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At least 19 recordsLinked to original sources
PubMed2000

Ropinirole for levodopa-induced complications in Parkinson's disease.

BACKGROUND: Long-term levodopa therapy for Parkinson's disease is complicated by the development of motor fluctuations and abnormal involuntary movements. One approach is to add a dopamine agonist at this stage of the disease to reduce the time the patient spends immobile or off and to reduce the dose of levodopa in the hope of reducing such problems in the future. OBJECTIVES: To compare the efficacy and safety of adjuvant ropinirole therapy versus placebo in patients with Parkinson's disease already established on levodopa therapy and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with SmithKline Beecham. SELECTION CRITERIA: Randomised controlled trials of ropinirole versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Three double-blind, parallel group, randomised, controlled trials have been conducted on 263 patients. The two phase II studies were relatively small, were conducted over the short term (12 weeks), and used relatively low doses of ropinirole. The other phase III study was medium term (26 weeks) and used ropinirole doses in line with the current UK licensed maximum. Additional data from the manufacturer showed that the difference in the reduction in off time was non-significantly greater with ropinirole than placebo (weighted mean difference [WMD] 0.19 hours; -0.63, 1.00 95% CI). As an adverse event, dyskinesia was significantly increased in those who received ropinirole (odds ratio [OR] 2.59; 1.35, 4.96 95% CI; p < 0.004). Measurements of motor impairments and disability were poor in these studies with incomplete information available. Levodopa dose could be reduced in two studies with a significantly larger reduction on ropinirole than on placebo (WMD 136.5mg/d; 74.5, 198.6 95% CI; p =0.00002). No significant differences in the frequency of adverse event reports were noted between ropinirole and placebo apart from the increase in dyskinesia with ropinirole. There was a trend towards fewer withdrawals from ropinirole but this did not reach statistical significance. REVIEWER'S CONCLUSIONS: Ropinirole therapy can reduce levodopa dose but at the expense of increased dyskinetic adverse events. No significant effect on off time reduction was found but this may have been due to under-powered trials and the low doses of ropinirole used in the phase II studies. Inadequate data on motor impairments and disability was collected to assess these outcomes. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of effectiveness, and also studies to compare the newer with the older dopamine agonists.

Antiparkinson Agents↗
PubMed2000

Ropinirole versus bromocriptine for levodopa-induced complications in Parkinson's disease.

BACKGROUND: Long-term levodopa therapy for Parkinson's disease is complicated by the development of motor fluctuations and abnormal involuntary movements. One approach is to add a dopamine agonist at this stage of the disease to reduce the time the patient spends immobile or off and to reduce the dose of levodopa in the hope of reducing such problems in the future. OBJECTIVES: To compare the efficacy and safety of adjuvant ropinirole therapy with bromocriptine in patients with Parkinson's disease already established on levodopa therapy and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with SmithKline Beecham. SELECTION CRITERIA: Randomised controlled trials of ropinirole versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: No significant differences between ropinirole and bromocriptine were found in off time reduction, dyskinesia as an adverse event, motor impairment and disability, or levodopa dose reduction. Withdrawal rates and adverse event frequency were similar with the two agents apart from significantly less nausea with ropinirole (odds ratio 0.50; 0.29, 0. 84 95% CI; p =0.01). REVIEWER'S CONCLUSIONS: Ropinirole is at least as good as bromocriptine in patients with Parkinson's disease with motor complications in terms of improving off time and reducing levodopa dose, without increasing adverse events including dyskinesia. However, these comparitor studies may have been underpowered to detect clinically meaningful differences between the agonists. Further, much larger, phase IV studies are required to examine the efficacy, effectiveness, and safety of all of the dopamine agonists as adjuvant therapy in Parkinson's disease.

Antiparkinson Agents↗
PubMed2004

Modeling the short- and long-duration responses to exogenous levodopa and to endogenous levodopa production in Parkinson's disease.

