Levodopa Pharmacodynamics Research Articles

Molecular Variability in Levodopa Absorption and Clinical Implications for the Management of Parkinson's Disease.

Levodopa is the most widely used medication for the symptomatic treatment of Parkinson's disease and, despite being an "old" drug, is still considered the gold standard for offering symptomatic relief. The pharmacokinetic and pharmacodynamics of levodopa have been studied extensively. Our review explores the molecular mechanisms that affect the absorption of this drug, focusing on the large intra- and interindividual variability of absorption that is commonly encountered in daily clinical practice, and on the interaction with other medications. In addition, we will explore the clinical implications of levodopa absorption variability and address current and future strategies for researchers and clinicians.

Continuous long-range measurement of tonic dopamine with advanced FSCV for pharmacodynamic analysis of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa, a dopamine prodrug, alleviates the motor symptoms of Parkinson's disease (PD), but its chronic use gives rise to levodopa-induced dyskinesia (LID). However, it remains unclear whether levodopa pharmacodynamics is altered during the progressive onset of LID. Using in vivo fast-scan cyclic voltammetry and second-derivative-based background drift removal, we continuously measured tonic dopamine levels using high temporal resolution recording over 1-h. Increases to tonic dopamine levels following acute levodopa administration were slow and marginal within the naïve PD model. However, these levels increased faster and higher in the LID model. Furthermore, we identified a strong positive correlation of dyskinetic behavior with the rate of dopamine increase, but much less with its cumulative level, at each time point. Here, we identified the altered signature of striatal DA dynamics underlying LID in PD using an advanced FSCV technique that demonstrates the long-range dynamics of tonic dopamine following drug administration.

Nonlinear pharmacodynamics of levodopa through Parkinson's disease progression.

The effect of levodopa in alleviating the symptoms of Parkinson's disease is altered in a highly nonlinear manner as the disease progresses. This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost. This alteration in the effect of levodopa complicates the optimization of a drug regimen. The present work aims at investigating the nonlinear dynamics of Parkinson's disease and its therapy through mechanistic mathematical modeling. Using a holistic approach, a pharmacokinetic model of levodopa was combined to a dopamine dynamics and a neurocomputational model of basal ganglia. The influence of neuronal death on these different mechanisms was also integrated. Using this model, we were able to investigate the nonlinear relationships between the levodopa plasma concentration, the dopamine brain concentration, and a response to a motor task. Variations in dopamine concentrations in the brain for different levodopa doses were also studied. Finally, we investigated the narrowing of a levodopa therapeutic index with the progression of the disease as a result of these nonlinearities. In conclusion, various consequences of nonlinear dynamics in Parkinson's disease treatment were studied by developing an integrative model. This model paves the way toward individualization of a dosing regimen. Using sensor based information, the parameters of the model could be fitted to individual data to propose optimal individual regimens.

PID controlled fully automated portable duodopa pump for Parkinson’s disease patients

Parkinson’s disease (PD) is a neurodegenerative disease that inhibits motor activities due to the impairment of brain cells which produce dopamine. Even though medications as well as Deep Brain Stimulations (DBS) are the two treatment options available to control parkinsonian symptoms, the first one is preferred mostly during the early stages of the disease. Continuous medication through Portable Duodopa Pump (PDP) without feedback is the existing method. This paper focuses on the development of a suitable closed-loop control strategy for traditional PDP; thereby ensuring fully automated drug infusion without wearing off. In fact, the drug infused by the controller is increased proportional to reduction in plasma level of dopamine. This results in the alleviation of side effects caused by incorrect dosages in medication therapy. The main control objective is set-point tracking of the closed-loop system with minimum settling time and good steady state accuracy even in the presence of large time delay, food and exercise disturbances as well as parameter variations present in the system. For achieving this objective, we modified the existing dose-effect model of Levodopa. The proposed model is enriched by (i) Levodopa to dopamine conversion factor, (ii) recirculation time delay and (iii) initial dopamine level present in patient’s BP (Blood Plasma). The in-silico analysis of oral medication is used to validate pharmacokinetics (PK), pharmacological activation (PA) and pharmacodynamics of Levodopa. The performance of the proposed fully automatic PDP has been evaluated by traditional Proportional Integral Derivative (PID) controller under two different tuning rules. It is revealed that, both Ziegler- Nichols (ZN) and Particle Swam Optimization (PSO) tuned PID controllers are robust regarding inter-patient variability and the dynamic performance of the later is superior in comparison with the former under intra-patient variability and disturbances.

