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Levodopa
Terms modified by Levodopa Selected AbstractsDirect injection horse-urine analysis for the quantification and confirmation of threshold substances for doping control.DRUG TESTING AND ANALYSIS, Issue 8 2009Abstract Levodopa and dopamine have been abused as performance-altering substances in horse racing. Urinary 3-methoxytyramine is used as an indicator of dopaminergic manipulation resulting from dopamine or levodopa administration and is prohibited with a urinary threshold of 4 µg mL,1 (free and conjugated). A simple liquid chromatographic (LC)/mass spectrometric (MS) (LCMS) method was developed and validated for the quantification and identification of 3-methoxytyramine in equine urine. Sample preparation involved enzymatic hydrolysis and protein precipitation. Hydrophilic interaction liquid chromatography (HILIC) was selected as a separation technique that allows effective retention of polar substances like 3-methoxytyramine and efficient separation from matrix compounds. Electrospray ionization (ESI) in positive mode with product ion scan mode was chosen for the detection of the analytes. Quantification of 3-methoxytyramine was performed with fragmentation at low collision energy, resulting in one product ion, while a second run at high collision energy was performed for confirmation (at least three abundant ions). Studies on matrix effects showed ion suppression depending on the horse urine used. To overcome the variability of the results originating from the matrix effects, isotopic labelled internal standard was used and linear regression calibration methodology was applied for the quantitative determination of the analyte. The tested linear range was 1,20 µg mL,1. The relative standard deviations of intra- and inter- assay analysis of 3-methoxytyramine in horse urine were lower than 4.2% and 3.2%, respectively. Overall accuracy (relative percentage error) was less than 6.2%. The method was applied to case samples, demonstrating simplicity, accuracy and selectivity. Copyright © 2009 John Wiley & Sons, Ltd. [source] Levodopa-induced ocular dyskinesia in Parkinson's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 10 2007H. Grötzsch Levodopa (LD)-induced dyskinesia (LID), one of the most common motor complications in advanced Parkinson's disease (PD), involve mostly the limbs, trunk and head, but unusual locations have been reported including respiratory muscles, the face and the eyes. The aim of this study was to further investigate the frequency and characteristics of LD-related abnormal involuntary eye movements (AIEMs) in PD. Thirty-two patients with advanced PD and various motor complications were evaluated and videotaped in an ON and OFF state. We found AIEMs in five patients (16%) which were present exclusively during the ON state and which completely disappeared when OFF. They consisted of repeated, stereotyped upward and/or sideways gaze deviation movements, sometimes phasic, brief and jerky, sometimes tonic and sustained for several seconds. The main direction of gaze deviation was toward the side more affected by parkinsonism. AIEMs typically paralleled limb and trunk LID and were modulated by the same facilitation and inhibitory maneuvers. We concluded that AIEMs are not uncommon in advanced PD and represent a particular topography of LID, hence the term ,ocular dyskinesia' to designate these AIEMs that seem to have a specific pattern in PD as compared with other forms of parkinsonism. [source] Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2003J. D. Schaafsma To assess the effect of levodopa on distinct freezing of gait (FOG) subtypes in patients with ,off' FOG. Nineteen patients (12 men, mean age 62.0 ± 8.4 years) with Parkinson's disease and clinically significant FOG during ,off' states were videotaped whilst walking 130 m during ,off' and ,on' states. Three independent observers characterized the type, duration, and clinical manifestations and quantified FOG by analyzing the videotapes. Their combined mean scores were used for statistical analysis. The intra-class correlation coefficient assessed inter-observer reliability. Wilcoxon and Friedman tests evaluated differences in mean frequencies of FOG characteristics. During ,off' states, FOG was elicited by turns (63%), starts (23%), walking through narrow spaces (12%) and reaching destinations (9%). These respective values were only 14, 4, 2 and 1% during ,on' states (P < 0.011). Moving forward with very small steps and leg trembling in place were the most common manifestations of FOG; total akinesia was rare. Most FOG episodes took <10 s and tended to be shorter during ,on' states. Levodopa significantly decreased FOG frequency (P < 0.0001) and the number of episodes with akinesia (P < 0.001). Distinction amongst FOG subtypes enables evaluation of distinctive therapeutic response. Levodopa helps in reducing the frequency and duration of ,off'-related FOG. [source] Brain dopaminergic modulation associated with executive function in Parkinson's disease,MOVEMENT DISORDERS, Issue 13 2009Karim Farid MD Abstract The progressive development of deficits in executive functions, including action planning, is a well-known complication of Parkinson's disease. A dysfunction of the prefrontal lobe, which is known to be involved in the control of inhibitory processes, could explain the difficulties