Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DOPA”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2006

Congenital hyperinsulinism: pancreatic [18F]fluoro-L-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion.

CONTEXT: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. OBJECTIVE: Positron emission tomography (PET) after injection of [18F]fluoro-L-DOPA (L-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]fluoro-L-dopa into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. PATIENTS AND METHODS: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. RESULTS: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. CONCLUSION: We validate PET with as a consistent test to differentiate diffuse and focal HI.

Adolescent↗
PubMed1993

The effects of L-dopa on the activity of methionine adenosyltransferase: relevance to L-dopa therapy and tolerance.

L-dopa, the major treatment for Parkinson's disease (PD), depletes S-adenosyl-L-methionine (SAM). Since SAM causes PD-like symptoms in rodents, the decreased efficacy of chronic L-dopa administered to PD patients may result from a rebound increase in SAM via methionine adenosyl transferase (MAT), which produces SAM from methionine and ATP. This was tested by administering intraperitoneally saline, or L-dopa to mice and assaying for brain MAT activity. As compared to controls, L-dopa (100 mg/kg) treatments of 1 and 2 times per day for 4 days did not significantly increase MAT activity. However, treatments of 3 times per day for 4 and 8 days did significantly increase the activity of MAT by 21.38% and 28.37%, respectively. These results show that short interval, chronic L-dopa treatments significantly increases MAT activity, which increases the production of SAM. SAM may physiologically antagonize the effects of L-dopa and biochemically decrease the concentrations of L-dopa and dopamine. Thus, an increase in MAT may be related to the decreased efficacy of chronic L-dopa therapy in PD.

Adenosine Triphosphate↗
PubMed1975

Type I cells of carotid body from rats treated with 5-OH-dopa and L-dopa: an electron microscopical study.

The ultrastructure of the Type I cells in rat carotid bodies was studied after treatment with 5-OH-Dopa and L-Dopa. Type I cells from the L-Dopa treated rats were also analysed by morphometric methods. After 5-OH-Dopa treatment, the majority of dense-cored vesicles of the Type I cells were almost completely filled with very electron-dense material. The vesicles were mainly distributed close to the plasma membrane. After L-Dopa treatment, the ultrastructure of the Type I cells resembled that after 5-OH-Dopa treatment, except that the increase in electron density of the vesicle content was less pronounced. The morphometric analysis revealed, as previously described for normal carotid bodies, two subclasses of Type I cells, small vesicle cells (SVC) and large vesicle cells (LVC). Compared to those of normal rats, the mean profile diameter of the vesicles in the L-Dopa treated rat carotid bodies were enlarged (for SVC from 47 to 55 nm and for LVC from 63 to 76-78 nm). Furthermore, the volume density of vesicles in both SVC and LVS was increased. The mean volume of the SVC was markedly increased after L-Dopa treatment for 60 h. These observations indicate that the Type I cells possess mechanisms for uptake of amine precursors and synthesis of monoamines. Though the vesicle may be involved in an 'endocrine-like' function, they may also be related to the chemoreceptor function of the carotid body.

Animals↗
PubMed1982

Substrate stereospecificity and selectivity of catechol-O-methyltransferase for DOPA, DOPA derivatives and alpha-substituted catecholamines.

The substrate specificity of highly purified pig liver catechol-O-methyltransferase has been investigated kinetically. This enzyme shows stereospecificity towards the naturally occurring L-isomer of 3,4-dihydroxyphenylalanine (DOPA) which has a higher affinity and maximal velocity as a substrate than the D-form. We have confirmed the implication of the in vivo study of Ito et al. [1], that methylation of 5-S-L-cysteinyl-L-DOPA is catalysed extremely slowly by catechol-O-methyltransferase, despite the comparatively high affinity of the enzyme for the substrate. Salbutamol is not a substrate for the enzyme and DL-threo-3,4-dihydroxyphenylserine (DOPS) is such a poor substrate that accurate kinetic analysis proved impossible. Alpha-substitution of DOPA, noradrenaline and isoprenaline causes a decrease in the affinity of catechol-O-methyltransferase for these compounds. However, the "suicide' inhibitors of aromatic-L-amino acid decarboxylase (DOPA decarboxylase), fluoro- and difluoro-alpha-methyl DOPA are more superior catechol-O-methyltransferase substrates than alpha-methyl DOPA, presumably because the electron-withdrawing effect of the presence of fluorine in their structure overcomes the steric influence of the alpha-methyl group. A DOPA decarboxylase inhibitor in clinical use, benserazide, is, however, a much superior catechol-O-methyltransferase substrate and may have the therapeutic advantage of decreasing methylation of L-DOPA [2]. Alpha-Methyl dopamine has a lower Km and higher Vmax than the parent compound.

