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PubMedDate not supplied

Concentration-effect relationship of levodopa-benserazide dispersible formulation versus standard form in the treatment of complicated motor response fluctuations in Parkinson's disease.

We compared the kinetic-dynamic profile of a postprandial dose of levodopa-benserazide dispersible formulation to that of the standard form in eight patients with parkinsonism presenting delayed or irregular patterns of after-meal levodopa dose effects. Patients were studied on two occasions, one week apart, according to an intra-subject randomized cross-over design. Thirty minutes after the consumption of a standard meal, patients received their usual levodopa-benserazide postprandial dose, on one occasion in the standard formulation and on the other one in the dispersible form. Blood venous samples for analysis of plasma levodopa concentrations were drawn at 15-minute intervals for the first 2 hours, then half-hourly until 5 hours after dosing. Motor response to the levodopa test dose was assessed by the finger tapping test at the same times as blood was sampled. The only statistically significant finding was a shorter time to peak plasma levodopa concentration with the levodopa-benserazide dispersible formulation compared with the standard form, whereas comparisons of levodopa pharmacodynamics showed little advantage of either formulation. Considering that liquid formulations of levodopa are less practical, we suggest reserving dispersible levodopa-benserazide tablets for selected patients and carefully monitoring drug dose motor response.

Aged↗
PubMed2000

Monitoring of the levodopa concentration-response relationship in Parkinson's disease.

Motor fluctuations and abnormal involuntary movements are common complications encountered in advanced Parkinson's disease (PD) patients with long-term levodopa therapy. Monitoring of plasma levodopa concentrations and clinical effects has been reported to benefit the management of these complications. However, to our knowledge, there is no data available in Taiwan concerning the correlation between the plasma levodopa levels and motor fluctuations. In this study, we developed the laboratory methodology for plasma levodopa determination by using the aluminum extraction procedure and HPLC-ED. Serial blood samples and motor scores were obtained from 7 PD patients, and the correlation between plasma levodopa levels and motor responses were studied individually. In three patients with wearing-off phenomenon, plasma levodopa concentrations are compatible with the clinical "on" and "off" states. In the other four patients with complex fluctuating responses, their levodopa dosages were adjusted by the results of monitoring. Better motor responses were achieved by optimization of the levodopa pharmacokinetics in these patients. Our preliminary data suggest that simultaneous monitoring of plasma levodopa concentrations and clinical effects might be helpful to improve the therapeutic strategy in some of the parkinsonian patients with fluctuating responses to levodopa.

Adult↗
PubMedDate not supplied

Role of integrative pharmacokinetic and pharmacodynamic optimization strategy in the management of Parkinson"s disease patients experiencing motor fluctuations with levodopa.

Parkinson's disease is a progressively debilitating motor neuron disease that affects the dopaminergic neurons within the nigral-striatal and surrounding pathways and which is characterized clinically by rigidity, resting tremor and bradykinesia with or without postural imbalance. Levodopa is the "gold standard" for the treatment and management of Parkinson's disease worldwide. However, following prolonged use of the drug, the "honey-moon" which was once enjoyed by patients on levodopa begins to wane. The clinical as well as the socio-economic costs associated with such failure in response to levodopa is enormous. Various approaches in the management of Parkinson's disease patients experiencing motor fluctuations with levodopa treatment have been suggested and include both pharmacologic and non-pharmacologic strategies involving invasive surgical intervention. Currently, the non-pharmacological approach, which is invasive, remains to be fully perfected and is associated with high morbidity and mortality. The use of the non-invasive, pharmacological approach is currently the most widely accepted approach but would require a review of all possible drug regimens used. This entails evaluating the pharmacokinetics and pharmacodynamic actions of the drug regimens used and possibly, dosage form and route of administration of the drugs. The use of levodopa formulated for transdermal or intranasal administration might help improve the ease of use and compliance. Controversy abounds as to the role of plasma pharmacokinetics of levodopa in the management of Parkinson's patients, vis a vis its dynamics at the central nerve terminal and its receptor site. However, it is worthy of mention that an integrated optimal pharmacological approach involving the peripheral, and central pharmacokinetics of levodopa as well as its central pharmacodynamics would ensure better treatment and management of this disease. In addition, the choice of alternate formulations and routes of administration will not only improve on the bioavailability and overall pharmacokinetics of levodopa, but also increase compliance. Furthermore, monitoring of both plasma and central concentrations of levodopa and its metabolites might play a major role in individualization of pharmacotherapy in special Parkinsonian patients experiencing motor fluctuations with levodopa.

