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PubMed2002

Response to levodopa in parkinsonian patients with bilateral subthalamic nucleus stimulation.

The response to levodopa changes over time in Parkinson's disease, probably due to alterations in the dopaminergic system, progression of the disease and pulsatile oral intake of the drug. Bilateral high-frequency stimulation of the subthalamic nucleus (STN) allows a large reduction or the complete cessation of levodopa intake in patients with advanced Parkinson's disease. We studied variation in the motor short-duration response (SDR) during a levodopa challenge in bilaterally STN-stimulated patients. Twenty-eight consecutive patients with a mean duration of Parkinson's disease of 16.6 +/- 6.0 years at the time of surgery were enrolled. Fourteen patients were evaluated both before STN stimulation and 3 months after surgery (group 1) whereas the other 14 patients were assessed before implantation and after a mean of 3 years of STN stimulation (group 2). After drug withdrawal for one night, the hand-tapping test (TT) was carried out every 15 min, together with evaluation of dyskinesias using a modified Goetz scale. The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was assessed every 30 min. In operated patients, STN stimulation was stopped 15 min before starting the clinical evaluations. A suprathreshold oral levodopa dose was given after one motor evaluation and two TTs. The clinical evaluation was carried out until the TT score returned to the baseline. In group 1, six patients continued without levodopa after surgery and the other eight received a daily mean dose of 337 mg; in group 2, seven patients continued without levodopa and the other seven received a daily mean dose of 386 mg. The main change in the levodopa SDR was a significant reduction in levodopa-induced dyskinesias in both groups. In those patients of group 1 who did not receive levodopa after surgery, the motor UPDRS magnitude decreased and the 'on' UPDRS motor score worsened. In group 2, the results were similar, but in the patients who continued to receive levodopa after surgery the TT magnitude increased. On the whole, chronic bilateral STN stimulation tended to decrease the magnitude of the levodopa SDR without changing the duration and latency of the response. These results suggest that continuous STN stimulation induces long-term plastic changes of the dopaminergic system, with slow and partial desensitization. In addition, the persistence of levodopa intake after surgery might hinder this beneficial process.

Adult↗

PubMedDate not supplied

Levodopa intake increases plasma levels of S-adenosylmethionine in treated patients with Parkinson disease.

Metabolism of levodopa via the enzyme catechol-O-methyltransferase requires S-adenosylmethionine (SAM) as a methyl donor. SAM caused Parkinson disease (PD)-like symptoms in rodents. Therefore, SAM could contribute to a decreased efficacy of levodopa in the long term. SAM levels were significantly reduced in levodopa-treated PD patients, but they showed increased enzyme methionine adenosyl transferase (MAT) activity, which induces SAM synthesis from methionine (MET). This may result from a rebound increase of SAM production. The objective of the study was to demonstrate an effect of acute levodopa intake on SAM synthesis in the plasma of treated PD patients. The authors measured SAM, MET, and levodopa plasma concentrations in 13 levodopa-treated PD patients before and after application of 125 mg levodopa/benserazide. Plasma levels of SAM and levodopa significantly increased, but MET concentrations did not significantly decrease. The SAM increase after levodopa intake may exert both a certain antidepressant and cognitive function improving effect. This is often observed in untreated PD patients who receive levodopa for the first time, or in more advanced, fluctuating PD patients, when they turn from the OFF to the ON phase. Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.

Administration, Oral↗

PubMed1999

Treating and preventing levodopa-induced dyskinesias: current and future strategies.

Prevention of levodopa-induced dyskinesias is a therapeutic challenge for physicians. At present, it seems only possible to delay dyskinesias and motor fluctuations. In younger patients (aged <50 years), the strategy is to use a dopamine D2 agonist as monotherapy and then to add levodopa treatment when the parkinsonian symptoms progress. In older patients, (aged >50 years to <70 years), the therapeutic approach is to use early combination therapy of levodopa and a D2 agonist. The treatment of levodopa-induced dyskinesias must be considered in regard to the subtype and the severity of dyskinesias, and the patient. The general approach to the treatment of peak dose dyskinesias is to maintain dopamine brain stimulation at as stable a level as possible by keeping plasma and brain levodopa concentrations in the therapeutic range (above the therapeutic threshold but below the dyskinesia threshold). An appropriate strategy is to reduce the individual dose of levodopa, to spread out the daily levodopa dose and/or to try treatment with the sustained-release form of the drug. Combination treatment with the standard and sustained-release levodopa formulations is also possible. Stopping selegiline (deprenyl) therapy may reduce dyskinesias; reducing the dose of, or stopping treatment with, a dopamine agonist may also be beneficial. Anti-dyskinetic drugs such as amantadine, buspirone, fluoxetine, propanolol and principally clozapine may be used. In severe dyskinesias, apomorphine infusion may be tried. In refractory dyskinesia, surgical procedures such as pallidotomy and chronic deep brain stimulation (globus pallidus/subthalamic nucleus) may be proposed. Theoretically, treatment of diphasic dyskinesias requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold. However, this approach leads to constant and severe dyskinesia after only a few weeks of treatment. Thus, the strategy used to treat diphasic dyskinesia is close to the treatment of peak-dose dyskinesias. Apomorphine (or the liquid form of levodopa) may be helpful to prevent diphasic dyskinesias. In selected patients, a midday rest in the 'off' phase may decrease the duration of dyskinesia. Treatment of early morning dystonia is based on the addition to the regimen of the sustained release formulation of levodopa before bedtime. Liquid levodopa and apomorphine injection may be used just before the appearance of the dystonic posture. Botulinum toxin may be helpful in severe dystonia.