Animals↗
PubMed1993

Identification of L-dopa immunoreactivity in some neurons in the human mesencephalic region: a novel dopa neuron group?

The presence of L-3,4-dihydroxyphenylalanine (L-DOPA) immunoreactivity is reported for the first time in some neurons in the human mesencephalic region, using an immunohistochemical method with a newly raised, highly specific anti-L-DOPA antiserum. We have found many L-DOPA-positive/dopamine (DA)-positive and a few L-DOPA-positive/DA-negative cell bodies in dopaminergic regions in the midbrain. The present results suggest the existence of more than one neuronal group of L-DOPA in the human mesencephalon. L-DOPA in one group is an intermediate metabolite for decarboxylation to DA and in another group may exist as an end-product. L-DOPA in the latter neurons could be a neuromodulator and/or neurotransmitter. Thus, we suggest that L-DOPA plays an important role besides being an intermediate of DA in the human mesencephalon.

Dopamine↗
PubMed1986

Nicotinic acid or N-methyl nicotinamide prolongs elevated brain dopa and dopamine in L-dopa treatment.

A peripheral dopa decarboxylase inhibitor, benserazide, was given ip, followed by intubation with L-dopa. Brain dopa and DA levels were elevated maximally between 0.5-2.5 hr and 1.0-2.5 hr, respectively. Dopa in serum, liver, and brain were at control values after 4 hr. Supplementation of dopa with NAM or NAC, as possible methyl group acceptors to lower catabolism of DA, showed that NAM had no effect on DA levels or on SAM. However, with both NAC and N-methyl NAM (a methylated compound intended as a control) at time periods where dopa and DA were normally decreasing, the brain levels were increased over control values with benserazide and dopa alone. NAC or N-methyl NAM appeared to extend the period of elevated brain DA levels with L-dopa treatment. The mechanism responsible for these results is uncertain.

Animals↗
PubMed1986

Delayed onset of responses to single doses of L-dopa in parkinsonian fluctuators on long-term L-dopa therapy.

Dose-related fluctuations in response to L-Dopa such as the "wearing-off" phenomenon are a common side effect of long-term L-Dopa therapy. In a retrospective clinical analysis, 18 of 32 chronically treated parkinsonian fluctuators developed a delay in onset of a beneficial effect induced by single doses of L-Dopa. In these patients, there was a threefold increase in latency from ingestion of the first morning dose to "start-up" of a response (from 0.4 +/- 0.2 to 1.1 +/- 0.3 h) in parallel to a twofold decrease in its duration (from 4.2 +/- 1.1 to 1.7 +/- 0.8 h). Longer durations of illness and of L-Dopa therapy, occurrence of totally ineffective doses, poorer responsiveness to afternoon and evening doses, and early-morning dystonia were more prevalent in this group. In 14 of the 32 parkinsonian fluctuators, monitored "start up" of clinical effect occurred at about an hour after the first morning oral dose of L-Dopa. The dose-induced elevations in plasma L-Dopa levels started after a mean of about 0.5 h and were maximal at 1.25 h. The study suggests that prolongation of "start-up" latencies in response to single doses of L-Dopa is a rather common complication of chronic treatment and may increase patients' disability by further decreasing the duration of daily "on" periods. Causes for this phenomenon are unknown but retarded absorption of orally administered L-Dopa may be important.

Aged↗
PubMedDate not supplied

The effects of different repeated doses of entacapone on the pharmacokinetics of L-Dopa and on the clinical response to L-Dopa in Parkinson's disease.

We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Adult↗
PubMed1975

Plasma concentrations of L-dopa and 3-methoxydopa and improvement in clinical ratings and motor performance in patients with Parkinsonism treated with L-dopa alone or in combination with amantadine.

