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PubMedDate not supplied

Spontaneous formation of conjugates of alpha-methyl-DOPA and DOPA with serum proteins and experimental production of specific antibodies against these haptens.

Alpha-methyldopa (alpha MD) and levodopa (DOPA) react readily with serum proteins at alkaline pH and form stable conjugates with them. Hapten specific antibodies in high titers are produced in rabbits by inoculation of the conjugates formed by alpha MD and DOPA with normal rabbit serum (alpha MD-NRS and DOPA-NRS), incorporated in incomplete Fruend adjuvant. No hapten specific antibodies were raised in rabbits inoculated with alpha MD as such, incorporated in adjuvant, with alpha MD mixed with autologous serum 24 hrs before inoculation, or with alpha MD conjugates with autologous serum administered without adjuvant. Hapten specific antibodies were, however, found in one of six rabbits inoculated with alpha MD conjugates with homologous serum proteins given without adjuvant. Extensive crossreactivity was found between alpha MD and DOPA immunological systems. High titers of antibodies directed against normal rabbit serum proteins as well as against human gamma globulin were also found in the sera of the rabbits immunized with alpha MD-NRS and DOPA-NRS conjugates incorporated in Freund adjuvant. A close correlation was found between the titers of hapten specific antibodies and of anti-protein antibodies.

Animals↗
PubMed1983

Accurate assay of dopa decarboxylase by preventing nonenzymatic decarboxylation of dopa.

The nonenzymatic decarboxylation of dopa was completely blocked by both 2-mercaptoethanol and EDTA together over the wide range of pH. This finding made it possible to measure the activity of dopa decarboxylase precisely even at an alkaline pH value. The pH optimum of dopa decarboxylase was found to be pH 7.0 and the Km value for dopa was determined to be 4 X 10(-5) M.

Animals↗
PubMed1993

Human striatal L-dopa decarboxylase activity estimated in vivo using 6-[18F]fluoro-dopa and positron emission tomography: error analysis and application to normal subjects.

DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient (k3D) of 6-[18F]fluoro-DOPA (FDOPA) to denote the relative activity of L-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of k3D in the presence of the inherent error of PET. To improve the accuracy of the k3D estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume (Ve) common to frontal cortex and striatum, and a fixed ratio (q) between the blood-brain barrier transport coefficients of O-methyl-[18F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of k3D. The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine k3D in striatum and other structures. We studied twelve healthy controls (age 45 +/- 15 years). The average k3D value was 0.081 +/- 0.024 min-1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 +/- 0.013 min-1 (COV 18%) for putamen, and 0.010 +/- 0.005 min-1 (COV 50%) for cerebral cortex.

Adult↗
PubMed1990

Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases.

Despite several decades of research aimed at elucidating the mechanisms underlying neuronal degeneration in Parkinson's and Huntington's diseases, these mysteries remain unfathomed. The brain contains high concentrations of the putative transmitters, glutamate and aspartate, which have neurotoxic (excitotoxic) potential and are thought to cause neuronal degeneration in certain acute neurological disorders. However, no mechanism has been identified by which these diffusely distributed agents might cause the regionally selective patterns of neuronal degeneration characterizing Parkinson's and Huntington's diseases. Here we report that L-DOPA, the natural precursor to dopamine, is a weak excitotoxin and its ortho-hydroxylated derivative, 6-OH-DOPA, is a powerful excitotoxin. We propose that an excitotoxic process mediated by L-DOPA or an acidic derivative such as 6-OH-DOPA might be responsible for degeneration of nigral neurons in Parkinson's disease or striatal neurons in Huntington's disease.

2-Amino-5-phosphonovalerate↗
PubMed2003

Influence of fungal infection on the DOPA-semiquinone and DOPA-quinone production in haemolymph of Galleriamellonella larvae.

