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We studied the effect of entacapone, a catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of a controlled-release (CR) levodopa-carbidopa preparation (Sinemet CR) in an open, randomized trial in 12 healthy male volunteers. The inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured. Single graded doses of entacapone (100-800 mg) were administered concomitant with a single oral dose of CR levodopa, or CR levodopa was given without entacapone (control treatment), at least 1 week apart. Plasma concentrations of levodopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone were determined for pharmacokinetic calculations. Entacapone decreased dose-dependently the activity of S-COMT in RBCs with a maximal inhibition of 66% after the highest dose (800 mg). Entacapone increased the area under the plasma concentration-time curve (AUC) of levodopa; the increase was highest (33%) after the 400-mg dose. Entacapone did not influence time to maximal concentration (Tmax) of levodopa. Entacapone was absorbed faster than levodopa from the CR preparation. The AUCs of 3-OMD and HVA decreased and that of DOPAC increased dose-dependently after entacapone, maximally by 69, 38, and 74%, respectively. Higher doses of entacapone (400 mg and 800 mg) decreased the AUC, but not Tmax of carbidopa. Over the dose range studied, entacapone was well tolerated. Entacapone is an effective COMT inhibitor. It improves the pharmacokinetic profile of levodopa when used in combination with a CR levodopa preparation, as it does with a standard levodopa preparation. The results justify further clinical studies with entacapone in combination with CR preparations of levodopa.
After overnight drug withdrawal and in the fasting state, 11 patients with Parkinson's disease (PD) and a fluctuating response to chronic levodopa treatment were given, in random sequence on consecutive days, equivalent levodopa doses (with peripheral decarboxylase inhibitor) (a) as levodopa methyl ester (ME), (b) as Sinemet CR, or (c) as half the dose of ME together with a halved tablet of Sinemet CR. All patients turned ON rapidly after treatments a and c, but only half did so after treatment b. On period duration was longest after treatment c, intermediate after treatment a, and shortest after treatment b. Pharmacokinetic analysis in a subset of 6 patients revealed no significant difference between treatments a and c, although there was a trend for t1/2 to be longer after treatment c. We conclude that giving ME with a halved tablet of Sinemet CR provided a useful clinical balance between rapid onset and extended duration of action of at least the first levodopa intake of the day. In view of differing release profiles between whole and halved tablets of Sinemet CR, similar single-dose pharmacokinetic studies, followed by sequential-dose clinical studies, are indicated when Sinemet CR 125 tablets soon become available.
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We present the case of a 21-year-old man with advanced refractory Parkinson's disease treated with Duodopa continuous infusion. With this therapy, the patient had a spectacular recovery but after six months, he experienced an aggravation of his symptoms. A failure of his pumping system was suspected but we discovered that the jejunal tube was blocked due to a knot around a bezoar. This is the first complication of this kind described with the Duodopa infusion technique.
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The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.
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Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16).
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Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease that responds poorly to pharmacologic intervention despite its clinical, neurochemical, and pathologic similarity to Parkinson's disease. We reviewed our experience with drugs used in the treatment of patients with PSP who were followed in the Department of Neurology, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School. Of 136 patients identified, adequate drug-response data were available for 87 (64%). Benefit and adverse effects of therapy were graded on a 4-point scale: 0, none; 1, minimal; 2, moderate; 3, marked. The three most frequently used drugs were amitriptyline (32% of patients benefited), imipramine (28% of patients benefited) and levodopa/carbidopa (Sinemet) (38% of patients benefited). Levodopa/carbidopa, amantadine, selegiline, and amitriptyline gave the best risk/benefit ratios. Monotherapy tended to show more benefit and fewer adverse effects than polypharmacy.
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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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Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.
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The combination of coumarin derivative (7-(1,3-dithiolan-2-yl)-9,10-dihydroxy-6H-benzofuro[3,2-c]chromen-6-on), (DC)-titanium dioxide nanoparticles (TiO2) and ionic liquid (IL) yields nanostructured electrochemical sensor, formed a novel kind of structurally uniform and electrocatalytic activity material. This new ionic liquid-TiO2 nanoparticles modified carbon paste electrode (IL-CTP) due to its enhanced conductivity presented very large current response from electroactive substrates. The modified electrode was characterized by different methods including a scanning electron microscope (SEM), electrochemical impedance spectroscopy (EIS) and voltammetry. A pair of well-defined quasi reversible redox peaks of coumarin derivative was obtained at the modified carbon paste electrode (DC/IL-CTP) by direct electron transfer between the coumarin derivative and the CP electrode. Dramatically enhanced electrocatalytic activity was exemplified at the DC/IL-CTP electrode, as an electrochemical sensor to study the electro oxidation of levodopa (LD) and carbidopa (CD). Based on differential pulse voltammetry (DPV), the oxidation of LD and CD exhibited the dynamic range between 0.10- 900.0 μM and 20.0-900.0 μM respectively, and the detection limit (3σ) for LD and CD were 41 nM and 0.38 μM, respectively. DPV was used for simultaneous determination of LD and CD at the DC/IL-CTP electrode, and quantitation of LD and CD in some real samples (such as tablets of Parkin-C Fort and Madopar, Sinemet, water, urine, and human blood serum) by the standard addition method.
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Inclusion criteria were patients with probable PD suffering from a wearing-off phenomenon and who had been treated using levodopa/carbidopa with or without entacapone, but not with other classes of anti-Parkinson agents. Patients were excluded if they had at least one condition that could be associated with high AVP levels. Ropinirole was initiated at 0.5 mg 3 times daily, and daily dosages were increased by 1.5 mg/day on a biweekly basis up to 6 mg/day. Plasma AVP levels were determined every two weeks. Effects of escalating ropinirole dosage on plasma AVP levels were evaluated using a one-way analysis of variance for repeated measures, an a priori Dunnett multiple comparison test, and a regression analysis.