Antiparkinson Agents↗
PubMed1998

Long-term follow-up of levodopa responsiveness in generalized dystonia.

OBJECTIVES: To assign an accurate diagnosis to patients with dystonia based on the presence of sustained levodopa responsiveness and to determine whether motor fluctuations occur in patients with dystonia who are withheld from levodopa. PATIENTS AND METHODS: Patients with generalized dystonia who responded to treatment in the 1970s with levodopa/carbidopa were surveyed by phone and then examined during a 3-day levodopa holiday. Functional imaging with fluorodopa positron emission tomography was performed on a subset of patients. RESULTS: In the phone interview, 4 of 7 patients with a diagnosis of dopa-responsive dystonia reported the wearing-off effect a short while (within 4-8 hours) after missing a dose of levodopa. Five patients with dopa-responsive dystonia were examined repetitively during levodopa withdrawal, and 3 developed recurrent symptoms of dystonia as the drug was withheld. In each case, worsening of dystonia did not occur until 29 hours or more after levodopa withdrawal, providing evidence for a response profile similar to the long duration response described in Parkinson disease. No significant changes were seen in the dystonia scores of the 3 patients with idiopathic torsion dystonia who were withheld from levodopa. CONCLUSIONS: We suggest that the subjective feeling of wearing off experienced by our patients with dopa-responsive dystonia may have been for one of the nonmotor effects of levodopa, such as mood elevation. Our data provide objective evidence for the often-repeated assertion that motor fluctuations (analogous to those in levodopa-treated patients with Parkinson disease) do not occur in patients with dopa-responsive dystonia.

Antiparkinson Agents↗
PubMed2003

Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease.

BACKGROUND: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels. OBJECTIVES: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia. DESIGN/METHODS: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test. RESULTS: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-naïve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04). CONCLUSIONS: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.

Aged↗
PubMed2006

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Adult↗
PubMed1992

Kinetic-dynamic relationship of oral levodopa: possible biphasic response after sequential doses in Parkinson's disease.

The potential difference in the concentration-effect relationship of oral sequential doses of levodopa was explored in six Parkinsonian patients with complex fluctuating response. These patients showed "wearing-off phenomena" characterized by a transient worsening of motor function at the end of the first morning dose response to below baseline values and complained of a progressive reduction of levodopa effect during the day. A first standard levodopa dose was given in the morning, after an overnight fast and levodopa withdrawal. A second equal levodopa dose was administered immediately at the end of the first dose deterioration phase. Postimprovement worsening of motor response was also observed after the second levodopa dose in all patients. No significant difference in the pharmacokinetics of levodopa or in duration or magnitude of motor response could be appreciated between the two doses. These results further support the suggestion that, under controlled dietary conditions, plasma levodopa levels and effects relationship is reproducible between doses. Moreover, even when transient deterioration of motor function occurs between levodopa doses, the central dopaminergic system appears to remain responsive to the drug.

Adult↗
PubMed1997

The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: an interim analysis of a Norwegian--Danish 5-year study. Norwegian-Danish Study Group.

In this study, we investigated the effects of selegiline on levodopa treatment and parkinsonian disability over several years of treatment in patients with early Parkinson's disease (PD). The 163 patients were randomized to receive either selegiline or placebo in addition to levodopa in a double-blind, parallel-group study design, and the patients were to be followed up until a defined termination point or for 5 years. All patients had previously either never (two thirds) or for < 6 months (one third) received levodopa. After 1 year of treatment or at withdrawal from study or both, the patients were divided according to specified diagnostic criteria into groups of definite, probable, possible, or unlikely PD. The efficacy parameters were levodopa therapy, Unified Parkinson's Disease Rating Scale (UPDRS) with subscales, and the time to develop wearing-off fluctuations or reaching the termination point. Evaluation of efficacy was performed for all patients with PD and for patients with a definite and probable disease. The results of this study are based on an interim analysis when 80% of the 163 randomized patients had been followed up for > or = 3 years. Nine patients were excluded from the study because of protocol violations or because the patients were diagnosed as unlikely PD. At the time of interim analysis, 39 patients had been withdrawn from the study because of adverse effects or their own wish. Eighteen patients had reached the termination point, and 97 patients (observation time, 30-54 months) were still in the study. Among the patients receiving selegiline, we found a rather stable daily levodopa dose during 54 months of therapy, compared with an anticipated increase among patients with levodopa monotherapy. Concurrently, patients in the selegiline group showed a trend to develop less severe parkinsonian disability and a lower frequency of motor fluctuations and need for additional antiparkinsonian medication. The results of this study indicate that early combination therapy of selegiline and levodopa compared with levodopa monotherapy has an increasingly favorable impact on the long-term daily levodopa dose and may possibly delay the development of disability in PD.

