The best approach to medical management of early Parkinson’s disease remains controversial. While enormous progress has been made in the treatment of the disease, challenges still remain. A variety of treatment-related and patient-related factors must be taken into account when making these decisions. The current approach to treatment of early Parkinson’s disease depends in part on individual patient factors, including age, severity and nature of symptoms and their impact, presence of cognitive dysfunction, possible underlying behavioral factors predisposing to impulse control disorders, and other comorbidities. Today, the once-daily extended-release formulation of pramipexole offers the advantages of easy continuous delivery of drug and convenience to patients, particularly early in the disease when monotherapy is the rule. Thus, a new “levodopa-sparing” paradigm for treating Parkinson’s disease may now be possible, whereby patients are initially treated with pramipexole and levodopa is added only as necessary.

Ten patients with Parkinson's disease and levodopa induced dyskinesias (LIDs) took part in this randomised, placebo controlled, double blind, crossover trial to assess the efficacy and tolerability of high dose oral naltrexone for LIDs in Parkinson's disease. Patients received naltrexone (5 mg/kg/day) or placebo for 2.5weeks with 1 week wash out in between. Dyskinesias and motor function were assessed with a levodopa challenge, unified Parkinson's disease rating scale (UPDRS), the unified dyskinesia rating scale (UDRS), and patient diaries. Eight patients completed the trial. There was a small reduction in LIDs measured by patient diaries with naltrexone (20.5 (SD 24.9)%) compared with placebo (−4.1 (SD 22.6)%), p<0.05, although no difference was found by other subjective or objective measures. Naltrexone was well tolerated and caused no significant differences in UPDRS motor scores or off time. This study suggests that short term therapy with high dose naltrexone (250-350 mg/day) has no or minimal effect on reducing LIDs in Parkinson's disease.



BACKGROUND—More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa.
OBJECTIVES—The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone.
METHODS—In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide.
RESULTS—After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P<0.01 v placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (P<0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (P<0.05), "on" time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea.
CONCLUSION—Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.



OBJECTIVES—To determine whether continous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease
METHODS—19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneoius apomorphine monotherapy for a minimum duration of 2.7 years
RESULTS—A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%)
CONCLUSION—Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency. Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.



Dopamine agonists such as pramipexole (PPX) have first been proposed as adjunctive treatment to levodopa (L-DOPA) for patients with Parkinson's disease (PD) and then as a monotherapy alternative to alleviate dyskinesia. Treatment with PPX has overall been associated with improvement in parkinsonian symptoms. Although the majority of placebo-controlled studies demonstrated that dyskinesia was more prevalent in the PPX compared to the placebo groups, some studies did not detect any dyskinesia as a side effect of this medication. PPX was consistently associated with lower risk for developing dyskinesia compared to L-DOPA. Moreover, the presence of these symptoms in the placebo groups suggests involvement of non-PPX-related factors for developing dyskinesia. It is suggested that future research should aim at ascertaining whether cotherapy with L-DOPA, PPX dosage, and other patient characteristics are contributory factors for the development of PPX-related dyskinesia in patients with PD.

The efficacy and tolerance of treatment with an 8-alpha-amino-ergoline derivative CU32-o85, Mesulergine, were compared with levodopa/benserazide (Madopar) in a 3 month double-blind controlled trial in 31 patients with Parkinson's disease, not previously treated with levodopa. The two treatments were equally well tolerated, and neither dyskinesias nor dose-related fluctuations developed. In 90% of the patients treated with Mesulergine, Parkinsonian symptoms improved, and at the dose given the overall therapeutical response was two-thirds that of levodopa. During further 9 months of open study the beneficial effect was maintained equally well in both groups. Compared with other dopamine agonists Mesulergine has a considerable antiparkinsonian effect. Unfortunately, further clinical evaluation of the compound recently has been stopped owing to sex and species specific histological alterations in rats. It is suggested that Mesulergine derivatives might well be of value in future treatment of early Parkinson's disease and of late incompensated stages.

Levodopa is the most effective drug for treating Parkinson's disease. However, long‐term use of levodopa is often complicated by significantly disabling fluctuations and dyskinesias negating its beneficial effects. Younger age of Parkinson's disease onset, disease severity, and high levodopa dose increase the risk of development of levodopa‐induced dyskinesias (LID). The underlying mechanisms for LID are unclear though recent studies indicate the importance of pulsatile stimulation of striatal postsynaptic receptors in their pathogenesis. The non‐human primates with MPTP‐induced parkinsonism serve as a useful model to study dyskinesia. Once established, LID are difficult to treat and therefore efforts should be made to prevent them. The therapeutic and preventative strategies for LID include using a lower dosage of levodopa, employing dopamine agonists as initial therapy in Parkinson's disease, amantadine, atypical neuroleptics, and neurosurgery. LID can adversely affect the quality of life and increase the cost of healthcare.

