[Early deep brain stimulation for Parkinson's disease]. / Brauchen wir die frühzeitige tiefe Hirnstimulation beim Morbus Parkinson?

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment for advanced Parkinson's disease with levodopa-induced motor complications. Randomized controlled studies have shown that motor fluctuations and quality of life are significantly more improved by STN-DBS than by best medical treatment. The main delay before neurosurgery is currently 14 years after diagnosis. Clinical pilot data suggest that neurosurgery performed already with beginning motor fluctuations and an average disease duration of 7 years may lead to earlier improvement of motor deficits and quality of life, thus preventing disease-related psycho-social decline, and extending the period of beneficial effects of STN-DBS. Results of an ongoing multicenter trial (EARLYSTIM) comparing the effects of STN-DBS and best medical treatment on motor symptoms, quality of life, and psycho-social adaptation will be available in 2 years time and will clarify whether or not early STN-DBS is superior to best medical treatment.

Drug costs for patients with Parkinson's disease in two different European countries.

OBJECTIVE: To examine factors that influence drug costs in patients with Parkinson's disease (PD) and to compare the costs in two different countries. METHODS: We examined drug costs among 438 patients with PD (286 from Germany and 152 from Norway) and collected information on the patients' age, medication, disease duration, and Hoehn & Yahr stage. RESULTS: Drug expenses rose with increasing severity and duration of the disease. This increase differed somewhat between the two countries. Mean drug costs per day and patient in the German group was Euro 5.78 while it was Euro 3.92 in the Norwegian group. A higher proportion of the German patients were treated with two or more drugs, and the switch from mono- to multi-drug therapy was done earlier in the course of the disease. Dopamine agonists caused 44% of total drug costs in both countries. CONCLUSION: Different management strategies of PD have a great impact on drug costs. Surveillance of prescription habits and careful cost/benefit analyses are therefore important.

The DONPAD-study--treatment of dementia in patients with Parkinson's disease with donepezil.

Inhibition of acetylcholinesterase improves symptoms of dementia in patients with Parkinson's disease (PD). Dementia in PD has a cumulative incidence of up to 80% and is mainly caused by a distinct cholinergic deficit. Objectives of this investigator initiated multicenter open label trial were to confirm the efficacy of donepezil in the treatment of dementia in PD patients and to investigate the tolerability and safety of donepezil. The Mini Mental State Examination (MMSE)-score significantly increased in patients, who finished the trial. A detailed analysis of the various items of the MMSE revealed, that only task performance of orientation and recall significantly improved. Scores of the short syndrome test and the Clinical Global Impression Scale improved, motor impairment did not increase. Only 14 out of 24 PD patients finished the trial due to predominant onset of vomiting, nausea, dizziness and confusion. This may result from the titration regime of donepezil, that allows only 5 and 10 mg dosages. Participants with premature study termination had a significant longer duration of PD, less motivation and sleep disturbances at night. Treatment with donepezil was only effective in PD patients with dementia, who experience nearly no side effects from the drug.

Which factors influence therapeutic decisions in Parkinson's disease?

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years, some but not all pathogenetic mechanisms causing dyskinesias in PD have become better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and colocalized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long-acting DA-agonists or highly selective D2-agonists. Another strategy is the use of NMDA antagonists.

Efficacy of cabergoline in long-term use: results of three observational studies in 1,500 patients with Parkinson's disease.

The tetracyclic ergoline derivative cabergoline was investigated in three studies to test its efficacy in treating the motor symptoms of Parkinson's disease. In two studies, it was used as an add-on agent to the previous medication regimen that included other parkinsonian drugs, including levodopa. In the third study, cabergoline was switched from another dopamine agonist. All studies proved this drug's effectiveness in treating such motor symptoms as akinesia, dyskinesia, and nocturnal akinesia. Quality of life and disability in activities of daily living assessments were measured by PDQ 39 or UPDRS VI. Treatment with cabergoline showed higher efficacy and greater safety than other parkinsonian drugs.

Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.

OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.

Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[18F]levodopa positron emission tomography in patients with Parkinson's disease.

OBJECTIVE: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. METHODS: Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model. RESULTS: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively). CONCLUSIONS: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.

The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa.

The aim of our study was to evaluate the influence of low-intensity exercise on levodopa absorption and levodopa motor effect. We studied the pharmacokinetics and pharmacodynamics of levodopa under resting conditions and under a workload of 50 watts for 2 hours on a cycle ergometer in 12 parkinsonian patients with predictable fluctuations of motor disability. The patients attended the hospital on both days in a provoked off state. After a baseline assessment of motor disability using the Columbia University rating scale (CURS scale) and a blood test for measurement of the baseline levodopa concentration in the plasma, 100 mg levodopa and 25 mg benserazide were administered as a single dose orally. Blood samples for measurement of the levodopa concentration in the plasma were taken, and motor assessments were conducted at 15-minute intervals for 240 minutes and at 30-minute intervals from 240 to 360 minutes. All patients were able to perform the exercise program. The baseline Columbia University rating scale score did not differ significantly between both days. The mean levodopa concentration in plasma at half-maximal motor effect tended to be higher during exercise and indicated that the patients needed a higher levodopa concentration in plasma to achieve the half-maximal motor effect. The maximal levodopa concentration in plasma tended to be higher with exercise. Both trends did not reach statistical significance. In summary, there was not a negative or a positive net effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. However, there were two counteracting trends: a trend toward better levodopa absorption and a trend toward a deteriorated concentration-effect correlation.

