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.     

Controlled release levodopa treatment of motor fluctuations in Parkinson''s disease.

A controlled release preparation of levodopa-carbidopa, CR III, given every 4 hours to 17 Parkinsonian patients for up to 10 months reduced plasma drug variations and improved motor response fluctuations compared with standard levodopa-carbidopa given every 2 hours. The results support the value of pharmaceutical approaches to the stabilisation of circulating levodopa levels in the treatment of Parkinson's disease.     

Levodopa and 3-O-methyldopa plasma levels in parkinsonian patients with stable and fluctuating motor response

Many parkinsonian patients with motor fluctuations in response to levodopa show a good response to initial morning doses but fail to respond in the afternoon and evening. We have studied levodopa and 3-O-methyldopa (3-OM-dopa) plasma profiles in 21 patients with fluctuations and eight patients with stable motor function throughout the day. Levodopa plasma peaks and valleys were similar for both group of patients. No significant difference for levodopa absorption index [defined as levodopa plasma levels after each dose divided by the quantity (mg) of ingested levodopa] was found between the first and the second levodopa-carbidopa dose in either group of patients. Even in patients who failed to improve after the second levodopa-carbidopa tablet (p.o.) on the day of the study, no significant variation in levodopa absorption index was observed. 3-OM-dopa values depended mainly upon levodopa consumption and were not different for patients with fluctuating or stable motor response. These findings provide further evidence of the prime role of central pharmacokinetic and pharmacodynamic factors in the pathogenesis of motor fluctuations in Parkinson's disease.     

Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations.

OBJECTIVES--To establish, in a double blind manner, the antiparkinsonian effects of repeated dosing with entacapone, a peripheral COMT inhibitor. METHODS--A one month, cross over study was conducted. During the two four-week treatment periods, entacapone (200 mg) or placebo was given with each levodopa dose four to 10 times daily. Motor responses were repeatedly quantified using the motor part of UPDRS. Plasma levodopa and its metabolites were measured. RESULTS--Entacapone prolonged the availability of levodopa in the plasma and thus to the brain by decreasing its peripheral O-methylation and slowing its elimination rate, without affecting the maximum plasma levodopa concentration or the time to maximum concentration. Corresponding with the pharmacokinetic findings, entacapone prolonged the duration of motor response to an individual levodopa/DDC inhibitor dose by 34 minutes (24%, P = 0.001) and dyskinesiae by 39 minutes (37%, P = 0.002) compared with placebo, without affecting their magnitude or starting time. Entacapone treatment resulted in a reduction of 16% in the mean total daily levodopa dose due to dyskinesiae. Also, according to the home diaries, the mean daily "on" time increased by 2.1 hours compared with placebo, despite the lowered mean levodopa intake. CONCLUSION--The efficacy of repeated entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson's disease with levodopa related fluctuations is verified.     

Plasma DOPA levels and growth hormone response to levodopa in parkinsomism.

It has been suggested that the therapeutic response to levodopa in patients with Parkinson's disease may be related to changes in plasma growth hormone concentration. In order to examine this problem, we have determined plasma DOPA and growth hormone levels after a standard oral levodopa load in 32 patients with Parkinson's disease. Levodopa caused an increase in plasma growth hormone concentration in 30 subjects. The magnitude and timing of this growth hormone response was not related to the clinical response, the presence or absence of response swings, or the occurrence of dyskinesias. The growth hormone response to levodopa is normal in patients with Parkinson's disease and not altered by long-term levodopa treatment.     

Oral solution of levodopa ethylester for treatment of response fluctuations in patients with advanced Parkinson's disease.

Levodopa ethylester (LDEE), a highly soluble prodrug of levodopa, may overcome the impaired absorption of regular levodopa, due mainly to a combination of levodopa's poor solubility and delayed gastric emptying. We conducted a double-blind, levodopa-controlled, multicenter study of oral LDEE solution compared with standard levodopa-carbidopa (LD-CD) tablets. Sixty-two patients with Parkinson's disease who had "delayed on" and "no-on" subtypes of response fluctuations were randomly assigned for treatment with LDEE-CD or LD-CD 250/25 mg for 4 weeks (phase A). Only the first morning and first post-lunch dose of LD were replaced. This was followed by a 2-week extension with a supplementation of carbidopa (25 mg) to each replaced dose (phase B). Patients filled home diaries 2 weeks before and during the trial period in which times of turning on and off for the two doses were reported. In phase A, mean latency to turning on was reduced by 21% (morning dose) and 17% (post-lunch dose) in the LDEE-CD group. Percentage of no-on episodes after the post-lunch dose was decreased by 21% in the LDEE-CD group but increased by 36% in the LD-CD group (P < 0.01). In phase B, LDEE-CD decreased latencies to on after the morning and post-lunch doses and no-on episodes after the post-lunch dose. The beneficial effects of LDEE were supported by the pharmacokinetic data. Results indicate that LDEE solution is beneficial in ameliorating delayed on and no-on response fluctuations. This effect of LDEE is due to more rapid levodopa absorption.     

