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PubMed1976

Clinical pharmacokinetics of levodopa in parkinson's disease.

Although levodopa has provided a major advance in the treatment of parkinsonism, its maximum benefits have not yet been realised, in part because of its complicated pharmacokinetics. This review summarises that available pharmacokinetic data involving levodopa, especially as it relates to therapeutic response of parkinsonian patients. A large number of factors, including protein intake, gastric emptying time, pyridoxine ingestion, and dopa decarboxylase activity, affect plasma levels of levodopa attained following oral administration of this drug. Other variables influence the rate of brain uptake of levodopa from the blood. Even so, plasma levodopa concentration correlates significantly with dosage size in a large parkinsonian population and also coincides with therapeutic response in many, but not all, patients. Therefore, in certain instances, valuable information may be derived by correlating clinical response with plasma levodopa concentration. Cerebrospinal fluid levels of homovanillic acid, a major metabolite of dopamine, may have some value in predicting clinical response to levodopa. This relationship, however, has not been firmly established. Concentration of homovanillic acid or levodopa in body fluids may also be closely related to certain adverse side-effects, including abnormal involuntary movements, gastric discomfort and psychiatric disturbances. Evidence indicates that a clearer understanding of levodopa pharmacokinetics may improve the clinical management of parkinsonism.

Carboxy-Lyases↗
PubMed1998

Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group.

This multicentre randomised double-blind 3- to 5-year trial was designed to assess whether initial therapy with cabergoline alone or in combination with levodopa prevents or delays the occurrence of long term motor complications in patients with early Parkinson's disease. Patients eligible for study inclusion (n = 412) had early idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 3) and had received no previous treatment with levodopa, selegiline or dopamine agonists. Patients were randomised to receive either cabergoline (0.25 to 4 mg once daily) or levodopa (100 to 600 mg/day) titrated over a maximum period of 24 weeks. Once the optimum or maximum tolerated dose was achieved, it was maintained up to the end-point (development of motor complications confirmed at 2 consecutive 3-month visits) or up to a minimum of 3 years' treatment. Open labelled levodopa was added in both treatment arms when the improvement in motor disability [Unified Parkinson's Disease Rating Scale (UPDRS) factor III] decreased below 30% vs baseline. Both treatments improved motor disability, decreasing UPDRS factor III scores and factor II scores for activities of daily living. The development of motor complications (end-point) was significantly less frequent in patients treated with cabergoline than in levodopa recipients (22% vs 34%; p < 0.02). The relative risk of developing motor complications during treatment with cabergoline was more than 50% lower than with levodopa. Serious adverse events, either drug related or not, were slightly more frequent in cabergoline-treated patients (31%) than in those treated with levodopa (25%). The withdrawal rate in the cabergoline vs levodopa group was 16 vs 13%. In conclusion, the study shows that, in patients with early Parkinson's disease, cabergoline is effective either as monotherapy or combined with levodopa. Moreover, starting treatment with cabergoline significantly delays the development of motor complications.

Activities of Daily Living↗
PubMedDate not supplied

Visual acuities after levodopa administration in amblyopia.

PURPOSE: To investigate the effect of the augmentation of levodopa with part-time and full-time occlusion on visual acuity and to determine its late results in amblyopia. METHODS: Seventy-two patients with amblyopia were prospectively studied and randomly distributed into groups A, B, and C consisting of 24 patients each. Group A patients received levodopa alone, group B received levodopa and part-time (3 hours/day) occlusion, and group C received levodopa and full-time (during all waking hours) occlusion of the dominant eye. Levodopa 0.50 mg/kg body weight, with a 25% fixed dose combination of carbidopa, was administered orally three times a day for 7 weeks. Snellen visual acuity and its logMAR equivalent were recorded before treatment, at weeks 1, 3, 5, and 7 after starting treatment, and every 6 weeks for 1 year after the completion of treatment. RESULTS: Fifty-three (74%) of the 72 patients had an improvement in visual acuity after treatment. Forty-four of the 53 patients with improved visual acuities completed 1-year post-treatment follow-up. Twenty-three (52%) of the 44 patients had a regression in visual acuity. CONCLUSION: The augmentation of levodopa with part-time or full-time occlusion does not enhance the recovery of vision in amblyopia. Improved visual acuity after levodopa administration persists at least 1 year in almost half of patients after cessation of treatment. Addition of full-time occlusion to levodopa helps maintain improved visual acuity for a longer duration compared to levodopa alone or combined with part-time occlusion.

