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PubMed1989

Increased dosage of carbidopa in parkinsonian patients on low carbidopa-levodopa regimen. Effect on levodopa bioavailability.

The effect of a 2.5-fold increase in daily carbidopa intake on the bioavailability of levodopa was studied in six patients with Parkinson's disease on a low chronic regimen of carbidopa-levodopa (Sinemet) at the fixed ratio of 1:10. The extent of levodopa absorption, expressed as the area under the 11-h plasma levodopa concentration-time curve (AUC0-11 h), was not enhanced by the higher carbidopa dose. A significant increase in the AUC was found for the levodopa metabolite 3-O-methyldopa at the higher carbidopa intake. Clinical performances of individual patients were identical with both carbidopa-levodopa ratios. From these data, an adequate inhibition of peripheral decarboxylation and hence a good bioavailability of levodopa may be expected in patients taking low doses of carbidopa-levodopa, using currently available commercial preparations.

Aged↗

PubMed1996

Effect of subcutaneous administration of levodopa ethyl ester, a soluble prodrug of levodopa, on dopamine metabolism in rodent striatum: implication for treatment of Parkinson's disease.

Levodopa ethyl ester (LDEE), a highly soluble prodrug of levodopa, was synthesized and administered to mice and rats subcutaneously or intraperitoneally. Striatal levels of levodopa, dopamine, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using high-performance liquid chromatography with electrochemical detection and compared with those obtained after intraperitoneal injections of levodopa. LDEE injections produced significant and rapid elevations of striatal levodopa, dopamine, and DOPAC, which were similar to those achieved after levodopa administration, with similar dose-response curves. The elevations achieved by LDEE given s.c. were higher than those achieved after i.p. administration and lasted for longer periods. In addition, intraperitoneal administration of levodopa or LDEE to rats with unilateral 6-hydroxydopamine (6-OHDA) nigral lesions produced similar contraversive circling responses. We suggest that LDEE may be a beneficial antiparkinsonian agent. It has potential pharmacokinetic advantages that are superior to those of levodopa itself, and its subcutaneous administration may become an effective rescue strategy to overcome "off" situations in patients with Parkinson's disease and response fluctuations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

The effect of an increased ratio of carbidopa to levodopa on the pharmacokinetics of levodopa.

A randomized, cross-over study was designed to compare the effects of an increased ratio (from 1:10 to 1:4) of carbidopa to levodopa on the fate of levodopa and carbidopa in 11 healthy subjects. Four combinations of carbidopa/levodopa (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg, 62.5/250 mg) were used. Plasma levodopa, carbidopa, dopamine and dopac concentrations as well as urinary excretions of levodopa and dopac were determined by a sensitive high-performance liquid chromatography with electrochemical detection after a single carbidopa/levodopa tablet. As the ratio of carbidopa to levodopa increased, there was a significant increase in apparent t1/2 and AUC values of levodopa. At the same time the urinary excretion of levodopa increased and that of dopac decreased. The plasma ratios of levodopa/dopamine and levodopa/dopac and the urinary ratio of levodopa/dopac also increased. There were less subjective side-effects in the 1:4 groups than in the 1:10 groups. It is concluded that increasing the amount of carbidopa in relation to levodopa may be beneficial and further clinical studies are clearly indicated.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

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

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

Adult↗

PubMed1991

Combined levodopa-anticholinergic therapy in the treatment of Parkinson's disease. Effect on levodopa bioavailability.

The effect of chronic intake of the anticholinergic drug orphenadrine on the bioavailability of levodopa was studied in six patients with Parkinson's disease. Plasma levodopa profiles and corresponding motor response to a standard dose of levodopa plus an inhibitor of peripheral L-aromatic aminoacid decarboxylase (benserazide) were followed, over a 5-h period, on two different sessions, with and without anticholinergic cotherapy. Six control patients were also included in the study for assessment of intrasubject variability in levodopa absorption under identical conditions. A considerable delay in levodopa absorption was found in one patient, and decreased absorption in an additional two patients while on anticholinergic. Patients' clinical performance corresponded well to plasma levodopa profiles. A significant impairment of basal clinical state was observed in two cases on anticholinergic withdrawal, probably as a result of pharmacodynamic interactions. Our observations suggest that chronic anticholinergic intake may contribute to a less predictable pattern of levodopa absorption and related therapeutic response in some subjects.

Adult↗

PubMed1995

Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. Parkinson's Disease Research Group of the United Kingdom.

