Levodopa In Parkinsonian Patients Research Articles

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. The cumulative additional levodopa dose throughout 37weeks and dose increase over 36weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. Japan Registry of Clinical Trials: jRCTs031180248.

Long Term Response to Levodopa in Parkinson's Disease.

Levodopa is the most efficacious medication in controlling the motor symptoms of Parkinson's disease (PD). There continues to be a controversy as to whether levodopa remains effective after years of therapy. To assess the long-term effectiveness of levodopa in PD patients. The response to levodopa in PD patients undergoing a levodopa challenge for deep brain stimulation (DBS) surgery evaluation from June 1997 through March 2017 were evaluated. The patients were broken into four groups based on disease duration (Group I: 0- 5 years, Group II: 6- 10 years, Group III: 11- 15 years, and Group IV:≥16 years). Levodopa response was calculated based on the changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) scores in the medication ON and OFF states. A total of 361 PD patients were included. The mean age in Group I was 59.4 years with a mean disease duration of 3.9 years (n = 29), Group II was 61 years with a mean disease duration of 8.1 years (n = 131), Group III was 64 years with a mean disease duration of 12.8 years (n = 143), and IV was 66.5 years with a mean disease duration of 18.5 years (n = 58). There was a significant improvement in UPDRS motor and ADL scores after the levodopa challenge for all groups. In a subgroup of PD patients who were evaluated for DBS surgery, there was a marked improvement in UPDRS motor and ADL scores which did not decrease with disease progression.

Dopaminergic influences on risk preferences of Parkinson’s disease patients

Clinicians are increasingly recognizing impulse control disorders (ICDs) as a complication of dopaminergic treatment in Parkinson's disease (PD). Considering the pivotal role of dopamine in reward information processing, ICDs may originate from dysregulation of reward-oriented behavior, and the behavioral changes may be reflected in shifts of psychological risk preference during decision-making. We used a behavioral economics paradigm to evaluate quantitatively the risk preferences of PD patients in levodopa on and off states. We also examined age-matched healthy controls. We found that levodopa increased the subjective value and prolonged the decision time in PD patients. These effects are apparently not explained by kinematic improvements but are attributed to psychological shifts of risk preferences and increased attention during risky decision-making. The risk preferences of healthy controls were similar to those of PD on levodopa treatment. The risk preferences of PD patients were not correlated with the scores of routine cognitive batteries, suggesting that dopamine-sensitive risk preferences are independent of cognitive capacities as measured by conventional batteries, including general intelligence, memory, and frontal functioning. By contrast, apathy and ICD partially predicted the risk attitude in PD patients, suggesting a common background of limbic origin behind these properties. The present results demonstrated that dopamine deficiency in off-state PD leads to risk-avoiding behavior and levodopa treatment increases the risk preferences. Behavioral economics framework is useful to evaluate short-term psychological changes in response to levodopa in PD patients.

Simultaneous low-frequency deep brain stimulation of the substantia nigra pars reticulata and high-frequency stimulation of the subthalamic nucleus to treat levodopa unresponsive freezing of gait in Parkinson's disease: A pilot study

IntroductionExperimental studies suggest that low-frequency (LF) (63 Hz) deep brain stimulation (DBS) of the substantia nigra pars reticulata (SNr) could be useful to regulate gait disorders refractory to medical treatment in Parkinson's disease (PD). The SNr neurons could act as high-frequency (HF) pacemakers within locomotor control systems. Currently, no specific therapies can treat gait disorders in PD with insufficient response to dopaminergic treatment. ObjectiveTo investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone. MethodsPatients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson's Disease Rating. ResultsWe included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient. ConclusionCOMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option.

Association between DRD2 and DRD3 gene polymorphisms and gastrointestinal symptoms induced by levodopa therapy in Parkinson's disease.

Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.

Effect of 3 Single-Dose Regimens of Opicapone on Levodopa Pharmacokinetics, Catechol-O-Methyltransferase Activity and Motor Response in Patients With Parkinson Disease.

