PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Levodopa”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed1992

The natural history of Parkinson's disease in the pre-levodopa and post-levodopa eras.

Since Parkinson's disease was first described by James Parkinson in 1817, the natural history has been confounded by various treatment modalities: the replenishment of deficient dopamine, the addition of the dopamine agonists, and the more recent addition of drugs whose putative action may slow the natural history of the disease. Nevertheless it remains a disease that is slowly and inexorably progressive over several decades. The quality of life during this progression can be improved, and the duration of life before inanition produces life-threatening complications can be extended. New approaches to identifying the disease before the overt symptoms appear and to slowing the progression of the underlying pathophysiology are being explored but to date have not produced significant changes in the prognosis for the individual patient.

Humans↗
PubMed2004

The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study.

OBJECTIVES: Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease. STUDY DESIGN AND METHODS: This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group. RESULTS: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. CONCLUSION: This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.

Adult↗
PubMed1999

Current management of motor fluctuations in patients with advanced Parkinson's disease treated chronically with levodopa.

Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the "delayed on" (increased time latencies from dose intake to start-up of clinical benefit) and "no-on" (complete failure of a levodopa dose to exert an "on" response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult "off" situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose. Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most effective pharmacological treatment for Parkinson's disease (Melamed, 1987). Undoubtedly, the outstanding therapeutic success of levodopa represents a dramatic and revolutionary breakthrough in medicine, in general, and in neurology, in particular. Although, since the introduction of levodopa, there have been many additional pharmacological and even surgical anti-parkinsonian strategies, it still stands out as a mandatory axis of treatment in the majority of patients (Steigler and Quinn, 1992). Indeed, levodopa therapy improves, sometimes markedly, the motor signs and symptoms of the illness, the functional capacity and quality of life and perhaps also life expectancy of the afflicted patients. It is therefore unfortunate that after an initial problem-free period of successful, smooth and stable clinical benefit from levodopa that lasts about two to five years, the responsiveness of many patients worsens with the emergence of a variety of complications (Marsden et al., 1982; Hardie et al., 1984). These adverse reactions include dyskinesias and dystonias, psychotic problems and, particularly, the troublesome motor fluctuations (Marsden and Parkes, 1977; Marsden, 1994). The latter phenomenon may be particularly complex, limiting and disabling. It is believed that most patients on long-term levodopa therapy will, sooner or later, develop response fluctuations of varying types and severity (Riley and Lang, 1993). Because of the serious impact of these phenomena on the quality of life and function of the patients, many efforts are now being undertaken to identify the responsible mechanisms and to devise preventive and therapeutic measures.

Antiparkinson Agents↗
PubMed2001

Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.

There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinson's disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series. We searched MEDLINE for all English language publications reporting the cumulative frequency of levodopa-induced dyskinesias or motor fluctuations during discrete intervals of treatment. This generated 2,478 publications spanning 1966 through September 2000. Papers with appropriate titles or abstracts were reviewed; reference lists from published clinical series were a source of additional papers for review. This ultimately yielded 74 publications with adequate data, relating to 112 intervals of levodopa treatment. Series that included patients with PD-onset well before levodopa availability (pre-levodopa era) were separately analyzed from all subsequent series. Series were grouped by duration of levodopa therapy and the median frequencies of dyskinesias and motor fluctuations were tabulated for each group. The data were analyzed both with and without adjustment for the number (N) in each series. Among series containing pre-levodopa era patients, the median dyskinesia frequency was already 50% by 5-6 months of treatment. This contrasts with the modern era series where dyskinesias were reported later in treatment. The median dyskinesia frequency was slightly less than 40% by 4-6 years of levodopa therapy among modern era patients. Motor fluctuations (wearing-off) were not tabulated in most of the early levodopa series. Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4-6 years of treatment. Similar results were found when the analyses were restricted to only prospective studies where levodopa motor complications were targeted outcome measures. The conclusions reached were: (1) patients from the pre-levodopa era experienced dyskinesias much earlier during levodopa treatment than modern era patients, perhaps because of longer durations of pre-existing PD; (2) in the present era, patients treated with levodopa therapy for 4-6 years have approximately a 40% likelihood of experiencing motor fluctuations and a risk of dyskinesias just short of 40%; and (3) these findings represent incident data and the prevalence of clinically important morbidity may be substantially less.

Adult↗
PubMed1987

Evaluation of long-term oral levodopa therapy in chronic congestive heart failure.