Adult↗
PubMed1991

Chronic levodopa impairs the recovery of dopamine agonist-induced rotational behavior following neural grafting.

The effect of chronic levodopa treatment on the function of embryonic mesencephalic tissue grafts was assessed in rats by monitoring rotational behavior elicited by dopamine (DA) agonists before and after neural grafting. Rats were given unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway and baseline measures of rotational behavior induced by D1 receptor stimulation, D2 receptor stimulation, or amphetamine were determined. Subsequently, DA grafts were implanted into the lesioned striatum and chronic regimens of either saline or levodopa began one day after neural grafting and were continued for 7 weeks. Rotational behavior elicited by the D1 agonist, SKF 38393, was completely attenuated throughout the six-week-period following the commencement of levodopa treatment, regardless of the absence or presence of a DA graft. Conversely, rotational behavior elicited by the D2 agonist, quinpirole, was significantly elevated in ungrafted animals receiving chronic levodopa. Grafted animals receiving chronic levodopa did not show a significant reduction in rotational behavior, whereas grafted animals receiving chronic saline showed a significant 67% reduction in quinpirole-induced rotational behavior. Amphetamine-induced rotational behavior was reduced in both levodopa and saline treated grafted animals, however grafted animals receiving chronic levodopa treatment showed a reduction of rotational behavior that was uncharacteristic and less compensatory than that observed in grafted animals receiving chronic saline treatment. Morphology of grafts indicate that there were areas of impaired neurite outgrowth of TH-positive fibers in animals treated with levodopa. The results of the present study suggest that the impaired recovery in quinpirole- and amphetamine-induced rotational behavior in grafted animals receiving chronic levodopa treatment may be related to (1) impaired graft function, (2) an alteration in pre- and postsynaptic mechanisms in the host DAergic system, or (3) a combined effect of (1) and (2).

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Levodopa-induced dyskinesia: clinical observations.

In 144 patients receiving prolonged treatment with levodopa for Parkinson's disease, an attempt was made to establish possible correlations between the incidence of levodopa-induced dyskinesias and the age of the patient at the onset of the disease, the clinical form of the disease, the duration of symptoms before initiation of the levodopa therapy, the duration of the levodopa therapy and the influence of the concomitant treatment. Levodopa-induced dyskinesia was observed in 92 patients (64%). The age at onset of the disease of patients with dyskinesia was significantly different from the age at onset of those without dyskinesia, the means being 54.8 and 68.9 years respectively. Levodopa-induced dyskinesia occurred less often in the group with preponderant tremor than in those with preponderant bradykinesia (29% vs. 69%). The patients treated with levodopa from the very beginning of their disease were less susceptible to dyskinesia than those who had parkinsonism for some time before receiving levodopa. The influence of the duration of levodopa treatment on the manifestation of dyskinesia could not be confirmed because this side-effect usually appeared during the first year of treatment. The concomitant anti-parkinsonian treatment appeared to have no influence on the incidence of dyskinesia. Biochemical and practical implications of these observations are discussed.

Adult↗
PubMed1991

Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa.

The clinical effects and pharmacokinetics of orally and intraduodenally administered levodopa, in four patients with Parkinson's disease have been compared. The patients had unpredictable fluctuations in motor function and episodic unresponsiveness to single doses of levodopa. The pharmacokinetic and clinical data of these patients were compared retrospectively with those of Parkinsonian patients with fluctuations in motor performance but with preserved clinical responses to single oral doses of levodopa. There was a threshold plasma concentration of levodopa associated with the "switch on or off" effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response. All the patients had delayed absorption of levodopa related to delayed and erratic gastric emptying, which contributed to the fluctuation in motor response. In contrast, the patients with fluctuating motor effects but a preserved clinical response after levodopa showed an absorption pattern comparable to that of four patients studied after duodenal delivery of levodopa. It is suggested that there is a subgroup of patients with fluctuating responses due mainly to altered peripheral pharmacokinetics of levodopa. The findings demonstrate the relevance of routine measurements of plasma levodopa in patients with Parkinson's disease in whom there are fluctuations in motor performance.