Clinical Trials as Topic↗

PubMed2002

[Effect of bushen yanggan recipe on nigrostriatal function in parkinsonian model rats after long-term levodopa treatment].

OBJECTIVE: To investigate the effect of Bushen Yanggan Recipe (BSYGR) on the function and morphology of nigrostriatal system in Parkinsonian model rats with long-term levodopa treatment. METHODS: Unilateral Parkinsonian rat models were established by injecting 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNpc) and ventral segmental area (VTA). Animals were randomly divided into four groups, the sham control group, model control group, levodopa group and levodopa plus BSYGR group. The content of striatal dopa (DA), digydroxy-phenyl acetic acid (DOPAC) and homovanilic acid (HVA) or the THmRNA expression level in the midbrain were measured. RESULTS: (1) Levels of striatal DA, DOPAC, HVA, DOPAC/DA, HVA/DA decreased in the model control group by about 90% as compared with those in sham control group (P < 0.05). These parameters in the levodopa group were higher than those in the sham control group, while in the levodopa plus BSYGR group, they were lower than those in the levodopa group (P < 0.01), approaching the levels in the sham control group (P > 0.05). (2) Striatal TH activity in the model group was lower than that in the sham control group significantly, but higher than that in the levodopa group, while in the levodopa plus BSYGR group, it showed a level obviously higher than that in the levodopa group (P < 0.05). (3) Levodopa plus BSYGR group had a higher midbrain THmRNA expression level than that in the levodopa group. CONCLUSION: BSYGR could effectively reduce the side effects resulting from the long-term treatment of levodopa.

Animals↗

PubMed2005

Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect.

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.

Antiparkinson Agents↗

PubMed1995

Does treatment with dopamine agonists affect utilization of exogenous levodopa in the parkinsonian striatum?

When the nigrostriatal projection is partially destroyed in Parkinson's disease, remaining neurons fire more rapidly and accelerate synthesis and release of dopamine (DA) from endogenous tyrosine and levodopa. It was suggested that such surviving hyperactive nigral neurons can also enhance the utilization of exogenous levodopa and generate adequate amounts of functional dopamine molecules to correct the reduced nigrostriatal neurotransmission. DA agonists stimulate presynaptic DA receptors and suppress nigrostriatal firing rates. Many parkinsonians are treated with a combination of DA agonists and levodopa. This could theoretically suppress both discharge of surviving dopaminergic neurons and their ability to convert exogenous levodopa to dopamine. To test this possibility, rats were injected i.p. with lisuride, bromocriptine or apomorphine alone or one hour after levodopa and decapitated one hour later. The DA agonists suppressed striatal DOPAC and DOPAC/DA ratios indicating attenuation of basic DA turnover. DA agonists given with levodopa did not decrease the levodopa-induced elevations in striatal levodopa, DA and DOPAC. Findings suggest that agonists do not affect entry of levodopa from the circulation into brain and do not alter striatal generation of DA from exogenous levodopa despite inhibition of nigrostriatal firing. Therefore, utilization of levodopa does not seem to depend on the state of discharge rates of nigral neurons and effect of levodopa and DA agonists in Parkinson's disease is additive.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Long-duration response to levodopa in patients with advanced Parkinson disease treated with subthalamic deep brain stimulation.

