Improvement of parkinsonian features correlate with high plasma levodopa values after broad bean (Vicia faba) consumption.
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Five healthy volunteers and six patients with Parkinson's disease (PD) ate 250 g cooked broad beans after 12 hours without treatment. During the next four hours a substantial clinical improvement was noted, three patients showed severe dyskinesias, and plasma levodopa concentrations rose. (+info)
Pathophysiology of parkinsonism due to hydrocephalus.
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We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson's disease. (+info)
Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses.
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AIM: The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa. METHODS: Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. RESULTS: The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. CONCLUSIONS: No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone. (+info)
Levodopa and the progression of Parkinson's disease.
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BACKGROUND: Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease. METHODS: In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake. RESULTS: The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6 percent among those receiving levodopa at 150 mg daily, -4 percent in those receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg daily, as compared with -1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. CONCLUSIONS: The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain. (+info)
Effects of deep brain stimulation and medication on strength, bradykinesia, and electromyographic patterns of the ankle joint in Parkinson's disease.
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We investigated the control of movement in 12 patients with Parkinson's disease (PD) after they received surgically implanted high-frequency stimulating electrodes in the subthalamic nucleus (STN). The experiment studied ankle strength, movement velocity, and the associated electromyographic patterns in PD patients, six of whom had tremor at the ankle. The patients were studied off treatment, ON STN deep brain stimulation (DBS), on medication, and on medication plus STN DBS. Twelve matched control subjects were also examined. Medication alone and STN DBS alone increased patients' ankle strength, ankle velocity, agonist muscle burst amplitude, and agonist burst duration, while reducing the number of agonist bursts during movement. These findings were similar for PD patients with and without tremor. The combination of medication plus STN DBS normalized maximal strength at the ankle joint, but ankle movement velocity and electromyographic patterns were not normalized. The findings are the first to demonstrate that STN DBS and medication increase strength and movement velocity at the ankle joint. (+info)
Delayed L-phenylalanine infusion allows for simultaneous kinetic analysis and improved evaluation of specific-to-nonspecific fluorine-18-dopa uptake in brain.
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The accumulation of 3-O-methyl-6-[18F]fluoro-L-DOPA (18F-30M-DOPA) in the brain from the circulation is responsible for most of the nonspecific background during 18F-DOPA positron emission tomography scanning. To increase the sensitivity of 18F-DOPA for imaging presynaptic dopamine systems, we took advantage of 18F-30M-DOPA's rapid clearance from the brain (T1/2 approximately 15-20 min). The infusion of the unlabeled amino acid L-phenylalanine, starting 75 min after 18F-DOPA administration, prevents 18F-30M-DOPA entrance into the brain through competition at the large amino acid transport system of the blood brain barrier. This method produces high specific-to-nonspecific contrast images of 18F accumulation beginning 15-30 min after onset of amino acid infusion and better sensitivity to small changes in 18F-DOPA uptake while still allowing for kinetic analysis of the data in the early time points. Kinetic and anatomical data were found to be strongly correlated. (+info)
Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat.
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1. We compared three new catechol O-methyltransferase (COMT) inhibitors (OR-611, Ro 40-7592 and CGP 28014; 10 and 30 mg kg-1, i.p.) in male rats given levodopa (L-DOPA, 50 mg kg-1, i.p.) and carbidopa ((-)-L-alpha-methyl dopa, 50 mg kg-1, i.p.). In some studies pretreatment with pargyline (80 mg kg-1, i.p.) was used to block the function of monoamine oxidase (MAO). 2. Decreases of hypothalamic and striatal 3-O-methyl-dopa (3-OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3-methoxytyramine (3-MT; after pargyline) levels. 3. The three COMT inhibitors studied had different individual characteristics. OR-611 was primarily a peripherally acting COMT inhibitor, decreasing 3-OMD levels in the striatum (to 31-52%) and in the hypothalamus (to 16-27%) both in the control and pargyline-treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3-MT. 3. Ro 40-7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3-OMD (always to less than 30%), HVA (to less than 50%) and 3-MT levels (to less than 23%) significantly both at 1 and 3 h. It was more potent than OR-611. 4. CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3-OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3-MT levels at 1 h (to 37-22% and 42-35% in the striatum, and to 57-33% and 64-35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR-611 and Ro 40-7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor. (+info)
The effects of carbidopa administration on 6-[18F]fluoro-L-dopa kinetics in positron emission tomography.
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Carbidopa (L-alpha-hydrazino-alpha-methyl-b-(3,4-dihydroxyphenyl) propionic acid is a known inhibitor of aromatic amino acid decarboxylase. In both humans and monkeys, we studied the effects of carbidopa on plasma and brain kinetics of 6-[18F]fluoro-L-DOPA (FDOPA), an analog of L-DOPA used for PET studies of the central dopaminergic system. Pretreatment with carbidopa resulted in increases in the plasma levels of FDOPA and 3-O-methyl-6-[18F]fluoro-L-DOPA (3-OMFD). Total striatal and cerebellar activities measured with PET were also increased. Furthermore, increases observed in the specific striatal activity (striatum minus cerebellum total activity) were correlated with increases in the plasma FDOPA curve. Carbidopa pretreatment did not affect the influx rate constant (K) for FDOPA from plasma to striatum in humans as determined by Patlak graphical analysis. Thus, an increase in measured striatal tomographic activity was secondary to the increase in plasma FDOPA levels rather than as a result of changes in the FDOPA influx rate constant. (+info)