Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects.

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range.

Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. METHODS: Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. RESULTS: In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). CONCLUSION: These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.

A new HILIC-MS/MS method for the simultaneous analysis of carbidopa, levodopa, and its metabolites in human plasma.

Monitoring of the plasmatic levels of levodopa (LEV) and carbidopa (CAR) is necessary to adjust the dose of these drugs according to the individual needs of Parkinson's disease patients. To support drug therapeutic monitoring, a method using HILIC mode and LC-MS/MS was developed for the simultaneous determination of carbidopa, levodopa, and its metabolites (3-o-methyldopa (3-OMD) and dopamine (DOPA)) in human plasma. A triple quadrupole mass spectrometry was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique. After straightforward sample preparation via protein precipitation, an Atlantis HILIC (150 × 2.1 mm, 3 µm, Waters, USA) column were used for separation under the isocratic condition of acetonitrile/water (79:21, v/v) containing 0.05% formic acid and 3 mmol/L ammonium formate and the total run time was 7 min. Deuterated LEV was used as internal standard for quantification. The developed method was validated in human plasma with a lower limit of quantitation of 75 ng/mL for LEV, 65 ng/mL for CAR and 3-OMD, and 20 ng/mL for DOPA. The calibration curve was linear within the concentration range of 75-800 ng/mL for LEV, 65-800 ng/mL for CAR and 3-OMD, and 20-400 ng/mL for DOPA (r>0.99). The assay was accurate and precise, with inter-assay and intra-assay accuracies within ±13.44% of nominal and inter-assay and intra-assay precision≤13.99%. All results were within the acceptance criteria of the US FDA and ANVISA guidelines for method validation. LEV, CAR, 3-OMD and DOPA were stable in the battery of stability studies, long-term, bench-top, autosampler, and freeze/thaw cycles. Samples from patients undergoing treatment were analyzed, and the results indicated that this new method is suitable for therapeutic drug monitoring in Parkinson's disease patients.

Kinetic approach for the enzymatic determination of levodopa and carbidopa assisted by multivariate curve resolution-alternating least squares.

A combination of kinetic spectroscopic monitoring and multivariate curve resolution-alternating least squares (MCR-ALS) was proposed for the enzymatic determination of levodopa (LVD) and carbidopa (CBD) in pharmaceuticals. The enzymatic reaction process was carried out in a reverse stopped-flow injection system and monitored by UV-vis spectroscopy. The spectra (292-600 nm) were recorded throughout the reaction and were analyzed by multivariate curve resolution-alternating least squares. A small calibration matrix containing nine mixtures was used in the model construction. Additionally, to evaluate the prediction ability of the model, a set with six validation mixtures was used. The lack of fit obtained was 4.3%, the explained variance 99.8% and the overall prediction error 5.5%. Tablets of commercial samples were analyzed and the results were validated by pharmacopeia method (high performance liquid chromatography). No significant differences were found (alpha=0.05) between the reference values and the ones obtained with the proposed method. It is important to note that a unique chemometric model made it possible to determine both analytes simultaneously.

Kinetic characterization of the oxidation of carbidopa and benserazide by tyrosinase and peroxidase.

Carbidopa and benserazide have been described as inhibitors of dopa decarboxylase and both have been used in the treatment of Parkinson's disease. Because of their chemical structure as polyphenols, these compounds can behave as substrates of tyrosinase and peroxidase. We demonstrate that these enzymes oxidize both substrates. Since o-quinones are unstable, a chronometric method for enzymatic initial rate determinations was used based on measurements of the lag period in the presence of micromolar concentrations of ascorbic acid to kinetically characterize these substrates. In the case of tyrosinase, the values of the Michaelis constant for both substrates were greater than those described for dopa, although the catalytic constants were lower, probably due to the greater size of the substitute group in carbon 1. As regards peroxidase, the saturation of the enzyme by both substrates is possible, however this effect does not occur with the isomers of dopa. The distance of the charges from the benzene ring may enable the ring to approach the iron of the active site and, therefore, act.

Oxidation of carbidopa by tyrosinase and its effect on murine melanoma.