BACKGROUND: Long-duration response (LDR) to levodopa is supposed to decrease with Parkinson disease (PD) progression, but direct observation of this response in advanced PD has never been performed. OBJECTIVE: To study the LDR to levodopa in patients with advanced PD treated with subthalamic deep brain stimulation (DBS). DESIGN AND SETTING: We studied 30 consecutive patients with PD who underwent subthalamic DBS. One group had no antiparkinsonian treatment since surgery (no-levodopa group), whereas medical treatment had to be reinitiated in the other group (levodopa group). MAIN OUTCOME MEASURE: Motor subscale score of the Unified Parkinson's Disease Rating Scale. RESULTS: Compared with preoperative assessment, evaluation 6 months postoperatively with DBS turned off for 3 hours found a worsening of the motor subscale score of the Unified Parkinson's Disease Rating Scale in the no-levodopa group. This worsening being absent in the levodopa group, it probably reflected the loss of the LDR to levodopa in the no-levodopa group. When DBS was turned on, postoperative motor subscale scores of the Unifid Parkinson's Disease Rating Scale in both groups were similar to preoperative scores while receiving medication, suggesting that subthalamic DBS compensated for the short-duration response and LDR to levodopa. CONCLUSIONS: Our results suggest that the LDR to levodopa remains significant even in advanced PD, and that subthalamic DBS compensates for the short-duration response and LDR to levodopa.

Aged↗

PubMed2000

The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa.

The aim of our study was to evaluate the influence of low-intensity exercise on levodopa absorption and levodopa motor effect. We studied the pharmacokinetics and pharmacodynamics of levodopa under resting conditions and under a workload of 50 watts for 2 hours on a cycle ergometer in 12 parkinsonian patients with predictable fluctuations of motor disability. The patients attended the hospital on both days in a provoked off state. After a baseline assessment of motor disability using the Columbia University rating scale (CURS scale) and a blood test for measurement of the baseline levodopa concentration in the plasma, 100 mg levodopa and 25 mg benserazide were administered as a single dose orally. Blood samples for measurement of the levodopa concentration in the plasma were taken, and motor assessments were conducted at 15-minute intervals for 240 minutes and at 30-minute intervals from 240 to 360 minutes. All patients were able to perform the exercise program. The baseline Columbia University rating scale score did not differ significantly between both days. The mean levodopa concentration in plasma at half-maximal motor effect tended to be higher during exercise and indicated that the patients needed a higher levodopa concentration in plasma to achieve the half-maximal motor effect. The maximal levodopa concentration in plasma tended to be higher with exercise. Both trends did not reach statistical significance. In summary, there was not a negative or a positive net effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. However, there were two counteracting trends: a trend toward better levodopa absorption and a trend toward a deteriorated concentration-effect correlation.

Administration, Oral↗

PubMed1991

Benefits of monitoring plasma levodopa in Parkinson's disease patients with drug-induced chorea.

We studied the temporal patterns of chorea and plasma levodopa profiles in 30 patients with Parkinson's disease whose motor fluctuations were difficult to characterize and treat on the basis of observation alone. We were able to determine whether chorea was associated with high levodopa concentrations or low levodopa concentrations or both. We found the following patterns of levodopa-associated chorea: chorea due to inadequate levodopa levels, chorea due to biphasic levodopa absorption, chorea associated with either rapid or slow levodopa absorption, and chorea due to long-duration levodopa absorption mimicking a sustained-release preparation. Seven patients benefited after their dosing schedules were rearranged as a result of information gained from monitoring. We conclude that any patient with levodopa-associated chorea who cannot be regulated on the basis of observation alone should be studied with simultaneous plasma levodopa measurements and clinical monitoring to detect an unusual plasma levodopa pattern that may be improved by adjustment of dosing schedule.

Chorea↗

PubMed1995

The subacute levodopa test for evaluating long-duration response in Parkinson's disease.

The clinical relevance of a long-duration response (LDR) to levodopa therapy in Parkinson's disease (PD) has not been widely recognized. In 25 patients with moderate PD, we measured LDR on motor function after short periods of treatment with levodopa (subacute tests). Each subacute test lasted 15 days and consisted of the oral administration of levodopa at various interdose intervals (IDIs) of 48, 24, 12, 8, 6, and 5 hours. The goal for a subacute test was to achieve a satisfactory antiparkinsonian effect before the last levodopa dose (day 15), i.e., an LDR greater than 50% of the maximal response following an acute levodopa test (LDR-endpoint). Twenty-one patients (84%) reached the LDR-endpoint. The IDI at which levodopa was administered clearly differentiated patients who were otherwise clinically indistinguishable when evaluated at baseline off medication or after an acute levodopa test. The IDI schedule that produced a satisfactory LDR was specific for each patient, since longer DIs failed to produce the required LDR, and a shorter IDI schedule (resulting in larger cumulative dosage of levodopa) did not significantly enhance the response. Also, the LDR decay rate after discontinuation of treatment was individual for each patient and independent of the cumulative amount of levodopa administered. Both the IDI schedule and the LDR decay rate may reflect the ability of nigrostriatal neurons to store and to release dopamine formed from the exogenous precursor. The assessment of the LDR to levodopa by subacute tests is useful for establishing the appropriate dose of the drug, as well as for developing levodopa sparing strategies in PD patients.

