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PubMed1998

Pallidotomy improves motor responses and widens the levodopa therapeutic window in Parkinson's disease.

Stereotactic posteroventral pallidotomy (PVP) as a treatment for Parkinson's disease (PD) symptoms has been increasingly used in moderate-advanced disease. We examined the pharmacodynamic responses of PD patients to single oral levodopa doses and intravenous levodopa infusions before and after PVP surgery. Nine subjects with advanced PD received a single oral dose and ramped intravenous levodopa infusions before and 3-5 weeks after unilateral PVP. Timed motor tasks, Unified Parkinson's Disease Rating Scale (UPDRS) evaluations, and ordinal dyskinesia rating were performed after oral levodopa and during i.v. levodopa infusions. Serum prolactin and dopa levels were measured during the levodopa infusions. Overall timed motor but not motor UPDRS scores were improved after PVP in both the worst ("off") and best ("on") states. Contralateral but not ipsilateral limb dyskinesias were substantially reduced at all serum (dopa) levels after PVP. Ipsilateral and contralateral timed motor performance at low serum (dopa) levels was improved by PVP. Walking speeds at all serum (dopa) levels were not changed by PVP. Serum prolactin was reduced equally by increasing (dopa) preoperatively and postoperatively. PVP significantly and favorably altered oral and intravenous levodopa pharmacodynamics by improving bilateral limb motor function and contralateral dyskinesia but did not alter walking speed. PVP appears to widen significantly the therapeutic window for levodopa in PD.

Administration, Oral↗
PubMed2006

Reversion of levodopa-induced motor fluctuations by the A2A antagonist CSC is associated with an increase in striatal preprodynorphin mRNA expression in 6-OHDA-lesioned rats.

The molecular mechanisms involved in the reversion of levodopa-induced motor fluctuations by the adenosine A2A antagonist 8-(3-chlorostryryl) caffeine (CSC) were investigated in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion and compared with the ones achieved by the kappa-opioid agonist, U50,488. Animals were treated with levodopa (50 mg/kg/day) for 22 days and for one additional week with levodopa + CSC (5 mg/kg/day), levodopa + U50,488 (1 mg/kg/day), or levodopa + vehicle. The reversion of the decrease in the duration of levodopa-induced rotations by CSC, but not by U50,488, was maintained until the end of the treatment and was associated with a further increase in levodopa-induced preprodynorphin mRNA in the lesioned striatum, being higher in the ventromedial striatum. The increase in striatal preprodynorphin expression, particularly in the ventromedial striatum, may be related to the reversion of levodopa-induced motor fluctuations in the CSC-treated animals, suggesting a role of the direct striatal output pathway activity in the ventromedial striatum in the pathophysiology of motor fluctuations.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2007

Different levodopa actions on the extracellular dopamine pools in the rat striatum.

Levodopa has been the mainstay treatment for Parkinson's disease for several decades, but the precise mechanism for its therapeutic action is still not well understood. To date, little distinction has been made between the effects of levodopa on the different brain DA pools. We studied the levodopa action on two extracellular DA pools: one was analyzed by microdialysis (often considered as indicative of volume transmission) and the other by in vivo amperometry during nigrostriatal cell stimulation (more indicative of neurotransmission). Levodopa administration induced a moderate (increased 200%) and tardy (began at 60 min) increase in the DA-pool measured by microdialysis, an effect that increased (increased 500%) and accelerated (began at 10 min) after DA-cell degeneration. Levodopa action on the DA-pool measured by amperometry was very fast (10 min) and prominent (increased 600%) in normal rats. The DA-denervated striatum showed a fast exhaustion during cell stimulation, which prevented further study of the levodopa effect on the DA amperometry-pool under this condition. This study suggests a different kinetic for levodopa action on the volume transmitter and neurotransmitter DA-pool, showing marked changes in levodopa action in the denervated striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Quetiapine attenuates levodopa-induced motor complications in rodent and primate parkinsonian models.

The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Aged↗
PubMed1997

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson's disease.

The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

Aged↗
PubMed2003

Experimental study on inhibition of neuronal toxical effect of levodopa by ginkgo biloba extract on Parkinson disease in rats.