Oxidation of the anti-Parkinsonian agent carbidopa by tyrosinase was investigated. The products of this reaction were identified as 3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and 6,7-dihydroxy-3-methylcinnoline. These results demonstrate that after oxidation of the catechol moiety to an o-quinone either a redox exchange with the hydrazine group or a cyclization reaction occur. The cyclization product underwent additional oxidation reactions leading to aromatization. The cyclization reaction is undesired in the case of hydrazine-containing anti-melanoma prodrugs and will have to be taken into account in designing such compounds. Carbidopa was tested against B16(F10) melanoma cells in culture and showed cytotoxicity significantly higher than either of its oxidation products and l-dopa. This effect, however, was not specific to this cell line.

Immunohistochemical detection of L-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats.

On the basis of our previous studies in the normal rat [Arai, R., Karasawa, N., Geffard, M., Nagatsu, I., 1995. L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study. Neurosci. Lett. 195, 195-198; Arai, R., Karasawa, N., Nagatsu, I., 1996a. Aromatic L-amino acid decarboxylase is present in serotonergic fibers of the striatum of the rat. A double-labeling immunofluorescence study. Brain Res. 706, 177-179; Arai, R., Karasawa, N., Nagatsu, I., 1996b. Dopamine produced from L-DOPA is degraded by endogenous monoamine oxidase in neurons of the dorsal raphe nucleus of the rat: an immunohistochemical study. Brain Res. 722, 181-184] we have assumed that exogenously administered L-dihydroxyphenylalanine (L-DOPA) is converted into dopamine (DA) in serotonergic (5-HT) fibers within the striatum (ST) and the substantia nigra pars reticulata (SNR). In the present study, an attempt was made to confirm the assumptions in Parkinsonian rats, which were produced by unilateral injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNC). The rats exhibiting more than 150 total controversial circles were regarded as satisfactory models of Parkinson disease (PD). Using a dual immunofluorescence histochemistry, we examined DA-immunoreactivity in the 5-HT fibers within the ST and the SNR of the PD model rats after L-DOPA was injected intraperitoneally. In experimental cases with the L-DOPA administration, DA-immunoreactivity was detected in 5-HT fibers in both the ST and the SNR on the 6-OHDA injection side; no DA-immunoreactivity was found in 5-HT fibers in the ST or the SNR in control cases without the L-DOPA administration. The results support the assumption that exogenously administered L-DOPA may be converted into DA within the 5-HT fibers in the ST and SNR of the PD model rats.

D-dopa is unidirectionally converted to L-dopa by D-amino acid oxidase, followed by dopa transaminase.

1. Many studies have shown that administration of d-3, 4-dihydroxyphenylalanine (D-dopa) produces contralateral rotation in hemi-parkinsonian animals comparable to L-dopa, with less potency and slower onset. It was postulated that D-dopa was converted to L-dopa to produce these effects. 2. To investigate the postulated chiral inversion of D-dopa to L-dopa and the related mechanism, an enantiomeric separation method for D- and L-dopa using HPLC was first established. Then, rat kidney homogenates containing D-dopa or L-dopa were incubated and subjected to HPLC to detect traces of respective enantiomer generation. The mechanism of the chiral inversion of d-dopa was explored by direct measurement of the production of L-dopa in kidney homogenates. D-dopa incubations containing different concentrations of an inhibitor of D-amino acid oxidase (DAAO) and an inhibitor of dopa transaminase were measured for L-dopa generation using HPLC. The role of DAAO in the chiral inversion of D-dopa to L-dopa was further investigated by using purified DAAO and mutant ddY/DAAO- mouse kidney lacking DAAO activity. 3. In rat kidney homogenate, D-dopa was, indeed, converted to L-dopa, whereas L-dopa was not converted to D-dopa. Sodium benzoate, a selective inhibitor of DAAO, blocked L-dopa generation in a concentration-dependant manner. In contrast with kidney homogenates of wild-type ddY/DAAO+ mice, those of mutant ddY/DAAO- mice lacking DAAO activity did not convert D-dopa to L-dopa unless exogenous DAAO protein was added. Conversely, when carbidopa, an inhibitor of dopa transaminase, was added to the homogenates, significant inhibition of L-dopa production was noted. 4. These results prove the proposal that d-dopa undergoes unidirectional chiral inversion and further suggest that D-dopa is first oxidatively deaminated by DAAO to its alpha-keto acid and then transaminated by dopa transaminase to L-dopa.

Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: effect of dose, frequency of administration, and brain exposure.

Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0-7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction.

Semicarbazide-sensitive amine oxidase (SSAO) gene expression in alloxan-induced diabetes in mice.

BACKGROUND: Plasma activity of semicarbazide-sensitive amine oxidase (SSAO) has been reported to be significantly higher in diabetic patients compared to healthy controls. Due to the production of highly angiotoxic substances in SSAO-catalyzed reactions, it has been speculated that this could be a cause for the vascular complications frequently associated with diabetes. Little is known about how the enzyme activity is regulated, and why it is high in these patients. In the present study, we assessed the possibility of transcriptional regulation by analyzing SSAO activity and SSAO-mRNA levels in mice with alloxan-induced diabetes. MATERIALS AND METHODS: Diabetes was induced in NMRI mice by a single intravenous injection of alloxan. The enzyme activity was analyzed by a radiometric assay using (14) C-benzylamine as a substrate, and the mRNA-levels were analyzed by real-time PCR. RESULTS: We found that the enzyme activity was increased in lung and adipose tissue 1 day after induction, as the glucose levels start to rise. Seven days after the injection of alloxan, the activity in serum was increased, and this activity was positively correlated with blood glucose levels in the alloxan-treated animals. Although the enzyme activity was increased in adipose tissue as a result of the treatment, SSAO-mRNA levels in this tissue were decreased, possibly suggesting a negative feedback on the gene expression. CONCLUSIONS: The main conclusion from this study is that the increased enzyme activity observed in diabetes is not a result of increased SSAO gene transcription. We speculate that the enzyme activity is controlled by posttranslational modifications of the protein, and that the catalytic activity controls the gene expression.

Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase.

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.

Dopaminergic therapy with carbidopa L-dopa for left neglect after stroke: a case series.

OBJECTIVE: To evaluate the efficacy of carbidopa L-dopa (Sinemet) in reducing left spatial neglect after stroke. DESIGN: Case series. SETTING: Inpatient neurorehabilitation unit in a regional rehabilitation center. PARTICIPANTS: A convenience sample of 4 women with right brain strokes and left neglect. INTERVENTION: A trial of carbidopa L-dopa to treat left neglect, if indicated by selected subtests of the Behavioral Inattention Test (BIT). MAIN OUTCOME MEASURES: Baseline and posttreatment evaluation with the modified BIT and the FIM instrument. RESULTS: Three of 4 subjects had significant improvements in their modified BIT scores (8%, 12%, 27%, respectively) and their functional status on the FIM. CONCLUSION: With further study, carbidopa L-dopa may be shown to reduce unilateral spatial neglect and thereby improve rehabilitation outcomes.

Simultaneous determination of levodopa, carbidopa and their metabolites in human plasma and urine samples using LC-EC.

In this study levodopa (L-DOPA), carbidopa (C-DOPA) and their metabolites were resolved from other endogenous components present in human plasma and urine and determined quantitatively. The developed technique involved the use of a second pump, a switching valve, and a pre-column in the LC system in order to perform on-line sample clean-up and enrichment. This procedure is dependent on an effective removal of the many interfering matrix components that vitiate HPLC analysis. Several unknown endogenous electroactive compounds, present in plasma, were eliminated by the purification step, or suppressed by the pre-treatment or detection conditions. The analyses were separated on an Octyl-bonded reversed-phase column followed by amperometric detection using a carbon fibre microelectrode flow cell operated at +0.8 V versus silver/silver phosphate reference electrode. The cell was compatible with the mobile and the stationary phase used in the flow system without any complex surface reaction. The peak currents obtained for the different analytes were directly proportional to the analyse over the concentration range 0.02-4.0 microg ml(-1). Using this method, the minimum detectable concentration was estimated to be 5 and 8 ng ml(-1) for L-DOPA and C-DOPA, respectively. Recovery studies performed on human plasma samples ranged from 93.83 to 89.76%, with a relative standard deviation of < 6%. The intra- and inter-assay coefficients of variation were < 7%. The accuracy of the assay, which was defined as the percentage difference between the mean concentration found and the theoretical (true) concentration, was 12% or better. The electrochemical pre-treatment regime described in this work permitted a longer application of the same microelectrode. The method showed a good agreement with other available methods described in the introduction and offers the advantages of being simple, less time and labour consuming, does not require additional solvents for extraction, inexpensive and suitable for routine analysis and kinetic purposes.