Administration, Oral↗
PubMed1992

Treatment strategies for extension of levodopa effect.

The initial benefits of levodopa decline for as many as half of all patients with Parkinson's disease treated for 2 years or more. Although levodopa is the most effective means for symptom relief, many parkinsonian patients lose the consistency of optimal symptom control. The variability experienced by such patients may arise from several alternative mechanisms at the level of the central nervous system (e.g., a narrowed therapeutic window for receptor-mediated effects or the loss of storage capability for dopamine in the parkinsonian brain). Whatever the cause, several practical methods have been developed. Dopaminergic agonists have played a major role in improving such problem. There are also several strategies for enhancing levodopa's dose by dose effectiveness, including sustained-release levodopa preparations and enteral infusions of levodopa. Another approach is the use of selegiline (deprenyl), MAO-B inhibitor slowing the breakdown of dopamine and thereby extending the duration of levodopa effect. Although selegiline can lessen the abruptness of levodopa wearing off, it can also exacerbate undesired peak effects of the drug. Clinical trials are planned with levodopa pro-drugs and inhibitors of catechol-O-methyltransferase to learn if these approaches can improve problems of long-term levodopa therapy.

Catechol O-Methyltransferase Inhibitors↗
PubMed2005

[Effects of different doses of levodopa on paraquat-induced neurotoxicity: an experiment with mice].

OBJECTIVE: To investigate the effects and mechanisms of different doses of levodopa on paraquat-induced neuro-toxicity. METHODS: 72 C57BL mice were divided into 2 equal groups: acute experiment group and chronic experiment groups. The acute experiment group was re-divided into 2 subgroup: subgroup A to be injected with levodopa of the doses of 0 (distilled water instead), 10 mg/kg, or 100 mg/kg and then paraquat 30 mg/kg (levodopa + paraquat), and then killed 90 minutes after; and subgroup B, to be injected with paraquat 30 mg/kg and then levodopa 0, 10 mg/kg, or 100 mg/kg (paraquat + levodopa), and then killed 2 hours after. The chronic experiment group was re-divided into 2 subgroups to be injected with levodopa + paraquat or paraquat + levodopa once a week for 3 weeks, and then killed 24 hours after the injection. Fluorescent microscopy was used to observe the fluorescent staining of paraquat in the substantia nigra in the acute experiment group and the fluorescent staining of tyrosine hydroxylase (TH) in the substantia nigra in the chronic experiment group. in the chronic experiment group Western blotting was used to examine the protein expression of TH; thioflavine double labeling was used to observe the alpha-synuclein aggregation by immunofluorescence staining and Western blotting. The slices of substantia nigra of the mice in the chronic experiment group treated with distilled water + paraquat were inoculated with or without 250 micromol/L levodopa and then underwent thioflavine staining to observe the alpha-Syn aggregation. RESULTS: The paraquat staining was strongly positive in the substantia nigra of the mice in Group A-1, and was decreased gradually in the group A-2 and A-3. The paraquat staining was strongly positive in the substantia nigra of Group B-1 without a significant difference between Group A-1 and Group B-1, and was not remarkable in Group B-2 and B-3. The TH staining and protein expression in the substantia nigra of Group A-2 were significantly stronger than that of Group A-1 (P < 0.05), and the TH staining was remarkably weaker in Group A-3 (P < 0.05), as shown by immunofluorescence staining and Western blotting. There was no significant difference in TH staining and protein expression in the substantia nigra among Group A-1, Group B-1, and Group B-2 (all P > 0.05). However, the TH staining was remarkably weaker in Group B-3 (P < 0.05). The thioflavine and alpha-Syn double staining was significantly weaker in Groups A-2 and A-3 in comparison with Group A-1. There was no significant difference in the double staining among Group A-1, Group B-1, and Group B-2 (all P > 0.05). However, the double staining was remarkably weaker in Group B-3 (P < 0.05). The thioflavine positive staining in the tissue slices inoculated with levodopa was significantly weaker in comparison with those un-inoculated. CONCLUSION: Pre-treatment with lower dose L-dopa before the paraquat administration is neuroprotective by preventing paraquat from access into central nervous system through a blood-brain barrier competitive uptake mechanism, while higher dose L-dopa shows neurotoxicity through disaggregating alpha-synuclein deposits in Parkinsonian mice.

Animals↗
PubMed1998

Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications?