Administration, Oral↗
PubMed1996

Chronic levodopa therapy enhances dopa absorption: contribution to wearing-off.

Effects of the chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon are re-evaluated. The concentration of plasma levodopa and clinical symptoms were determined 4 hours after oral levodopa (levodopa 100 mg + benserazide 25 mg) administration on 55 parkinsonian patients. Long-term levodopa therapy markedly increased the peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC); whereas, it decreased time to the peak concentration (Tmax) and the elimination half-life (T1/2). These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. The wearing-off group (n = 23), however, had a markedly higher Cmax and AUC, and a shorter Tmax and T1/2 than the stable group (n = 32). We speculate that the clinical expression of "stable" or "wearing-off" depends on the absorption of levodopa as well as the presynaptic terminal and post synaptic receptors.

Aged↗
PubMed2005

Importance of within subject variation in levodopa pharmacokinetics: a 4 year cohort study in Parkinson's disease.

The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson's disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72 hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V1), peripheral volume (V2), clearance (CL) and inter-compartmental clearance (CL(ic)) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V2 27.3 l/70 kg (0.27), and CL(ic) 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V1, 0.13 CL, 0.15 V(2), 0.28 CL(ic), within trial variability (WTV) which was 0.16 V1, 0.13 CL, 0.08 V2, 0.18 CL(ic) and between trial variability (BTV) which was 0.40 V1, 0.17 CL, 0.21 V2, 0.34 CL(ic.) Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.

Administration, Oral↗
PubMed2004

Neuroprotection by pergolide against levodopa-induced cytotoxicity of neural stem cells.

Neural stem cells (NSCs) are currently considered very hopeful candidates for cell replacement therapy in neurodegenerative pathologies such as Parkinson's disease (PD), but like embryonic neural tissue transplantation, levodopa medication may still be required to improve symptoms even after cell transplantation. The issues of whether levodopa induces cytotoxicity and apoptosis of NSCs following transplantation, as well as the means to prevent these processes from occurring remain to be elucidated. In this study, the possible cytotoxicity of levodopa at different doses on C17.2 neural stem cells and subsequent neuroprotection by pergolide were investigated. The cell viability was determined by the MTT assay. Cell proliferation was assayed by BrdU labeling, while apoptosis was detected by Annexin-V-FLUOS staining and flow cytometry. Levels of p53, Bax, Bcl-2, NFkB, cytochrome c, caspase-3 as well as cleavage of caspase-3 were measured by western blotting. We found levodopa induced a concentration- and time-dependent decrease in cell viability and proliferation. Apoptotic cells were observed at different stages, specifically 12 and 24 h following exposure to levodopa (200 microM). Elevated p53, Bax, cytochrome c, caspase-3 and active fragments of caspase-3 protein were observed in the cells exposed to levodopa. These alterations were partly inhibited by pergolide, a dopamine receptor agonist, while Bcl-2 and NFkB p65 levels remained constant at the various time-points in all the groups examined. These observations indicate that levodopa at high concentrations (> or = 200 microM) was neurotoxic to C17.2 neural stem cells via inhibition of DNA synthesis and cell proliferation. Activation of the mitochondria-dependent pathway and caspase-3 protease may contribute to the mechanism by which levodopa induces apoptosis. Pergolide, an anti-Parkinson drug, has a neuroprotective effect and partly blocks levodopa-induced cytotoxicity.

Animals↗
PubMed1994

The effects of chronic continuous versus intermittent levodopa treatments on striatal and extrastriatal D1 and D2 dopamine receptors and dopamine uptake sites in the 6-hydroxydopamine lesioned rat--an autoradiographic study.