The formation of reactive oxygen metabolites in haemolymph of Galleria mellonella larvae was studied by ESR spectroscopy. The inhibition of the production of the reactive oxygen metabolites of DOPA in haemolymph under the action of fungal infection was shown using spin trap 1-hydroxy-3-carboxy-pyrrolidine. This inhibition correlated with decrease of phenoloxidase activity in haemolymph of infected insects. Simultaneously, the decrease of production of DOPA-semiquinone was detected using method of spin stabilization by diamagnetic metal ions. Moreover, it was shown that the formation of DOPA-quinone was slowed down in haemolymph of infected insects. Our results suggest that the DOPA-derived quinones/semiquinones may be involved in immune response of insects as part of its defense mechanism.

Animals↗
PubMed1978

Long-term treatment of Parkinson's disease with L-Dopa and Dopa-decarboxylase inhibitor: therapeutic results and side effects.

The authors present a review of their clinical experience in the treatment of 127 Parkinsonian patients with L-Dopa alone and in association with a Dopa-decarboxylase inhibitor; the follow-up lasted more than 7 years. In all cases the dosages of L-Dopa, either alone or associated with the decarboxylase inhibitor, were fairly low; the strategy was to reach in each case the minimal effective dose instead of the maximal tolerable one. After 7 years of treatment about 60-65% of the patients had shown improvement, even though to a lesser degree than during the first and second year of therapy; the remaining 35-40% were unchanged or worse. The authors conclude that, despite the decreased efficacy of the therapy with time, the L-Dopa treatment remains of great significance in lengthening and in improving the quality of life of Parkinsonian patients.

Aromatic Amino Acid Decarboxylase Inhibitors↗
PubMed1978

Late endocrine effects of L-dopa, 5-HTP, and 6-OH-dopa administered to neonatal rats.

Neonatal rats were injected with L-dopa, 5-hydroxytryptophan (5-HTP) or 6-hydroxy-dopa (6-OH-dopa) and allowed to mature. Eye opening, vaginal opening, endocrine organ weights and pituitary hormone concentration in the serum were measured. Treatment with either the dopamine (DA) precursor or the serotonin (5-HT) precursor caused an acceleration in eye opening, a significant decrease in serum TSH (males) an elevation of serum prolactin (Prl; males), and a lowering of serum growth hormone (females). After chemical sympathectomy (6-OH-dopa) vaginal opening was delayed, thyroid weights were increased and serum TSH decreased (males). It is concluded that during the critical neonatal period overloading either of 2 of the principal monaminergic systems results in similar and persistent alterations in pituitary function. Chemical sympathectomy produced a different pattern of abnormalities.

5-Hydroxytryptophan↗
PubMed1988

Affinity of drugs for dopa-auto-oxidation melanin and tyrosinase-catalyzed dopa-melanin in vitro.

We examined spectrophotometrically the ability of drugs to bind with dopa-auto-oxidation melanin or tyrosinase-catalyzed dopa-melanin. Each drug, at 5 X 10(-5) M, was incubated at 37 degrees C for 8 h with 0.4 mg of synthetic melanins in 20 mM potassium phosphate buffer at pH 7.0 or in 20 mM acetate buffer at pH 4.8. Chloroquine, thioridazine, befunolol, pindolol, daunomycin and 5-fluorouracil bound to melanin at pH 7.0 and 4.8. Methotrexate bound to melanin at pH 4.8, but not at pH 7.0. Pilocarpine, epinephrine, acyclovir, vincristine and colchicine did not bind to dopa-auto-oxidation melanin or tyrosinase-catalyzed dopa-melanin.

Catechol Oxidase↗
PubMed1994

Pharmacokinetic and pharmacodynamic studies of L-dopa in rats. II. Effect of L-dopa on dopamine and dopamine metabolite concentration in rat striatum.