Levodopa-carbidopa (LD) in low dosages adequately controls symptoms in most patients with Parkinson's disease and delays the appearance of fluctuations and dyskinesias. It has been suggested that early combination therapy with bromocriptine and levodopa delays or prevents the onset of late treatment complication associated with LD monotherapy in Parkinson's disease. We have conducted this study to assess the possible benefit of combined therapy compared with levodopa monotherapy. Seventy-eight previously untreated patients with Parkinson's disease were recruited over a period of 54 months and randomly allocated to either a levodopa-carbidopa (LD) Group or a levodopa-carbidopa in combination with low-dose bromocriptine (LD-Br) Group. The appearance of motor complications determined the end point of the study. We gradually increased the doses of bromocriptine (2.5-15 mg/d) or levodopa (125-500 mg/d) until the maximum "on" time was reached. In six patients, the doses of levodopa had to be increased up to the optimal dose (625-1000 mg/day). In the last evaluation the on-time and parkinsonian disability were similar in both treatment groups. We did not find statistically significant differences in the frequency of motor complications when comparing the two groups of treatment. Our study suggests that early combination of levodopa and bromocriptine does not confer any clinical benefit over levodopa alone in treating early Parkinson's disease, nor will it influence the evolution of the disease.Copyright Lippincott-Raven Publishers

Journal Article↗
PubMed1986

Management of levodopa failures: the use of dopamine agonists.

In the past decade, dopamine agonists have emerged as important treatment options for patients with Parkinson's disease. Originally, dopamine agonists were used only in patients with advanced disease in whom the response to levodopa had decreased (levodopa failures). The decreased response to levodopa, usually associated with diurnal oscillations in performance and the 'wearing-off' and 'on-off' phenomena, is secondary to disease progression with continued degeneration of the nigrostriatal neurons. In addition, chronic levodopa treatment itself may contribute to the decreased drug response and the diurnal oscillations in performance. Dopamine receptor agonists bypass the degenerating nigrostriatal neurons and directly stimulate the striatal dopamine receptors. Dopamine receptor agonists also permit a reduction in the dose of levodopa. Five ergoline dopamine agonists--bromocriptine, lergotrile, pergolide, lisuride, mesulergine, and the nonergoline agonist, ciladopa--have undergone clinical trials in Parkinson's disease. In 10 years, we treated a total of 278 patients with advanced Parkinson's disease, a declining response to levodopa, and diurnal oscillations in performance with five ergoline dopamine agonists (in addition to levodopa). The mean duration of treatment was one year (with a range of 1-60 months). Improvement was noted in 140 (50%) of our patients. Adverse effects necessitating discontinuation of the agonist occurred in 131 patients (46%). We compared our results with those of others who, unlike us, began treatment with a dopamine agonist earlier, using the agonist alone or adding it to levodopa before the response to levodopa had decreased. Many of the patients so treated had mild or moderate Parkinson's disease. A total of 1,599 patients were treated with ergoline dopamine agonists. Of these patients, 976 (61%) improved, while 407 (25%) experienced adverse effects. We believe that a greater number of these patients improved and fewer experienced adverse effects, in comparison to our patients, because the patients had less advanced disease.

Animals↗
PubMed1980

Increased ratio of carbidopa to levodopa in treatment of Parkinson's disease.

A randomized, double-blind clinical trial was designed to compare two ratios of carbidopa to levodopa (10 mg of carbidopa to 100 mg of levodopa [Sinemet 10/100] and 20 mg of carbidopa to 100 mg of levodopa [Sinemet 20/100]) with levodopa (100 mg) alone. Twenty-nine male patients (46 to 78 years of age) with clinically definite idiopathic Parkinson's disease of mild to moderate severity were selected and hospitalized for the three-week period of the study. Medications being taken at time of entry were phased out during week 1. Fixed daily increments of medications were given during week 2, and adjusted during week 3 to achieve best clinical response with fewest side effects. Qualitative and quantitative examinations of neurologic function showed that upper extremity measurements of resting tremor, rigidity, and finger-tapping speed, and lower extremity measurements of foot coordination and tandem gait (both types of speed tests) showed significantly more improvement in patients receiving the 20:100 combination than in those receiving the 10:100 combination or levodopa alone. Adverse effects were similar and minimal in each of the three groups. Results indicate that increasing the amount of carbidopa from 10 to 20 mg per 100-mg dose of levodopa gives a greater therapeutic response in Parkinson's disease than does a 10:100 carbidopa-levodopa ratio or levodopa alone.