Aberrant learning in Parkinson's disease: A neurocomputational study on bradykinesia.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive decline in motor functions, such as bradykinesia, caused by the pathological denervation of nigrostriatal dopaminergic neurons within the basal ganglia (BG). It is acknowledged that dopamine (DA) directly affects the modulatory role of BG towards the cortex. However, a growing body of literature is suggesting that DA-induced aberrant synaptic plasticity could play a role in the core symptoms of PD, thus recalling for a "reconceptualization" of the pathophysiology. The aim of this work was to investigate DA-driven aberrant learning as a concurrent cause of bradykinesia, using a comprehensive, biologically inspired neurocomputational model of action selection in the BG. The model includes the three main pathways operating in the BG circuitry, that is the direct, indirect and hyperdirect pathways, and use a two-term Hebb rule to train synapses in the striatum, based on previous history of rewards and punishments. Levodopa pharmacodynamics is also incorporated. Through model simulations of the Alternate Finger Tapping motor task, we assessed the role of aberrant learning on bradykinesia. The results show that training under drug medication (levodopa) provides not only immediate but also delayed benefit lasting in time. Conversely, if performed in conditions of vanishing levodopa efficacy, training may result in dysfunctional corticostriatal synaptic plasticity, further worsening motor performances in PD subjects. This suggests that bradykinesia may result from the concurrent effects of low DA levels and dysfunctional plasticity and that training can be exploited in medicated subjects to improve levodopa treatment.

Motor fluctuations due to interaction between dietary protein and levodopa in Parkinson's disease.

BackgroundThe modulation of levodopa transport across the blood brain barrier by large neutral amino acids is well documented. Protein limitation and protein redistribution diets may improve motor fluctuations in patients with Parkinson’s disease but the pharmacokinetics and pharmacodynamics of levodopa and amino acids are highly variable.MethodsClinical records of 1037 Parkinson’s disease patients were analyzed to determine the proportion of patients with motor fluctuations related to protein interaction with levodopa. Motor fluctuations due to protein interaction with levodopa were defined as dietary protein being associated with (i) longer time to levodopa effectiveness, (ii) reduced benefit or duration of benefit, (iii) dose failures or (iv) earlier wearing off from a previously effective dose. Dose failures, sudden, painful or behavioral wearing-off periods, gait freezing, nausea, hallucinations, orthostasis, and dyskinesias were taken as markers of motor fluctuations, disease severity, and levodopa side effects potentially influenced by protein.Results5.9 % of Parkinson’s disease patients on levodopa, and 12.4 % with motor fluctuations on levodopa correlated their fluctuations with the relative timing of levodopa and protein intake. These patients were younger at disease onset, had worse motor fluctuations and had a higher incidence of family members with Parkinson’s disease. Early wearing off or decreased dose efficacy were most commonly associated with protein interaction. 60 % of patients who modified their diets had weight loss.ConclusionsThis study suggests that clinically significant protein interaction with levodopa may occur mostly in a subset of Parkinson’s disease patients with earlier disease onset and those with familial disease.

Population Pharmacodynamics of IPX066: An Oral Extended‐Release Capsule Formulation of Carbidopa–Levodopa, and Immediate‐Release Carbidopa–Levodopa in Patients With Advanced Parkinson's Disease

A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson’s disease (PD) treated with immediate-release (IR) carbidopa–levodopa (CD–LD) or an extended-release (ER) formulation of CD–LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single-and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.