in initiating behavior or inhibiting ongoing actions in patients with PD. The strong dopaminergic innervation of the prefrontal cortex raises questions about the putative effects of dopa therapy on this cognitive impairment. In the present study, we used fMRI to examine the functional influence of dopa therapy on neural activity during a go/no-go task in nine patients with and without levodopa treatment and in matched controls. Whereas the patient and control subjects exhibited the same performance during the go/no-go task, different patterns of brain activation were observed depending on the dopaminergic status. The drug-off state was characterized by more widely distributed brain activity, mainly in the bilateral caudate. Levodopa did not fully restore normal brain activation and induced changes in the pattern of cingulate cortex activity, which was more pronounced in the rostral part in the drug-off state and in the caudal part after levodopa intake. These results support the idea of a critical role for dopamine in the control of executive functions in patients with PD. © 2009 Movement Disorder Society [source] Homocysteine levels after acute levodopa intake in patients with Parkinson's disease,MOVEMENT DISORDERS, Issue 9 2009Thomas Müller MD Abstract Levodopa (L -dopa) administered with a dopadecarboxylase inhibitor (DDI) increases homocysteine plasma levels. This may support the onset of atherosclerosis-related disorders and neuropsychiatric complications in patients with Parkinson's disease (PD). This homocysteine elevation is considered as long-term effect of chronic L -dopa/DDI treatment. Little is known about the acute effects of L -dopa/DDI intake on homocysteine generation. The objective of this trial was to investigate the relations between L -dopa and homocysteine after acute L -dopa/DDI administration in PD patients with different L -dopa metabolism. Thirty PD patients were divided into groups with superior (I) and less (II) L -dopa absorption after standardized intake of 125 mg L -dopa/benserazide with determination of L -dopa, 3- O -methyl-dopa (3-OMD) and homocysteine in plasma at baseline, 30, 60, and 90 minutes. There was a homocysteine increase in Group I (F = 5; P = 0.005) and a moderate decrease in Group II (F = 4.27; P = 0.01). A rise of 3-OMD (F = 10.51; P < 0.0001) appeared in Group I, but not in Group II (F = 0.91; P = 0.44), accordingly L -dopa accumulation was better in Group I than in Group II. Thus, in conclusion, L -dopa metabolism is an important component for homocysteine elevation after one time L -dopa/DDI administration in PD patients. © 2009 Movement Disorder Society [source] Levodopa affects functional brain networks in parkinsonian resting tremor,MOVEMENT DISORDERS, Issue 1 2009Bettina Pollok PhD Abstract Resting tremor in idiopathic Parkinson's disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor-dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122-channel whole-head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast-acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro-cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus,premotor,motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas. © 2008 Movement Disorder Society [source] Adenosine A2A receptors, dopamine D2 receptors and their interactions in Parkinson's diseaseMOVEMENT DISORDERS, Issue 14 2007Kjell Fuxe MD Abstract Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor,receptor interactions in DA receptor containing heteromeric receptor complexes. The A2A/D2 heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A2A/D2 receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A2A antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D2 signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A2A activated adenylyl cyclase by persistent D2 activation and a compensatory up-regulation of A2A receptors in response to intermittent Levodopa treatment. An increased dominance of A2A homomers over D2 homomers and A2A/D2 heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A2A antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigro-striatal DA system. © 2007 Movement Disorder Society [source] Continuous dopaminergic stimulation: Is it the answer to the motor complications of Levodopa?MOVEMENT DISORDERS, Issue 1 2007John G. Nutt MD Abstract Continuous dopaminergic stimulation (CDS) is a treatment strategy hypothesized to avoid or reduce the motor complications of long-term levodopa therapy, motor fluctuations, and dyskinesia, by preventing or reversing sensitization induced by pulsatile dopaminergic stimulation. The CDS hypothesis is itself based on several hypotheses. First, tonic dopaminergic stimulation is physiological. Second, sensitization is undesirable and should be reversed. Third, reduction of off time and dyskinesia can be induced simultaneously. Finally, clinical studies substantiate the CDS hypothesis. The evidence for these hypotheses is reviewed, and the need for randomized clinical trials that rigorously test the CDS hypothesis is emphasized. © 2006 Movement Disorder Society [source] High dose levodopa therapy is not toxic in multiple system atrophy: Experimental evidenceMOVEMENT DISORDERS, Issue 7 2007Nadia Stefanova MD Abstract Levodopa is generally regarded the first choice therapy for parkinsonism associated with multiple system atrophy (MSA-P). However, MSA-P patients often show