Aged↗
PubMed2000

Levodopa withdrawal after bilateral subthalamic nucleus stimulation in advanced Parkinson disease.

CONTEXT: Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. OBJECTIVES: To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. DESIGN: Before-after trial. SETTING: Referral center, hospitalized care. PATIENTS: Fifteen patients with advanced PD. INTERVENTIONS: Microelectrode-guided bilateral STN high-frequency stimulation. OUTCOME MEASURES: Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred. CONCLUSIONS: Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

Aged↗
PubMed2001

Response to levodopa treatment in dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia (DRD) is similar to Parkinson disease in that both disorders have impaired dopamine synthesis and respond to levodopa treatment. Dopa-responsive dystonia differs in that dopamine storage is intact in contrast to Parkinson disease in which it is markedly reduced. OBJECTIVE: To examine the short- and long-duration responses to levodopa dosing in subjects with DRD. METHODS: The response to brief infusions of levodopa was examined in 4 subjects with DRD and the effects of withdrawal of levodopa for 3 to 7 days studied in the 3 subjects receiving long-term levodopa therapy. Motor function was measured with tapping speed, Unified Parkinson's Disease Rating Scale motor score, and global dystonia score. RESULTS: The short-duration response to levodopa dosing seems to develop more slowly and persists longer in subjects with DRD than in subjects with Parkinson disease. Withdrawal of levodopa leads to a gradual decline in tapping speed and reemergence of dystonia over several days, similar to the rate of decay of motor function in Parkinson disease. The short- and long-duration responses were not clearly differentiated in DRD. CONCLUSIONS: This pilot study suggests that retained dopamine storage in DRD may prolong the short-duration response and blur the distinction of the short- and long-duration responses. The decline in motor function in DRD on withdrawal of long-term levodopa therapy resembles that in Parkinson disease, suggesting that a long-duration response, if it exists in DRD, is unrelated to dopamine storage.

Adult↗
PubMed1990

Which risk factors predict the levodopa response in fluctuating Parkinson's disease?

Three putative risk factors to the pathogenesis of end-of-dose-related fluctuations--severity of Parkinson's disease (PD), duration of PD, and duration of levodopa therapy--were evaluated in 39 patients with PD by measuring response duration and response magnitude to a single levodopa dose. After discontinuing levodopa therapy for 12 hours, the motor status of each patient was assessed before a single dose of 100 mg of levodopa plus 25 mg of decarboxylase inhibitor was given and at five 45-minute intervals thereafter. Multiple regression analysis showed that the response duration was best predicted by the severity of PD. The response magnitude was significantly correlated both to the duration of PD and to the duration of levodopa therapy. It is argued, however, that the response magnitude was predicted by the duration of levodopa therapy. Our results are in accordance with those of other recent studies and indicate that variances in levodopa response duration and in levodopa response magnitude are caused by their own differential risk factor.

Adult↗
PubMed1977

Effects of levodopa on the renin-aldosterone system.

Plasma renin activity and plasma aldosterone, supine and erect, and urinary aldosterone levels were measured in 18 patients on normal sodium diets and 11 patients on low sodium diets, all of whom also were on long-term levodopa therapy. Of the 230 hormone measurements, 185 were normal, 11 were high, and 34 were low. Most of the low levels were in 3 patients who had recently received fludrocortisone for orthostatic hypotension, and the renin-aldosterone systems might have been suppressed by it. In another phase of this study, 4 subjects were maintained on a constant diet for 6 wk, while the effect of gradually increasing dosages of levodopa on mineral balance and renin-aldosterone was determined. In 3 of the 4 patients there was a mild natriuretic effect of levodopa (previously demonstrated for acute levodopa therapy). There were no significant consistent changes in renin or aldosterone levels while levodopa was being administered. These studies indicate that levodopa does not usually suppress the elements of the renin-aldosterone system and that such a mechanism is unlikely to be the cause of orthostatic hypotension during the course of levodopa therapy. Since levodopa may induce natriuresis, in this situation unchanged lvels of renin and aldosterone may, however, represent an inappropriately low set of this hormonal system.

Aldosterone↗
PubMed2002

Interaction of levodopa and cues on voluntary reaching in Parkinson's disease.