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.     

Clinical and pharmacokinetic evaluation of controlled-release levodopa/carbidopa (CR-4) in parkinsonian patients with severe motor fluctuations: a six month follow-up study

The results of a six month open-label study comparing the efficacy of controlled-release levodopa-carbidopa (Sinemet CR-4 200 mg/50 mg) with standard levodopa/carbidopa (250 mg/25 mg) in 17 patients with idiopathic Parkinson's disease and severe response fluctuations, are reported. Major clinical benefits included; improvement of disability, reduction of the number of ‘off’ periods (predominantly end-of-dose hypokinesia) and a slight increase in ‘on’ time. No improvement was observed in two of our patients. Mean levodopa plasma levels were comparable between the two types of formulations during optimal treatment, however systemic bioavailability was significantly higher with CR-4. Delayed onset of antiparkinsonian effect of CR-4, resulting from an increase of Tmax for levodopa, was one of the major complaints and required additional small amounts of standard levodopa in three patients.     

No effect of chronic bromocriptine therapy on levodopa pharmacokinetics in patients with Parkinson's disease.

We studied the effect of chronic bromocriptine cotherapy on levodopa kinetics in seven patients with Parkinson's disease who were receiving levodopa therapy. Plasma levodopa concentrations were measured after a standard oral levodopa fasting dose over a 5-hour period, on two different sessions, without and with bromocriptine at a fixed daily dose of 15 mg. We found no statistically significant difference in the rate and extent of levodopa absorption between the two treatments, with minimal intrasubject variability. Our observations suggest that chronic bromocriptine cotherapy is unlikely to affect the plasma levodopa pharmacokinetics under standardized intake conditions or to contribute to a less predictable pattern of drug plasma concentrations.     

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.     

Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson''s disease.

Catechol-O-methyltransferase (COMT) inhibitors may be useful in the treatment of Parkinson's disease by improving the bioavailability of levodopa and by prolonging its effects. Entacapone (OR-611), a novel COMT inhibitor, which does not cross the blood brain barrier, was assessed in 12 patients with Parkinson's disease and motor fluctuations in a randomised, double-blind, cross-over, single dose study. The magnitude and duration of the therapeutic response to a single dose of 200 mg levodopa/50 mg carbidopa was evaluated after concomitant placebo, or 200 or 800 mg entacapone. A significant increase in the duration of the motor response to levodopa was seen when 200 mg entacapone was given with levodopa/carbidopa. Plasma levodopa concentrations were increased with both doses of the COMT inhibitor. The latency to onset of motor response did not differ significantly between active drug and placebo. Entacapone may prove useful in prolonging the duration of the benefit obtained from individual doses of levodopa.     

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.     

The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson's disease

OBJECTIVES: Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an adjunct to standard levodopa preparations, but there is little experience of the effect of entacapone on controlled release levodopa preparations. METHODS: A double blind, placebo controlled, single dose, randomised, cross over trial was performed in 14 patients with Parkinson's disease with motor fluctuations to investigate the clinical effect of a single dose of entacapone (200 mg) when administered with either standard levodopa-carbidopa (Sinemet) or controlled release levodopa-carbidopa preparations (Sinemet CR). RESULTS: When entacapone was administered with standard Sinemet the duration of the clinical response to standard Sinemet was longer in comparison with the response after placebo (p=0.02). Moreover, in the same patients, entacapone significantly increased the duration of the clinical response to Sinemet CR (p=0.05) without prolonging the latency of response or enhancing dyskinesias. CONCLUSIONS: These data confirm the clinical efficacy of entacapone-standard Sinemet combination. They also indicate that adding entacapone to controlled release levodopa preparations might provide a useful treatment option in patients with Parkinson's disease with motor fluctuations. A double blind clinical trial with a chronically administered entacapone-Sinemet CR combination is, however, required to verify this viewpoint.     

Bromocriptine treatment in Parkinson's disease.

Thirty-one patients with Parkinson's disease were treated with the ergot alkaloid bromocriptine, a drug which stimulates dopamine receptors. Bromocriptine had a slight therapeutic effect in patients on no other treatment and an additional effect in patients on levodopa. The mean optimum dosage of bromocriptine, established over a 12 week period, was 26 mg daily. In 20 patients bromocriptine was compared with placebo in a double-blind controlled trial. Active treatment caused a significant (P less than 0.02) reduction in total disability and akinesia scores. The least disabled patients showed the greatest response. Side-effects of bromocriptine--nausea, vomiting, hallucinations, and abnormal involuntary movements--were similar to nature to those of levodopa. In most normal subjects, bromocriptine causes an increase in plasma growth hormone concentration. This was determined in 20 patients with Parkinson's disease after 1-15 mg bromocriptine. Only a single patient showed an obvious increase up to 120 minutes after dosage. Bromocriptine was not effective treatment in two patients who had not previously responded to levodopa and replacement of this drug by bromocriptine in patients with end-of-dose akinesia after chronic levodopa treatment did not totally abolish response swings.     

Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease

BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.     

Sustained-release of levodopa: single dose study of a new formulation

Summary Motor fluctuations and dyskinesias in Parkinsonian patients may be at least partially due to fluctuations of levodopa plasma concentrations. Sustained-release (SR) formulations of levodopa may present a promising, effective solution of this problem. Therefore we performed a 4-fold, crossover double-blind trial with a new SR preparation, tested in healthy volunteers (Gerlach et al., 1988) before, in 12 Parkinsonian subjects. Two different dosages of the pure new levodopa SR-preparation, a composition of 70% SR and 30% levodopa immediate release (IR) and a conventional IR levodopa preparation were compared by their pharmacokinetic behaviour and their clinical effects. The relative bioavailability of levodopa in plasma was 69% for the combination of SR and IR levodopa release, for the pure SR formulations (100mg levodopa) 54% and (200 mg levodopa) 55%, compared to the 100% of the standard form of IR release of 100 mg levodopa. In contrast to the conventional IR formulation the pharmacokinetic behaviour of the SR preparations showed no initial sharp peak, but more continuous and longer maintaining plasma concentrations of levodopa. Due to the small numbers of cases and the missing homogenity of the selected patients no statistical significant differences between the four preparations regarding the clinical response were observed. But the described pharmacokinetic behaviour gives hope, that these newly developed SR-preparations may lead to progress in the treatment of Parkinson's disease (prolongation of dosage intervals, reduction of motor fluctuations).     

Diurnal motor variations to repeated doses of levodopa in Parkinson's disease

Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.     

Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations

Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 microg/mL and peak concentrations between 0.95 to 13.75 microg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.     

L-deprenyl, levodopa pharmacokinetics, and response fluctuations in Parkinson's disease

Six patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) on levodopa treatment participated in an open-label trial of L-deprenyl (Eldepryl) in conjunction with Sinemet. Deprenyl (10 mg/day) allowed a slight but not statistically significant 22% reduction of total daily levodopa intake after 4 weeks of treatment, with a significant but unsustained reduction in the number of daily "off" periods and an increase in the portion of waking day spent "on." Pharmacokinetic studies revealed no effect of deprenyl on the plasma levodopa concentration vs. time curve, or the coefficient of variation (C.V.) of plasma levodopa levels measured over an 8-h period. Plasma DOPAC levels were unaffected, suggesting that the majority of peripheral DOPAC is generated by action of MAO-A. For most patients, benefit was not maintained. Two patients have continued taking the drug, and both have enjoyed significant reductions in total levodopa dose. Both have mild end-of-dose failure and little dyskinesia. Since no changes in peripheral pharmacokinetics of levodopa could be demonstrated, any therapeutic action of deprenyl in PD would appear to be due to prolongation of dopaminergic activity within the CNS.     

Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease

OBJECTIVE: To quantify postural sway in subjects with Parkinson's disease and elderly controls, and determine the effects of Parkinson's disease, deep brain stimulation, levodopa, and their interactions on postural control during quiet stance. METHODS: Centre of foot pressure (CoP) displacement under each foot was measured during three 60 s trials of quiet stance with eyes open in 11 controls and six patients with Parkinson's disease. Subjects with Parkinson's disease were tested in four treatment conditions: off both deep brain stimulation and levodopa (off condition); on deep brain stimulation; on levodopa; and on both deep brain stimulation and levodopa. The variables extracted from CoP included: root mean square distance (rms), mean velocity, 95% power frequency (f(95%)), area of the 95% confidence ellipse (ellipse area), direction of its major axis (mdir), and postural asymmetry between the feet. RESULTS: rms and area of postural sway were larger than normal in subjects with Parkinson's disease in the off condition, increased further with levodopa, and significantly decreased with deep brain stimulation. Mean velocity and f(95%) were also larger than normal but were restored to normal by all treatments, especially by deep brain stimulation. The combined effect of deep brain stimulation and levodopa resulted in a postural sway that was an average of the effect of each treatment individually. Levodopa increased sway more in the mediolateral than in the anterior-posterior direction. Subjects with Parkinson's disease had asymmetrical mean velocity and f(95%) between the feet, and this asymmetry increased with levodopa but decreased with deep brain stimulation. The f(95%) of the CoP correlated with tremor, posture, and gait subcomponents of the unified Parkinson's disease rating scale. CONCLUSIONS: Subjects with Parkinson's disease have abnormal postural sway in stance. Treatment with levodopa increases postural sway abnormalities, whereas treatment with deep brain stimulation improves postural sway. Quantitative evaluation of static posturography may be a useful adjunct to clinical measures in patients with Parkinson's disease.