Standard Levodopa Research Articles

Central Levodopa Influx and the Clinical Motor Response to Levodopa in Patients With Parkinson Disease Complicated With Motor Fluctuations and Dyskinesias

To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease. 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. 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). 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.

DOES CLINICAL INTOLERANCE TO A DIAGNOSTIC ACUTE LEVODOPA CHALLENGE DIFFERENTIATE MULTIPLE SYSTEM ATROPHY FROM PD?

Background: The diagnosis of multiple system atrophy (MSA) remains challenging. Objective: To determine if the occurrence of symptoms of clinical intolerance such as nausea, vomiting, hypotension, and profuse perspiration during a standard acute levodopa challenge may be a useful marker of MSA. Methods: A total of 507 dopaminergic acute challenge tests performed for different purposes in the last 10 years in a movement disorders clinic were reviewed, identifying patients who manifested symptoms of clinical intolerance during test performance. Only those tests completed for diagnostic purposes were included and these were matched by the presence or absence of response to levodopa, sex, and age, with a group of patients undergoing acute challenge without any symptoms of clinical intolerance. Presumptive diagnosis for each patient was performed by means of accepted clinical criteria after a significant follow-up period. Only patients with a final diagnosis of Parkinson's disease (PD) or MSA were analyzed. Results: Twenty-three out of the 507 patients (women: 50%) presented symptoms of clinical intolerance and received a final diagnosis of PD or MSA, and underwent further analysis. Four out the 23 patients with intolerance (17%) and one out the 16 patients from the control group (6%) were diagnosed as having MSA (Chi-square = 1.05, p = .3). Overall sensitivity and specificity of the presence of clinical intolerance to predict diagnosis of MSA were 80% (95%IC: 45%–100%) and 44% (95%CI: 27%–61%) respectively. Conclusions: Symptoms of clinical intolerance during an acute levodopa challenge do not appear to be useful in the diagnosis of MSA.

Do dyskinesia and pain share common pathophysiological mechanisms in Parkinson's disease?

Plastic changes within the striatum resulting from pulsatile dopaminergic stimulation are thought to lead to dyskinesia in patients with Parkinson's disease (PD). The basal ganglia play a role in processing pain. We hypothesized that the plastic changes that lead to dyskinesia may also mediate pain responses. Our objective was to compare the change in pain sensitivity after levodopa administration between stable responders, fluctuators without dyskinesia, and dyskinetic patients, and to compare pain sensitivity between PD and healthy subjects. Fifty patients with PD were assessed with cold water immersion after overnight withdrawal of dopaminergic medications and again after a standard levodopa challenge, and carefully classified into stable responder (n = 12), fluctuator (n = 15), and dyskinetic (n = 23) groups. Twenty age-matched controls were also tested. PD patients "off"-medication had a lower threshold (P = 0.016) and tolerance (P < 0.0001) to cold pain compared to controls. After levodopa administration, dyskinetic patients experienced a large increase in cold pain threshold (48%) and tolerance (66%) that was absent in stable responders (P = 0.038 and P = 0.015); there was no significant difference in pain sensitivity change scores between the fluctuator and either the stable responder or dyskinetic groups. Our results suggest that dyskinesia and pain may share common pathophysiological mechanisms in PD.

Direct inhibition of levodopa-induced beginning-of-dose motor deterioration by subthalamic nucleus stimulation in a patient with Parkinson disease

Beginning-of-dose motor deterioration (BDMD) is a complication of levodopa medications in Parkinson disease (PD) that is presumably caused by inhibitory effects of levodopa. Only limited experience of BDMD has been described in the literature. The authors report the case of a patient with PD who demonstrated a marked BDMD while being treated with standard levodopa medications. This 55-year-old woman had a 12-year history of PD and a 10-year history of levodopa treatment. Marked exacerbation of symptoms occurred 15 to 20 minutes after every dose of levodopa at 100 mg and lasted approximately 15 minutes. The PD symptoms, particularly tremor and rigidity, were exacerbated more markedly during this period than during the wearing-off deterioration. The BDMD could be controlled very well by subthalamic nucleus (STN) stimulation without any change in the regimen of levodopa medications. These observations suggest that the BDMD was inhibited by STN stimulation through a direct effect.