Six patients with idiopathic Parkinsonism were treated with a combination of amantadine and L-dopa and after 12 to 24 weeks amantadine was replaced by placebo for a six week period in a double-blind trial. Although there was a tendency for clinical disability ratings and scores on objective ratings of motor skills to deteriorate initially after amantadine removal, there was no significant deterioration in clinical improvement or motor performance during the period of amantadine withdrawal. Amantadine withdrawal also failed to cause any significant change in plasma concentrations of L-dopa or its metabolite 3-methoxy-dopa in these patients. In a group of 27 patients seen regularly as outpatients measurements of plasma L-dopa failed to correlate significantly with either oral dose or with clinical improvement scores. The plasma concentration of 3-methoxy-dopa, however, was on average 2.8 times higher than that of L-dopa, and there was a significant correlation between plasma levels of this metabolite and clinical improvement. It is suggested that 3-methoxy-dopa may contribute significantly to the therapeutic actions of L-dopa in Parkinsonism.

Activities of Daily Living↗
PubMed1976

Absence of relationships between L-dopa plasma levels and therapeutic effect in Parkinson's disease treated with L-dopa.

The plasma concentration of dopa was studied in 15 parkinsonian patients after a single administration of L-dopa. The study was undertaken in order to determine if correlation between plasma dopa concentration and clinical performance as a result of the tests carried out before and after a single dose of dopa, was present. Our data confirm the absolute absence of correlation between dopa levels in plasma and clinical improvement during long-term treatment. Moreover, clinical responses to the performance tests were not related to the concentration of circulating L-dopa in the plasma. Therefore dopa levels cannot be useful in clinical practice but only for the prevention of too high concentrations of plasma L-dopa which often cause a few side-effects.

Administration, Oral↗
PubMedDate not supplied

Influence of the therapy with pergolide mesylate plus L-DOPA and with L-DOPA alone on serum cGMP level in PD patients.

The aim of our study was to investigate serum cGMP level in patients treated with L-DOPA alone and L-DOPA with pergolide mesylate (PM) and to compare the obtained values with age-matched healthy subjects. PD patients treated with L-DOPA or with PM + L-DOPA had significantly higher cGMP levels in serum as compared to control. Moreover, cGMP level was significantly higher after treatment with PM + L-DOPA then L-DOPA alone. We did not observed significant differences in UPDRS scores between both PD groups. Our data suggest that changes in serum cGMP level in PD patients are related with PM + L-DOPA or L-DOPA alone therapy.

Aged↗
PubMed1983

Methaemoglobin-catalysed formation of dopa and 6-OH-dopa from tyrosine.

An extract of bovine retina and choroid with tyrosine hydroxylating and dopa-oxidizing capacity also showed marked formation of 6-OH-dopa on incubation with tyrosine and ascorbic acid. The extract contained appreciable amounts of methaemoglobin as determined spectrophotometrically, and boiled extracts also showed catalytic activity. The effect of methaemoglobin on the oxidation of tyrosine and dopa was therefore investigated. Methaemoglobin catalysed the formation of dopa and 6-OH-dopa in the presence of tyrosine and ascorbic acid. Hydrogen peroxide plays an important role in this reaction: the rates of formation of both dopa and 6-OH-dopa were increased by addition of hydrogen peroxide but diminished by addition of catalase. Methaemoglobin also catalysed the formation of cysteinyldopa from dopa and cysteine.

Animals↗
PubMed1994

[Slow-release L-dopa vs. standard L-dopa in Parkinson patients in various stages of the disease. Studies of pharmacokinetics and motor effectiveness].