Plasma levodopa peak delay and impaired gastric emptying in Parkinson's disease

ObjectivesWhereas delayed gastric emptying is believed to be a causative factor for producing delayed-on and motor fluctuation in Parkinson's disease (PD), few studies have directly measured levodopa pharmacodynamics and gastric emptying together. In order to determine the relationship, we measured these two parameters in a single PD patients cohort. MethodsThirty-one patients with PD were enrolled in the study. They were 11 men and 20 women; age, 68.1±7.8years; disease duration, 4.2±3.8years; Unified Parkinson's Disease Rating Scale Part 3 Motor Score 18.37±8.60; bowel movement <3 times a week in 20; all taking 301mg±94mg/day levodopa/carbidopa. All patients underwent levodopa pharmacokinetic study and the gastric emptying study using 13C-octanoic acid expiration breath test. Statistical analysis was performed by Student's t-test and Mann–Whitney's U test. ResultsPharmacokinetic study showed that the plasma levodopa peak was at 2hours in 42% (13/31 patients) whereas at 1hour in 58% (18/31 patients), total of 50.7±16.4min (mean±standard deviation) in all 31 patients. The gastric emptying study showed that Tmax (13C)>60min was more common in patients with a plasma levodopa peak at 2hours (14/18, 69%) than in those with a plasma levodopa peak at 1hour (4/13, 22%) (p<0.05), total of 50.7±16.4min in all 31 patients. ConclusionWe found a significant relationship between levodopa pharmacokinetics and gastric emptying in PD patients, suggesting that delayed gastric emptying is a causative factor for producing delayed-on in PD. Therefore, studies of improved gastric emptying in order to ameliorate delayed-on in PD are warranted.

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease

Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. To examine the effects of a dopamine agonist on the motor response to levodopa. Double-blind, randomized, placebo-controlled, crossover clinical trial. Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment. Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to "ON" (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC. Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute x minutes (P = .006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P = .02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P = .004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion. Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia. Trial Registration clinicaltrials.gov Identifier: NCT00666653.

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease

Reconsideraciones en el tratamiento de la enfermedad de Parkinson con levodopa: evidencias farmacodinámicas

To review the current literature on the use of levodopa in the treatment of Parkinson's disease (PD), with an emphasis on pharmacodynamical aspects. Levodopa has been used successfully for treatment of PD since its discovery, being still the drug of choice. It has shown decreasing motor disability and reduce mortality in PD patients, however, still maintains long-term problems, particularly in relation to the motor response, the onset of dyskinesias and apparent neurotoxicity. The pharmacodynamical evidence indicates that pharmacological effects such as short-term response (SDR) and the long-term response (LDR) are an integral part of the therapeutic response to levodopa. Both responses have pharmacodynamical changes in time and its effects are expressed in terms of amplitude, duration and onset latency of pharmacological action. Investigations in this area, show that LDR would the expression of the physiological release of dopamine, and the treatment of PD should be based on LDR and its pharmacological characteristics. The pharmacodynamics of levodopa is complex. However, the available evidence suggests that a therapeutic strategy based on the use of the LDR is better than those based on the control of the SDR. The knowledge of the pharmacological characteristics of levodopa is central to the therapeutic decision, which should be effective in reducing symptoms and have minimal side effects.

Pharmacokinetics and pharmacodynamics of levodopa

The pharmacokinetics and pharmacodynamics of levodopa are dominated by two features: the short plasma half-life of the drug and the portion of the antiparkinsonian response that parallels the plasma levodopa levels, the so-called short-duration response. These features are the basis of motor fluctuations that complicate long-term therapy with levodopa. Motor fluctuations will predictably improve with measures that prolong the elevations of plasma levodopa or prolong the efficacy of dopamine synthesized from exogenous levodopa. Because dyskinesia is closely linked to the short-duration response and conceivably part of the short-duration response, it is less clear that dyskinesia will be improved by therapeutic strategies that reduce motor fluctuations.