Clinicians recognize levodopa has a short-duration response (measured in hr) and a long-duration response (measured in days) in Parkinson's disease. In addition there is a diurnal pattern of motor function with better function in the morning. Previous pharmacokinetic-pharmacodynamic modeling has quantified only the short-duration response. We have developed a pharmacokinetic-pharmacodynamic model for the short- and long-duration responses to exogenous levodopa and the effects of residual endogenous levodopa synthesis in patients with Parkinson's disease. Thirteen previously untreated (de novo) patients with Parkinson's disease and twelve patients who had received levodopa orally for 9.7+/-4.0 years (chronic) were investigated. A 2 hr IV infusion of levodopa with concomitant oral carbidopa was given on two occasions separated by 3 days with no levodopa in between. A two compartment pharmacokinetic model was used to fit plasma levodopa concentrations. A sigmoid Emax model was used to relate concentrations from endogenous and exogenous sources to tapping rate (a measure of motor response). A model incorporating three effect compartments (fast equilibration (half life, Teqf). slow equilibration (Teqs) and dopa synthesis (Teqd)), yielded the most descriptive model for levodopa pharmacokinetics and pharmacodynamics. Baseline tapping rate reflected endogenous levodopa synthesis and the long-duration response. Partial loss of the long-duration response during the 3 days without levodopa in the chronic group lowered baseline tapping (36+/-7%, mean+/-SEM) and increased maximum levodopa induced response above baseline (112+/-31%). The maximum levodopa induced response after the drug holiday is a result of lowered baseline tapping due to the loss of long-duration response and not due to a change in levodopa pharmacokinetics or pharmacodynamics.

Adult↗
PubMed1986

Comparison of levodopa with carbidopa, and levodopa with domperidone in Parkinson's disease.

In a comparison of the effects of domperidone and carbidopa during levodopa treatment, 20 patients with idiopathic Parkinson's disease were treated with fixed dose regimens of either levodopa 500 mg-domperidone 20 mg or levodopa 100 mg-carbidopa 25 mg; each for 8 weeks. Clinical response, incidence of side effects, and plasma levodopa concentration resulting from each treatment were compared. Overall, in the dosages used, Parkinson's disease was less well controlled with levodopa-domperidone than with levodopa-carbidopa. In eight subjects there was a severe deterioration 2 to 7 days after changing from a fixed dose of levodopa-carbidopa to levodopa-domperidone. In nine subjects who completed the trial, the clinical response, occurrence of dyskinesias and of nausea and vomiting, were similar with both treatments, although peak plasma levodopa concentration and levodopa bioavailability were greater on levodopa-domperidone than on levodopa-carbidopa.

Adult↗
PubMed1995

Effect of entacapone, a COMT inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of controlled-release levodopa-carbidopa in volunteers.

We studied the effect of entacapone, a catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of a controlled-release (CR) levodopa-carbidopa preparation (Sinemet CR) in an open, randomized trial in 12 healthy male volunteers. The inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured. Single graded doses of entacapone (100-800 mg) were administered concomitant with a single oral dose of CR levodopa, or CR levodopa was given without entacapone (control treatment), at least 1 week apart. Plasma concentrations of levodopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone were determined for pharmacokinetic calculations. Entacapone decreased dose-dependently the activity of S-COMT in RBCs with a maximal inhibition of 66% after the highest dose (800 mg). Entacapone increased the area under the plasma concentration-time curve (AUC) of levodopa; the increase was highest (33%) after the 400-mg dose. Entacapone did not influence time to maximal concentration (Tmax) of levodopa. Entacapone was absorbed faster than levodopa from the CR preparation. The AUCs of 3-OMD and HVA decreased and that of DOPAC increased dose-dependently after entacapone, maximally by 69, 38, and 74%, respectively. Higher doses of entacapone (400 mg and 800 mg) decreased the AUC, but not Tmax of carbidopa. Over the dose range studied, entacapone was well tolerated. Entacapone is an effective COMT inhibitor. It improves the pharmacokinetic profile of levodopa when used in combination with a CR levodopa preparation, as it does with a standard levodopa preparation. The results justify further clinical studies with entacapone in combination with CR preparations of levodopa.