a poor or unsustained levodopa response which inflicts high dose therapy. This is generally attributed to progressive striatal degeneration with loss of dopamine receptors. Experimental evidence suggests that dopaminergic stimulation may accelerate the striatal disease process in MSA, possibly by pro-oxidative mechanisms. Intact nigrostriatal dopamine release augments striatal lesion size in the unilateral nigral and striatal double lesion rat model of MSA-P. Further, neuronal vulnerability to exogenous oxidative stress is increased in a transgenic MSA mouse model with oligodendroglial ,-synuclein inclusions. The aim of the present study was to analyze whether high dose levodopa delivery in the transgenic MSA model is associated with neurotoxicity exacerbated by the presence of oligodendroglial ,-synuclein inclusion pathology. Control and transgenic MSA mice underwent pulsatile treatment with either vehicle, low or high dose levodopa for a period of 1 month. Behavioral and neuropathological indices failed to show evidence for neurotoxic effects of high-dose levodopa in this ,-synuclein transgenic MSA model. These findings support the idea that high dose levodopa therapy in MSA is not detrimental to the underlying neuropathological process. © 2007 Movement Disorder Society [source] Current controversies: Levodopa in the treatment of Parkinson's diseaseMOVEMENT DISORDERS, Issue 5 2005Jagdish C. Sharma FRCP Companion letters have been published in Movement Disorders: Levodopa in the Treatment of Parkinson's Disease: Current Controversies, by Gerlach, Reichmann, and Riederer and Reply: Levodopa in the Treatment of Parkinson's Disease, by Olanow, Agid, and Mizuno. [source] Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's diseaseMOVEMENT DISORDERS, Issue 12 2004Padraig E. O'Suilleabhain MB Abstract Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) ,mol/L increased to 10.1 (3.1) ,mol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L -dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 ,mol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined. © 2004 Movement Disorder Society [source] Levodopa in the treatment of Parkinson's disease: Current controversiesMOVEMENT DISORDERS, Issue 9 2004C. Warren Olanow Abstract Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy. © 2004 Movement Disorder Society [source] Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposureMOVEMENT DISORDERS, Issue 5 2003Lance A. Smith MSc Abstract Levodopa (L -dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L -dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L -dopa with the peripheral catechol- O -methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0,7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L -dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L -dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L -dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L -dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L -dopa alone, but with no obvious change in duration of L -dopa's effect. However, combining entacapone with L -dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L -dopa alone. Importantly, increasing pulsatile exposure of brain to L -dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society [source] Metabolic changes detected in vivo by 1H MRS in the MPTP-intoxicated mouseNMR IN BIOMEDICINE, Issue 6 2010Carine Chassain Abstract We used in vivo proton (1H) Magnetic Resonance Spectroscopy (MRS) to measure the levels of the main excitatory amino acid, glutamate (Glu) and also glutamine (Gln) and GABA in the striatum and cerebral cortex in the MPTP-intoxicated mouse, a model of dopaminergic denervation, before and after dopamine (DA) replacement. The study was performed at 9.4T on control mice (n,=,8) and MPTP-intoxicated mice (n,=,8). In vivo spectra were acquired in a voxel (8,µL) centered in the striatum, and in the cortex (4.6,µL). Three days after basal MRS acquisitions new spectra were acquired in the striatum and cortex, after levodopa (200,mg.kg,1). Glu, Gln and GABA concentrations obtained in the basal state were significantly increased in the striatum of MPTP-lesioned mice (Glu: 20.2,±,0.8 vs 11.4,±,0.9,mM, p,<,0.001; Gln: 5.4,±,1.6 vs 2.0,±,0.6,mM, p,<,0.05; GABA: 3.6,±,0.8 vs 1.6,±,0.2,mM, p,<,0.05). Levodopa lowered metabolites concentrations in the striatum of MPTP-lesioned mice (Glu: 20.2,±,0.8 vs 11.2,±,0.4,mM (+ Ldopa), p,<,0.001; Gln: 5.4,±,1.6 vs 1.6,±,0.4,mM (+ Ldopa), p,<,0.05; GABA: 3.6,±,0.8 vs 1.7,±,0.4,mM (+ Ldopa), p,<,0.01). Metabolite levels in the striatum of MPTP-intoxicated mice + levodopa were not significantly different from those in the striatum of controls. No change was found in the cortex after DA denervation and after DA replacement between the two animals groups. These results strongly support a predominant change in striatal Glu synaptic activity in the cortico-striatal pathway. Acute levodopa administration reverses the increase of metabolites in the striatum. Copyright © 2010 John Wiley & Sons, Ltd. [source] Anti-parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damagePHYTOTHERAPY RESEARCH, Issue 12 2007Binu Tharakan Abstract Levodopa is considered the ,gold standard' for the treatment of Parkinson's disease. However, a serious concern is dyskinesia and motor fluctuation that occurs after several years of use. In vitro experiments have shown