In order to observe neuronal toxical effect of Levodopa and investigate if using Levodopa together with Ginkgo Bilobar Extract (EGb) would be an workable method to treat Parkinson disease, rat models of Parkinson disease (PD) were made by injecting 6-OHDA stereotaxically to right side of the mesencephic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Rotational behavioral observation, TUNEL, immunocytochemistry, Nissl's body staining were performed to measure the difference between group treated by Levodopa (50 mg/kg every day for 3 days, 5 days, 7 days, L-dopa group) and group treated by Levodopa combined with EGb (100 mg/kg every day, E-D group). The results showed that in the L-dopa group, the numbers of apoptosis of substantial nigra, rings of rotational behavior were more than those in the E-D group (P < 0.05). The numbers of Nissl's cells in L-dopa group were fewer than in E-D group (P < 0.05). The results suggested that Levodopa had neur toxic effect and EGb may decrease the toxicity of levodopa. The combined use of EGb with Levodopa may be a workable method to treat PD and may be better than using Levodopa alone.

Animals↗
PubMed1998

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/ carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg and once with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and once with placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa was unaffected by tolcapone in all treatment groups and the maximum plasma concentration (Cmax) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60-90% and levodopa t1/2 by 20-60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD Cmax decreased by 80% and AUC by 70% with tolcapone. The tolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.

Administration, Oral↗
PubMed2000

An open-label, multicentre clinical trial to determine the levodopa dose-sparing capacity of pramipexole in patients with idiopathic Parkinson's disease.

Ninety-three patients with idiopathic Parkinson's disease (PD) entered a 12 week open-label, baseline controlled, multicentre study. The study was designed to determine the levodopa sparing effect of pramipexole as add-on treatment in PD while maintaining an optimal clinical improvement in motor performance. The overall reduction in adjusted levodopa dose was the primary endpoint. Unified Parkinson's Disease Rating Scale (UPDRS) subscores as well as motor fluctuations, frequency and severity of dyskinesia (assessed by patient diaries) were secondary endpoints. Pramipexole permitted a median reduction of adjusted levodopa by 40% while maintaining or improving the UPDRS scores in 61 patients (per protocol [PP] analysis). The intent-to-treat (ITT) analysis (90 patients) similarly revealed a median reduction of 40%. An anticipated short-term levodopa dose reduction as substantiated by 95% confidence interval calculations lies within a range of 35% to 50%. If unadjusted levodopa doses were considered, a median reduction of 42% (PP) or 43% (ITT) was achieved. 47% patients (ITT) had a levodopa dose reduction (adjusted) of more than 40% while maintaining or improving their level of efficacy, and 72.2% had a reduction of at least 20%. Motor fluctuations improved compared to baseline according to patient diaries and UPDRS part IV. These findings suggest that pramipexole can markedly reduce the daily levodopa dosage without deterioration of motor response and support that this new selective D2/D3 receptor agonist also improves later levodopa-associated motor complications.

Aged↗
PubMed1980

The effect of levodopa treatment on the visual evoked potentials in Parkinsonian patients.

There is extensive literature on the effects of levodopa treatment on the visual evoked potentials (VEP) in laboratory animals and in depressed patients. The effects of levodopa on the VEP of parkinsonian patients were overlooked to a certain extent. In this work we searched for levodopa effects on the VEP of 42 parkinsonian patients. The VEP were data-reduced and analyzed by several techniques: (a) 256 data values (256 msec) were reduced to 70 variables by averaging; (b) time-domain parametric extraction: latencies to peak-and-trough points, amplitudes, etc., resulted in 14 variables; (c) frequency transformation into power spectral density bands resulted in 14 variables. Each one of the above variables was univariate, paired t-tested for levodopa effects. The overall effects of levodopa on the power variables and the time-domain parameters were evaluated by Hotelling paired T2. The 70 time variables were further reduced by the tolerance function of the discriminant procedure and analyzed both by direct and by stepwise discriminant analyses and by SAS-MANOVA in a pairwise design. Only few sporadic univariate t values reached significance levels. No overall multivariate significant effects of levodopa were found. In view of known dopaminergic involvement in parts of the visual system it is postulated that levodopa might have antagonizing effects at different levels of the visual pathways. This hypothesis and better understanding of levodopa effects on the visual system should probably be achieved by recording VEP from the visual subsystems.

Evoked Potentials↗
PubMed1977

Effects of levodopa and dopamine of plasma glucose concentration in mice.

