Levodopa-carbidopa Research Articles

L-Deprenyl (Selegiline) Added to Sinemet CR in the Management of Parkinsonʼs Disease Patients With Motor Response Fluctuations

L-deprenyl (Eldepryl) added to Sinemet CR in the treatment regimens of seven patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) allowed a statistically significant reduction in total daily levodopa intake and an increase in the mean interdose interval. Trends were noted towards a reduction in the number of daily "off" periods and an increase in the portion of the waking day spent "on." Three patients suffered an increase in the intensity of their dyskinesias, and discontinued taking deprenyl. Four patients, all of whom reported improved functioning during "off" periods, have continued taking the combination. Sinemet CR and deprenyl can safely be used together in patients with advanced PD, and the combination may result in improved control of motor fluctuations in selected patients.

Results of long-term treatment with controlled-release levodopa/carbidopa (Sinemet CR)

35 Parkinson's disease patients with motor response fluctuations (RF) participated in controlled clinical trials comparing Sinemet CR to Standard Sinemet (STD) at our institutions. 13 of 25 eligible patients continued to two years (the longest possible follow-up from the second study), and 5 of 11 have continued taking CR up to 4 years. At the end of both two and four years, patients were taking significantly fewer medication doses, with a significantly longer interdose interval, and up to two years, experienced fewer "off" periods than when on Standard Sinemet (STD) alone. Most patients required STD at at least one dose each day to hasten to onset of antiparkinson effect. Sinemet CR is a useful adjunct in the long-term management of motor response fluctuations in Parkinson's disease.

New Drugs for Parkinsonʼs Disease

Parkinson's disease continues to be a tragic debilitator of close to half a million Americans. As more is learned about the disease, pharmacological treatment improves. Just recently, deprenyl became a part of our therapeutic armamentarium, and it appears that Sinemet CR will soon be following. It is hoped that these drugs will improve the quality and quantity of life for patients with PD until the disease can be cured.

Randomized Double-Blind Cross-Over Study of Sinemet-Controlled Release (CR4 50/200) versus Sinemet 25/100 in Parkinson’s Disease

Sinemet-controlled release (CR4) consisting of 50 mg carbidopa/200 mg levodopa was compared with Sinemet 25/100 in 24 Parkinson's disease (PD) patients during a 16-week double-blind cross-over study. The mean age of the patients was 66.2 years, their mean duration of PD was 9.3 years. All of the patients had response fluctuations consisting mainly of the 'wearing-off' phenomenon. Some of the patients also experienced the 'on-off' phenomenon. All patients were evaluated using the unified Parkinson disease rating scale. The following significant differences were noted on Sinemet CR4. More patients noted a decrease in dyskinesias and response fluctuations; more patients experienced a decrease in stage when 'on'; more patients were 'on' longer during the day, and more patients were globally improved. The mean number of doses per day were significantly less on Sinemet CR4 (mean 5.0, range 3-8) than on Sinemet 25/100 (mean 6.2, range 4-11 doses/day). The mean dose of levodopa in Sinemet CR4 was 1,186 +/- 458 mg and the mean dose of carbidopa was 797 +/- 115 mg. The mean dose of levodopa in Sinemet 25/100 was 873 +/- 304 mg and the mean dose of carbidopa was 218 +/- 76 mg. This study indicates that Sinemet CR4 is a useful addition for patients with response fluctuations.

Pharmacodynamic modeling of concentration‐effect relationships after controlled‐release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

Magnitude of response to levodopa in Parkinson disease as it relates to peripheral and central measurements of levodopa and associated metabolites.

The relationships between magnitude of response to orally administered carbidopa/levodopa (CD/LD) and serum/cerebrospinal fluid (CSF) concentrations of levodopa (LD), 3-O-methyldopa (3-O-MD), and homovanillic acid (HVA) were studied in 15 patients with chronic LD-treated Parkinson disease. The degree of clinical benefit derived from a 25/250 tablet of CD/LD could not be correlated with absolute serum levels of LD, 3-O-MD or LD/3-O-MD ratios. CSF levels of LD and 3-O-MD were also not associated with improvement. CSF levels of HVA, however, did significantly correlate with magnitude of response to LD. Furthermore, CSF HVA levels were not dependent on previous LD dosage. Our data suggest that in chronic LD-treated patients, central factors related to the integrity of the nigrostriatal tract may be a more important determinant of magnitude of response to LD than peripheral elements affecting the amount of LD entering the central nervous system.