that in the presence of divalent copper ions, levodopa may induce intense DNA damage. Mucuna pruriens cotyledon powder (MPCP) has shown anti-parkinson and neuroprotective effects in animal models of Parkinson's disease that is superior to synthetic levodopa. In the present study two different doses of MPCP protected both plasmid DNA and genomic DNA against levodopa and divalent copper-induced DNA strand scission and damage. It exhibited chelation of divalent copper ions in a dose-dependent manner. The copper chelating property may be one of the mechanisms by which MPCP exerts its protective effects on DNA. Copyright © 2007 John Wiley & Sons, Ltd. [source] Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson diseaseANNALS OF NEUROLOGY, Issue 1 2010Cory Toth MD Objective Peripheral neuropathy (PN) is thought to be coincidental in patients with idiopathic Parkinson disease (IPD). We sought to examine the prevalence of PN in a population of IPD patients and a potential relationship to levodopa use and fasting methylmalonic acid (MMA) levels. Methods In a prospective cohort study, IPD patients randomly selected from a comprehensive database were compared to control subjects regarding the presence and severity of PN using clinical and electrophysiological measures. IPD severity was determined using the Unified Parkinson's Disease Rating Scale (UPDRS). We determined the relation of levodopa use with serum levels of cobalamin, MMA, and homocysteine (Hcy). We also explored the association between presence and severity of PN and age, duration of IPD, cumulative levodopa dosing, cobalamin, MMA, and Hcy levels. Results Fifty-eight randomly selected IPD patients were compared to 58 age- and sex-matched controls. PN was present in 55% of IPD patients and 9% of controls. Patients with IPD had greater prevalence of PN and fasting MMA/Hcy levels than controls. IPD patients with PN were older and exhibited higher UPDRS scores, fasting MMA/Hcy levels, and cumulative levodopa exposure. PN severity in IPD subjects positively correlated with both levodopa exposure and MMA levels. Interpretation IPD patients have a higher prevalence of PN than controls. Although causality is not established, levodopa exposure is associated with MMA elevation and sensorimotor neuropathy in IPD patients. Cobalamin replacement concurrent with levodopa therapy should be considered to protect against development of PN in IPD patients. ANN NEUROL 2010;67:28,36 [source] Levodopa: Faster and better word learning in normal humansANNALS OF NEUROLOGY, Issue 1 2004Stefan Knecht MD Dopamine is a potent modulator of learning and has been implicated in the encoding of stimulus salience. Repetition, however, as required for the acquisition and reacquisition of sensorimotor or cognitive skills (e.g., in aphasia therapy), decreases salience. We here tested whether increasing brain levels of dopamine during repetitive training improves learning success. Forty healthy humans took 100mg of the dopamine precursor levodopa or placebo daily for 5 days in a randomized double-blind and parallel-group design. Ninety minutes later on each day, subjects were trained on an artificial vocabulary using a high-frequency repetitive approach. Levodopa significantly enhanced the speed, overall success, and long-term retention of novel word learning in a dose-dependent manner. These findings indicate new ways to potentiate learning in a variety of domains if conventional training alone fails. [source] Early versus delayed initiation of entacapone in levodopa-treated patients with Parkinson's disease: a long-term, retrospective analysisEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2009H. Nissinen Background:, We analysed data from three clinical trials in Parkinson's disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long-term outcomes than delayed entacapone treatment. Methods:,Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to entacapone (,early-start' group) or placebo (,delayed-start' group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and entacapone treatment for up to 5 years. Results:, A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson's Disease Rating Scale Part III (motor) score of ,1.66 (95% confidence intervals [,3.01, ,0.31]) points compared with the delayed-start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early-start group. Conclusions:, These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing-off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years. [source] Pyruvate dehydrogenase deficiency presenting as dystonia in childhoodDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 10 2004R A Head MA Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense mutations in the gene for the E1, subunit (PDHA1) presented during childhood with dystonia. The first patient, a male, presented at age 4 years with dystonia affecting the lower limbs, which responded to treatment with combined carbidopa and levodopa. The second patient, a female, was first investigated at age 6 years because of a dystonic gait disorder. In both patients, the main clue to the biochemical diagnosis was a raised concentration of lactate in the cerebrospinal fluid. PDH activity was significantly reduced in cultured fibroblasts in both cases. Dystonia is a previously unrecognized major manifestation of PDH deficiency and is of particular interest as the mutations in the PDHA1 