This study determined the effects of single doses of opicapone (OPC), a novel third-generation catechol-O-methyltransferase (COMT) inhibitor, on levodopa and 3-O-methyl-levodopa (3-OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double-blind manner, 25, 50, and 100 mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100 mg OPC, respectively. Maximum S-COMT inhibition (Emax ) ranged from 67.8% (25 mg OPC) to 100% (100 mg OPC). Peak and extent of S-COMT inhibition were dose-dependent. Maximum decrease in the plasma 3-OMD was observed following administration of 100 mg OPC. Opicapone administered concomitantly with standard-release 100/25 mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations.

P03-29 - Parkinson's disease and predictors of impulse control disorders in MMPI-2

This was a case control study involving 46 patients suffering from Parkinson disease (PD); 13 with impulse control disorder (ICD) and 33 without ICD; and 56 controls. The personality traits in these groups were analyzed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). 46 patients with PD and 56 control group subjects were included into study. ICD were identified in 13 patients from PD group. There were higher scores than pathological threshold (65) in four domains of MMPI-2 Clinical scales: D (Depression), Pt (Psychastenia), Sc (Schizophrenia) and SI (Social introversion) in PD patients with ICD; but there were not statistical difference in any of these scales in comparison with the group of PD patients without ICD. In the case of MMPI-2 Subscales and Content scales there were higher scores than pathological threshold in eight domains of MMPI-2: SOD (Social Discomfort), PD4 (Psychopatic deviate - social alienation), PA1 (Paranoia - persecutory ideas), SC1 (Schizophrenia), PA_O (Paranoia - subtle), MA_O (Hypomania - obvious), SI1 (Syness/Self-Consciousness), SI3 (Alienation self and others) and Ho (Hostility), but there were statistical differences only in one of these domains in comparison with the PD patients without ICD: SI3 (alienation self and others). There was earlier onset of the disease and higher dose of levodopa in PD patients with ICD than in PD patients without ICD.Supported by project IGA MZ ČR NS 10301-3/2009

Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson´s disease patients with motor complications

One of the complications of long-term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti-Parkinsonian treatments (dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another. This meta-analysis aims to assess more reliably the benefits and risks of the three classes of drugs (dopamine agonists, COMTIs and MAOBIs) currently used as adjuvant treatment to levodopa in PD patients suffering from motor complications. The three drug classes were compared with the aim of determining whether one class of drug provides better symptomatic control than another. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. Randomised trials comparing an orally administered dopamine agonist, COMTI or MAOBI versus placebo, both on a background of levodopa therapy, in PD patients experiencing motor complications. Two authors independently extracted data on off-time, levodopa dose, motor complications, side-effects, treatment concordance, clinician-rated disability, mortality, quality of life and health economic data. Forty-four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off-time (-1.05 hours/day, 95% confidence interval (CI) -1.19 to -0.90; P<0.00001), the required levodopa dose (-55.65 mg/day, CI -62.67 to -48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: -1.31 points, CI -1.62 to -0.99; P<0.00001; UPDRS motor score: -2.84 points, CI -3.36 to -2.32; P<0.00001; UPDRS total score: -3.26 points, CI -4.52 to -2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side-effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy.Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off-time (dopamine agonist: -1.54 hours/day; COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores - dopamine agonist: -10.01 points versus COMTI: -1.46 points versus MAOBI: -2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P=0.07). Compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side-effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed.

Levodopa Intake Increases Plasma Levels of S-Adenosylmethionine in Treated Patients With Parkinson Disease

Metabolism of levodopa via the enzyme catechol-O-methyltransferase requires S-adenosylmethionine (SAM) as a methyl donor. SAM caused Parkinson disease (PD)-like symptoms in rodents. Therefore, SAM could contribute to a decreased efficacy of levodopa in the long term. SAM levels were significantly reduced in levodopa-treated PD patients, but they showed increased enzyme methionine adenosyl transferase (MAT) activity, which induces SAM synthesis from methionine (MET). This may result from a rebound increase of SAM production. The objective of the study was to demonstrate an effect of acute levodopa intake on SAM synthesis in the plasma of treated PD patients. The authors measured SAM, MET, and levodopa plasma concentrations in 13 levodopa-treated PD patients before and after application of 125 mg levodopa/benserazide. Plasma levels of SAM and levodopa significantly increased, but MET concentrations did not significantly decrease. The SAM increase after levodopa intake may exert both a certain antidepressant and cognitive function improving effect. This is often observed in untreated PD patients who receive levodopa for the first time, or in more advanced, fluctuating PD patients, when they turn from the OFF to the ON phase. Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.