In nialamide-treated, fasted mice levodopa produced a dose-dependent hypoglycaemic response. The response was also seen in pargyline-treated mice but not in animals which were not treated with a monoamine oxidase inhibitor. Dopamine did not affect plasma glucose under these conditons. In doses which were ineffective when injected i.v., both levodopa and dopamine produced hypoglycemia when injected intracerebroventriculary (i.c.v.). The hypoglycaemic response to levodopa was prevented by the dopamine antagonists, haloperidol and pimozide. The possible involvement of 5HT in the hypoglycaemic response to levodopa was suggested by the blockade of the response by cyproheptadine and methysergide together with the observations that hypoglycaemia is produced by 5HTP and by i.c.v. 5HT. p-Chlorophenylalanine (PCPA) also reduced the response to levodopa but the usefulness of PCPA as an inhibitor of 5HT synthesis in these experiments in doubtful since it also inhibited the hypoglycaemic effects of 5HTP and i.c.v. 5HT. Hypoglycaemia produced by levodopa did not appear to involve stimulation of insulin secretion since plasma IRI levels were not increased by levodopa and the hypoglycaemia was accompanied by a elevation of plasma FFA and no significant change in the liver glycogen content. It is suggested that the hypoglycaemic effect of levodopa is mediated through dopamine acting in the brain, although the involvement of 5HT in the response and the mechanisms involved remain to be determined.

Animals↗
PubMed2005

Hydrosoluble fiber (Plantago ovata husk) and levodopa I: experimental study of the pharmacokinetic interaction.

Fiber therapy could be used in patients with Parkinson disease to reduce the symptoms of gastrointestinal disorders; however, it could interact with levodopa reducing its effectiveness. In this experimental study we have investigated whether the presence of Plantago ovata husk (water-soluble fiber) modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route at the same time. We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). The extent of levodopa absorbed when administering 100 mg/kg of fiber (AUC=43.4 mug min ml(-1)) is approximately the same as when levodopa is administered alone (AUC=47.1 microg min ml(-1)); however, Cmax is lower (1.04 versus 1.43 microg ml(-1)). Results obtained indicate that fiber at the higher dose increases the extent of levodopa absorbed (AUC=62.2 microg min ml(-1)), being the value of Cmax similar (1.46 microg ml(-1)). The value of tmax increases from 10 min when levodopa is administered alone to 20 min when the animals receive fiber. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 60 min with 100 mg/kg fiber and 20 min with 400 mg/kg fiber. Fiber also increases the mean residence time (MRT). P. ovata husk administration with levodopa could be beneficial, not only in patients with constipation, due to: lower adverse reactions (lower values of Cmax) and longer and more stable effects (higher final concentrations and more time in the body).

Administration, Oral↗
PubMed2004

NR2B selective NMDA receptor antagonist CP-101,606 prevents levodopa-induced motor response alterations in hemi-parkinsonian rats.

Sensitization of NMDA receptors containing the NR2B subunit has been increasingly associated with various forms of synaptic plasticity, including those implicated in the pathogenesis of extrapyramidal motor dysfunction. To determine whether activation of NR2B containing receptors contributes to the development and maintenance of levodopa-induced response changes in parkinsonian animals, we evaluated the effects of the selective NR2B antagonist CP-101,606 on these response alterations in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Three weeks of twice-daily levodopa treatment decreased the duration of the rotational response to acute levodopa challenge. The response alteration was associated with an increase in GluR1 (S831) phosphorylation in medium spiny neurons of the dorsolateral striatum. Both the attenuated rotational response and augmented GluR1 phosphorylation were decreased by CP-101,606 treatment. These CP-101,606 effects were observed when the compound was administered either at the end of chronic levodopa treatment (ameliorative effect) or together with the twice-daily levodopa treatment for 3 weeks (preventive effect). Furthermore, concurrent administration of CP-101,606 with levodopa potentiated the ability of levodopa challenge to reverse the 6-OHDA lesion-induced contralateral forelimb movement deficit as measured in a drag test. These results suggest that activation of NR2B subunit containing NMDA receptors contributes to both the development and maintenance of levodopa-induced motor response alterations, through a mechanism that involves an increase in GluR1 phosphorylation in striatal spiny neurons.

Animals↗
PubMed2003

Development of levodopa-induced dyskinesias in parkinsonian monkeys may depend upon rate of symptom onset and/or duration of symptoms.

Levodopa-induced dyskinesias (LIDs) present a major problem for the long-term management of Parkinson's disease (PD) patients. Due to the interdependence of risk factors in clinical populations, it is difficult to independently examine factors that may influence the development of LIDs. Using macaque monkeys with different types of MPTP-induced parkinsonism, the current study evaluated the degree to which rate of symptom progression, symptom severity, and response to and duration of levodopa therapy may be involved in the development of LIDs. Monkeys with acute (short-term) MPTP exposure, rapid symptom onset and short symptom duration prior to initiation of levodopa therapy developed dyskinesia between 11 and 24 days of daily levodopa administration. In contrast, monkeys with long-term MPTP exposure, slow symptom progression and/or long symptom duration prior to initiation of levodopa therapy were more resistant to developing LIDs (e.g., dyskinesia developed no sooner than 146 days of chronic levodopa administration). All animals were similarly symptomatic at the start of levodopa treatment and had similar therapeutic responses to the drug. These data suggest distinct differences in the propensity to develop LIDs in monkeys with different rates of symptom progression or symptom durations prior to levodopa and demonstrate the value of these models for further studying the pathophysiology of LIDs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Concentration-response relationship of levodopa in patients at different stages of Parkinson's disease.