OBJECTIVE: To compare effectiveness of levodopa and levodopa combined with selegiline in treating early, mild Parkinson's disease. DESIGN: Open, long term, prospective randomised trial. SETTING: 93 hospitals throughout United Kingdom. SUBJECTS: 520 patients with early Parkinson's disease who were not receiving dopaminergic treatment. INTERVENTIONS: Treatment with levodopa and dopa decarboxylase inhibitor (arm 1) or levodopa and decarboxylase inhibitor in combination with selegiline (arm 2). MAIN OUTCOME MEASURES: Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes. RESULTS: After average of 5-6 years' follow up, mortality ratio in arm 2 compared with arm 1 was 1.57 (95% confidence interval 1.09 to 2.30), and difference in survival between the two arms was significant (log rank test, P = 0.015). Hazard ratio adjusted for age and sex was 1.49 (1.02 to 2.16), and after adjustment for other baseline factors it increased to 1.57 (1.07 to 2.31). Patients in arm 1 had slightly worse disability scores than those in arm 2, but differences were not significant. Functionally disabling peak dose dyskinesias and on/off fluctuations were more frequent in arm 2 than arm 1. During the trial the dose of levodopa required to produce optimum motor control steadily increased in arm 1 (median daily dose 375 mg at 1 year and 625 mg at 4 years), but median dose in arm 2 did not change (375 mg). CONCLUSIONS: Levodopa in combination with selegiline seemed to confer no clinical benefit over levodopa alone in treating early, mild Parkinson's disease. Moreover mortality was significantly higher with combination treatment, casting doubts on its chronic use in Parkinson's disease.

Antiparkinson Agents↗

PubMed1994

A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow up.

This pilot study was performed to compare the occurrence of long term motor complications in Parkinson's disease when the introduction of levodopa was delayed by an initial treatment with high doses of bromocriptine alone. The trial was a prospective randomised controlled study comparing 31 previously untreated patients with Parkinson's disease initially given bromocriptine alone to which levodopa was later added (group B/D) and 29 other previously untreated patients with Parkinson's disease immediately given levodopa alone (group D). The end point was the occurrence of the first motor complications (wearing off or dyskinesia). Group B/D patients received bromocriptine (52 (SEM 5) mg/day) for 2.7 years, to which levodopa was later added (471 (SEM 46) mg/day). Group D patients received a comparable dose of levodopa alone (569 (SEM 47) mg/day). Both had similar disability scores at the end of the study. Motor complications were fewer and appeared later in group B/D than in group D (56% after 4.9 (SEM 0.5) years of treatment v 90% after 2.7 (SEM 0.5) years, p < 0.01). Wearing off appeared later (p < 0.01) in group B/D (4.5 (SEM 0.6) years) than in group D (2.9 (SEM 0.6) years). Peak dose dyskinesia occurred less often in group B/D patients (three v 14 cases, p < 0.01). This study showed that a three year initial monotherapy with high doses of bromocriptine followed by addition of levodopa delayed the occurrence of long term motor complications usually found in patients with Parkinson's disease treated with levodopa alone from the beginning.

Bromocriptine↗

PubMed1996

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.

Aged↗

PubMedDate not supplied

Should levodopa therapy for Parkinson's disease be started early or late? Clinical course of the major tetrad in 122 parkinsonian patients treated with levodopa over 14 years.

The study was carried out to clarify whether levodopa should be started early or late in the course of Parkinson's disease. In this study, 122 patients treated with levodopa over 14 years were included. The time course of each of the four major signs (rigidity, static tremor, akinesia and postural instability) and Yahr stage was investigated in three groups, Yahr stage I/II group, Yahr stage III group and Yahr stage IV/V group, taking into consideration the time period preceding the initiation of levodopa therapy. When the time periods in years since onset of symptoms were matched, no significant differences were recognized among the three groups. There seemed to be no benefit in delaying levodopa therapy but, rather, levodopa therapy should be started as early as possible. The declining efficacy often recognized during levodopa therapy was thought probably due to progression of Parkinson's disease itself rather than to levodopa.

Drug Administration Schedule↗

PubMed1997

Comparison of standard carbidopa-levodopa and sustained-release carbidopa-levodopa in Parkinson's disease: pharmacokinetic and quality-of-life measures.