Most strategies for the therapeutic management of L-dopa-dependent fluctuations in Parkinsonian patients aim at the continuous stimulation of postsynaptic dopaminergic receptors. Slow release- (s.r.-) preparations of L-dopa appear to present a promising and effective solution for this objective. Clinical experience with the available s.-r.-preparations has lead to the identification of some specific areas for their use. It has not been possible, however, to sharply define their entire range of application. The present study, therefore, compared single dose kinetics and pharmacodynamic effects of three dosages of L-dopa/bensearazid-s.r.-preparation (ASTA H995 125 mg, 250 mg, 275 mg) in a controlled, randomised, 4-fold, double blind, cross over design. The effects were studied in 12 Parkinsonian patients with vs. without motor fluctuations. Motor responses were monitored multimodally (according to the Columbia University Rating Scale, the Purdue Pegboard, and a modified version of the Webster Step Second Test). The pharmacokinetic effectiveness of the s.r.-approach could be demonstrated in both groups. It was possible to ascertain significant differences in kinetics between the various L-dopa-s.r.-dosages and L-dopa standard. No significant difference, however, appeared in the pharmacokinetic characteristic values (Cmax, Tmax, AUC0-->infinity, T1/2) between the fluctuating and non-fluctuating patients. A circumscribed motor effect was demonstrable only for those patients with fluctuations. As expected, motor responses were delayed and lasted longer in these patients after applying the L-dopa-s.r.-dosage. A three times greater dosage of L-dopa-s.r. was required in order to obtain a superior motor effect to the L-dopa-standard-preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Effect of L-dopa on plasma renin activity with and without inhibition of extracerebral dopa decarboxylase in dogs.

The aim of the present study was to investigate the possibility that catecholaminergic pathways within the central nervous system play a role in the control of renin secretion. Plasma renin activity (PRA) was measured after intravenous administration of L-dopa with and without prior inhibition of extracerebral dopa decarboxylase by carbidopa (MK-486) in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were minimized by means of a suprarenal aortic clamp. When L-dopa (20 mg/kg ) was administered intravenously without carbidopa. PRA and blood pressure increased. In contrast, administration of L-dopa (20 mg/kg i.v.) after blockade of extracerebral, but not cerebral dopa decarboxylase by intravenous carbidopa (20 mg/kg), produced significant decrease in both PRA and blood pressure. Larger doses of l-dopa (30-50) mg/kg i.v.) also lowered both PRA and blood presure in three carbidopa-treated animals, whereas a smaller dose of L-dopa (10 mg/kg i.v.) significantly lowered blood pressure but not PRA. In dogs with both kidneys acutely denervated, L-dopa (20 mg/kg i.v.) with carbidopa lowered arterial pressure but did not consistently alter PRA. These data suggest that catecholamines formed within the central nervous system can act to lower renin secretion as well as blood pressure.

Animals↗
PubMed2003

The parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) mediates release of l-3,4-dihydroxyphenylalanine (l-DOPA) and inhibition of l-DOPA decarboxylase in the rat striatum: a microdialysis study.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS), particularly peroxynitrite, have been implicated as key participants in the dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)). However, on the basis of available information, it is not clear whether the MPP(+)-induced overproduction of ROS and RNS occurs in the intraneuronal and/or extracellular compartment. Early steps in the neurotoxic mechanism evoked by MPP(+) include a profound dopaminergic energy impairment, which mediates a massive release of dopamine (DA), glutathione (GSH), and cysteine (CySH). In the event that MPP(+) mediates extracellular generation of ROS (such as superoxide and/or hydroxyl radicals) and/or peroxynitrite, released DA, GSH, and CySH should be oxidized forming thioethers of DA and disulfides. Using microdialysis experiments in which MPP(+) was perfused into the striatum of awake rats, the present study was unable to detect the presence of such biomarkers of extracellular ROS and/or RNS generation. However, MPP(+) induced a transient, concentration-dependent rise of extracellular l-3,4-dihydroxyphenylalanine (l-DOPA), identified on the basis of dialysate analysis using several HPLC methods and its conversion to DA by purified l-DOPA decarboxylase (DDC). Methamphetamine (30 mg/kg, i.p.) similarly caused a significant but transient rise of l-DOPA in the rat striatum. Antioxidants such as salicylate and mannitol had no effect on the MPP(+)-mediated elevation of extracellular l-DOPA, suggesting that it is not formed by nonenzymatic hydroxylation of l-tyrosine by ROS or RNS. Rather, in vivo, but not in vitro, MPP(+) caused rapid inhibition of DDC, which appears to result in intraneuronal accumulation and subsequent release of l-DOPA. Because l-DOPA can mediate l-glutamate release, as well as be an excitotoxin, the possibility is raised that l-DOPA may play a role in the dopaminergic neurotoxicity of MPP(+).