Disease progression, drug action and Parkinson’s disease: Why time cannot be ignored

A clinician administers medications both seeking immediate benefits but also calculating the long-term effects of the medications on the course of the disease. It is this attempt to anticipate the effects of the drugs on the course of the disease that has created the most uncertainty and controversy in the field of Parkinson’s disease (PD) therapeutics. The challenge has been to disentangle symptomatic drug effects, long-term adverse effects and disease progression. We have previously described a pharmacological interpretation of the effects of levodopa in PD [1]. That review focussed on the time course of motor effects within a dosing interval of minutes to hours and identified the pharmacological features of effects of levodopa that might distinguish the clinical patterns of stable and fluctuating response. In particular, we pointed out that the shorter equilibration half-life of levodopa in fluctuating patients was the most influential single parameter explaining the differing time course of response in these patient groups. In the decade that has passed we have taken a longer term view of the response to levodopa and studied its evolution in cohorts of patients over several years [2–6]. This long-term approach has enabled us to identify and describe new features of the clinical pharmacology of levodopa in which we have relied heavily on appreciating the role of the passage of time on a longer time scale than the dosing interval. Our approach involves examining changes in the response to antiparkinsonian medications as well as progression of the disease as measured by clinical function over years. Our aim here is to summarize these findings and propose a further level of integration of a model for levodopa pharmacodynamics in PD and discuss its implications for long-term treatment strategies and the evaluation of new treatments.

The Pharmacokinetics and Pharmacodynamics of Levodopa in the Treatment of Parkinsons Disease

Levodopa, a prodrug of dopamine, remains to be one of the main drugs in the treatment of Parkinson's disease. All current levodopa products are formulated with aromatic amino acid decarboxylase inhibitors such as carbidopa or benserazide to prevent the metabolism of levodopa in the gastrointestinal tract and systemic circulation. Levodopa pharmacokinetic profiles remain unchanged after multiple doses, and are similar between healthy volunteers and patients and among patients at different stages of disease. Entacapone inhibits the metabolism of levodopa therefore increases the area under the plasma concentration-time profile of levodopa; however, it may decrease the initial absorption rate of levodopa in some patients probably due to competitive absorption. Food appears to affect the absorption of levodopa, but its effects vary with formulations. The results of positron emission tomography study suggest that a high protein diet may compete with the uptake of levodopa into the brain, therefore, may result in reduced levodopa effects. Since infusion studies demonstrated that it is beneficial to maintain stable plasma concentrations of levodopa, controlled-release formulations have been designed to provide prolonged absorption of levodopa. However, subsequent pharmacokinetic and pharmacodynamic studies demonstrated that a threshold concentration of levodopa appears to be necessary to switch patients "on". Once patients are turned "on", the duration of levodopa effects may be correlated with plasma concentration of levodopa. As such, more recent studies have demonstrated significant clinical benefits such as shorter time to "on" and longer duration of "on" when combining the immediate- and controlled-release levodopa products as compared to controlled-release levodopa products. Given these findings, it is important for physicians to understand the relationship between the pharmacokinetics and pharmacodynamics of levodopa in order to provide dosage regimens that meet patient needs. The pharmacokinetics and pharmacodynamics data of levodopa reported in the literature are reviewed here.

Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations.

Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 microg/mL and peak concentrations between 0.95 to 13.75 microg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

Interactions between deep brain stimulation and levodopa in Parkinson's disease.