The bradykinesia associated with Parkinson's disease (PD) can be improved by both levodopa and the use of external cues. We examined the combined effect of levodopa and external cueing on the voluntary reaching movements of individuals with PD. Nine subjects with PD and nine matched controls were studied reaching to a ball target. Subjects with PD were studied after being off levodopa overnight and again on their morning dose. Kinematic data were collected as all subjects made both accurate and fast reaches under two different cue conditions: noncued (self-initiated) and cued (triggered by a light). Subjects with PD reached more slowly than controls under all conditions. PD subjects increased their reach velocity and decreased movement time after taking levodopa and also when moving to a cue. However, the effects of levodopa and cueing were not additive. Instead, levodopa improved reach velocity to a greater extent in the noncued vs. cued condition. We also found that levodopa improved accurate (self-paced) reaches more than fast reaches. These data suggest that levodopa may preferentially improve voluntary reaches that are more internally generated.

Antiparkinson Agents↗
PubMed2002

Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

Long-term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase gamma-aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14-23; P < 0.05). This effect was more marked during the onset period (0-20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease.

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) micromol/L increased to 10.1 (3.1) micromol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L-dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 micromol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined.

Aged↗
PubMed2005

Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients.

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinson's disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O-methylation of levodopa catalyzed by catechol-O-methyltransferase (COMT) that produces S-adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT-I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT-I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT-I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa-treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT-I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT-I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT-I effectively reduces HHcy.

Aged↗
PubMed2006

Coadministration of entacapone with levodopa attenuates the severity of dyskinesias in hemiparkinsonian rats.

Levodopa-induced dyskinesias (LIDs) have been associated with a sequence of events that includes pulsatile stimulation of dopamine receptors. The degree of nigrostriatal degeneration, the half-life of dopaminomimetic agents, and the dose of levodopa used to treat parkinsonian symptoms are factors directly correlated with the development of motor complications in Parkinson's disease patients. Long-acting agents producing continuous dopaminergic stimulation are less likely to prime for dyskinesia than short-acting drugs that produce pulsatile stimulation of dopamine receptors. Inhibition of the enzyme catechol-O-methyl transferase (COMT) by entacapone extends the half-life of levodopa and minimizes variability in plasma levodopa levels. The aim of the present study was to characterize the effect of the early administration of the COMT inhibitor entacapone in the recently described model of LIDs in rats with a nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. Animals were treated either with levodopa (6 mg/kg, twice at day, i.p.) plus entacapone (30 mg/kg per day, i.p.) or levodopa (6 mg/kg, twice at day, i.p.) plus vehicle for 22 consecutive days. Early administration of entacapone, in association with levodopa, induces a decrease in the severity of dyskinesia and delays their onset in hemiparkinsonian rats. All dyskinesia subtypes evaluated, such as axial, limb, and orofacial dyskinesias, have shown similar reductions. These results suggest that entacapone, by extending levodopa elimination half-life, might reduce its propensity to induce motor complications.

Analysis of Variance↗
PubMed1997

Motor fluctuations during continuous levodopa infusions in patients with Parkinson's disease.

The cause of motor fluctuations occurring during constant-rate levodopa infusions is unknown. We examined whether known pharmacokinetic factors could explain the fluctuations and looked for clues to pharmacodynamic causes. Eleven subjects with stage III-V Parkinson's disease (PD) and a fluctuating response to levodopa underwent constant-rate infusions for 36-110 h. Levodopa, 3-O-methyldopa (3-OMD), and plasma large neutral amino acids (LNAAs) were measured at 2- to 6-h intervals and PD was monitored hourly from 07:00 to 22:00 h with tapping speed. Ten subjects had motor fluctuations during the infusions. Zero to 68% of the variability of tapping speed could be explained by variation in plasma LNAA concentrations in individual subjects. Fluctuations occurred more commonly later in the day, which may be related to the tendency for LNAAs to increase during the day. Motor fluctuations were not associated with minor variations in levodopa or 3-OMD concentrations. Fluctuations during constant infusions were more marked in patients using larger daily doses of oral levodopa; severity of PD did not predict fluctuations during the infusions. There was no trend for fluctuations or dyskinesia to decrease or increase during several days of constant-rate levodopa infusion. A portion of motor fluctuations occurring during constant levodopa infusions can be explained by peripheral pharmacokinetic mechanisms. Fluctuations are more prominent in subjects who have taken larger daily doses of levodopa, implicating pharmacodynamic factors as well.

Adult↗