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)

In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic function with L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analyses included two direct determinations of DOPA decarboxylase activity (k3D, k3*), the slope-intercept plot based on plasma concentration (K), two slope-intercept plots based on tissue content (k3r, k3s), and the striato-occipital ratio [R(T)]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarboxylase activity (k3D, k3*), tissue slope-intercept plots (kr3, ks3); and striato-occipital ratio [R(T)] analyses significantly discriminated between the normal volunteers and the patients with Parkinson's disease (p < 0.005) [with least significance for k3* (p < 0.05)], while the plasma slope-intercept plot (K) failed to do so. For the putamen, the values for k3D, k3*, K, k3r, k3s, and R(T) of normal volunteers were significantly higher than those of patients (p < 0.005) [with least significance for K (p < 0.025)]. Linear correlations were significant between k3D and k3s; k3D and k3r; k3D and R(T); and k3D and k3*, in this order of significance. We found no correlation between k3D and K values in the caudate nucleus.
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PMID:6-[18F]fluoro-L-dopa metabolism in living human brain: a comparison of six analytical methods. 841 11

We have established a method for measuring L-dopa in plasma and urine, including the metabolites dopamine and L-dopac, using separation by ion-pair reversed-phase HPLC and quantification with an electrochemical detector. The assay was applied to the therapeutic monitoring of elderly patients with established Parkinson disease being treated with L-dopa plus a dopa decarboxylase inhibitor. Plasma L-dopa was evaluated in relation to dosage and postdose sampling time in 71 outpatients with Parkinson disease. L-Dopa concentrations were greatest in the patients taking the highest dosages prescribed and decreased significantly with increasing time after postdose sampling. Comparison of plasma L-dopa concentrations with a published therapeutic range established by intravenous administration of L-dopa was helpful in assessing the suitability of each patient's drug dosage, assessing patients' compliance, and avoiding overdosage but was not useful in the overall clinical assessment of progression of disease or of the long-term therapeutic response. Urine measurements confirmed the plasma concentrations but showed no further advantage. The recommended time for sample collection is between 1.5 and 3 h after the first morning dose. Plasma is the preferred matrix but if blood sampling is difficult, particularly from elderly/infirm individuals, an untimed urine collection could be used.
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PMID:Measuring L-dopa in plasma and urine to monitor therapy of elderly patients with Parkinson disease treated with L-dopa and a dopa decarboxylase inhibitor. 847 57

We studied the relationship between levodopa response and antituberculous treatment in a patient with idiopathic Parkinson's disease whose parkinsonism deteriorated when treatment with rifampicin and isoniazid (Rifinah) for pulmonary tuberculosis was started. A levodopa challenge test with regular recording of motor function was performed during, and again after stopping, antituberculous treatment. Plasma levodopa and levodopa metabolite pharmacokinetic profiles were determined using standard techniques. "On" period duration was 75% longer after antituberculous treatment had been stopped. These clinical findings correlated with a 37% increase in area under the concentration versus time curve (AUC), a 103% increase in apparent elimination half-life (t1/2), a 41% increase in time to maximum concentration (Tmax), and a 33% decrease in maximum concentration (Cmax) of levodopa. A concurrent increase in plasma 3-O-methyldopa (3-OMD) and a decrease in plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the three major metabolites of levodopa, suggests an inhibition of the enzyme dopa decarboxylase, probably by isoniazid.
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PMID:A clinical and pharmacokinetic case study of an interaction of levodopa and antituberculous therapy in Parkinson's disease. 855 21

The study of Heafield et al. (1990) has prompted us to compare the levels of sulfate cysteine and homocysteine in the plasma of healthy subjects and of patients with Parkinson's disease treated by L-Dopa and dopa decarboxylase inhibitors. The levels of sulfate and cysteine in the plasma of controls and patients with Parkinson's disease were not statistically different but the level of homocysteine was higher in patients.
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PMID:Sulfate and cysteine levels in the plasma of patients with Parkinson's disease. 858 84

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.
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PMID:Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. 864 May 65

Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.
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PMID:Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyltransferase: effect of the plasma 3-O-methyldopa fraction on data analysis. 878 30

