Levodopa-carbidopa intestinal gel therapy may cause “Supra-ON freezing of gate” in patients with Parkinson's disease with diphasic dyskinesia
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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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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.
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Summary The pharmacokinetics of the clinically determined optimal dose of controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100) after 12 weeks of therapy was studied in nine parkinsonian patients without prior exposure to levodopa. The pharmacokinetics of single oral doses of controlled release levodopa/carbidopa 25/100 and 50/200 were also compared. As predicted from the plasma half-life (1.7 ± 0.3 h) and confirmed by morning trough levels, levodopa did not accumulate when controlled released levodopa/carbidopa 25/100 was administered twice daily. The absorption and bioavailability of CR 25/100 are minimally greater than CR 50/200. Controlled released levodopa/carbidopa 25/100 levodopa plasma levels peak slightly faster than controlled release levodopa/carbidopa 50/200.
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Abstract To evaluate the ability of orally administered liquid levodopa/carbidopa (LD/CD) to stabilize plasma levodopa levels and reduce motor reponse fluctuations in Parkinson's disease, five patients received LD/CD hourly, as standard tablets or as an aqueous solution on two separate days in a double‐blind, placebo‐controlled, cross‐over design. Except for a slightly earlier peak plasma levodopa level, no significant advantage of the liquid formulation over tablet therapy was found. However, liquid LD/CD could be helpful in quickly resolving “off” states and by facilitating small dose adjustments that are not possible with tablets.
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To the Editor.—
The recent report by Tourtellotte et al (Archives1980; 37:723-726) describing their study of the use of an increased ratio of carbidopa to levodopa in the treatment of Parkinson's disease is rather difficult to interpret. The authors used an investigational design that allowed them to study three separate groups of patients with Parkinson's disease who had ceased receiving levodopa or carbidopa-levodopa (10:100) for at least one month. These groups of patients were treated with either levodopa, carbidopa-levodopa (10:100), or carbidopa-levodopa (20:100), and their degree of parkinsonian disability was evaluated. The response of the patients to these three different treatment regimens after a two-week period was used to conclude that increasing the amount of carbidopa in presently available drugs is a desirable treatment modality. Although the authors do state that their study "was conducted over a relatively short period," Parkinson's disease, in particular the therapy of Parkinson's diseaseCarbidopa
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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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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.
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ABSTRACT – 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.
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Abstract The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended‐release formulation of carbidopa‐levodopa, with an immediate‐release carbidopa‐levodopa formulation in advanced Parkinson's disease. We performed an open‐label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate‐release carbidopa‐levodopa followed by IPX066 or IPX066 followed by immediate‐release carbidopa‐levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple‐dose administration). Following a single dose of IPX066 or immediate‐release carbidopa‐levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate‐release carbidopa‐levodopa ( P < .0001). Multiple‐dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C max was approximately 30% compared with immediate‐release carbidopa‐levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate‐release carbidopa‐levodopa. Larger, longer‐term, well‐controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066. © 2011 Movement Disorder Society
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Summary: In a comparison of the effects of domperidone and carbidopa during levodopa treatment, 20 patients with idiopathic Parkinson's disease were treated with fixed dose regimens of either levodopa 500 mg- domperidone 20 mg or levodopa 100 mg-carbidopa 25 mg; each for 8 weeks. Clinical response, incidence of side effects, and plasma levodopa concentration resulting from each treatment were compared. Overall, in the dosages used, Parkinson's disease was less well controlled with levodopa-domperidone than with levodopa-carbidopa. In eight subjects there was a severe deterioration 2 to 7 days after changing from a fixed dose of levodopa-carbidopa to levodopa-domperidone. In nine subjects who completed the trial, the clinical response, occurrence of dyskinesias and of nausea and vomiting, were similar with both treatments, although peak plasma levodopa concentration and levodopa bioavailability were greater on levodopa-domperidone than on levodopa-carbidopa.
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