[Inhibition of the COMPT with entacapone in the treatment of motor fluctuations in Parkinson disease]. / Inhibición de la COMT con entacapone en el tratamiento de las fluctuaciones motoras de la enfermedad de Parkinson.

Motor fluctuations are a common problem in the long-term treatment of Parkinson's disease (PD). Entacapone (Comtan) is a potent, peripherally acting, reversible and selective inhibitor of catechol-O-methyltransferase (COMT). Used as an adjuvant to levodopa therapy, entacapone slows the elimination of levodopa by decreasing peripheral conversion to 3-O-methyldopa, increasing central extracellular levodopa and striatal dopamine concentrations. Coadministered with levodopa/carbidopa or levodopa/benserazide, at doses of 200 mg 2 to 10 times daily in patients with end-of-dose fluctuations, entacapone may increase the duration of clinical response, both after the first single dose and after repeated dosing. At this dosage, it has a time to peak plasma concentration of 1.2 h and an elimination half life of 3.4 h. In two multicentric, long-term (24 weeks), parallel, randomized and placebo-controlled studies, entacapone increased the duration of 'on' time (by approximately 1 hour daily) and decreased the duration of 'off' time with a concomitant reduction in the mean daily levodopa dose. In these and other phase III studies, entacapone was generally well tolerated, with most adverse effects being dyskinesias and gastrointestinal disorders. Increased dyskinesia were generally controlled by reducing levodopa doses. Entacapone appears to be a useful adjunct in extending the benefit of each levodopa dose in PD patients with end-of-dose fluctuations.

Successful orchestration of antiparkinsonian pharmacotherapy.

As is true with the orchestration of essentially all forms of pharmacotherapy, the overall quality of therapy should not be judged as a simple binary function (it is either good or bad). Rather, it should be judged along a continuum, spanning adequate through excellent and peaking at truly elegant, where two or more disease states are optimally managed with a single, simple drug. Because the difference between adequate and elegant therapy often depends on fine-tuning the drug choice, dosage, and route of administration, it is no surprise that pharmacists are often intimately involved in many highly successful specialty clinics, including Parkinson's disease clinics.

Effect of tolcapone on plasma levodopa concentrations after coadministration with levodopa/carbidopa to healthy volunteers.

Tolcapone (Ro 40-7592) is a novel inhibitor of catechol-O-methyltransferase that is being developed for clinical use in the treatment of Parkinson's disease as add-on therapy to a combination of levodopa and a peripheral amino acid decarboxylase inhibitor (benserazide or carbidopa). The current single-blind, randomized study was designed to evaluate the effect of tolcapone compared with placebo on plasma levodopa concentrations in healthy volunteers concomitantly receiving 25 mg of carbidopa and 100 mg of levodopa (Sinemet 25-100) and to assess the tolerability and safety of this combination. Placebo or tolcapone at doses of 5, 10, 25, 50, 100, 200, 400, and 800 mg was coadministered orally with Sinemet 25-100. Each dose was tested in a crossover fashion in a new group of six participants who each received active drug on one occasion and placebo on the other. Tolcapone increased the area under the plasma concentration-time curve and half-life of levodopa approximately twofold, without appreciably increasing the peak concentration. The maximum effect on levodopa half-life was observed with the 200-mg dose. Adverse effects were minor at all doses.

Analysis of mortality in pergolide-treated patients with Parkinson's disease.

Parkinson's disease, because of its progressive degenerative nature, is associated with increased disability and mortality compared with mortality in the general population. We examined mortality data from three clinical trials involving 1,330 patients with Parkinson's disease treated with pergolide as an adjunct to levodopa or levodopa/carbidopa therapy. The ratio of observed deaths to expected deaths in the general population of the same age, gender, race distribution, and period of observation was 2.3 for the 3 studies combined. The ratio is lower than that in Parkinson's disease patients treated prior to the introduction of levodopa, consistent with ratios with levodopa and levodopa combination therapy. The ratio is slightly higher than in Parkinson's disease patients treated with levodopa and levodopa combination therapy, which may be attributable to differing patient characteristics in the populations studied.