OBJECTIVES—Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance.
METHODS—Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings.
RESULTS—There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%—resulting in 1.7 more hours "on" time a day—compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams.
CONCLUSION—Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.



OBJECTIVES—Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an adjunct to standard levodopa preparations, but there is little experience of the effect of entacapone on controlled release levodopa preparations.
METHODS—A double blind, placebo controlled, single dose, randomised, cross over trial was performed in 14 patients with Parkinson's disease with motor fluctuations to investigate the clinical effect of a single dose of entacapone (200 mg) when administered with either standard levodopa-carbidopa (SinemetTM) or controlled release levodopa-carbidopa preparations (Sinemet CRTM).
RESULTS—When entacapone was administered with standard SinemetTM the duration of the clinical response to standard SinemetTM was longer in comparison with the response after placebo (p=0.02). Moreover, in the same patients, entacapone significantly increased the duration of the clinical response to Sinemet CRTM (p=0.05) without prolonging the latency of response or enhancing dyskinesias.
CONCLUSIONS—These data confirm the clinical efficacy of entacapone-standard SinemetTM combination. They also indicate that adding entacapone to controlled release levodopa preparations might provide a useful treatment option in patients with Parkinson's disease with motor fluctuations. A double blind clinical trial with a chronically administered entacapone-Sinemet CRTM combination is, however, required to verify this viewpoint.



Fluctuations in response to levodopa are a common and serious complication of long-term levodopa therapy. It may be possible to prolong the effect of each dose of levodopa by retarding the breakdown of dopamine. The selective monoamine oxidase type B inhibitor deprenyl, which is extensively metabolised to amphetamine and methamphetamine, has this effect as well as possible actions on dopamine release and re-uptake. In a double-blind crossover trial against placebo, deprenyl prolonged the action of levodopa and produced an objective improvement in mobility in five of 10 patients with dose-related response swings, and a subjective improvement in a further four patients. In another group of seven patients with random fluctuations in symptoms, only two noted subjective improvement, and there was an apparent increase in the severity of response swings in five patients. Deprenyl exacerbated dyskinesias, but had no serious side-effects. We conclude that deprenyl is unlikely to benefit patients with random response swings, and may cause deterioration in such cases. However, it may be a useful adjuvant in the management of dose-related response fluctuations in patients already on optional levodopa therapy.

A wide variety of drugs is available for treating Parkinson's disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.

Aims

To study the association of pain with motor complications in 117 patients with Parkinson's disease.

Methods

Patients were asked to refer any pain they experienced at the time of study and lasting since at least 2 months. Basic parkinsonian signs and motor complications (including motor fluctuations and dyskinesia) were assessed and Unified Parkinson's Disease Rating Scale (UPDRS) motor score part III (during on) and part IV were calculated. Information on age, sex, duration of disease, use of dopamine agonists and levodopa, years of levodopa treatment and current levodopa dosage, medical conditions possibly associated with pain, and depression were collected. Single and multiple explanatory variable logistic regression models were used to check the association of pain with the investigated variables.

Results

Pain was described by 47 patients (40%) and could be classified into dystonic (n.19) and non dystonic pain (n.16); in 12 patients both types coexisted. Multiple explanatory variable logistic regression models indicated a significant association of pain with motor complications (adjusted OR, 5.7; 95% CI, 2 to 16.5; p = 0.001). No association was found between pain, dystonic or non dystonic, and the other investigated variables including medical conditions known to be associated to pain in the general population. There was a significant correlation (r = 0.31, p<0.05) between severity of pain (measured on a Visual Analogue Scale) and severity of motor complications (UPDRS part IV).

Conclusions

Pain may be a representative feature of Parkinson's disease frequently associated with motor complications. The association is independent of a number of potentially relevant demographic and clinical variables.

The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.

Introduction:

Parkinson’s disease (PD) is a common neurodegenerative disease. In the 1960s, it was shown that the degeneration of dopamine producing neurons in the substantia nigra (SN) caused the motor features of PD. Dopamine replacement with levodopa, a dopamine precursor, resulted in remarkable benefit. Yet, the intermittent administration of levodopa is a major cause of motor complications, such as “wearing-off” of levodopa’s benefit and involuntary movements, known as dyskinesia. Therefore, agents that prolong levodopa’s half-life were employed, such as carbidopa, an aromatic amino acid decarboxylase (AADC) inhibitor, and entacapone, a catechol-O-methyltransferase (COMT) inhibitor. The combination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients.

Aims:

To assess the evidence for the place of CLE in the treatment of PD.

Evidence review:

CLE has a good efficacy, safety and tolerability profile, similar to that of entacapone taken separately with carbidopa/levodopa (CL). Compared to CL alone, it prolongs levodopa’s benefit, and improves the quality of life but not the motor performance in PD patients with nondebilitating “wearing-off” or dyskinesia. However, it increases the dyskinesia rate in early PD patients, and has adverse events in advanced patients with significant motor complications. There is insufficient evidence regarding cost-effectiveness.