Aged↗

PubMed1998

Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions.

Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.

Amphetamine↗

PubMed1992

Muscarinic cholinergic receptor-mediated modulation on striatal c-fos mRNA expression induced by levodopa in rat brain.

To clarify the interactions between dopamine receptors and muscarinic cholinergic receptors by which neurotransmitters may affect genetic responses, we studied the effects of the muscarinic cholinergic agonist, carbachol, and the muscarinic cholinergic antagonist, trihexyphenidyl, on levodopa-induced c-fos messenger RNA (mRNA) expression in rat striatum. Animals were administered levodopa (levodopa with one-tenth dosage of carbidopa), carbachol or thrihexyphenidyl alone or administered in combination as levodopa (100 mg/kg) + carbachol, or levodopa+trihexyphenidyl given as a single bolus. Levodopa given alone increase the expression of c-fos mRNA. Although carbachol or trihexyphenidyl alone was ineffective in inducing c-fos mRNA, the combination of levodopa and carbachol (> or = to 0.1 mg/kg) significantly suppressed the induction of c-fos mRNA as compared with levodopa given alone. The combined administration of levodopa and trihexyphenidyl showed a trend toward an additive effect on the induction of c-fos mRNA vs levodopa alone. These findings suggest that the muscarinic cholinergic system may modulate the levodopa-induced c-fos mRNA expression which then regulates the expression of other mRNAs.

Actins↗

PubMed1996

Sustained-release of levodopa: single dose study of a new formulation.

Motor fluctuations and dyskinesias in Parkinsonian patients may be at least partially due to fluctuations of levodopa plasma concentrations. Sustained-release (SR) formulations of levodopa may present a promising, effective solution of this problem. Therefore we performed a 4-fold, cross-over double-blind trial with a new SR preparation, tested in healthy volunteers (Gerlach et al., 1988) before, in 12 Parkinsonian subjects. Two different dosages of the pure new levodopa SR-preparation, a composition of 70% SR and 30% levodopa immediate release (IR) and a conventional IR levodopa preparation were compared by their pharmacokinetic behaviour and their clinical effects. The relative bioavailability of levodopa in plasma was 69% for the combination of SR and IR levodopa release, for the pure SR formulations (100 mg levodopa) 54% and (200 mg levodopa) 55%, compared to the 100% of the standard form of IR release of 100 mg levodopa. In contrast to the conventional IR formulation the pharmacokinetic behaviour of the SR preparations showed no initial sharp peak, but more continuous and longer maintaining plasma concentrations of levodopa. Due to the small numbers of cases and the missing homogenity of the selected patients no statistical significant differences between the four preparations regarding the clinical response were observed. But the described pharmacokinetic behaviour gives hope, that these newly developed SR-preparations may lead to progress in the treatment of Parkinson's disease (prolongation of dosage intervals, reduction of motor fluctuations).

Aged↗

PubMed1996

MK-801 prevents levodopa-induced motor response alterations in parkinsonian rats.

The systemic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) , has previously been found to reverse the motor response alterations that develop during long-term levodopa treatment of parkinsonian rats. To determine whether co-administration of MK801 with levodopa might prevent the initial appearance of these response changes, rats, rendered parkinsonian by a 6-hydroxydopamine lesion of the medial forebrain bundle, received either levodopa alone or levodopa with the NMDA receptor antagonist. After four weeks of treatment with levodopa alone, the duration of the turning response declined by 37% (P < 0.05) and the number of ineffectual levodopa injections had more than doubled (P < 0.05). MK801 co-treatment completely blocked the shortening in response duration and prevented the frequency of ineffectual levodopa injection from exceeding baseline levels in animals receiving levodopa alone. The total magnitude of the turning response to levodopa was not affected. These results suggest that NMDA receptor blockade may act prophylactically to prevent the appearance of motor response alterations in levodopa-treated parkinsonian rodents that resemble those occurring in levodopa-treated patients with Parkinson's disease.

Animals↗

PubMed2006

Cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications.