Adult↗
PubMedDate not supplied

Motoric sensitization and levodopa accumulation after chronic levodopa treatment in an animal model of Parkinson's disease.

One month after rats were subjected to unilateral injections of either 6-hydroxydopamine (6-OHDA) or vehicle into the midbrain tegmentum, they were given daily injections of either saline or levodopa (10 mg/kg and 1 mg/kg carbidopa) for 30 days. On the first and last day of treatment the spontaneous behavior of the rats was evaluated with a video image analysis system that detected directional movement asymmetries. Although vehicle-injected rats exhibited very little movement asymmetry, the 6-OHDA rats were strongly asymmetric. On day 1, both saline and levodopa-treated 6-OHDA rats exhibited rotational movement directed toward the dopamine-deficient hemisphere. On day 30 of treatment, however, the chronic levodopa group displayed a complete reversal and exaggeration of the rotational bias, and all asymmetric movement was directed toward the dopamine-intact hemisphere. Thus chronic levodopa treatment shifted behavioral dominance from the intact to the dopamine-denervated hemisphere. Subsequent biochemical measurement of dopamine and levodopa in striatal and limbic tissue samples indicated that chronic levodopa treatment did not alter dopamine tissue concentrations but did substantially increase levodopa concentrations, both in the dopamine-denervated striatum and in limbic tissue. This increased levodopa loading in brain with chronic levodopa treatment occurring in 6-OHDA rats but not in vehicle-injected rats that were given the same levodopa regimen. This selectivity in the effect of chronic levodopa treatment to the 6-OHDA rats appeared to rule out the possibility of peripheral metabolic factors for the levodopa accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

[Optimization of use of levodopa in Parkinson's disease: role of levodopa-carbidopa-entacapone combination].

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Akathisia, Drug-Induced↗
PubMed1981

Dosage form design for improvement of bioavailability of levodopa V: Absorption and metabolism of levodopa in intestinal segments of dogs.

Plasma levels of levodopa, total dopamine, and residual amounts of levodopa and its metabolites at the administered site were analyzed following administration of single 100-mg doses of levodopa in solution into isolated segments of the duodenum, jejunum, and ileum of the dog. The largest area under the plasma concentration-time curve (AUC) of levodopa during the 1.0-hr study was obtained following administration in the duodenum, followed by the jejunum and ileum. In addition, the residual amounts of levodopa and its metabolites detected at the administration sites were: ileum, 23%; jejunum, 7% and duodenum, less than 1%. The largest AUC of total dopamine was obtained following administration in the jejunum, followed by the ileum and duodenum. This order was consistent with the order of levodopa decarboxylase enzyme activity reported previously. Therefore, it can be concluded that the major absorption site of levodopa in the intestine resides in the upper small intestine. Levodopa in 10-, 50-, and 100-mg doses was administered into isolated duodenal segments. The AUC of levodopa increased nonlinearly with increasing dose. Negligible amounts of both levodopa and its metabolites were observed in the segment at 1.0 hr after administration, indicating that the duodenal absorption of levodopa was not saturable within the dose range tested.

Animals↗
PubMedDate not supplied

Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with Sinemet CR.

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

Adult↗
PubMed1994

Effect of brief levodopa holidays on the short-duration response to levodopa: evidence for tolerance to the antiparkinsonian effects.

