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PubMed1998

Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias.

Parkinson's disease (PD) is a progressive neurologic condition characterized by tremor, slowness, stiffness, and unstable posture. Degeneration of dopamine-producing neurons in the substantia nigra causes PD. Treatment with levodopa, a precursor of dopamine, initially ameliorates the clinical manifestations of PD. However, chronic levodopa treatment can produce severe involuntary movements (so-called dopa-induced dyskinesias or DID), limiting treatment. Pallidotomy, placement of a surgical lesion in the internal segment of the globus pallidus, reduces DID. Because this result is inconsistent with current theories of both basal ganglia function and DID, it prompted us to investigate the brain's response to levodopa. We measured regional cerebral blood flow response to levodopa with positron-emission tomography in 6 PD patients with DID, 10 chronically treated PD patients without DID, 17 dopa-naïve PD patients, and 11 normals. The dose of levodopa was chosen to produce clinical benefit without inducing DID. This strategy allowed us to examine the brain response to levodopa across groups without the confounding effect of differences in motor behavior. We found that the DID group had a significantly greater response in ventrolateral thalamus than the other groups. This was associated with decreased activity in primary motor cortex. These findings are consistent with increased inhibitory output from the internal segment of the globus pallidus to thalamus after levodopa administration. They provide a physiological explanation for the clinical efficacy of pallidotomy and new insights into the physiology of the basal ganglia.

Adult↗
PubMed2005

Effects of subthalamic nucleus deep brain stimulation and levodopa on energy production rate and substrate oxidation in Parkinson's disease.

Patients with Parkinson's disease (PD) often lose weight, but after subthalamic nucleus deep brain stimulation (STN-DBS), they gain weight. We compared daily energy intake (DEI), resting energy expenditure (REE) and substrate oxidation rates (measured by indirect calorimetry) in nineteen STN-DBS-treated patients (Group S), thirteen others on pharmacologic treatment by levodopa (Group L) and eight control subjects. We also determined the acute effects of STN-DBS and levodopa on REE and substrate oxidation rates. STN-DBS treated patients gained 9.7 (SEM 7.1) kg after surgery, whereas patients on pharmacologic treatment lost 3.8 (SEM 10.0) kg since diagnosis. In STN-DBS-treated patients, REE (-16.5 %; P<0.001), lipid oxidation (-27 %; P<0.05) and protein oxidation (-46 %; P<0.05) were decreased, whereas glucose oxidation was elevated (+81 %; P<0.05) as compared to patients on pharmacologic treatment. Levodopa acutely reduced REE (-8.3 %; P<0.05) and glucose oxidation (-37 %; P<0.01) with a slight hyperglycaemic effect (after levodopa challenge: 5.6 (SEM 0.8) v. before levodopa challenge: 5.3 (SEM 0.6) mmol/l; P<0.01). Switching 'on' STN-DBS acutely reduced REE (-17.5 %; P<0.01) and lipid oxidation (-24 %; P<0.001) 30 min after starting stimulation. Fasting glycaemia was slightly but significantly reduced (5.4 (SEM 1.4) v. 5.5 (SEM 1.3) mmol/l; P<0.01). After STN-DBS, the normalization of REE and the reduction in lipid and protein oxidation contribute to the restoration of weight. As levodopa decreases glucose oxidation, the reduction in daily dose of levodopa in STN-DBS-treated patients helps prevent the effect of weight gain on glycaemia.

Antiparkinson Agents↗
PubMed1996

Effects of levodopa and viscosity on the velocity and accuracy of visually guided tracking in Parkinson's disease.

Deficits in velocity generation and movement accuracy occur in Parkinson's disease and are postulated to contribute to the characteristic bradykinesia. In the present study, we attempted to clarify the relationship between the deficits in velocity generation and movement accuracy. Patients with Parkinson's disease and normal controls tracked visually displayed sinusoidal and step targets with the wrist. Performance was evaluated using measurements of velocity and error. Movement velocity was manipulated by two methods: (i) administration of levodopa; (ii) viscous loading. Dependencies of velocity and error on disease state, medication state and viscosity were examined. Visually guided pursuit tracking was characterized by intermittent and frequent velocity excursions in both the patients and controls. For sinusoidal tracking, levodopa significantly increased velocity in the severely affected parkinsonian patients. Prior to the administration of levodopa, step tracking velocity was significantly lower in all patients than in controls. The "on' state produced an increase in velocity to control levels. Error was significantly greater in the parkinsonian subjects than in controls, but was unchanged by levodopa for both tracking tasks. Manipulations of viscosity produced greater changes in velocity than did levodopa, yet a similar independence with respect to accuracy remained. Velocity significantly changed by 40-60% in the two tracking tasks from the viscous to antiviscous loads. Error did not change significantly in 12 out of 14 comparisons of subgroups based on disease and medication state. This contradicts the hypothesis that patients with Parkinson's disease primarily reduce velocity during tracking to maintain acceptable accuracy in the presence of a defective error correction system. Although parkinsonian subjects tracked with reduced accuracy, both normal and parkinsonian subjects were able to compensate for significant changes in velocity due to external loading. Thus a propulsion deficit exists in parkinsonism that may be alleviated with either antiviscosity or levodopa. An error correction deficit is also present in parkinsonism, but is not modified by antiviscosity or levodopa.