To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease

Annals of NeurologyVolume 49, Issue 3 p. 285-287 Editorial The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease Kirk A. Frey MD, PhD, Kirk A. Frey MD, PhD Departments of Radiology (Division of Nuclear Medicine) and Neurology, University of Michigan, Ann Arbor, MISearch for more papers by this author Kirk A. Frey MD, PhD, Kirk A. Frey MD, PhD Departments of Radiology (Division of Nuclear Medicine) and Neurology, University of Michigan, Ann Arbor, MISearch for more papers by this author First published: 01 March 2001 https://doi.org/10.1002/ana.62Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume49, Issue31 March 2001Pages 285-287 RelatedInformation

The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease

The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease

Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease

Dopamine receptor agonists were originally developed as adjunctive therapies to ‘smooth out’ motor response fluctuations to levodopa in patients with advanced Parkinson’s disease. However, they are now used in the early stages of the disease, in monotherapy or combination with low doses of levodopa, to delay the onset of levodopa therapy and its complications. Oral dopamine agonists currently available worldwide for Parkinson’s disease include the older ergot derivatives bromocriptine and pergolide and the second generation non-ergoline compounds ropinirole and pramipexole. Other dopamine agonists that are used less frequently include cabergoline (a new ergoline drug, only recently released in some European countries as an antiparkinsonian drug), lisuride (an ergot derivative) and piribedil (an older non-ergot compound). Data on the pharmacokinetics of oral dopamine agonists, especially the older ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, are subject to extensive enterohepatic first-pass metabolism. Their bioavailability is low and shows high intra- and interindividual variability. The pharmacodynamic properties of dopamine agonists relevant to their antiparkinsonian effect have not been clearly defined. As a result, an optimal dosage schedule for the treatment of Parkinson’s disease is generally identified using highly individualised empirical assessment. This involves considerable time expenditure and creates difficulty for patients, who have to follow complex titration schedules. Dopamine agonists appear to have a low potential for pharmacokinetic interaction with levodopa. Few data have been reported on the effect of coadministration on the pharmacodynamics of levodopa. The available data indicate that pergolide and bromocriptine significantly increase the duration of the motor response to levodopa, while baseline motor effects and the magnitude of motor response are substantially unchanged. Cabergoline also significantly prolongs the motor response to a dose of levodopa in patients experiencing motor fluctuations, but baseline motor scores are also significantly improved, suggesting a long-lasting effect. Subcutaneous apomorphine is currently the only non-oral formulation of a dopamine agonist available; it is used as add-on rescue therapy for patients who have advanced Parkinson’s disease and a wide spectrum of complex motor, sensory, autonomic and cognitive ‘wearing-off ’ phenomena not controlled by optimal oral dopaminergic therapy. Attempts to deliver apomorphine and other soluble dopamine agonists by more practical non-oral routes, such as intranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.

Pallidotomy improves motor responses and widens the levodopa therapeutic window in Parkinson's disease.

Stereotactic posteroventral pallidotomy (PVP) as a treatment for Parkinson's disease (PD) symptoms has been increasingly used in moderate-advanced disease. We examined the pharmacodynamic responses of PD patients to single oral levodopa doses and intravenous levodopa infusions before and after PVP surgery. Nine subjects with advanced PD received a single oral dose and ramped intravenous levodopa infusions before and 3-5 weeks after unilateral PVP. Timed motor tasks, Unified Parkinson's Disease Rating Scale (UPDRS) evaluations, and ordinal dyskinesia rating were performed after oral levodopa and during i.v. levodopa infusions. Serum prolactin and dopa levels were measured during the levodopa infusions. Overall timed motor but not motor UPDRS scores were improved after PVP in both the worst ("off") and best ("on") states. Contralateral but not ipsilateral limb dyskinesias were substantially reduced at all serum (dopa) levels after PVP. Ipsilateral and contralateral timed motor performance at low serum (dopa) levels was improved by PVP. Walking speeds at all serum (dopa) levels were not changed by PVP. Serum prolactin was reduced equally by increasing (dopa) preoperatively and postoperatively. PVP significantly and favorably altered oral and intravenous levodopa pharmacodynamics by improving bilateral limb motor function and contralateral dyskinesia but did not alter walking speed. PVP appears to widen significantly the therapeutic window for levodopa in PD.