To determine whether tolerance to the antiparkinsonian actions of levodopa develops during longterm levodopa therapy, we compared the response to 2-hour levodopa infusions before and after 2- to 4-day levodopa holidays using tapping and walking speeds and tremor/dyskinesia scores as measures of response in 17 parkinsonian patients with a fluctuating response to levodopa. As expected, motor function deteriorated during the levodopa holiday, but the maximum motor tapping and walking speeds and dyskinesia scores produced by the levodopa infusion before the holiday were the same as those produced by the infusion after the holiday. Because the baseline motor function was lower after the holiday, the increment in tapping and walking speeds (ie, the difference between the baseline and the maximum response) was larger with the postholiday infusion (p < 0.01). The postholiday infusion produced a longer response than did the preholiday infusion as measured by tapping score (p = 0.047), walking speed (p = 0.02), and tremor or dyskinesia scores (p = 0.02). The prolongation of the response was greater in patients receiving larger daily doses of levodopa (r = 0.55; p = 0.03). These changes in the duration of response suggest that progressive shortening of the response to levodopa during long-term therapy is partially caused by development of tolerance to levodopa and not just by loss of dopamine storage sites. Tolerance to levodopa should be considered in establishing oral dosing regimens and in developing new strategies for drug delivery.

Adult↗
PubMedDate not supplied

Liquid chromatographic determination of levodopa and levodopa-carbidopa in solid dosage forms: collaborative study.

A liquid chromatographic method for the determination of levodopa in tablets and capsules and levodopa-carbidopa in tablets was collaboratively studied by 6 laboratories. Collaborators were supplied with duplicate powdered composites of levodopa (1 synthetic formulation, 1 commercial tablet, and 1 commercial capsule) and levodopa-carbidopa (1 synthetic formulation and 2 commercial tablets), along with individual levodopa-carbidopa tablets for content uniformity determinations. The repeatability coefficient of variation (CVo) and reproducibility coefficient of variation (CVx) for levodopa single component were 0.48 and 0.87%; for levodopa in combination, 0.50 and 0.90%; and for carbidopa, 0.77 and 1.20%, respectively. Overall, the recovery values for levodopa and carbidopa from synthetic formulations simulating tablets were 100.4 and 99.5%, respectively. The pooled CVDo and CVDx values for the individual tablet assays were 2.07 and 2.30% for levodopa, and 1.80 and 2.24% for carbidopa, respectively. The method has been adopted official first action for determination of the active ingredients in levodopa tablets and capsules and in levodopa-carbidopa tablets and for content uniformity testing in the combination dosage form.

Capsules↗
PubMed2004

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

Previous pharmacokinetic trials with standard levodopa formulations showed a different behavior of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various advanced stages. The objective of this trial was to compare levodopa plasma metabolism in PD patients with and without previous long-term levodopa intake after oral intake of a dispensable levodopa/benserazide formulation (DLB). The over a 150 min interval computed area under the curve values of levodopa plasma levels after DLB administration were significantly (ANCOVA: F(1,19) = 7.88, P = 0.01) higher in PD patients with chronic levodopa treatment compared to patients without prior levodopa treatment. The maximum plasma levodopa concentration did not differ (ANCOVA: F(1.19) = 1.17, P = 0.29). Long-term levodopa administration results in an increased levodopa plasma bioavailability in PD patients.

Adult↗
PubMed1977

The clinical picture and plasma levodopa metabolite profile of parkinsonian nonresponders. Treatment with levodopa and decarboxylase inhibitor.

Three parkinsonian patients who were nonresponders to levodopa treatment did not improve when shifted to levodopa-decarboxylase inhibitor combination but, instead, experienced involuntary movements. Their plasma levodopa and metabolite profiles showed unusually high baseline 3-0-methyldopa concentrations that further increased significantly during the decarboxylase inhibitor regimen. All patients had 3-0-methyldopa to levodopa ratios greater than 1, even two hours after therapy. Patients who are responders to levodopa-decarboxylase inhibitor combination or to levodopa alone had 3-0-methyldopa to levodopa ratios of less than 1. We discuss the role of 3-0-methyldopa as a metabolite and the significance of the 3-0-methyldopa to levodopa ratio as a predictor of patients' response to levodopa.

Adult↗
PubMed1997

Short- and long-duration responses to levodopa during the first year of levodopa therapy.