5-HT1A autoreceptor stimulation can act to attenuate supraphysiological swings in extracellular dopamine levels following long-term levodopa treatment and may be useful in the treatment and prevention of the motor complications. The purpose of this study was to investigate cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg, twice daily), intraperitoneally (i.p.) for 22 days. On day 23, animals received either 8-OH-DPAT (1 mg/kg, i.p.) or 8-OH-DPAT plus WAY-100635 (0.1 mg/kg, i.p) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg, i.p.) plus 8-OH-DPAT (1 mg/kg, i.p.) or levodopa (50 mg/kg, i.p.) plus vehicle, administered twice daily for 22 consecutive days. Our study showed that 8-OH-DPAT plus levodopa both prolonged the duration of the motor response and reduced peak turning. 8-OH-DPAT plus levodopa also decreased the frequency of failures to levodopa. Co-administration of WAY-100635, a 5-HT1A receptor antagonist, with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications indicating that the observed 8-OH-DPAT responses were probably mediated at the 5-HT1A autoreceptor. Moreover, 8-OH-DPAT plus levodopa significantly reduced hyperphosphorylation of GluR1 at serine 845, which was closely associated with levodopa-induced motor complications.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2003

Effect of acute and chronic administration of U50,488, a kappa opioid receptor agonist, in 6-OHDA-lesioned rats chronically treated with levodopa.

To evaluate the possible involvement of kappa opioid receptor-mediated mechanisms in levodopa-induced motor fluctuations, we have investigated the effects of U50,488, a selective kappa opioid agonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of U50,488 has been studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, ip) for 22 days and, on Day 23 U50,488 (0.5, 1, or 3 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and U50,488 (1 or 3 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of U50,488 on Day 23 reversed this effect when low doses were administered (P < 0.05). Chronic U50,488 administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the kappa opioid receptor agonist U50,488 reverses but does not prevents levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for kappa opioid receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the stimulation of kappa opioid receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.

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

PubMed1996

Risk factors for peak dose dyskinesia in 100 levodopa-treated parkinsonian patients.

BACKGROUND: No clinical parameter other than "sufficient" dopamine denervation and exposure to exogenous levodopa has been unquestionably linked to dyskinesia in levodopa-treated Parkinson's disease patients. METHODS: We retrospectively analyzed data on 100 consecutive patients treated with levodopa for 1 to 18 years to identify clinical risk factors for dyskinesia. The cumulative dyskinesia-free survival probability in relation to levodopa therapy was assessed using the Kaplan-Meier method. RESULTS: Overall, 56% of patients developed dyskinesia after a mean of 2.9 years, a figure similar to the average duration of levodopa treatment in the non-dyskinetic group. Dyskinetic patients were significantly younger at disease onset, but their mean latency to dyskinesia induction after levodopa initiation was not different from older dyskinetic individuals and the overall dyskinesia-free survival of younger subjects was not worse either. Dyskinetic patients were on a higher daily levodopa dose than non-dyskinetic subjects when dyskinesia emerged, but the cumulative levodopa dose used prior to dyskinesia did not discriminate dyskinetic from non-dyskinetic patients. A delay in initiating levodopa therapy of more than three years after disease onset and levodopa treatment initiation in Hoehn-Yahr stage II compared to stage I patients did not increase the probability of developing dyskinesia over time. CONCLUSIONS: Since withholding levodopa therapy did not increase the risk for dyskinesia in our patients and can delay the emergence of dyskinesia after onset of parkinsonian symptom, a trial with a dopaminomimetic agonist as initial treatment appears logical.

Adult↗

PubMed1989

Ferrous sulfate reduces levodopa bioavailability: chelation as a possible mechanism.

This study examined the effect of ferrous sulfate, a widely used iron treatment, on levodopa bioavailability in normal subjects. A 250 mg tablet of levodopa was taken with and without a 325 mg tablet of ferrous sulfate by eight normal subjects in a randomized crossover trial. When levodopa was taken with ferrous sulfate there was a 55% decrease in peak levodopa levels (3.6 +/- 2.6 vs 1.6 +/- 0.82 nmol/ml; p less than 0.05) and a 51% decrease in AUC (257 +/- 133 vs 125 +/- 51 nmol.min/ml; p less than 0.01). Persons with the highest peak levodopa levels and AUC after levodopa alone had the greatest reduction in peak levodopa levels and AUC after levodopa ingestion with ferrous sulfate. Iron in its ferrous state is oxidized rapidly to the ferric state in the presence of levodopa at pHs found in the small intestine. In the ferric state, iron binds very strongly to levodopa. Chelation of iron by levodopa is the likely mechanism for this drug interaction. The clinical significance of this interaction is yet to be established.

Adult↗