Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.
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PMID:Rationale for continuous dopaminomimetic therapy of Parkinson's disease. 268 53

The efficacy of an oral controlled-release preparation of carbidopa/levodopa (Sinemet CR 50/200 mg) was compared with conventional carbidopa/levodopa (25/250 mg) in an open-label study. Twenty patients with idiopathic Parkinson's disease and severe response fluctuations participated. At the end of 6 months of CR treatment, the major clinical benefits included improvement of disability, reduction in number of "off" periods (predominantly end-of-dose hypokinesia), and increase in percentage of "on" time. Although dosages of CR required for an optimal therapeutic response were not significantly higher compared with conventional levodopa, bioavailability significantly increased. Delayed onset of antiparkinsonian effect of CR, resulting from an increase of Tmax for levodopa, was one of the major patient complaints and required additional small amounts of standard levodopa in some patients.
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PMID:Controlled-release carbidopa/levodopa (CR) in parkinsonian patients with response fluctuations on standard levodopa treatment: clinical and pharmacokinetic observations. 268 54

The combination of carbidopa and levodopa (Sinemet) is a highly effective treatment for the symptoms of Parkinson's disease. However, side effects, such as abnormal involuntary movements, fluctuations in motor performance, and "wearing off" phenomena limit its long-term usefulness in some patients. Open-label studies show that controlled-release Sinemet CR is effective in reducing motor fluctuations. This report discusses the results of a 14-week double-blind crossover study comparing the efficacy and tolerability of standard Sinemet with controlled-release Sinemet CR. Overall, there were no statistically significant differences in efficacy between Sinemet CR and standard Sinemet on any of the major efficacy measures, suggesting a clinical equivalence in terms of treating the symptoms of Parkinson's disease. The study also supports the tolerability of Sinemet CR. In summary, Sinemet CR holds the promise of reducing some disturbing side effects of long-term levodopa therapy, thus achieving optimal control of parkinsonian symptoms.
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PMID:Double-blind comparison of standard Sinemet and Sinemet CR in patients with mild-to-moderate Parkinson's disease. 268 55

Twenty-one patients with Parkinson's disease and motor fluctuations who completed a double-blind study comparing controlled-release carbidopa/levodopa (Sinemet CR4) with standard Sinemet (SS) were evaluated one year following completion of the study. Five patients remained on CR4 alone; 16 continued on CR4 plus SS, and one also required addition of bromocriptine. Patients were significantly worse (p less than 0.05) at one year compared with double-blind CR4 phase (DBCR) for nine parameters of the motor exam, six activities of daily living (ADL), Hoehn & Yahr staging, and physician's global assessment. Compared with baseline SS, patients were worse at one year for four points of the motor exam, two of mentation, behavior, and mood, and 11 parameters of ADL. Improvement at one year was noted for less action and postural tremor and decreased duration of dyskinesias for both comparison periods. There was elimination of early morning dystonia at one year over the DBCR period and more hours "on" without dyskinesias and fewer hours "on" with dyskinesias compared with baseline SS. Total levodopa dosage was not significantly changed over the year. These data suggest that, in long-term use, CR4 remains more efficacious than SS alone for Parkinson's patients experiencing motor fluctuations, although disease progression continues despite optimal medication.
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PMID:Long-term efficacy of controlled-release carbidopa/levodopa in patients with advanced Parkinson's disease. 269 Jul 30

The efficacy of Sinemet CR4 (50/200) was compared to standard Sinemet (25/100) in an open label crossover study in 22 patients with Parkinson's disease. All patients experienced end of dose failure and 11 had dyskinesia. Unified Parkinson's disease, Hoehn and Yahr, Schwab and England scores, number of hours on per day, number of hours of dyskinesia per day, daily dose of levodopa, and number of doses per day were monitored at the end of each treatment period and the results compared. The only significant difference in these parameters between the CR4 and standard Sinemet treatment periods in the entire group was a decrease in hours of dyskinesia per day. Two subgroups of CR4 responders were specifically examined. The first subgroup was characterised by a significant increase in on time per day with CR4 therapy. These patients had an older age of onset of Parkinson's disease and a shorter duration of disease and fluctuations than the rest of the patients. The second subgroup was characterised by the presence of dyskinesia with standard Sinemet therapy and a significant decrease in hours of dyskinesia per day with CR4 therapy. Both subgroups required a significantly higher daily dose of levodopa while on CR4. It is concluded that CR4 may be useful in increasing hours on per day in subgroups of Parkinson's disease patients who have less severe fluctuations. It may also be useful in decreasing the number of hours of dyskinesia per day.
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PMID:Efficacy of sinemet CR4 in subgroups of patients with Parkinson's disease. 270 40

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.
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PMID:Increased dosage of carbidopa in parkinsonian patients on low carbidopa-levodopa regimen. Effect on levodopa bioavailability. 271 68

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.
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PMID:An open trial of controlled release carbidopa/L-dopa (sinemet CR) for the treatment of mild-to-moderate Parkinson's disease. 274 46

PHNO, a new D-2 agonist, was investigated in five patients with Parkinson's disease. In an acute, open, oral, dose-ranging study comparing benefit from single doses, 4 mg of PHNO was found to be equivalent to one tablet of Sinemet 25/250 mg. Adverse reactions were those anticipated for a dopaminomimetic agent. Because of its novel structure and apparent transcutaneous penetration, further studies on PHNO are desirable.
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PMID:Antiparkinsonian activity of a single oral dose of PHNO. 290 20

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.
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PMID:Controlled-release Sinemet (CR-4): a double-blind crossover study in patients with fluctuating Parkinson's disease. 304 35

Previous short-term studies have shown that the dopamine agonist pergolide improves control of Parkinson's disease when used in conjunction with carbidopa-levodopa (Sinemet). We assessed the long-term outcome (2 1/2- to 3-year follow-up) in patients with Parkinson's disease who participated in our previous pergolide double-blind trial and were subsequently switched to open-label pergolide therapy. Of 41 evaluable patients who began pergolide therapy, 10 (24%) experienced sustained substantial benefit that persisted to the end of this investigation. A total of 23 patients (56%) remained on pergolide therapy and, as a group, had considerable improvement over baseline at 2 1/2 to 3 years on the basis of several measurements of efficacy. A tendency toward deterioration could be reversed in many patients by larger or more frequent doses of carbidopa-levodopa; nevertheless, all but four patients were still taking the same dose or less of carbidopa-levodopa at the end of this study as at the onset. Patients with the best initial response to pergolide seemed most likely to experience long-term benefit. Confusion and hallucinations were the side effects most likely to necessitate discontinuation of pergolide. Symptoms suggestive of dose-related angina pectoris occurred in four patients in the open-label phase and two patients in the earlier double-blind phase (13% of patients who started pergolide therapy); these symptoms were easily controlled by dose reduction or discontinuation of pergolide, without sequelae. Dose-related leukopenia developed in one patient.
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PMID:Pergolide: long-term use in Parkinson's disease. 305 Mar 1


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