A dose-response study of the effects of entacapone on the pharmacokinetics and metabolism of levodopa and on the clinical response to levodopa was carried out in 20 parkinsonian patients with levodopa-related fluctuations. A randomized, double-blind, single-graded-dose, crossover design of five 1-day treatment periods each 1 week apart was used. Entacapone (50, 100, 200, or 400 mg) or placebo was given at 8 a.m. with the patient's individual dose of levodopa/dopa decarboxylase inhibitor. The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) and plasma concentrations of levodopa, its metabolites, and entacapone were measured and motor responses were quantified at 30min intervals using the motor part of the Unified Parkinson's Disease Rating Scale. Entacapone brought about a dose-dependent decrease in S-COMT activity in the RBCs, maximally by 48% at 400 mg. With a 200-mg dose of entacapone, the area under the plasma concentration-time curve (AUC) and half-life of levodopa increased (p < 0.001); the AUCs of 3-O-methyldopa and homovanillic acid decreased (p = 0.01 and p < 0.001, respectively) and that of 3,4-dihydroxyphenylacetic acid increased (p < 0.001). Entacapone prolonged the duration of the motor response to levodopa by 33 min (p = 0.04) and dyskinesias by 45 min (p = 0.003) without affecting their magnitude; the highest increase in duration of these responses occurred with 200 mg of entacapone. Thus, on pharmacokinetic and clinical grounds, the 200-mg dose of entacapone was the most effective. Dose-related responses to entacapone demonstrated its value in the treatment of parkinsonian patients with levodopa-related fluctuations by prolonging the antiparkinsonian response to the levodopa dose.
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PMID:A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson's disease. 882 91

We present a 71 year old woman with predominantly right sided parkinsonism of sudden onset, but without tremor. Magnetic resonance imaging (MRI) depicted lesions affecting the substantia nigra (SN) bilaterally, but more pronounced on the left side. There were no other discernible structural lesions. Using positron emission tomography (PET), we investigated regional cerebral metabolic rate of glucose (rCMRG) using the tracer [18F]-fluorodeoxyglucose (FDG), and striatal dopa decarboxylase capacity using the tracer [18F]-L-6-fluorodopa (FDOPA). The degree and pattern of distribution of FDOPA uptake reductions (putamen > caudate nuclei) were similar to those in idiopathic Parkinson's disease (PD). FDG uptake also revealed similar changes (reductions in frontal cortex and cerebellum, but increases in thalamus), except for putamen which showed reduced rCMRG. In conclusion, the absence of tremor at rest accords with experimental SN lesions. The PET findings in this atypical condition are explained in terms of deafferentation of various brain regions involved in motor control. Furthermore, they illustrate the metabolic effects related to acute focal lesions of the SN as opposed to the progressive degeneration in idiopathic PD and may serve to help unravel the complicated pathophysiology underlying these conditions.
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PMID:Secondary parkinsonism due to focal substantia nigra lesions: a PET study with [18F]FDG and [18F]fluorodopa. 883 98

Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. On the other hand, an electrical focal lesion in the brain, neurotoxin to dopaminergic neurons such as 6-hydroxydopamine (6-OHDA) or I-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), cholinomimetic tremorogenic agents such as oxotremorine or tremorine, monoamine depleting agents such as reserpine or tetrabenazine, or dopamine receptor antagonists such as haloperidol are applied to render animal parkinsonism. The estimation of locomotor activity can be done accurately in animal models. Tremor can be studied using the animals treated by cerebral focal lesion, neurotoxins or cholinomimetics. Skillfulness is hard to estimate in animals, however, it can be done in primates. Freezing appeared in patients with levodopa treatment over a long period. This is a specific motor sign in Parkinson's disease, and cannot be observed in animals. Supplementing dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by dopa decarboxylase inhibitor (DCI), monoamine oxidase inhibitor type B (MAO-B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/ uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists, adenosine receptor antagonists, neurotrophic factors, GM1-ganglioside and nicotinic receptor agonists have been applied in the treatment of Parkinson's disease or are under investigation for patients. Agents to facilitate nerve growth or to inhibit the degeneration of nerves will be developed in the future.
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PMID:[Recent progress in development of psychotropic drugs (3)--Antiparkinsonian agents applied in the treatment of Parkinson's disease or are under investigation for patients or model animals]. 890

6-[18F]-fluorodopa (FDOPA) was developed as an analogue of L-DOPA across the blood-brain-barrier and to carry into nigrostriatal dopaminergic neurons. PET study using FDOPA revealed presynaptic dopaminergic function in the striatum of nigrostriatal system of the human brain and many studies have performed to clarify the pathogenesis of Parkinson's disease. FDOPA is also an efficient tracer to analyze pharmacokinetics of L-DOPA by measuring radioactivities of its metabolites in the peripheral blood by HPLC and to evaluate pharmacological effects on dopamine metabolism by pretreatment of dopa decarboxylase inhibitor or COMT inhibitor. PET study using FDOPA is useful not only to diagnose Parkinson's disease but also to differentiate from parkinsonism in combination with other radioactive ligands and with other neuroimaging methods such as MRI.
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PMID:[PET study using 6-[18F]-fluorodopa in Parkinson's disease]. 901 52


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