The effects of L-dihydroxyphenylalanine on alertness and mood in alpha-methyl-para-tyrosine-treated healthy humans. Further evidence for the role of catecholamines in arousal and anxiety.

Treatment with alpha-methyl-para-tyrosine (AMPT), a catecholamine synthesis inhibitor, has been shown to produce pronounced increases in sleepiness and mild increases in negative mood and anxiety when administered to healthy male adults. The present study was conducted to ascertain whether these effects of AMPT are secondary to decreases in brain catecholamines or whether they represent nonspecific drug effects. Forty-one healthy males were randomized to one of four treatment groups. (1) Treatment with AMPT alone (AMPT/placebo); (2) treatment with AMPT plus L-dopa/carbidopa (AMPT plus L-dopa/carbidopa); (3) treatment with L-dopa/carbidopa alone (placebo plus L-dopa/carbidopa); or (4) treatment with placebo alone (placebo plus placebo). Repeated measures of alertness, mood, and anxiety were obtained over a three-day period of drug treatment and following drug discontinuation. As before, AMPT treatment led to increased sleepines. In addition, AMPT treatment led to decreased calmness, increased tension and anger, and a trend for increased depression. Replacement of catecholamine stores with L-dopa reversed the effects of AMPT and was associated with a more rapid recovery from AMPT's effects. These findings indicate that AMPT's effects on alertness and anxiety are catecholamine-specific. Further, they provide additional evidence that catecholamines are involved in the regulation of normal states of arousal, and they are consistent with the view that brain catecholaminergic dysregulation is involved in pathological anxiety states.

Motoric sensitization and levodopa accumulation after chronic levodopa treatment in an animal model of Parkinson's disease.

One month after rats were subjected to unilateral injections of either 6-hydroxydopamine (6-OHDA) or vehicle into the midbrain tegmentum, they were given daily injections of either saline or levodopa (10 mg/kg and 1 mg/kg carbidopa) for 30 days. On the first and last day of treatment the spontaneous behavior of the rats was evaluated with a video image analysis system that detected directional movement asymmetries. Although vehicle-injected rats exhibited very little movement asymmetry, the 6-OHDA rats were strongly asymmetric. On day 1, both saline and levodopa-treated 6-OHDA rats exhibited rotational movement directed toward the dopamine-deficient hemisphere. On day 30 of treatment, however, the chronic levodopa group displayed a complete reversal and exaggeration of the rotational bias, and all asymmetric movement was directed toward the dopamine-intact hemisphere. Thus chronic levodopa treatment shifted behavioral dominance from the intact to the dopamine-denervated hemisphere. Subsequent biochemical measurement of dopamine and levodopa in striatal and limbic tissue samples indicated that chronic levodopa treatment did not alter dopamine tissue concentrations but did substantially increase levodopa concentrations, both in the dopamine-denervated striatum and in limbic tissue. This increased levodopa loading in brain with chronic levodopa treatment occurring in 6-OHDA rats but not in vehicle-injected rats that were given the same levodopa regimen. This selectivity in the effect of chronic levodopa treatment to the 6-OHDA rats appeared to rule out the possibility of peripheral metabolic factors for the levodopa accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

MAO and L-dopa treatment of Parkinson's disease.

The aim of this study was to determine whether there were differences in the oxidative deamination of dopamine in patients with Parkinson's disease who demonstrated a long-duration response (LDR) to treatment with dopa and carbidopa and in patients who demonstrated only a short-duration response (SDR) to the drugs. The patients who demonstrated LDR had received dopa and carbidopa for a shorter time (3.4y) than had the SDR patients (9.5y). The concentrations of dopamine and 3-methoxytyramine and their deaminated metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were measured in 24-h urine samples collected from patients in both groups. The ratios of homovanillic acid to 3-methoxytyramine and dopamine were greater in SDR than in LDR patients suggesting increased oxidative deamination of dopamine in this group. Increased oxidative deamination could be caused by an increase in MAO activity as Parkinson's disease progresses or by the treatment with L-dopa.