To evaluate the long-term effects of orally administered levodopa, 11 patients with chronic congestive heart failure (NYHA III-IV) were studied during maintenance therapy (30 +/- 1 days) and after withdrawal from levodopa. The daily levodopa dose was 4 g in six patients; because of side effects the levodopa dose was reduced to 2-3 g in the remaining patients. After withdrawal of levodopa, mean pulmonary capillary wedge pressure and mean right atrial pressure increased significantly (from 19 +/- 2 to 24 +/- 3 and from 7 +/- 2 to 9 +/- 2 mmHg, respectively). Effective renal plasma flow was 329 +/- 57 during levodopa therapy and decreased significantly to 252 +/- 27 ml/min after withdrawal of levodopa. The number of ventricular premature contractions and couplets increased during levodopa therapy and decreased again significantly after withdrawal of levodopa. No significant differences between on and off levodopa were observed in resting heart rate, arterial blood pressure, cardiac index, stroke work index, systemic vascular resistance, sodium and water excretion, or creatinine clearance. Seven patients improved on levodopa therapy by one NYHA class; four of these seven patients deteriorated again by one NYHA class after withdrawal of levodopa. Regarding both clinical and hemodynamic changes after withdrawal of levodopa, three patients were classified as responders to long-term levodopa therapy. All three responders received 4 g levodopa per day. Average dopamine plasma level was 5.3 +/- 0.8 ng/ml in the responder group and 2.0 +/- 0.5 ng/ml in the nonresponder group. Long-term administration of oral levodopa is associated with beneficial clinical and hemodynamic response in only a minority of patients with chronic congestive heart failure.

Administration, Oral↗
PubMed1995

Concentration-effect relationship of levodopa in patients with Parkinson's disease.

Studies on the concentration-effect relationship of levodopa in Parkinson's disease have established that: (1) in patients with a fluctuating response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e. potency is decreased) compared with those patients whose symptoms are adequately controlled; (2) with controlled-release (CR) preparations, the concentration-effect relationship indicates a decreased potency compared with conventional immediate-release (IR) preparations; and (3) coadministration of a dopamine receptor agonist (even at a subclinical dose) enhances the potency of levodopa. These findings support some current hypotheses on the origin of, and the pathophysiological process underlying, response fluctuations. In patients with response fluctuations, metabolism of levodopa and storage of dopamine in the striatum are reduced. Levodopa is decarboxylated in the extracellular space, with the result that dopamine is released directly to the effect site. Thus, without dopamine storage acting as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa concentrations. Even small fluctuations of levodopa concentrations around the EC50 value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylation of levodopa) are required. The storage buffer is responsible for a time lag between decline in peripheral plasma concentrations of levodopa and dopamine-induced motor response. Low doses of a dopamine receptor agonist increase the basal tonus of the striatum, but do not reach the threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switch from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-pharmacodynamic modelling does not give a clear answer as to whether response fluctuations are additionally induced by receptor desensitisation or inhibition of the active transport of levodopa across the blood-brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Nevertheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations are compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response fluctuations. The interindividual variability of EC50 values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical effects). However, considering the short elimination half-life of levodopa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interval with CR preparations might be limited by the higher threshold concentrations of levodopa necessary to maintain clinical effects.

Antiparkinson Agents↗
PubMed2005

Does levodopa slow or hasten the rate of progression of Parkinson's disease?