Adult↗
PubMed2005

A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson's disease.

Endocannabinoids and cannabinoid CB1 receptors play a role in the control of movement by modulating GABA, glutamate, and other neurotransmitters throughout the basal ganglia. Roles for abnormalities in endocannabinoid signaling in Parkinson's disease (PD) and the major side effect of current treatments, levodopa-induced dyskinesia (LID), have been suggested by rodent studies. Here we show that signaling by endocannabinoids contributes to the pathophysiology of parkinsonism and LID in MPTP-lesioned, non-human primate models of Parkinson's disease. In MPTP-lesioned marmosets previously treated with levodopa to establish LID, attenuation of CB1 signaling by systemic administration of rimonabant (1 and 3 mg/kg) had anti-parkinsonian actions, equivalent to a 71% increase in motor activity at 3 mg/kg. Rimonabant did not elicit dyskinesia. Co-administration of levodopa (8 mg/kg) and rimonabant (1 and 3 mg/kg) resulted in significantly less dyskinesia than levodopa alone, without significantly affecting the anti-parkinsonian action of levodopa. These data suggest that enhanced endocannabinoid signaling may be involved in the pathophysiology of both parkinsonism and LID. To define potential mechanisms by which such a role might be mediated, we determined the levels of the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) throughout the basal ganglia in normal and three groups of MPTP-lesioned cynomolgus monkeys (untreated; acutely treated with L-DOPA, non-dyskinetic; long-term treated, with levodopa-induced dyskinesia). In the untreated, MPTP-lesioned primate, parkinsonism was associated with increases in both 2-AG (+88%) and anandamide (+49%) in the striatum, and of 2-AG (+97%) in the substantia nigra, changes that are consistent with the previously suggested role for endocannabinoids in mechanisms attempting to compensate for loss of dopamine in untreated parkinsonism. Increased levels of anandamide (+34%) in the external globus pallidus of MPTP-lesioned animals were normalized by levodopa treatment and may contribute to the generation of parkinsonian symptoms. However, no clear alteration in endocannabinoid levels could be correlated with the expression of LID. These data highlight the potential roles played by endocannabinoids and CB1 in PD and LID and suggest the need for further research to pursue the multiple therapeutic opportunities for manipulating this system in movement disorders.

Animals↗
PubMed1992

Pharmacodynamics of the hypotensive effect of levodopa in parkinsonian patients.

Blood pressure effects of i.v. levodopa were examined in parkinsonian patients with stable and fluctuating responses to levodopa. The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small hypotensive response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater hypotensive effects. Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes. Phenylalanine, a large neutral amino acid (LNAA) competing with levodopa for transport across the blood-brain barrier, reduced the hypotensive and antiparkinsonian effects of levodopa. We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients. The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients.

Amino Acids↗
PubMed1994

Safety of long-term levodopa therapy in malignant melanoma.

Levodopa therapy is contraindicated in malignant melanoma because of its apparent carcinogenic effects reported by physicians in the early 1970s. We discuss the case of a 74-year-old man with Parkinson's disease who was treated with levodopa and whose malignant melanoma was later diagnosed. Before development of malignant melanoma, the patient received an estimated 5.7 kg levodopa over 6 years. Therapy with levodopa was continued for > 10 years, with a total dose of approximately 4.3 kg levodopa (together with carbidopa.) Recurrence of the melanoma was not observed. Based on our experience with this patient and an extensive literature review, we conclude that the natural history of malignant melanoma is not adversely influenced by concurrent levodopa therapy. Levodopa therapy should not be withheld for fear of accelerating malignant melanoma in parkinsonian patients.

Aged↗
PubMedDate not supplied

Clinical, pharmacokinetic, and pharmacodynamic effects of tolcapone withdrawal in levodopa-treated patients with parkinsonism.