The effects of chronic 'continuous' infusion and 'intermittent' modes of levodopa/carbidopa administration on apomorphine induced circling behaviour, DA uptake sites (labelled with [3H]mazindol) and D1 and D2 DA receptor binding (labelled with [3H]SCH 23390 and [3H]sulpiride, respectively) were investigated in rats with unilateral 6-OHDA lesions of the medial forebrain bundle. The circling behaviour in response to apomorphine was greatly enhanced following chronic 'intermittent' but not 'continuous' levodopa treatments. Following the 'intermittent' regime, the lower dose of apomorphine induced a period of intense circling with delayed onset and rapid offset, than in rats given either 'continuous' infusion of levodopa or saline. The 6-OHDA lesion itself induced gross depletion of [3H]mazindol binding in all striatal subregions, NAc and OT, but not frontal cortex. [3H]Sulpiride binding in the ventrolateral striatal quadrant was increased on the denervated side and this correlated with the peak contralateral turns in response to 0.5 mg/kg apomorphine challenge. This asymmetry in striatal [3H]sulpiride binding was reduced in both groups of rats receiving levodopa. [3H]sulpiride binding in the NAc and OT and [3H]SCH 23390 binding in the striatum, NAc, OT and SNr were unaffected by DA denervation or either regime of levodopa treatments. 'Continuous' infusion and not 'intermittent' injections of levodopa reduced [3H]mazindol binding in the striatal subregions and the frontal cortex on both the denervated and intact sides. The potentiation of the behavioural response to apomorphine by chronic 'intermittent' levodopa treatment does not correspond with the levodopa induced alterations in striatal or extrastriatal DA receptors. In the same group of animals the narrowing of the duration of response to the lower dose of apomorphine may mimic the fluctuations in response to levodopa, seen clinically in long-term levodopa treated parkinsonian patients.

Animals↗
PubMed1994

Excitatory amino acid receptor antagonists modify regional cerebral metabolic responses to levodopa in 6-hydroxydopamine-lesioned rats.

Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.v.) and the N-methyl-D-aspartate antagonist MK-801 (0.1 mg/kg, i.v.) on cerebral metabolic responses to levodopa (25 mg/kg, i.v., with 12.5 mg/kg benserazide) in rats with a unilateral nigrostriatal pathway lesion. Levodopa increased glucose utilization ipsilateral to the lesion in substantia nigra pars reticula (up to 104%), entopeduncular nucleus (up 90%) and subthalamic nucleus (up 30%), indicating that levodopa alters striatal output through the striatonigral, striatoentopeduncular and striatopallidal pathways. Levodopa also decreased metabolic rate in lateral habenula (down 39%), a target of projections from entopeduncular nucleus, implying a reduction in basal ganglia output. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 by themselves did not affect glucose utilization in any of these regions. Pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline reduced the effect of levodopa in substantia nigra pars reticulata but not in entopeduncular nucleus or subthalamic nucleus, while MK-801 attenuated the effect of levodopa in all three of these structures; neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 altered the effect of levodopa in lateral habenula. When given at the same doses to a separate group of lesioned animals, neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 affected rotational behavior elicited by levodopa. These findings indicate that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate receptor antagonists differentially modify dopamine receptor-mediated striatal output. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor blockade may preferentially attenuate the effect of dopamine receptor activation on the striatonigral pathway, while N-methyl-D-aspartate blockade appears to reduce the actions of dopamine on the striatonigral, striatoentopeduncular and striatopallidal pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats.

The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of "wearing-off" phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines "wearing-off" motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.

Animals↗
PubMed1996

Effect of levodopa and carbidopa on recovery of visual function in patients with nonarteritic anterior ischemic optic neuropathy of longer than six months' duration.

PURPOSE: We conducted a pilot clinical trial to determine the efficacy of levodopa in promoting visual recovery in eyes with nonarteritic anterior ischemic optic neuropathy of greater than six months' duration. METHODS: This prospective, randomized, double-masked, placebo-controlled clinical trial involved 20 subjects with nonarteritic anterior ischemic optic neuropathy of 30 months' mean duration. Subjects were randomly assigned to receive either low-dose levodopa and carbidopa or a placebo for three weeks. At 12 weeks after the baseline visit, the levodopa group then was provided a higher, conventional dose of levodopa and carbidopa for three more weeks. Change in visual function was monitored at four, 12, 16, and 24 weeks after the baseline visit. RESULTS: At 12 weeks after the baseline visit, the levodopa group experienced a significant (P = .016) mean difference in improvement of visual acuity of 5.9 letters from the placebo group. At 24 weeks after the baseline visit, a significant treatment effect (P = .036) for visual acuity was still evident; the levodopa group had a mean gain in improvement of 7.5 letters difference from baseline from the placebo group. Three subjects in the levodopa group experienced a doubling of the visual angle as denoted by a gain of at least 15 letters. Significant improvement was not observed for color vision (P = .82) or mean deviation of visual field loss (P = .82). CONCLUSION: The study found significant improvement of visual acuity among subjects receiving levodopa and carbidopa despite long-standing visual loss from nonarteritic anterior ischemic neuropathy. Confirmation of our results is awaited from larger population studies and with a longer follow-up time interval regarding the efficacy of levodopa in reversing visual loss in this disease.

Aged↗