1-Methyl-4-phenylpyridinium↗
PubMed2002

A comparison of the progression of early Parkinson's disease in patients started on ropinirole or L-dopa: an 18F-dopa PET study.

OBJECTIVE: To study the relative rates of progression of early Parkinson's disease (PD) in patients started on a dopamine agonist, ropinirole, or L-dopa. METHODS: A double-blind study of 45 early PD patients [mean age 61 +/- 9.8 SD and mean symptom duration, 26 +/- 16 SD months] randomized 2 : 1 (ropinirole : L-dopa). Supplementary L-dopa was allowed if, during the trial, there was lack of a therapeutic effect. (18)F-dopa PET scans were performed at baseline (n = 45) and 2 years (n = 37). RESULTS: At two years, the mean percentage reduction in putamen (18)F-dopa uptake (Ki(o)) was not significantly different between the two groups (13% ropinirole, n = 28 versus 18% L-dopa, n = 9). CONCLUSIONS: We found no significant overall difference in underlying PD progression, after two years treatment, between patients groups. In summary, (18)F-dopa PET can be employed to objectively evaluate the effect of potential neuroprotective agents on dopaminergic function.

Aged↗
PubMed1990

Comparative in vivo metabolism of 6-[18F]fluoro-L-dopa and [3H]L-dopa in rats.

In vivo double-label experiments in rats were designed to correlate the peripheral and cerebral metabolism of 6-[18F]fluoro-L-DOPA [( 18F]FDOPA) with that of [3H]L-DOPA. Authentic samples of the major [18F]FDOPA metabolites were synthesized to identify the 18F-labeled metabolites. After carbidopa pretreatment and intravenous administration of the compound, the products of peripheral metabolism in plasma were analyzed at times from 3 to 60 min. In the periphery, amine conjugates were detected but they accounted for less than 15% of the total radioactivity; the major metabolites were 3-O-methyl-6-[18F]fluoro-L-DOPA and 3-O-methyl-[3H]L-DOPA. The rate and extent of 3-O-methylation of [18F]FDOPA exceeded that of [3H]L-DOPA. Both 3-O-methylated products entered the striatum and cerebellum where they contributed significant but uniform activity. Analysis of cerebral metabolism in these structures indicated a linear accumulation of total radioactivity: a striatum/cerebellum ratio of 2 was observed by 60 min. 6-[18F]Fluorodopamine (35%) and [3H]dopamine (55%) were the major metabolites formed in the striatum: however, the methylated [18F]FDOPA and [3H]DOPA products of predominantly peripheral origin represented 55% (18F) and 35% (3H) of the total radioactivity respectively. Other [3H]dopamine metabolites and their 18F-labeled analogs represented less than 10-15% at all times analyzed. The cerebellum radioactivity was composed only of [18F]FDOPA, [3H]DOPA and their 3-O-methylated products. These data will serve as the basis for the development of kinetic models of [18F]FDOPA metabolism that can be applied to the evaluation of central dopamine biochemistry with positron emission tomography in humans.

Animals↗
PubMed1995

Metabolism and blood-brain clearance of L-3,4-dihydroxy-[3H]phenylalanine ([3H]DOPA) and 6-[18F]fluoro-L-DOPA in the rat.

6-[18F]fluoro-L-DOPA (FDOPA) has been used as a tracer for the cerebral activity of L-3,4-dihydroxyphenylalanine (DOPA)-decarboxylase in studies of positron emission tomography (PET). However, the substitution of fluorine on the aromatic ring may alter the disposition and metabolism of FDOPA from that of endogenous DOPA. In the present study, the kinetics of the peripheral metabolism and the facilitated unidirectional blood-brain clearance of [3H]DOPA and FDOPA were compared in Wistar rats pretreated with carbidopa. In arterial plasma, FDOPA was O-methylated with an apparent rate constant (0.031 min-1) 3-fold that of [3H]DOPA in the same rats. The O-methylated metabolite of FDOPA (OMe-FDOPA) was eliminated from plasma at a rate constant (0.018 min-1) 3-fold that of OMe-[3H]DOPA. The mean unidirectional blood-brain clearance of FDOPA (4.5 mL.hg-1.min-1) in six brain regions was 60% higher than that of [3H]DOPA.

Animals↗