The effect and clinical significance of tolcapone withdrawal on erythrocyte catechol-O-methyltransferase (COMT) activity, levodopa pharmacokinetics, and levodopa requirements were investigated in 59 patients with fluctuating parkinsonism who were randomized to receive placebo or tolcapone 100 or 200 mg three times daily for 6 weeks. Tolcapone withdrawal caused a transient elevation in COMT activity by 64% in patients receiving 100 mg three times daily and by 128% in those receiving 200 mg three times daily at approximately 1-2 weeks after discontinuation of drug. Thereafter, COMT activity was declining but did not reach baseline values by the 12-week study endpoint. However, this had no effect on plasma levodopa and 3-O-methyldopa (3-OMD) concentrations or on levodopa requirements. During treatment, tolcapone increased "on" time and decreased "off" time; after discontinuation of study medication and levodopa dose adjustment, on and off times were similar to baseline. Withdrawal was generally well tolerated; no patients withdrew from the trial during the posttreatment period, and no serious adverse events were observed. In conclusion, the transient increase in erythrocyte COMT activity observed after discontinuation oftolcapone is not associated with changes in peripheral levodopa metabolism and therefore has no significant clinical consequences in terms of levodopa requirements, clinical symptoms, or adverse events.

Aged↗
PubMedDate not supplied

Effect of late initiation of levodopa treatment in patients with long-standing Parkinson's disease.

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.

Adult↗
PubMedDate not supplied

Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release.

OBJECTIVE: Restless legs syndrome (RLS) is a common neurologic condition characterized by uncomfortable and unpleasant sensations in the legs, occurring primarily at rest, which are usually worse in the evening and are alleviated by movement. RLS is present in 20-40% of patients with renal failure. This study was a 14-week open, randomized, crossover trial of ropinirole vs. levodopa sustained release (SR) in 11 patients with RLS on chronic hemodialysis. METHODS: Eleven patients (7 men, 4 women) were enrolled in the study. They received either levodopa SR or ropinirole for 6 weeks, followed by a washout week, then the alternate treatment for 6 weeks. Patients rated the severity of RLS by means of a 6-item questionnaire developed by the International Restless Legs Study Group (6-item IRLS), by the Clinical Global Impression (CGI) scale, and by sleep diaries. RESULTS: Under treatment with levodopa SR, 1 patient presented severe vomiting, leading to study discontinuation. The 10 patients who completed the study reported a 33.5% improvement (from 16.7 +/- 3.2 to 11.1 +/- 4; P < 0.001) of the 6-item IRLS scores during levodopa SR treatment and a 73.5% improvement (from 16.6 +/- 2.8 to 4.4 +/- 3.8; P < 0.001) during ropinirole treatment. By the end of the study the mean levodopa SR dosage was 190 mg/d and the mean ropinirole dosage was 1.45 mg/d. Ropinirole was superior to levodopa SR in reducing 6-item IRLS scores (P < 0.001) and in increasing sleep time (P < 0.001). The patient CGI scale showed a significant difference favoring ropinirole (P < 0.01). There was no significant carryover or period effect for any outcome measure. Four patients reported a complete reversion of RLS symptoms during ropinirole treatment at doses ranging from 0.25-2 mg/d. CONCLUSIONS: These results suggest that ropinirole is more effective than levodopa SR in the treatment of RLS in patients on chronic hemodialysis.

Antiparkinson Agents↗
PubMedDate not supplied

Switching from levodopa to the long-acting dopamine D2/D3 agonist piribedil reduces the expression of dyskinesia while maintaining effective motor activity in MPTP-treated primates.

BACKGROUND: The control of motor complications following dopaminergic medication in late-stage Parkinson disease remains problematic. OBJECTIVE: We now investigate the potential of oral administration of the long-acting dopamine D2/D3 agonist piribedil to decrease the expression of dyskinesia induced by prior exposure to levodopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates. METHODS: MPTP-treated common marmosets were treated with equieffective doses of levodopa (10.0-12.5 mg/kg PO, twice daily) or piribedil (3.0-4.0 mg/kg PO, once daily) for 30 days and then switched to the alternative treatment for a further 35 days. RESULTS: Levodopa administration markedly improved motor function, but dyskinesia rapidly appeared and intensified as treatment progressed. Administration of piribedil produced a similar reversal of MPTP-induced motor deficits but with comparatively mild dyskinesia. On switching from levodopa to piribedil, the intensity of dyskinesia decreased without altering the improvement in motor deficits. However, on switching from piribedil to levodopa, the rapid increase in dyskinesia despite the improvement in motor function being maintained suggests that piribedil also primes for but does not markedly express dyskinesia. CONCLUSION: The study confirms the low dyskinesia expression resulting from piribedil treatment compared with an equieffective dose of levodopa. Importantly, the results show that switching from levodopa to piribedil rapidly results in a sustained decrease in dyskinesia intensity.

Animals↗
PubMed1986

The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on-off fluctuations.

We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on-off fluctuations whilst receiving long-term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32-80 mg h-1 (0.5-1.3 mg kg-1 h-1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l-1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3-OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two-compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on-off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.

Absorption↗
PubMed1978

Effect of a slow release preparation of levodopa on Parkinson's disease in combination with a peripheral decarboxylase inhibitor.

Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.

Adult↗
PubMed2006

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability.

5-Hydroxytryptamine 1a (5-HT(1a)) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT(1a) receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT(1a) agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(+)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(+)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(+)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(+)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT(1a) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY-100635) (1.0 mg/kg s.c.). Administration of (R)-(+)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D(2)/D(3) dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT(1a) agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson's disease.

To assess the relative influence of central pharmacodynamic and peripheral pharmacokinetic factors on the duration of motor response to levodopa, the relationship between motor function and plasma levodopa levels was studied in 31 Parkinsonian patients. Duration of benefit from single levodopa doses while fasting depended on the degree to which the plasma levodopa level had declined over four hours; wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.

Administration, Oral↗
PubMed1996

Motor fluctuations in levodopa treatment: clinical pharmacology.

Fluctuations in motor performance and dyskinesias are a common problem in the long-term management of Parkinson's disease. The pharmacokinetics and the pharmacodynamics of levodopa, loss of presynaptic dopamine terminals, alterations in postsynaptic dopamine receptor sensitivity, or changes in the modulatory influences of nondopaminergic transmitter system could play a pathogenic role. The short half-life of levodopa and its absorption and transport are important factors. The pharmacodynamic response to levodopa changes during long-term therapy. An absolute threshold in plasma levodopa level, below which the patients are off, appears. The patients show a therapeutic window for levodopa which becomes narrower with time. This therapeutic window can be widened by giving continuous infusion of dopaminergic drugs. Motor fluctuations can be ameliorated by a more physiological continuous stimulation of the receptor site and by avoiding repeated shifting in levodopa levels. Long-term complications are attenuated by an early combination of levodopa with dopamine agonist.

Antiparkinson Agents↗
PubMedDate not supplied

Effects of bromocriptine on dopamine turnover with or without levodopa.

Bromocriptine, a dopamine agonist, alleviates symptoms of Parkinson's disease, even when administered alone, and is used for its treatment. Better therapeutic effects are, however, achieved when bromocriptine is used in combination with levodopa. In this study, we examined the biochemical changes caused by bromocriptine administration with and without levodopa, and evaluated the effects of the treatments on dopamine turnover in the mouse striatum. Results show that dopamine turnover is suppressed by the administration of bromocriptine alone with a slight decrease in the amount of dopamine, and dopamine turnover is very strongly promoted by the administration of levodopa. When the two drugs are administered together, bromocriptine enhances the levodopa-induced increase in dopamine turnover in the striatum. These findings indicate that bromocriptine therapy in combination with levodopa enhances the dopaminergic function and suggest that the combination therapy of bromocriptine and levodopa shows good efficacy. The results of this study may, thus, provide a theoretical basis for the combination therapy of bromocriptine and levodopa.

Analysis of Variance↗
PubMed2003

Effects of levodopa on motor sequence learning in Parkinson's disease.

BACKGROUND: Dopaminergic therapy with levodopa improves motor function in PD patients, but the effects of levodopa on cognition in PD remain uncertain. OBJECTIVE: To use H(2)(15)O and PET to assess the effect of levodopa infusion on motor sequence learning in PD. METHODS: Seven right-handed PD patients were scanned "on" and "off" levodopa while performing a sequence learning task. The changes in learning performance and regional brain activation that occurred during this intervention were assessed. RESULTS: During PET imaging, levodopa infusion reduced learning performance as measured by subject report (p < 0.05). This behavioral change was accompanied by enhanced activation during treatment in the right premotor cortex and a decline in the ipsilateral occipital association area (p < 0.01). Levodopa-induced changes in learning-related activation responses in the occipital association cortex correlated with changes in learning indexes (p < 0.01). CONCLUSIONS: Levodopa treatment appears to have subtle detrimental effects on cognitive function in nondemented PD patients. These effects may be mediated through an impairment in brain activation in occipital association cortex.

Aged↗
PubMed1991

Acute effects of pulsatile levodopa administration on central dopamine pharmacodynamics.

Inconsistencies in the response to individual levodopa doses occur in most patients with advanced Parkinson's disease (PD). To investigate the possible development of acute tachyphylaxis, we evaluated the effects of repeated injections of intravenous levodopa in 10 PD patients with motor fluctuations by administering, during a single day, a previously determined optimal levodopa dose repeatedly each time motor function returned to baseline. Peak antiparkinsonian response was lower by 20%, and peak plasma levodopa levels lower by 35% following the first dose compared with all subsequent doses. Neither peak dyskinesia scores nor the duration of motor response changed significantly with successive levodopa doses. These data suggest that pulsatile levodopa administration does not acutely alter dopamine receptor responsiveness, and that other pharmacokinetic and pharmacodynamic factors contribute to the dose-to-dose variability in response to levodopa.

Dopamine↗