An open trial of controlled release carbidopa/L-dopa (sinemet CR) for the treatment of mild-to-moderate Parkinson's disease.

Nineteen patients with mild-to-moderate Parkinson's disease completed a 1-year open label study of a controlled release preparation of carbidopa/L-DOPA (Sinemet CR). Twelve patients were thought to have improved compared with baseline, and only one was worse. The total daily dose of L-DOPA was not significantly changed, but dosing frequency was almost halved. Patients with complex drug schedules on standard Sinemet liked the drug most. "Wearing off" patients also benefitted from the change, whereas "on/off" patients did not do significantly better on Sinemet CR.

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.

Controlled-Release Sinemet (CR-4): A Double-Blind Crossover Study in Patients With Fluctuating Parkinson's Disease

Patients with moderate to advanced Parkinson's disease may have prominent levodopa-related motor fluctuations. In a double-blind crossover study, we compared the anti-Parkinson effects of standard Sinemet with a controlled-release formulation (Sinemet CR-4) in 23 patients with short-duration responses to standard Sinemet. With Sinemet CR-4, approximately half the patients who completed the study displayed a prolongation of their "on" response (optimal response to treatment), as assessed by monitoring individual drug-response cycles. A few patients experienced prolonged delays before the peak anti-Parkinson response developed to Sinemet CR-4. End-of-dose "wearing off" was favorably affected by Sinemet CR-4, but patients still had unpredictable "off" (parkinsonian) periods. Subjective ratings of Sinemet CR-4 varied, and 39% of patients who completed the study actually preferred standard Sinemet to the new formulation. We conclude that Sinemet CR-4 may benefit some patients with Parkinson's disease with a short-duration response to standard Sinemet; however, not all patients found it preferable to the standard formulation.

Controlled-Release Levodopa/Carbidopa III

Five patients with advanced Parkinson's disease and fluctuations in therapeutic response to levodopa participated in, and four completed, an open label study of the efficacy of Sinemet CR5. Reductions in the number of daily doses and "off" periods as well as the increase in interdose interval and percent "on" time versus standard Sinemet were comparable to those achieved with Sinemet CR4 in these same patients. As compared with Sinemet CR4, there was a greater delay in the occurrence of peak plasma levodopa concentrations, and relative bioavailability was reduced. Sinemet CR5 appears to offer no advantages over Sinemet CR4 in the treatment of response fluctuations in Parkinson's disease.

Controlled-release levodopa/carbidopa. II. Sinemet CR4 treatment of response fluctuations in Parkinson's disease.

Sixteen patients with Parkinson's disease and therapeutic response fluctuations entered an open-label trial of a controlled-release carbidopa/levodopa preparation, Sinemet CR4. Sinemet CR4 behaved as a slow release preparation. At the end of 6 weeks CR4 treatment, there was an increase in percent "on" time and mean interdose interval; the number of daily doses and "off" periods were diminished and a slight reduction in the variability of plasma levodopa levels was observed. Overall benefit waned over the next 6 months, despite addition of standard levodopa or Sinemet to overcome the delayed onset of antiparkinsonian effect of CR4 which resulted from prolongation in the Tmax for levodopa. The major benefits of CR4 were reduction in off time and in the number of daily off periods, with fewer levodopa doses per day and prolongation of the interdose interval.

Sinemet in Parkinsonʼs Disease

Sinemet in Parkinsonʼs Disease

COMPARISON OF ENTERIC‐COATED LEVODOPA WITH LEVODOPA–CARBIDOPA COMBINATION

Twenty-seven patients with idiopathic Parkinson's disease completed a double-blind crossover trial which compared enteric-coated levodopa (Prodopa) with levodopa–carbidopa combination (Sinemet). It was easy to stabilize the patients’ condition with either drug, and the dose-sparing effect both of the enteric-coated preparation, and of the levodopa–carbidopa combination was again noted. At the dosages used, the levodopa–carbidopa combination was objectively shown to be more effective in 71% of the patients investigated, although there was no clear personal preference for either preparation when patients compared the two parts of the trial. Both drugs play a valuable role in the treatment of Parkinson's disease.