The purpose of this investigation was to quantitatively describe the time courses of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations in the striatum after L-dopa injection using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was determined before and after the rapid i.v. injection of 10, 50 and 100 mg/kg using the same animals as in the previous report. The endogenous dopamine, DOPAC and HVA concentrations in the striatum before L-dopa administration were 5.9 +/- 0.7 micrograms, 3.6 +/- 0.4 micrograms and 1.0 +/- 0.2 micrograms/g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9 +/- 0.5 micrograms/g) occurring at 3 min; then it returned to the pre-medication level until 2 h at 100 mg/kg dosing. The time course of dopamine concentration in the striatum was analyzed on a constructed dopamine metabolism model which has a zero-order production rate for the production of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which was estimated in the previous report, and the other from dopamine to dopamine metabolites (DOPAC and HVA). However, the time course of dopamine concentration in the striatum could not be described by this model.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

An analysis of long-term L-dopa therapy in 122 cases of Parkinson's disease over 14 years--when should L-dopa therapy be initiated?

L-Dopa was administered to 122 patients with Parkinson's disease over a time period up to 14 years. The results were summarized below. The akinesia and postural instability scores were significantly improved up to the 9th year. The rigidity and static tremor scores and the Parkinson score were significantly improved up to the 11th year. The Yahr stage was significantly improved up to the 8th year. The time course of Parkinson score was investigated in three groups, Yahr stage I/II group, Yahr stage III group, and Yahr stage IV/V group, taking into account the time interval between the onset of the disease and initiation of L-dopa therapy. No significant difference was found among the three groups. The above results suggested that the long-term prognosis of patients on L-dopa therapy in Japan was better than in Western countries. It was also though that L-dopa therapy should be instituted at the earliest possible stage of the disease.

Adult↗
PubMed1976

Effects of aging on LH and prolactin after LHRL L-dopa, methyl-dopa, and stress in male rat.

Hypothalamic-pituitary control of prolactin and LH secretion was tested in young (4-6 months) and aged (22-30 months) male Long-Evans rats given L-dopa, methyl dopa, LHRH, or stress treatments. Pretreatment serum LH levels were consistently higher in young than in the aged groups. The increase in serum LH after LHRH injection was only about half as much in aged as compared to young control males. Although acute stress caused a prompt increase in serum LH in young male rats, this treatment was without effect in the aged group. Methyl dopa treatment stimulated serum prolactin secretion in both young and old rats. Although L-dopa treatment caused a reduction in serum prolactin in both age groups, the sensitivity, magnitude, and duration of the reduction was smaller in the aged rats.

Aging↗
PubMed1981

DOPA in sympathetic nerve tissue--a possible source of serum DOPA in albino animals.

Dopa, catecholamines, and dopac were determined in superior cervical ganglia of albino rats. The average amount of dopa in ganglia of control animals was 1.1--1.6 micrograms/g. The concentrations of catecholamines and dopac were similar to values reported by others. The tyrosine hydroxylase inhibitor alpha-methylparatyrosine methyl ester caused marked decrease in the dopa concentration in the ganglia. The effect of reserpine was less pronounced. The aromatic amino acid decarboxylase inhibitor NSD 1015 markedly increased the dopa concentration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Determination of free DOPA and 3-O-methyl-DOPA in human plasma by high-performance liquid chromatography with electrochemical detection.

A procedure was devised for the determination of the unconjugated non-protein-bound fraction of 3,4-dihydroxyphenylalanine (DOPA) and 3-O-methyl-DOPA (3-OMD) in plasma using a reversed-phase liquid chromatographic system coupled with electrochemical detection. Sample preparation involves rapid isolation of the unbound drugs from the drug-protein complex by ultrafiltration through a membrane with a molecular weight cut-off of 10,000 dalton. One chromatographic run requires less than 10 min. The relative standard deviation is less than 3% for the within-assay imprecision and less than 4% for the between-assay imprecision. The detection limits for DOPA and 3-OMD are 0.2 and 1.3 ng/ml, respectively.

Dihydroxyphenylalanine↗
PubMed1978

Enhancement of L-dopa incorporation into melanoma by dopa decarboxylase inhibition.