Dyskinesia in Parkinson's disease. Pathophysiology and clinical risk factors.

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years some but not all pathogenetic mechanisms causing dyskinesias in PD have been better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and co-localized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long acting DA agonists or highly selective D2 agonists. Another strategy is the use of NMDA antagonists.

Workshop III: late motor complications of Parkinson's disease.

The aim in the current treatment of Parkinson's disease is to delay L-Dopa administration and to keep the L-Dopa dosage as low as possible. Such a treatment strategy can delay the onset of late motor complications and reduce their severity. L-Dopa remains the most potent anti-parkinsonian medication, but its use for the initial therapy of Parkinson's disease is limited to elderly patients. In all other cases, dopamine agonists, budipine, amantadine and selegiline are primarily used. With the occurrence of late motor complications continuous dopamine receptor stimulation becomes essential. In this situation, combination therapy has to be individualized, with dopamine agonists playing a key role. In addition, COMT inhibitors, budipine, amantadine and selegiline may be used. Anticholinergic drugs are of very limited importance in the current treatment of Parkinson's disease.

Therapeutic value of exercise training in Parkinson's disease.

PURPOSE: The objective of this study was to investigate the influence of an intensive exercise training on motor disability, mood, and subjective well-being in parkinsonian patients. METHODS: The study was designed as an open long-term pilot trial over 20 wk. Sixteen slightly to moderately affected idiopathic parkinsonian patients (PD) were included. An intensive standardized exercise training was performed twice weekly over 14 wk in all patients. Evaluations were performed before the start of the study (exam. 1), after 7 wk (exam 2), 14 wk (exam 3), and 20 wk (exam 4/long-term effect). The test battery included: 1) basic motor test (BMT) [test for muscle strength, flexibility, and coordination]; 2) Unified Parkinson's Disease Rating Scale (UPDRS) and Columbia University Rating Scale (CURS) for PD-specific motor disability; and 3) registration of psychometric data by Mini Mental State (MMS) for dementia and the Adjective Mood Questionnaire of Zeersen (AMQZ) and Sickness Impact Profile (SIP) for subjective well-being. RESULTS: UPDRS sigma score (P < 0.0001), CURS sigma score (P < 0.0001) and BMT 2 score (P < 0.0001) improved significantly by exercise training. Six weeks after termination of the training program, the majority of the patients had lost only minor components of their regained motor skills. There was no significant change in cognitive function during the study. The results of open interviews referring to subjective well-being were confirmed by the AMQZ and SIP. As an unexpected side effect, dyskinesias seemed to be better controlled. CONCLUSION: Motor disability as well as mood and subjective well-being can be clearly improved by intensive sports activities in early to medium stage PD patients. A sustained ongoing benefit outlasting the active training period for at least 6 wk can be achieved but the exact duration of this benefit is open.

Exercise test in Parkinson's disease.

UNLABELLED: In this study we assessed cardiovascular performance and metabolic response after an exercise test in Parkinsonian patients (PD patients). METHODS: 15 PD patients (10 male, 5 female; mean age:63 +/- 6.17 y; mean weight: 72.2 +/- 9.5 kg) and 15 sex, age (mean: 63.8 +/- 5.38 y), and weight-(mean: 72.2 +/- 8.69 kg) matched controls performed an exercise test using a cycle ergometer and a ramp protocol. All patients and control subjects underwent a heart rate variability test prior to the exercise test. At rest and at the end of each interval blood pressure (BP) and capillary lactate samples were taken. Heart rate was monitored continuously. RESULTS: The heart rate variability tests were abnormal in Parkinson's patients. All patients and control subjects achieved an intensity level of 75 watts, 12/15 PD patients managed 100 watts, and 7/15 PD patients managed 150 watts. 12/15 control subjects performed at an intensity level of 125 Watts and 9/15 at an intensity level of 150 Watts. There was no statistically significant difference in heart rate increase but there was a tendency to lower lactate levels at high intensity levels in PD patients. PD patients had a statistically lower systolic BP at 75, 100, 125, and 150 watts. CONCLUSION: We did not find striking differences in cardiovascular adaptation to physical work in PD patients and we propose, therefore, that it should be possible to improve cardiovascular endurance in PD patients. Previously, reports have suggested respiratory chain impairment in Parkinson's disease and poor endurance performance. However, our results do not support a clinically relevant impairment of the respiratory chain.

Concentration-response relationship of levodopa in patients at different stages of Parkinson's disease.