Place in therapy:

CLE is an attractive alternative for patients with nondisabling “wearing-off” or dyskinesia taking CL with or without entacapone. It cannot be recommended for early PD patients, as it can induce more dyskinesia than CL alone, or in any patients who seem to have more adverse events.

The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson’s disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.

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

The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.

Many patients with idiopathic Parkinson's disease treated with levodopa for more than five years develop fluctuations in their clinical response to this drug. Such fluctuations may be unpredictable, but more commonly occur in a regular pattern related to the size and timing of the levodopa dosage. Theories as to their cause have emphasised both the progression of the underlying Parkinson's disease and the possibility of a late side-effect of levodopa. We report two children with Parkinsonism, one after recurrent obstructive hydrocephalus and the other following an encephalitic illness. Both patients had striking improvement with levodopa, but developed predictable and unpredictable dramatic response fluctuations within weeks of starting levodopa therapy. This suggests that neither the pathology of idiopathic Parkinson's disease, nor the long-term use of levodopa are essential for the development of predictable or unpredictable fluctuations in response to levodopa therapy.

The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.

Background

Levodopa remains the most effective drug in the treatment of Parkinson’s disease. However, long-term administration of levodopa induces motor complications, such as levodopa-induced dyskinesia. The mechanisms underlying levodopa-induced dyskinesia are not fully understood.

Methods

In this study, we prepared levodopa methyl ester (LDME)/benserazide-loaded nanoparticles, which can release LDME and benserazide in a sustained manner. Dyskinesia was induced in rats by repeated administration of levodopa then treated with LDME plus benserazide or the same dose of LDME/benserazide-loaded nanoparticles. Apomorphine- induced rotations and abnormal involuntary movements (AIMs) were measured on treatment days 1, 5, 10, 15, and 20. In addition, the levels of phosphorylated dopamine- and cyclic adenosine monophosphate- regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, and ΔfosB were determined by Western blot. Tau levels were determined by Western blot and immunohistochemistry. Dynorphin levels in the striatum and cortex of rats were measured using enzyme-linked immunosorbent assay.

Results

Over the course of levodopa treatment, the rats developed abnormal AIMs, classified as locomotive, axial, orolingual, and forelimb dyskinesia. The degree of reduction of apomorphine-induced rotations was comparable in dyskinetic rats treated with LDME plus benserazide or LDME/benserazide-loaded nanoparticles. The axial, limb, and orolingual (ALO) AIMs of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 14 ± 2.5, 9 ± 2.0, and 10 ± 2.1 on treatment days 10, 15, and 20, respectively, which were significantly reduced compared with dyskinetic rats treated with LDME plus benserazide (25 ± 3.7, 27 ± 3.8, and 25 ± 3.5, respectively). The locomotive AIMs of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 2.3 ± 0.42, 1.7 ± 0.35, and 1.6 ± 0.37 on treatment days 10, 15, and 20, respectively, which were also reduced compared with dyskinetic rats treated with LDME plus benserazide (4.4 ± 0.85, 4.7 ± 0.95 and 4.8 ± 0.37, respectively). Western blot showed that the levels of phosphorylated dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, tau, and ΔfosB in dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 134.6 ± 14.1, 174.9 ± 15.1, 134.2 ± 19.3, and 320.5 ± 32.8, respectively, which were significantly reduced compared with those of dyskinetic rats treated with LDME plus benserazide (210.3 ± 19.7, 320.8 ± 21.9, 340.4 ± 27.1, and 620.7 ± 48.3, respectively). Immunohistochemistry indicated that the level of phosphorylated tau was (7.2 ± 1.1) × 104 in dyskinetic rats treated with LDME/benserazide-loaded nanoparticles. However, the tau level was only (14.6 ± 2.3) × 104 in LDME plus benserazide-treated dyskinetic rats. There was a significant difference between the two groups. Enzyme-linked immunosorbent assay showed that dynorphin levels in the striatum and cortex of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 5.7 ± 1.2 and 4.8 ± 0.87, respectively, which were significantly reduced compared with LDME plus benserazide-treated dyskinetic rats (13.3 ± 2.1 and 8.1 ± 1.1 for the striatum and cortex, respectively).

Conclusion

Results suggest that LDME/benserazide-loaded nanoparticles can be used to reduce the expression of dyskinesia in dyskinetic rats.

Pramipexole is a non-ergot dopamine agonist shown to be efficacious in the treatment of Parkinson’s disease (PD). This review addresses the literature concerning pramipexole’s efficacy in treating motor and non-motor symptoms in PD, its impact on the development of dyskinesias and response fluctuations, the issue of neuroprotection, and the risk for developing adverse events such as increased somnolence, attacks of sudden onset of sleep, cardiac valvulopathy and impulse control disturbances.