Melanoma cells possess a special biochemical pathway for the conversion of L-dopa to melanin. Selective incorparation of exogenous L-dopa into melanoma cells in vivo has been limited by extensive decarboxylation to dopamine. Pretreatment of animals bearing the S-91 Cloudman or ACI melanomas with Ro4-4602, a potent dopa decarboxylase inhibitor limited incorporation of label into adrenal tissue and enhanced entry of label into tumor. Six hours following pretreatment, the ratio of tumor to adrenal specific activities was altered from 0.25 to 1.5 for the S-91 melanoma and 0.68 to 1.99 for the ACI melanoma indicating diversion of metabolism away from catecholamine formation. The possibility of a selective diagnostic and/or therapeutic approach is proposed.

Adrenal Medulla↗
PubMed2004

Time profile of cerebral [18F]6-fluoro-L-DOPA metabolites in nonhuman primate: implications for the kinetics of therapeutic L-DOPA.

At least two rates of dopamine turnover have been demonstrated in vivo, including a slow turnover rate that is associated with synaptic vesicles, and a faster rate that leads to rapid production of dopamine metabolites. Similarly, [18F]6-fluorodopamine (FDA), the decarboxylation product of the PET tracer [18F]6-fluoro-L-DOPA (FDOPA), may have multiple turnover rates which could substantially affect the interpretation of FDOPA uptake. To better characterize FDA turnover in vivo, we measured the formation of FDOPA metabolites in primate brain following bolus FDOPA injection with carbidopa pretreatment. FDOPA was allowed to circulate for either 30 minutes or 90 minutes, prior to removal of brain samples. The primary metabolites in striatum were [18F]6-fluoro-3-methyl-L-DOPA (3-OMFD), FDA, [18F]6-fluoro- L-3,4-dihydroxyphenylacetic acid (FDOPAC), and [18F]6-fluorohomovanillic acid (FHVA). The percentages of total radioactivity in striatum at 30 minutes and 90 minutes were: FDOPA(5%, 2%), FDA (39%, 23%), FDOPAC (12%, 3%), FHVA (14%, 34%), and 3-OMFD (29%, 39%). In cortex and cerebellum most of the activity (73%, 80%) was 3-OMFD. These data were compared against the metabolite profiles predicted by two compartmental models of FDOPA metabolism. A model that assumes only a single slow rate of FDA turnover predicted much lower concentrations of FDA metabolites (FDOPAC, FHVA) in striatum than were found in the brain assay, while a model that includes both slow and fast FDA turnover was in much better agreement. These findings extend and confirm previous observations of FDOPA metabolites. The implications for the interpretation of FDOPA PET, particularly in terms of the availability of dopamine synthesized from therapeutic L-DOPA, are discussed.

Animals↗
PubMedDate not supplied

L-dopa plus dopa-decarboxylase inhibitor. Sleep organization in Parkinson's syndrome before and after treatment.

Sixty-four all-night sleep polygraphic recordings have been carried out in patients affected by Parkinson's syndrome, before and after treatment with an association of l-dopa plus a peripheral dopa-decarboxylase inhibitor. Without any drug, parkinsonian patients showed sleep disruption with frequent awakenings, reduction of total sleeping time and lessening of REM stage rather than slow sleep. Treatment with l-dopa plus inhibitor appeared to be able to restore good night sleep organization with a noteworthy increase in the REM stage.

Adult↗
PubMed1975

Enteric-coated L-dopa (prodopa). A new approach to L-dopa therapy in Parkinson's disease.

Seventeen patients treated for a mean period of 9-4 months with an enteric-coated form of L-dopa (Prodopa), obtained the usual spectrum of benefit as from conventional L-dopa. There was a significant dose-sparing effect with the use of the enteric-coated prepartion of the order of 40% to 50%, whilst reducing gastrointestinal side effects to a minimum, at the same time as achieving optimal clinicl benefit. Enteric-coated L-dopa appears to be a useful and welcome addition to the therapeutic armamentarium for Parkinson's disease.

Female↗