OBJECTIVE: To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment. METHODS: We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life). RESULTS: The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05). CONCLUSIONS: The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.

Dose response and concentration response relationship of apomorphine in patients with Parkinson's disease and end-of-dose akinesia.

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease presenting end-of-dose motor fluctuations. Aim of the study was to investigate the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuators. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) elicited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg dose, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is considered clinically relevant, a response was seen in 0/10 patients (0.5 mg), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg). The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentration vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of the individual curves averaged 20 pMol/ml. However, several curves exhibited proteresis, making the application of a PK-PD model impossible. The reason for proteresis is not clear, it might indicate acute tolerance as well as a redistribution of apomorphine from the effect site.

Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations.

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agonist apomorphine was investigated in parkinsonian patients with end-of-dose motor fluctuations. The relation between levodopa plasma concentrations and motor response was examined in a double-blind, randomized, crossover design in 10 patients with idiopathic Parkinson's disease with end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each patient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores (sigma score) of the Columbia University Rating Scale (CURS) were used as effect parameters for pharmacodynamic assessment. A sigmoidal Emax model was fitted to the data using a semiparametric pharmacokinetic-pharmacodynamic approach. Levodopa pharmacokinetics were not significantly modified by the coadministration of apomorphine. The area under the curve was 1599 +/- 615 ng.ml-1 h. (levodopa + saline) and 1821 +/- 625 ng.ml-1.h (levodopa + apomorphine). Cmax was 1094 +/- 476 ng.ml-1 (levodopa + saline) and 1129 +/- 435 ng.ml-1 (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (Emax) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.ml-1 (levodopa + saline) to 315 +/- 123 ng+ml-1 (levodopa + apomorphine) (95% confidence interval [CI] 0.51 -0.98, point estimator 0.75). The mean duration of the motor response rose from 1.9 +/- 0.5 h (levodopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold levels for levodopa (EC50) was accompanied by approximately 50% gain in on-phase duration, but not in an increased magnitude of the motor response (Emax).

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

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

Quantification of IBZM dopamine receptor SPET in de novo Parkinson patients before and during therapy.

A number of neurodegenerative diseases have been evaluated with 123I-iodobenzamide (123I-IBZM) dopamine receptor scintigraphy, including Parkinson's disease. Differential diagnosis is based on the semi-quantitative determination of striatal uptake in the basal ganglia. Seven procedures for calculating basal ganglia uptake were compared and checked statistically in (1) 28 previously untreated de novo parkinsonian patients before and (2) 14 patients after (mean of 9 months) commencement of anti-Parkinson medication. Of the 21 hemi-parkinsonian patients, 16 demonstrated increased uptake contralaterally (mean right-to-left difference = 8%, sensitivity = 76%) using the most robust uptake procedure. The difference in uptake between the affected and contralateral sides (mean = 6%) was significant (P = 0.02). The mean (+/- S.D.) basal ganglia/frontal cortex (BG/FC) ratio was 1.55 +/- 0.14 (attenuation-corrected). Attenuation correction did not affect the relative ratio of basal ganglia uptake (P = 0.01). The anti-Parkinson medication did not result in any significant changes in the BG/FC ratio at follow-up, but responders could be differentiated from non-responders based on initial uptake (mean BG/FC ratio of 1.58 and 1.39 respectively). We conclude that 123I-IBZM can be used routinely to identify which Parkinson patients will benefit from dopaminergic medication.

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P

Concentration-effect relationship of levodopa in patients with Parkinson's disease.

Studies on the concentration-effect relationship of levodopa in Parkinson's disease have established that: (1) in patients with a fluctuating response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e. potency is decreased) compared with those patients whose symptoms are adequately controlled; (2) with controlled-release (CR) preparations, the concentration-effect relationship indicates a decreased potency compared with conventional immediate-release (IR) preparations; and (3) coadministration of a dopamine receptor agonist (even at a subclinical dose) enhances the potency of levodopa. These findings support some current hypotheses on the origin of, and the pathophysiological process underlying, response fluctuations. In patients with response fluctuations, metabolism of levodopa and storage of dopamine in the striatum are reduced. Levodopa is decarboxylated in the extracellular space, with the result that dopamine is released directly to the effect site. Thus, without dopamine storage acting as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa concentrations. Even small fluctuations of levodopa concentrations around the EC50 value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylation of levodopa) are required. The storage buffer is responsible for a time lag between decline in peripheral plasma concentrations of levodopa and dopamine-induced motor response. Low doses of a dopamine receptor agonist increase the basal tonus of the striatum, but do not reach the threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switch from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-pharmacodynamic modelling does not give a clear answer as to whether response fluctuations are additionally induced by receptor desensitisation or inhibition of the active transport of levodopa across the blood-brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Nevertheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations are compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response fluctuations. The interindividual variability of EC50 values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical effects). However, considering the short elimination half-life of levodopa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interval with CR preparations might be limited by the higher threshold concentrations of levodopa necessary to maintain clinical effects.