Effect of levodopa on pain threshold in Parkinson's disease: A clinical and positron emission tomography study

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa.

Effects of Gabapentin on the Motor Response to Levodopa

Motor fluctuations and dyskinesias affect many parkinsonian patients chronically treated with levodopa. Imbalance between gabaergic direct and indirect striatopallidal pathways may originate them. Manipulating GABA neurotransmission may be effective in the treatment of these patients. Gabapentin is an antiepileptic drug that increases the synthesis and release of GABA. Previous studies suggest that gabapentin may be useful in Parkinson disease (PD). To know the effects of gabapentin on the motor response to levodopa in PD patients with motor complications. A randomized double-blind, placebo-controlled, cross-over trial with four weeks of treatment. A tertiary referral center. Twenty subjects with PD and motor fluctuations and dyskinesias on stable antiparkinsonian treatment, took gabapentin up to a maximum dose of 2.400 mg/d in three doses and placebo. Three levodopa challenges were performed: at the beginning of the study and at the end of each period of treatment (4 weeks). Basal (off) and best (on) motor status were assessed by the UPDRS III. Latency to peak effect, magnitude of motor response (difference between "on" and "off" scores in the UPDRS III), duration of motor response and severity and duration of dyskinesias after each levodopa challenge were assessed. Patients' diaries were administered. : Fifteen patients completed the study. A significant improvement in the basal UPDRS III resulting in a significant reduction in the magnitude of the motor response after gabapentin was obtained (P < 0.001). No other changes were observed, either on pharmacological parameters or in levodopa-induced dyskinesias. Number of daily hours spent in "on," "on with dyskinesias" and "off" also remained unchanged. Tolerance was good, dizziness being the most common side effect. Gabapentin improved parkinsonian symptoms (basal UPDRS III and magnitude of the motor response) following levodopa. This improvement was not reflected in the daily motor situation of patients. Dyskinesias remained unchanged. Gabapentin was well tolerated. Further studies are needed to know the impact of these results in the long-term.

3-30-06 Improvements in function and pharmacodynamic response to levodopa in Parkinsonian patients following treatment with fluoxetin

3-30-06 Improvements in function and pharmacodynamic response to levodopa in Parkinsonian patients following treatment with fluoxetin

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Somatosensory evoked potentials and dopaminergic responsiveness to apomorphine and levodopa in parkinsonian patients.

Short-latency somatosensory evoked potentials (SSEPs) were recorded from 10 parkinsonian patients in 'off' and 'on' states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p<0.01) in N30 frontal component amplitude whereas in six of eight patients similarly assessed with levodopa we obtained a comparable improvement in SSEPs (p<0.01). Parietal SSEPs remained unchanged. This normalization of frontal SSEPs was concomitant with the clinical response and in some patients preceded the motor response. No changes were obtained in control subjects. The improvement in N30 potential occurred regardless of disease duration or the presence of motor fluctuations. SSEPs may represent an objective approach for assessing the dopaminergic response and the fluctuations of motor disability in parkinsonian patients.

Somatosensory Evoked Potentials and Dopaminergic Responsiveness to Apomorphine and Levodopa in Parkinsonian Patients

Short-latency somatosensory evoked potentials (SSEPs) were recorded from 10 parkinsonian patients in ‘off’ and ‘on’ states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p

Acute effects of levodopa on neuropsychological performance in stable and fluctuating Parkinson's disease patients at different levodopa plasma levels.