OBJECTIVE: To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment. METHODS: We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life). RESULTS: The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05). CONCLUSIONS: The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.

Aged↗
PubMed2001

Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study.

BACKGROUND: Functional disability is generally caused by hemiplegia after stroke. Physiotherapy used to be the only way of improving motor function in such patients. However, administration of amphetamines in addition to exercise improves motor recovery in animals, probably by increasing the concentration of norepinephrine in the central nervous system. Our aim was to ascertain whether levodopa could enhance the efficacy of physiotherapy after hemiplegia. METHODS: We did a prospective, randomised, placebo-controlled, double-blind study in which we enrolled 53 primary stroke patients. For the first 3 weeks patients received single doses of levodopa 100 mg or placebo daily in combination with physiotherapy. For the second 3 weeks patients had only physiotherapy. We quantitatively assessed motor function every week with Rivermead motor assessment (RMA). FINDINGS: Six patients were excluded from analyses because of non-neurological complications. Motor recovery was significantly improved after 3 weeks of drug intervention in those on levodopa (RMA improved by 6.4 points) compared with placebo (4.1), and the result was independent of initial degree of impairment (p<0.004). The advantage of the levodopa group was maintained at study endpoint 3 weeks after levodopa was stopped. At the end of the study the total RMA score gain for the levodopa group was 8.2 points compared with 5.7 in the placebo group (p=0.020). INTERPRETATION: A single dose of levodopa is well tolerated and, when given in combination with physiotherapy, enhances motor recovery in patients with hemiplegia. In view of its minimal side-effects, levodopa will be a possible add- on during stroke rehabilitation.

Aged↗
PubMed2000

Levodopa may improve vision loss in recent-onset, nonarteritic anterior ischemic optic neuropathy.

OBJECTIVE: To study the effect of levodopa in improving visual function in patients treated within 45 days of onset of nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: Nonrandomized, retrospective, comparative trial. PARTICIPANTS: The study involved 37 patients with NAION of less than 45 days duration. METHODS: Eighteen patients who had been treated with levodopa were assigned to the case group, and 19 untreated patients were assigned to the control group. Snellen visual acuity converted to logMAR and mean deviation on Humphrey automated perimetry (Program 24-2, Humphrey Instruments, San Leardro, CA) were evaluated at the initial and 6-month visits. INTERVENTION: The 18 patients in the case group were administered a capsule of 100 mg levodopa/25 mg carbidopa (Sinemet 25-100) three times daily for 3 weeks. MAIN OUTCOME MEASURES: The primary outcome measures were changes in visual acuity and visual field at 6 months from baseline. Improvement in visual acuity was defined as a difference of -0.3 logMAR or less between the 6-month and initial visual acuities, whereas worsened visual acuity was a difference of +0.3 logMAR or more. Each 0.3 LogMar represented a doubling of the visual angle, i.e., a change by three lines on the eye chart. Improvement in visual field was defined as a difference in mean deviation of +3.0 dB or more between the 6-month and initial visual field tests, whereas worsened visual field was a difference in mean deviation of -3.0 dB or less. RESULTS: The proportions of patients with worsened, unchanged, and improved visual acuity at 6 months were compared for the levodopa and control groups. There was a significant difference (P = 0.012) between the groups. Examination of the proportions showed that a higher proportion of patients who received levodopa had improved visual acuity with a corresponding lower proportion having worsened visual acuity as compared with the control patients. Ten of 13 patients (76.9%) in the levodopa group with 20/40 visual acuity or worse at baseline had improved visual acuity at 6 months, and none of the 18 patients had worsened visual acuity. In contrast, 3 of 10 control patients (30%) with 20/40 visual acuity or worse at baseline had improved visual acuity at 6 months, and 3 of 19 control patients (16.3%) had worsened visual acuity. The proportions of patients with worsened, unchanged, and improved visual fields at 6 months were compared for the levodopa and control groups. There was no significant difference between the groups (P = 0.25). CONCLUSIONS: Patients treated with levodopa within 45 days of onset of NAION were more likely to experience improvement and less likely to have worsened visual acuity than untreated patients. Levodopa appears to be beneficial in the treatment of recent-onset NAION.

Aged↗
PubMed2003

Rapid intravenous loading of levodopa for human research: clinical results.

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).

Adult↗