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PubMed2003

Effects of oligonucleotide antisense to dopamine D3 receptor mRNA in a rodent model of behavioural sensitization to levodopa.

Levodopa-induced dyskinesias are abnormal involuntary movements that develop as a side-effect of long-term treatment with levodopa for Parkinson's disease. The mechanisms underlying such effects are unclear but may include abnormal stimulation of dopamine D(3) receptors. Elevations in dopamine D(3) receptor mRNA and binding are seen in the denervated striatum of hemiparkinsonian rats treated chronically with levodopa, and these changes correlate well with behavioural sensitization in this model. Further investigation of dopamine D(3) receptor involvement in levodopa-induced dyskinesias is hampered by the lack of appropriately selective ligands for this receptor. Here, in vivo administration of an antisense oligonucleotide designed to reduce striatal dopamine D(3) receptor expression provides a level of specificity not available through traditional pharmacological approaches. Following chronic treatment with levodopa, hemiparkinsonian rats received intrastriatal infusion of oligonucleotide antisense to dopamine D(3) receptor mRNA for 5 days. Antisense treatment effectively and selectively reduced striatal dopamine D(3) receptor binding and blocked behavioural sensitization to the effects of repeated levodopa. These findings confirm the importance of the D3 receptor in the expression of behavioural sensitization to levodopa in animals with dopaminergic denervation and contribute to our limited understanding of the functional significance of this receptor. In that sensitization to the effects of repeated levodopa in this setting may be analogous to medication-induced dyskinesias in humans, our findings furthermore suggest that drugs which block D(3) function may be helpful in the treatment of dyskinesias, without necessarily exacerbating Parkinsonism.

Animals↗
PubMed1994

The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum.

Food ingestion can influence the absorption of levodopa in the intestine and thereby contribute to fluctuations of motor functions in Parkinson patients. Obstruction of the active transport of levodopa by amino acids can be one factor. Paracellular drug absorption, a route proposed to be influenced by net transport of water across the intestinal epithelium, might occur for a small and hydrophilic drug such as levodopa. In the present study we studied how luminal L-leucine (60 mmol/L), alone or combined with hypotonicity, might stimulate net water absorption, and levodopa uptake in the human small intestine, since this possibly can contribute to the variable intestinal absorption of levodopa. The Loc-I-Gut perfusion technique was used in 10 healthy volunteers to study the effects of induced net fluid absorption on the small intestinal absorption of levodopa (2.5 mmol/L). An induced net fluid absorption was observed only when L-leucine was combined with a hypoosmolar perfusion solution. However, this did not enhance the intestinal permeability of levodopa. In conclusion, we suggest that the variability in the absorption of levodopa in Parkinson's disease cannot be explained by differences in transmucosal water flux in the human small intestine.

Antipyrine↗
PubMed1994

Pharmacokinetics of levodopa and carbidopa in rats following different routes of administration.

This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.

Absorption↗
PubMed2002

Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study).

OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

Aged↗
PubMed1980

Interaction of levodopa and metoclopramide on gastric emptying.

Dopamine is postulated as an inhibitory neurotransmitter in the alimentary tract. The purposes of this study were to determine the effect of levodopa on the rate of gastric emptying in man and to investigate the interaction of levodopa and metoclopramide (a putative dopamine antagonist) on gastric emptying. On separate days, 7 normal male subjects received oral levodopa, 1,000 mg, and placebo in a randomized double-blind fashion 20 min before taking a mixed solid-liquid test meal labeled with 99mtechnetium(Tc)-diethylenetriamine pentaacetic acid. Gastric emptying was measured over 90 min by a gamma camera technique. At 90 min, the mean percent isotope remaining in the stomach after placebo, 54.7 +/- 5.0%, was less than after levodopa, 85.1 +/- 4.9% (p less than 0.01). Four of these normal subjects were studied further, and received levodopa, 1,000 mg, and metoclopramide, 10 mg, by intramuscular injection, 20 min before the same labeled test meal. In these 4 subjects, at 90 min, mean percent isotope remaining in the stomach after the combination of levodopa and metoclopramide, 48.5 +/- 2.2%, was less than after levodopa alone, 83.3 +/- 7.0% (p less than 0.05), and in the same range as mean percent after placebo, 47.3 +/- 3.6%. It is concluded that (1) levodopa inhibited gastric emptying of isotope in a mixed solid-liquid meal in normal subjects; (2) metoclopramide antagonized this effect returning gastric emptying to normal; and (3) the data suggest the possibility that dopaminergic receptors have an inhibitory effect on gastric emptying of the human stomach.