Levodopa/dopamine replacement strategies in Parkinson's disease-Future directions

After 40 years, levodopa remains the most effective therapy for the treatment of PD. However, long-term therapy is complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients. Other medical therapies that are currently available for the treatment of PD primarily represent an attempt to prevent or treat motor complications. Surgical therapies improve motor complications in appropriate candidates, but do not provide antiparkinsonian benefits that are superior to levodopa, and are themselves associated with potentially serious side effects. Increasing information suggests that levodopa-induced motor complications relate to pulsatile, nonphysiologic dopamine replacement. A therapeutic strategy that could deliver levodopa/dopamine to the brain in a more continuous and physiologic manner might be expected to provide all of the benefits of standard levodopa with reduced motor complications. Such a levodopa formulation might replace all current dopaminergic antiparkinsonian medications and avoid the need for surgery in most PD patients. However, problems of continuous dopaminergic stimulation must be addressed and avoided, and the issue of nondopaminergic features remains to be addressed.

Functional organization of the basal ganglia: Therapeutic implications for Parkinson's disease

The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.

Entacapone Prolongs the Reduction of PLM by Levodopa/Carbidopa in Restless Legs Syndrome

Levodopa is effective in the treatment of restless legs syndrome (RLS). However, due to the short duration of action of conventional levodopa/decarboxylase inhibitor formulations, multiple dosing may be required in individual patients with persisting symptoms. We assessed whether a new levodopa formulation containing levodopa, carbidopa, and entacapone (LCE) improves levodopa action in RLS. Twenty-eight RLS patients with periodic limb movement (PLM) received single doses of Stalevo 50 (LCE50; 50/12.5/200 mg), Stalevo 100 (LCE100; 100/25/200 mg), Stalevo 150 (LCE150; 150/37.5/200 mg), Sinemet 100 (LC100; 100/25 mg), or placebo in a randomized, double-blind, crossover study with polysomnography. Periodic limb movements per hour (PLM/h) during total sleep time and PLM during total time in bed were the primary and secondary variables, respectively. Mean PLM/h during total sleep time after Stalevo 50 (12.6/h, P < 0.05), LCE100, LCE150, and LC100 (6.4/h, 3.5/h and 9.5/h, respectively; P < 0.01) were significantly reduced compared with placebo (25.7/h). Improvement was also observed in PLM/h during total time in bed for all treatments (P < 0.01) and a significant dose response observed between LCE doses (P < 0.05). Compared with LC100, LCE100 and LCE150 reduced PLMs during the second half (P = 0.06 and P < 0.001, respectively) or during the last 3 early morning hours (hours 5-7 from the start of recording) of the night (P < 0.05 and P < 0.01, respectively). All formulations were well tolerated. Single doses of LCE tablets decreased PLMs in a dose-related manner in RLS patients. Prolonged effects of levodopa on PLMs suggest that, compared with standard levodopa, this new levodopa formulation provides longer symptom control throughout the night in patients with previously untreated RLS.

Levodopa availability improves with progression of Parkinson’s disease

Previous pharmacokinetic trials with standard levodopa formulations showed a different behaviour of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various stages. To investigate associations between levodopa plasma levels in relation to the scored intensity of PD. We administered water soluble 100 mg levodopa and 25 mg benserazide to 50 PD patients, taken off medication for at least 12 hours, and assessed the levodopa plasma concentrations during an 180 minutes period under standardised conditions. The computed area under the curve (AUC) values of levodopa plasma levels were significant higher in advanced PD patients. PD rating scores significantly correlated to the AUC outcomes and the maximum levodopa plasma concentration. Levodopa availability improves with progression of PD. This may result from deteriorated peripheral activity of levodopa metabolising enzymes or an increasing enteric dysfunction with subsequent better duodenal levodopa absorption or both.

Cost-Utility Model of Rasagiline in the Treatment of Advanced Parkinson's Disease in Finland

The economic burden of Parkinson's disease (PD) is high, especially in patients experiencing motor fluctuations. Rasagiline has demonstrated efficacy against symptoms of PD in early and advanced stages of the disease. To assess the cost-utility of rasagiline and entacapone as adjunctive therapies to levodopa versus standard levodopa care in PD patients with motor fluctuations in Finland. A 2 year probabilistic Markov model with 3 health states: "25% or less off-time/day," "greater than 25% off-time/day," and "dead" was used. Off-time represents time awake with poor or absent motor function. Model inputs included transition probabilities from randomized clinical trials, utilities from a preference measurement study, and costs and resources from a Finnish cost-of-illness study. Effectiveness measures were quality-adjusted life years (QALYs) and number of months spent with 25% or less off-time/day. Uncertainty around parameters was taken into account by Monte Carlo simulations. Over 2 years from a societal perspective, rasagiline or entacapone as adjunctive therapies to levodopa showed greater effectiveness than levodopa alone at no additional costs. Benefits after 2 years were 0.13 (95% CI 0.08 to 0.17) additional QALYs and 5.2 (3.6 to 6.7) additional months for rasagiline and 0.12 (0.08 to 0.17) QALYs and 5.1 (3.5 to 6.6) months for entacapone, both in adjunct to levodopa compared with levodopa alone. The results of this study support the use of rasagiline and entacapone as adjunctive cost-effective alternatives to levodopa alone in PD patients with motor fluctuations in Finland. With a different mode of action, rasagiline is a valuable therapeutic alternative to entacapone at no additional charge to society.