We compared clinical, pharmacokinetic, and quality-of-life measures in patients with Parkinson's disease (PD) who were on standard carbidopa-levodopa (Std-L) and after conversion to sustained-release carbidopa-levodopa 50/200 (L-CR). A total of 20 PD patients with motor fluctuations participated in the study and 18 completed it. There were 10 women and eight men, with a mean age of 67.5 years and a mean disease duration of 9.9 years. All patients underwent 10-h pharmacokinetic and clinical evaluations while on Std-L and again while on L-CR. The patients maintained diaries for 2 days before the 10-h evaluations and completed a sickness impact profile (SIP) while on Std-L and again while on L-CR. The total daily levodopa intake was significantly greater with L-CR because of the reduced bioavailability of the L-CR. The mean daily levodopa dosage was 569 mg for Std-L compared with 751 mg for L-CR. The patients performed better in walking time, Unified Parkinson's Disease Rating Scale (motor score), and tapping total with L-CR, although the improvement was not statistically significant. There was no significant difference in dyskinesias between the two preparations. The plasma levodopa levels and the areas under the curve were significantly greater with L-CR. "On" time as measured by patient diaries was significantly greater for L-CR. There was no significant difference in the total SIP scores for patients on the two preparations, but patients had significantly better home management and mobility while on L-CR. In conclusion, L-CR resulted in more "on" time with greater plasma levodopa levels, which resulted in better home management and mobility.

Activities of Daily Living↗

PubMed1975

Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone in Parkinson's disease.

A double-blind study comparing the effects of carbidopa and levodopa combined in a single tablet with levodopa alone was undertaken in 50 patients with Parkinson's disease. After 6 months, there was a statistically significant improvement over baseline in total score, rigidity, and tremor only in the patients randomized to carbidopa/levodopa. In addition, 40 percent of the patients treated with carbidopa/levodopa showed obvious clinical improvement (a greater than 50 percent reduction in their total score) over treatment with levodopa alone. However, after 2 years, only 20 percent continued to show this improvement. Nausea, vomiting, and anorexia developed in 56 percent of patients on levodopa but in only 27 percent of patients on carbidopa/levodopa. However, abnormal involuntary movements, observed in 48 percent of patients on levodopa, were present in 77 percent of patients on carbidopa/levodopa. Despite the increase in abnormal involuntary movements, carbidopa/levodopa is more effective than levodopa.

Adult↗

PubMed1975

Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone on the cardiovascular system of patients with parkinson's disease.

The effects of carbidopa combined with levodopa (carbidopa/levodopa) and levodopa alone on the cardiovascular system of patients with Parkinson's disease were evaluated. Thirty-eight patients who had been on stable doses of levodopa underwent a complete cardiac examination, including measurement of recumbent and erect blood pressure and 24 hour ambulatory electrocardiographic monitoring. Patients were classified with respect to the presence or absence of clinically significant heart disease and ventricular arrhythmias. Nineteen of the 38 patients (50 percent) had heart disease, and 12 (32 percent) had significant ventricular arrhythmias. Eleven of the 12 with arrhythmias had underlying heart disease. The incidence of arrhythmias did not correlate with the dose of levodopa. The patients were subsequently randomly assigned to treatment groups receiving either carbidopa/levodopa or levodopa alone. There was no significant difference in the severity of ventricular arrhythmias or in the incidence of orthostatic hypotension in the group assigned to carbidopa/levodopa compared with the group receiving levodopa.

Adult↗

PubMed1980

Dosage form design for improvement of bioavailability of levodopa II: bioavailability of marketed levodopa preparations in dogs and parkinsonian patients.

To estimate the absolute bioavailability of oral levodopa, plasma concentrations and urinary excretion of levodopa and its metabolites were determined in beagle dogs and in parkinsonian patients after intravenous and oral drug administration. The absolute bioavailability of orally administered levodopa was estimated to be about 35% in both dogs and patients; however, the total amount absorbed of intact drug and levodopa metabolites was estimated to be 80--90% of the administered dose. Due to the similarities of the pharmacokinetic characteristics of levodopa found in beagle dogs and in humans, beagle dogs can serve as a model to study bioavailability, absorption, and metabolic mechanisms.

Administration, Oral↗

PubMed2001

Long-term mortality results of the randomized controlled study comparing bromocriptine to which levodopa was later added with levodopa alone in previously untreated patients with Parkinson's disease.

The present paper compares, in terms of mortality, two treatment regimens for Parkinson's disease (PD), i.e., bromocriptine later combined with levodopa versus levodopa only. Between 1982 and 1989, 60 PD patients (29 treated with levodopa alone [group D] and 31 receiving first bromocriptine followed by an association of bromocriptine + levodopa [group B/D]) were recruited. Data were updated in January 2000. Survival functions were estimated using Kaplan Meier product-limit method and comparison between the two groups with the log-rank test. Mortality was also compared with that of the general French population using standardized mortality ratios (SMRs). The mean duration of follow-up was 10.3 +/- 3.0 years. Seventeen patients died during the follow-up: nine in the group B/D and eight in the group D. The probability of survival at 10 years was 79.0% [95% confidence interval [CI]: 71.4-86.6] in group B/D and 72.9% [95% CI: 63.3-82.6] in group D. In comparison with the general French population, SMRs were not statistically different from 1, in the whole sample of PD patients (1.21, 95 % CI [0.71-1.95]), in group D (0.98 [0.42-1.93]), or in group B/D (1.53 [0.70-2.92]). In this population, we were unable to find any favourable effect of an early use of bromocriptine on mortality in PD in comparison with levodopa alone.