Adult↗
PubMed1984

The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport.

To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the "on-off" phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 per cent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease.

Administration, Oral↗
PubMed2000

Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease.

We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0. 001), with almost no AIM when the density of dopamine nerve terminals was >10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.

Animals↗
PubMed1996

Effect of one month's treatment with peripherally acting catechol-O-methyltransferase inhibitor, entacapone, on pharmacokinetics and motor response to levodopa in advanced parkinsonian patients.

Twelve parkinsonian patients with levodopa-related end-of-dose fluctuations in disability were studied in an open-label trial to examine the effects of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on pharmacokinetics and metabolism of levodopa and on clinical response to levodopa after a single dose and after 4 weeks' medication with entacapone. The clinical response was assessed with continuous monitoring using the motor part of Unified Parkinson's Disease Rating Scale. Entacapone increased statistically significantly the mean area under the plasma concentration-time curve (AUC) of levodopa by 29% after a single dose and by 21% after 4 weeks' administration, without affecting other pharmacokinetic parameters of levodopa. The AUC of 3-O-methyldopa decreased by 45% and AUC of homovanillic acid by 21% after 4 weeks' dosing with entacapone. The duration of motor response to levodopa increased significantly from 2.3 h to 3.2 h (i.e., by 39%) after a single dose and to 3.4 h (i.e., by 48%) after 4 weeks' medication with entacapone. The magnitude of clinical response remained unchanged, but peak latency of motor response was prolonged after 4 weeks' medication. The duration and magnitude of dyskinesias also increased. Peripheral COMT inhibition with entacapone increased significantly the bioavailability of levodopa and prolonged its antiparkinsonian effect after a single dose and after repeated dosing for 4 weeks. Thus entacapone seems to be a valuable adjuvant to levodopa treatment in parkinsonian patients with end-of-dose failure.

Aged↗
PubMed1996

A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson's disease.

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.

Aged↗
PubMedDate not supplied

Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations.

Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 microg/mL and peak concentrations between 0.95 to 13.75 microg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

Activities of Daily Living↗
PubMedDate not supplied

Levodopa infusion therapy in Parkinson disease: state of the art in 2004.

Orally administered levodopa, in combination with a decarboxylase inhibitor, is the gold standard therapy for Parkinson disease (PD). The problems in management of motor fluctuations in the advanced stages of the disorder are due to the close relationship between plasma levodopa levels and availability of dopamine at striatal receptor sites. The fluctuating levodopa concentrations are mainly explained by the fact that levodopa absorption only occurs in the proximal small intestine. The patient's motor function thus depends on gastric emptying, which is erratic and may even be delayed in PD. Oral therapy with sustained-release formulations and COMT inhibitors have not solved the problems satisfactorily. Therefore, infusions of levodopa by intravenous and enteral (duodenal/jejunal) routes of administration have been studied. In this review of the literature on clinically relevant levodopa infusion studies, it is shown that improvements regarding fluctuations in both plasma levodopa levels and motor performance have been repeatedly reported. The results acquired so far suggest that levodopa infusion is a safe and efficacious therapy. Recent drug delivery development and long-term studies have shown that infusion is a clinically feasible alternative to treat advanced PD.

Adult↗
PubMed1983

Problems associated with long-term levodopa treatment of Parkinson's disease.

Levodopa treatment improves significantly not only the parkinsonian disability but also the mortality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia. In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctuations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of Parkinson's disease nor the disability of the patients. A readjustment of the levodopa dosage, and as an adjuvant drug treatment, deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuations in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.