UNLABELLED: Levodopa therapy, as originally established by George Cotzias [2, 3], is the most powerful treatment for Parkinson's disease (PD). Levodopa's toxicity to neurons in vitro has raised concerns if it might hasten the progression of PD, although in vivo animal studies suggest it may be neuroprotective. OBJECTIVE: To discuss the results of the ELLDOPA trial that was carried out to determine if levodopa therapy influences the rate of progression of Parkinson's disease (PD). DESIGN: ELLDOPA was a multicenter, parallel-group, double-blind, dosage-ranging, randomized, controlled clinical trial. SETTING: Academic movement disorders clinics at 38 sites in the United States and Canada. PATIENTS: Three hundred and sixty-one patients with early PD of less than 2 years' duration who did not require symptomatic therapy. INTERVENTIONS: Subjects were randomly assigned to one of four treatment groups: carbidopa/levodopa 12.5/50 mg t. i. d. (N=92), 25/100 mg t. i. d. (N=88), 50/200 mg t. i. d. (N=91), or matching placebo (N=90). The dosage was gradually escalated over 9 weeks and then maintained until Week 40, at which time active treatment was withdrawn over 3 days. After 2 weeks without active treatment (Week 42), a final assessment of PD severity was obtained. OUTCOME MEASURES: The prespecified primary clinical outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and Week 42, comparing the four treatment groups. The primary neuroimaging component of the study in a subgroup of 142 subjects was the percent change in striatal (123)iodine 2-beta-carboxymethoxy-3-beta-(4-iodophe nyl)tropane (beta-CIT) uptake between baseline and Week 40 visits. The neuroimaging substudy utilized single photon emission computed tomography (SPECT) of the dopamine transporter. RESULTS: All dosages of levodopa exerted clinical benefit compared to placebo on the UPDRS scores throughout the study, including 2 weeks after discontinuing levodopa. The UPDRS scores at Week 42 failed to reach the level encountered in the placebo group (change of 7.8+/-9.0, 1.9+/-6.0, 1.9+/-6.9, and -1.4+/-7.8, for placebo, 150 mg/day, 300 mg/ day, and 600 mg/day, respectively, p<0.0001). Nausea (p=0.001) and dyskinesias (p=0.0001) were more common in the levodopa groups, especially with the higher dosages. Freezing appeared around the same time, but was more common in the placebo (14 %) and 150 mg/day group (10 %). The percent decline of beta-CIT uptake in the striatum was significantly more pronounced in the levodopa groups than the placebo group (-7.2%, -4%, -6%, and -1.4% in 600 mg/day, 300 mg/day, 150 mg/day, and placebo, respectively; p=0.035). CONCLUSIONS: The clinical outcomes not only indicate that levodopa is effective in a dose-dependent manner in overcoming the signs and symptoms of PD, they also support the concept that the drug does not hasten the disease progression, but rather may slow down the rate of the disease. The clinical study failed to demonstrate any evidence of levodopa worsening early PD. However, the beta-CIT SPECT substudy indicates the opposite effect, namely that levodopa causes a more rapid decline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals in the striatum. These contradictory findings warrant further investigation into the effect of levodopa on PD. OTHER OBSERVATIONS: The ELLDOPA study was the first levodopa dose-response study ever conducted. It showed that dose is a factor in the cause of producing motor complications of dyskinesias and wearing-off, and that these can develop as early as 5 to 6 months. On the other hand, freezing of gait could be delayed or its occurrence reduced by high dosage levodopa, compared to placebo or low-dose levodopa. Withdrawal of levodopa over a 3-day step-down can be safely carried out without inducing the neuroleptic-like syndrome. The UPDRS was shown to be a reliable linear marker for disease progression. The ELLDOPA study also called into question the interpretation of beta-CIT SPECT in the presence of dopaminergic agents. Neuroimaging in ELLDOPA also showed that some people diagnosed with early PD do not have a dopaminergic deficit, calling into question how difficult the correct diagnosis may be in people with early symptoms of PD.

Antiparkinson Agents↗
PubMedDate not supplied

Pharmacokinetics of etilevodopa compared to levodopa in patients with Parkinson's disease: an open-label, randomized, crossover study.

"Dose failures" and "delayed on" phenomena following an intake of levodopa dose in patients with Parkinson's disease (PD) with motor fluctuations may be caused by stagnation of poorly soluble levodopa in the atonic stomach. Etilevodopa is a unique, highly soluble prodrug of levodopa. When ingested, etilevodopa is more readily dissolved in the stomach than levodopa. It passes unchanged through the stomach to the duodenum, where it is rapidly hydrolyzed by local esterases and rapidly absorbed as levodopa. To compare the pharmacokinetics of three different modes of etilevodopa/carbidopa administration with standard levodopa/carbidopa tablets in fluctuating PD patients, 29 patients with PD and response fluctuations were enrolled in an open-label, randomized, four-way crossover study of single doses of 4 treatments: swallowed etilevodopa/carbidopa tablets, etilevodopa/carbidopa tablets dissolved in water, etilevodopa oral solution with carbidopa tablets, and standard levodopa/carbidopa tablets. To measure the maximal concentration (Cmax), time to Cmax (tmax), and area under the curve (AUC) of plasma levodopa, etilevodopa, and carbidopa, blood samples were drawn before drug administration and at intervals up to 240 minutes thereafter. Plasma levodopa tmax was significantly shorter with all three modes of administration of etilevodopa (mean of about 30 minutes) than with levodopa treatment (mean of 54 minutes). During the first 45 minutes after drug ingestion, plasma levodopa AUC was significantly greater after etilevodopa administration than after levodopa administration. Levodopa AUC for 0 to 1 hour and 0 to 2 hours were also significantly greater following administration of etilevodopa/carbidopa swallowed tablets than following administration of levodopa/carbidopa tablets. Mean levodopa Cmax was in the range 2.3 to 2.7 microg/mL for all treatments. Levodopa Cmax was significantly greater following treatment with etilevodopa swallowed tablets than with levodopa tablets. Etilevodopa/carbidopa was well tolerated, with a safety profile comparable to that of levodopa/carbidopa. The shorter levodopa tmax observed with etilevodopa potentially translates to a shorter time to "on". Clinical trials with etilevodopa/carbidopa tablets should be carried out in PD patients with response fluctuations such as "delayed on" and "dose failures".

Adult↗