RNA knockdown as a potential therapeutic strategy in Parkinson's disease

Parkinson's disease is a prevalent progressive degenerative disorder of the elderly. There is a current need for novel therapeutic strategies because the standard levodopa pharmacotherapy is only temporarily efficacious. Recently, there have been some high-profile successful preclinical results obtained in animal models of neurological disorders using small interfering RNAs delivered by viral vectors. RNA interference can theoretically be applied to Parkinson's disease since over-expression of various proteins is known to kill the dopamine neurons of the substantia nigra in animal models and in familial forms of Parkinson's disease. Potential RNA interfering strategies and caveats are discussed in this review.

Noisy vestibular stimulation improves autonomic and motor responsiveness in central neurodegenerative disorders

The vestibular nerves are known to influence neuronal circuits in the medullary cardiovascular areas and, through the cerebellar vermis, the basal ganglia and the limbic system. By means of noisy galvanic vestibular stimulation (GVS), it might be possible to ameliorate blunted responsiveness of degenerated neuronal circuits of patients with multi system atrophy or Parkinson's disease, or both. We evaluated the effect of 24-hour noisy GVS on long-term heart rate dynamics in 7 patients with multi system atrophy and on daytime trunk activity dynamics in 12 patients with either levodopa-responsive Parkinson's disease or levodopa-unresponsive parkinsonism. Six of the latter patients were also examined for cognitive performance by means of a continuous performance test. Short-range or high-frequency fluctuations of heart rate were significantly increased by the noisy GVS compared with sham stimulation, suggestive of improved autonomic, especially parasympathetic, responsiveness. Long-range antipersistency of trunk activity patterns probed by an autocorrelation measure was significantly increased by the noisy GVS, suggestive of quickening of bradykinesic rest-to-active transitions. The mean reaction time of the continuous performance test was also significantly decreased by the noisy GVS, without significant changes in either the omission or commission error ratios, which is suggestive of improved motor execution during the cognitive task. In conclusion, the noisy GVS is effective in boosting the neurodegenerative brains of patients with multi system atrophy or Parkinson's disease, or both, including those unresponsive to standard levodopa therapy; it is also effective in improving these patients' autonomic and motor responsiveness.

Entacapone Increases Levodopa Exposure and Reduces Plasma Levodopa Variability When Used With Sinemet CR

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

Chronic levodopa intake increases levodopa plasma bioavailability in patients with Parkinson's disease

Previous pharmacokinetic trials with standard levodopa formulations showed a different behavior of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various advanced stages. The objective of this trial was to compare levodopa plasma metabolism in PD patients with and without previous long-term levodopa intake after oral intake of a dispensable levodopa/benserazide formulation (DLB). The over a 150 min interval computed area under the curve values of levodopa plasma levels after DLB administration were significantly (ANCOVA: F (1,19)=7.88, P=0.01) higher in PD patients with chronic levodopa treatment compared to patients without prior levodopa treatment. The maximum plasma levodopa concentration did not differ (ANCOVA: F (1,19)=1.17, P=0.29). Long-term levodopa administration results in an increased levodopa plasma bioavailability in PD patients.

Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation.

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

The origin of motor fluctuations in Parkinson's disease: importance of dopaminergic innervation and basal ganglia circuits.

The severity of dopamine depletion and the consequent pathophysiologic changes that occur in basal ganglia circuits determine the severity of parkinsonian signs. Restoring the dopamine deficit or the downstream physiologic abnormalities improves Parkinson's Disease (PD) main motor features and as a result, attenuates the short-duration response (SDR). Therefore, both the magnitude and duration of the motor response are a function of the degree of motor severity, which is primarily governed by the loss of tonic dopaminergic activity and disruption of basal ganglia homeostatic mechanisms among which the STN-GPe/GPi circuits play a fundamental role. As neurodegeneration advances, standard levodopa administration give rises to wider oscillations in striatal dopamine availability and "pulsatile" stimulation of striatal dopamine receptors becomes predominant. This induces molecular and physiologic changes that further accentuate and aggravate the SDR that sustains motor fluctuations. Treatments capable of providing and restoring more tonic and physiologic dopaminergic stimulation may avoid many of these abnormalities and lead to better clinical outcomes.

Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease

We studied 48 patients after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) who were evaluated 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS) in a standardized levodopa test. Additional follow-up was available in 32 patients after 12 months and in 20 patients after 24 months. At 6 months follow-up, STN-DBS reduced the UPDRS motor score by 50.9% compared to baseline. This improvement remained constant at 12 months with 57.5% and at 24 months with 57.3%. Relevant side effects after STN-DBS included intraoperative subdural hematoma without neurological sequelae (n = 1), minor intracerebral bleeding with slight transient hemiparesis (n = 1), dislocation of impulse generator (n = 2), transient perioperative confusional symptoms (n = 7), psychotic symptoms (n = 2), depression (n = 5), hypomanic behaviour (n = 2), and transient manic psychosis (n = 1). One patient died because of heart failure during the first postoperative year. The current series demonstrates efficacy and safety of STN-DBS beyond the first year after surgical procedure. Complications of STN-DBS comprise a wide range of psychiatric adverse events which, however, were temporary.

Etilevodopa* is not superior to standard levodopa in the treatment of Parkinson's disease,

Etilevodopa* is not superior to standard levodopa in the treatment of Parkinson's disease,

Tapping and peg insertion after levodopa intake in treated and de novo parkinsonian patients.

Investigators use instrumental tasks for objective assessment of parkinsonian motor disability and its drug response. To date, such studies on treated parkinsonian patients have not addressed acute and long-term effects of dopaminergic drugs. To determine the impact of long-term dopaminergic therapy within a standardized levodopa challenge test design in combination with two repeatedly performed instrumental tasks, peg insertion and tapping, in previously treated and untreated parkinsonian patients. Tapping significantly deteriorated in previously untreated, but not in treated parkinsonian patients after levodopa intake. In contrast, motor symptoms and peg insertion significantly improved in both groups of parkinsonian patients. Results of both tests differed between parkinsonian patients and matched controls. Worsening of cognitively less demanding tapping may result from upregulated presynaptic inhibitory feedback regulation, sedative effects of levodopa or dopamine overflow in untreated parkinsonian patients, who are sensitive to these effects in contrast to treated parkinsonian patients. Tapping is a task with autonomic repetitive performance and programming of standardised movements with a low need for cognitive effort. This autonomic functioning of attentional control and selective processing is intact in Parkinson's disease. Peg insertion depends on more complex movements and thus hypothetically on dopamine-associated cognitive processes. Therefore, impairment of peg insertion responded to dopaminergic stimulation in both groups of parkinsonian patients. Future studies on the efficacy of antiparkinsonian drugs, using instrumental tasks for objective assessment, should consider long-term impact of antiparkinsonian drug therapy and associated cognitive efforts.

Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach.

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic-dynamic modeling for both effects was carried out according to the "link" effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (H&Y II, III, and IV). Median effective concentrations (EC 50 ) were increased at the more advanced clinical stage (p < 0.001), from a median 0.2 microg/mL in patients at H&Y stage I to 0.9 microg/mL in patients at H&Y stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.

Choice reaction time after levodopa challenge in parkinsonian patients

Various types of choice reaction time paradigms demonstrated deficits in the preparation and execution of movements in parkinsonian subjects. These studies showed controversial results, since they included parkinsonian individuals being: (i) previously untreated; (ii) off; or (iii) on anti-parkinsonian medication. Moreover, these trials do not take into consideration the acute effects of levodopa administration. Objective of this study was to determine the effect of long-term dopaminergic substitution therapy within a standardized levodopa challenge test in combination with a repeatedly performed choice reaction time task in parkinsonian individuals. Parkinsonian participants consisted of previously untreated, so-called “de-novo” patients and of individuals, who were chronically substituted with dopaminergic drugs, but were taken off medication for at least 12 h. All participants took 250 mg levodopa/benserazide after assessment of baseline data. Then we repeatedly measured choice reaction- and movement time within the next 90 min. No significant change of the assessed task data appeared in the “de-novo” group, but reaction- and movement time significantly shortened in previously treated subjects. Sedative effects of levodopa and/or dopaminergic overstimulation hypothetically explain the results of the previously untreated patients, whereas long-term dopaminergic substitution therapy hypothetically causes tolerance to these phenomena in treated parkinsonian individuals. Future studies on parkinsonian subjects should discuss their results on the basic pathophysiology or basal ganglia dysfunction in the light of a putative impact of long-term anti-parkinsonian drug therapy.