Dementia↗
PubMed1995

Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease.

In an earlier report of our placebo-controlled selegiline trial on de novo parkinsonian patients, we have shown that the need to start additional levodopa therapy is significantly postponed by using selegiline monotherapy. Now we report the two-year interim results of the double-blind continuation of the trial in 44 patients after the introduction of levodopa to the earlier therapy with placebo or selegiline (21 and 23 patients, respectively). The clinical disability was assessed by three rating scales. The daily dose of levodopa needed to maintain an optimal condition had to be increased progressively up to a 52% higher level in the placebo group than in the selegiline group (543 +/- 150 and 358 +/- 117 mg, respectively, p < 0.001). The number of daily doses of levodopa was also statistically significantly higher in the placebo group during the 24 months' observation period (p < 0.01). The ratio of levodopa doses that was expected to stay the same contrarily significantly increased suggesting that selegiline would, besides having the levodopa potentiating effect, also have a beneficial influence on the progression of the basic cerebral dopamine deficiency. The combination of selegiline and levodopa was well tolerated, and the adverse event profiles did not differ from each other. In conclusion, early selegiline therapy allows a significant saving in the subsequent levodopa dosage. This saving seems to become even stronger along with the treatment time.

Aged↗
PubMed1998

Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson's disease.

OBJECTIVE: To evaluate the effects of continuous duodenal infusion of levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of levodopa constant. MATERIAL AND METHODS: In view of the low water solubility of levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2 1/2 years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma levodopa concentrations were analysed every 15 min. RESULTS: The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2 1/2 years levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased. CONCLUSION: Continuous duodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.

Activities of Daily Living↗
PubMed2004

The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease.

OBJECTIVES: The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. MATERIALS AND METHODS: A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. RESULTS: No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). CONCLUSION: The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Adult↗
PubMed1998

Effect of oral levodopa treatment on articulatory function in Parkinson's disease: preliminary results.

To quantify lip function in 16 patients with Parkinson's disease, a computerized semiconductor lip pressure transducer system was used prior to subjects being administered oral levodopa and at approximately 0.5 hr, 1.5 hr, and 3.0 hr postmedication. Two blood samples were taken from each subject at varying times during the levodopa dosage interval, and the exact time and dosage of levodopa were noted. Lip function measurements were expressed as percentage changes from baseline and were plotted for each subject against time and levodopa concentrations to determine the effects of levodopa therapy on articulatory function. The results supported the effectiveness of levodopa therapy in improving lip function. In particular, lip pressures recorded during both speech and nonspeech tasks tended to improve after levodopa administration, the lip measures improving somewhat in parallel with the rise and fall of blood plasma levodopa concentrations. Evidence of a hysteresis effect was noted.

Aged↗
PubMed1976

Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa.

Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature.

Aged↗
PubMed1990

L-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans.

To determine whether levodopa reduces the levels of S-adenosylmethionine in the human central nervous system, cerebrospinal fluid (CSF) concentrations of S-adenosylmethionine, methionine, 3-methoxytyrosine, levodopa and 5-methyltetrahydrofolate were measured in six children with dopamine deficiency before and after treatment. In four, the lack of dopamine was secondary to a reduction in concentration of levodopa and these were treated with levodopa together with a peripheral dopa-decarboxylase inhibitor. In the other two, levodopa in the central nervous system naturally accumulated due to a congenital deficiency of aromatic-L-amino acid decarboxylase and these were treated with pyridoxine (which in this condition lowers central levodopa concentrations). Raising levodopa concentrations in the central nervous system caused a fall in CSF S-adenosyl-methionine concentration and a rise in CSF 3-methoxytyrosine concentration. No change was observed in CSF methionine concentration and in all patients CSF 5-methyltetrahydrofolate concentration was normal. With one exclusion there was a linear relationship between CSF S-adenosylmethionine and 3-methoxytyrosine concentrations. This is the first demonstration of such effects in humans and the implications upon levodopa therapy are discussed.

Adolescent↗