The contribution of dopaminergic systems to cognitive defects in Parkinson's disease and the cognitive effects of levodopa remain controversial. The levodopa plasma levels and the neuropsychological performance of 10 parkinsonian patients with a stable motor response to the drug and 10 matched parkinsonian patients with a 'wearing-off' phenomenon were studied 12 h after levodopa was withdrawn (time zero), and at 1 h and 4 h after an oral dose of levodopa (i.e. at '+1H' and '+4H'), to investigate whether discrete cognitive domains are more sensitive to levodopa in parkinsonian patients with the wearing-off phenomenon. Considering the 20 patients as a whole, levodopa significantly diminished the response time in verbal and visuospatial memory tests, the extradimensional matching test and the Wisconsin card sorting test (WCST), without significantly improving or worsening the patient's accuracy. A significant group-by-time effect was only evident in the WCST; while in stable patients levodopa produced no changes, wearing-off patients significantly reduced the number of categories achieved and had more perseverative errors at +1H, recovering at +4H. These results confirm previous findings of selective adverse effects of levodopa on highly demanding executive tasks in Parkinson's disease and additionally suggest that some previous discrepancies between studies may be accounted for by lack of differentiation between stable and wearing-off conditions. 'Frontal' disturbances on neuropsychological tests with levodopa may become evident only after massive degeneration of the dopamine systems has occurred.

Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: PHARMACODYNAMICS OF LEVODOPA IN PARKINSON'S DISEASE

1. Levodopa markedly reduces parkinsonism during the first years of treatment. However, with continued therapy the response to levodopa becomes erratic and is complicated by involuntary movements. To improve the therapy of parkinsonism, the challenge is to understand why fluctuations in response develop and, once developed, what controls the moment to moment motor status. 2. In patients with a fluctuating response to levodopa, three distinct responses can be recognized: a short-duration response, a long-duration response and a negative response. 3. The short-duration response, measured in minutes to hours, has a steep concentration-response relationship such that the response appears 'all or nothing.' The duration of effect is dose-responsive. The short-duration response becomes shorter during chronic therapy, possibly because of tolerance. The onset to effect becomes briefer and the magnitude of the response becomes larger during chronic therapy, possibly because of sensitization. 4. The long-duration response, measured in days to weeks, develops and decays slowly. The rate of decay is proportional to the severity of the parkinsonism and therefore this response may relate to dopamine storage capacity of remaining nerve terminals. 5. The negative response, measured in minutes, is a worsening of motor function as the short-duration improvement wears off. It may reflect a biphasic concentration-response relationship. 6. The response to levodopa in parkinsonian patients is a complex interplay between responses with different time courses and variably affected by sensitization, tolerance and disease progression.

Pharmacokinetic model of oral levodopa and role of carbidopa in parkinsonian patients.

A pharmacokinetic model of oral levodopa is proposed to elucidate the effects of carbidopa on the pharmacokinetics of levodopa. The propriety of the model was evaluated by simultaneous computer Multi-Line fitting for the plasma concentration-time data of levodopa and dopamine-3-O-sulfate (DA-S), a major metabolite of levodopa, after oral administration of three different levodopa doses to parkinsonian patients. Plasma profiles of levodopa and DA-S were also determined in 12 parkinsonian patients during daily oral administration of Neodopaston, a levodopa preparation containing carbidopa in tablet form. We investigated the role of carbidopa by comparing the populational mean parameters calculated in the levodopa alone model with those obtained in patients coadministered levodopa and carbidopa. The results indicated that the pharmacokinetics of levodopa coadministered with carbidopa were dose-independent and that carbidopa reduces the first-pass metabolism of levodopa in the gut wall to less than 10% of the dose absorbed, and decreases the systemic clearance of levodopa by 35-39%. The proposed pharmacokinetic model and the evaluation of carbidopa in this study will provide useful information for the development of drug delivery systems for levodopa or catechol-O-methyltransferase inhibitors, for further stabilization of plasma concentrations of levodopa in parkinsonian patients.

Effect of peripheral catechol‐O‐methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

Acute motor responses to intravenous levodopa in Parkinsonian patients

Acute motor responses to intravenous levodopa in Parkinsonian patients