We examined the response to 2-hour levodopa infusions in 18 Parkinson's disease subjects before starting long-term levodopa treatment and after 6 and 12 months of treatment using tapping speed as an index of bradykinesia. The long-duration response (LDR), measured as the increase in baseline (overnight without levodopa) tapping speed, increased by 29 +/- 18 at 6 months and by 35 +/- 24 at 12 months. The magnitude of the short-duration response (SDR) to a 2-hour levodopa infusion after an overnight levodopa withdrawal did not differ at 6 and 12 months (16 +/- 8 and 20 +/- 13 taps/min) from that before long-term levodopa (21 +/- taps/min). However, when levodopa was withheld for 3 days, it was evident that the SDR magnitude was increasing in magnitude (19, 23, and 31 taps/min at 0, 6, and 12 months). Duration of SDR did not change. A diurnal motor pattern with faster tapping speeds in the morning and slower in the evening was apparent on the days no levodopa was administered. These observations indicate (1) the LDR is responsible for much of the sustained response to levodopa during the first year of treatment, (2) the SDR magnitude increases but is obscured by the LDR, and (3) a diurnal pattern of motor function is present that may be partially responsible for the poorer motor function in the afternoons and evenings.

Adult↗
PubMed1981

Dosage form design for improvement of bioavailability of levodopa IV: Possible causes of low bioavailability of oral levodopa in dogs.

Several potential mechanisms for reduced levodopa bioavailability following oral administration to dogs and humans were investigated by studying the influence of the administration route on plasma levodopa levels after intravenous, hepatoportal, and duodenal administrations to dogs. The observed average areas under the plasma concentration-time curves (AUC) of levodopa following hepatoportal injection and intravenous injection were virtually identical; but following duodenal administration a decrease in the AUC of levodopa was observed with a concomitant increase in the AUC of total dopamine. The possible involvement of intestinal microorganisms in levodopa metabolism was explored in dogs that had been administered a combination of paromomycin and kanamycin to reduce intestinal microflora. Similar patterns of plasma level profiles and urinary excretion were observed between control and treated dogs. As measured by the release of [14C]carbon dioxide from [14C]levodopa, the distribution of levodopa decarboxylase enzyme activity in various parts of the intestine was studied in homogenates prepared from isolated intestinal segments of the duodenum and upper, middle, and lower parts of the jejunum and ileum. The jejunum showed the highest decarboxylase activity followed by the ileum and duodenum. These data indicate that the reduced bioavailability of orally administered levodopa occurs as a result of metabolism by levodopa decarboxylase enzyme in the gut wall.

Administration, Oral↗
PubMed2003

Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias.

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Delta 9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.

Animals↗
PubMed1996

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.

Aged↗
PubMed2003

Effect of subthalamic nucleus or entopeduncular nucleus lesion on levodopa-induced neurochemical changes within the basal ganglia and on levodopa-induced motor alterations in 6-hydroxydopamine-lesioned rats.

Inactivation of the subthalamic nucleus (STN) or the internal segment of the pallidum (GPi)/entopeduncular nucleus (EP) by deep brain stimulation or lesioning alleviates clinical manifestations of Parkinson's disease (PD) as well as reducing the side-effects of levodopa treatment. However, the effects of STN or entopeduncular nucleus (EP) lesion on levodopa-related motor fluctuations and on neurochemical changes induced by levodopa remain largely unknown. The effects of such lesions on levodopa-induced motor alterations were studied in 6-hydroxydopamine (6-OHDA)-lesioned rats and were assessed neurochemically by analyzing the functional activity of the basal ganglia nuclei, using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase as molecular markers of neuronal activity. At the striatal level, preproenkephalin (PPE) mRNA levels were analyzed. We found in 6-OHDA-lesioned rats that a unilateral STN or EP lesion ipsilateral to the 6-OHDA lesion had no effect on either the shortening in the duration of the levodopa-induced rotational response or the levodopa-induced biochemical changes in the basal ganglia nuclei. In contrast, overexpression of PPE mRNA due to levodopa treatment was reversed by the STN or EP lesion. Our study thus shows that lesion of the EP or STN may counteract some of the neurochemical changes induced by levodopa treatment within the striatum.

Animals↗