Aged↗

PubMed1998

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy subjects.

A multiple-dose study was performed to assess the pharmacokinetic profile of a new levodopa/benserazide dual-release formulation (DRF) in comparison with a conventional slow-release formulation (SRF). The study was of an open label, randomized, two-way cross-over design and was conducted in 18 subjects. Assessment of the two formulations was at day 1 (single-dose) and at day 7 after a 5-day t. i.d. pre-treatment (100 mg levodopa and 25 mg benserazide) in fasting state. The pharmacokinetic parameters reflecting bioavailability, accumulation and metabolism of levodopa were determined. The levodopa pharmacokinetics of the new DRF showed rapid absorption (tmax=1.1 h), followed by sustained levodopa plasma concentrations, similar to the SRF. Following multi-dose administration, the peak plasma concentration of the new DRF was 90% higher compared to the SFR (Cmax=2.1 and 1.1 microg/ml, respectively). The bioavailability was significantly increased by 40% (AUC0-infinity=6.1 and 4.3 microg x h/ml, respectively). The new DFR was well tolerated as shown by the low incidence of mild side effects. In conclusion, the results of this study confirmed the levodopa dual-release properties of this new levodopa/benserazide formulation.

Benserazide↗

PubMed2005

Levodopa challenge neuroimaging of levodopa-related mood fluctuations in Parkinson's disease.

Some patients with advanced Parkinson's disease (PD) develop dose-related fluctuations in mood. This may reflect alterations in dopamine-influenced brain circuits that mediate emotion. However, there is no available information to localize which dopamine-influenced neurons may be most affected. Eight patients with PD and clinically significant levodopa-related mood fluctuations (mania, depression, or anxiety) were compared to 13 patients with similarly severe PD and fluctuations of motor function but not of mood. Regional cerebral blood flow (rCBF) was measured with positron emission tomography before and after levodopa (in the presence of carbidopa). The rCBF response to levodopa in medial frontal gyrus and posterior cingulate cortex (PCC) significantly differed between mood fluctuators and control patients (corrected p<0.02). Other regions with uncorrected p<0.001 in this comparison were cortical Brodmann areas 22, 40, 13, 11, and 28, hippocampus, and claustrum. The levodopa activation paradigm detected group differences not evident in a comparison of resting rCBF. Abnormalities of dopamine innervation may produce mood fluctuations via effects on PCC, an area strongly linked to mood and anxiety and with known rCBF responsiveness to levodopa or D2-like dopamine receptor agonists. We speculate that mood fluctuations may arise in parkinsonian patients who have abnormal dopaminergic modulation of caudate nucleus, anterior cingulate cortex, or orbital frontal cortex, all of which innervate PCC. The findings require confirmation in larger and better-matched groups.

Affect↗

PubMed2003

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy volunteers.

The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C(max) 1.99 vs. 0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18 mg x h x l-1). The respective values after multiple doses (day 8) were: C(max) 1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96 mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C(max) within a predefined range of 80-125 and 70-143%, respectively. In conclusion, the observed differences in C(max), t(max) and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.

Adult↗

PubMed1984

Chronic low-dose levodopa therapy in Parkinson's disease: an argument for delaying levodopa therapy.

Levodopa is the most useful drug for treatment of Parkinson's disease today. But after continued use for several years, the effectiveness declines, and the undesirable side effects become more frequent, leading to unsatisfactory control. Once the treatment failure emerges, further management is difficult and often unsuccessful. One alternative for preventing side effects and treatment failure is to use a low dose. We are reporting our 12-year experience on uninterrupted treatment with levodopa, 3 grams (approximate) daily. The improvement was comparable with the best reports on higher dosage, and the side effects were significantly less frequent. The frequency of dyskinesia and on-off phenomena showed a strong correlation with duration of treatment. Psychiatric side effects were more common on treatment, but frequency of dementia did not correlate with duration of therapy. Improvement reached a peak after 6 months and remained statistically significant for 3.5 years. By the end of 5 years, the disability profile in the group was similar to that prior to levodopa treatment. So far, there is no satisfactory method for preventing treatment failure. From our observations, low dosage of levodopa is a desirable alternative, but not the answer to therapeutic failure. We recommend that levodopa use be delayed until the patient has a functional and/or psychological handicap that cannot be satisfactorily controlled with less potent antiparkinsonian agents.

Humans↗