gene in these patients have both been identified previously in individuals with typical presentations of the condition. [source] Novel non-sense GCH1 mutation in a South African family diagnosed with dopa-responsive dystoniaEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2010S. Bardien Background:, Dopa-responsive dystonia (DRD), a movement disorder characterized by onset in early childhood and a dramatic response to low doses of levodopa, has been shown to be caused by a number of different mutations in the GCH1 gene. Methods:, We identified a South African family which presented with DRD in three family members. Polymerase chain reaction (PCR) primers were designed to span all six exons of GCH1 and the PCR products were screened for pathogenic mutations using direct sequencing. Results:, A novel non-sense mutation (c.233delT; p.I78fsX79) was identified in the DRD patients, which would produce a markedly truncated protein of only 78 amino acids. This mutation was also present in a number of asymptomatic family members. Conclusions:, A novel non-sense mutation in the GCH1 gene can be associated with DRD and reduced penetrance in South African patients. [source] Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weightEUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2008J. C. Sharma Purpose:, Levodopa dose per kilogram body weight is reported to be a significant factor for dyskinesia in Parkinson's disease. We have investigated this hypothesis in data from the studies comparing ropinirole versus levodopa as the initial therapy. Methods:, Data from the ropinirole versus levodopa studies 056 and REAL-PET in early Parkinson's disease were pooled and manipulated to calculate levodopa dose per kilogram body weight. Logistic regression analysis was performed to investigate significant variables for the development of dyskinesia. Only the patients on levodopa monotherapy or with ropinirole were analyzed. Results:, Analysis of levodopa therapy patients revealed that dyskinetic patients had received significantly higher absolute levodopa dose and levodopa dose per kilogram body weight. Logistic regression revealed that the most significant factor was the higher levodopa dose per kilogram body weight, P = 0.005, odds ratio 1.078, 95% CI 1.023,1.135; younger age was the second factor ,P = 0.026. Variables of gender, absolute levodopa dose, weight, disease duration and initial motor Unified Parkinson's disease rating score were not significant. Conclusion:, Higher levodopa dose per kilogram body weight is an independently significant factor for developing dyskinesia. This relationship should be considered in treatment of Parkinson's disease patients aiming to prevent and manage dyskinesia. [source] Should levodopa dose be reduced when switched to stalevo?EUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2008G. Linazasoro The addition of entacapone to levodopa-carbidopa (LC) or the switch from LC to a tablet containing levodopa,carbidopa,entacapone (LCE) improves the wearing-off phenomenon, increases the ,on' time and decreases the ,off' time, but the appearance or exacerbation of dyskinesias is the more frequent side-effect. Thus, a reduction of the total levodopa dosage would be recommended. However, this could result in a lack of efficacy against the wearing-off. We report on the results of a clinical trial conducted to determine the best way in terms of efficacy, tolerability and safety of switching from LC to LCE in patients with Parkinson's disease (PD) and end of dose wearing-off. 39 patients with PD and wearing-off without or with mild dyskinesias were randomly assigned to either a group receiving the same LC dosage or to a group in which the total LC amount was reduced by 15,25%. Four weeks after the change, both groups showed an increase in daily ,on' time and a reduction in the daily time spent in ,off'. Two patients in each group experienced an increase in basal dyskinesias. No differences in clinical assessment between groups were found. Tolerance was excellent. This study suggests that switching from LC to LCE in patients with mild-to-moderate wearing-off can be done safely with or without reducing the total LD amount, but in the clinical setting it would be more practical to keep the dosage of LC unchanged unless severe dyskinesias are present. [source] Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2003J. D. Schaafsma To assess the effect of levodopa on distinct freezing of gait (FOG) subtypes in patients with ,off' FOG. Nineteen patients (12 men, mean age 62.0 ± 8.4 years) with Parkinson's disease and clinically significant FOG during ,off' states were videotaped whilst walking 130 m during ,off' and ,on' states. Three independent observers characterized the type, duration, and clinical manifestations and quantified FOG by analyzing the videotapes. Their combined mean scores were used for statistical analysis. The intra-class correlation coefficient assessed inter-observer reliability. Wilcoxon and Friedman tests evaluated differences in mean frequencies of FOG characteristics. During ,off' states, FOG was elicited by turns (63%), starts (23%), walking through narrow spaces (12%) and reaching destinations (9%). These respective values were only 14, 4, 2 and 1% during ,on' states (P < 0.011). Moving forward with very small steps and leg trembling in place were the most common manifestations of FOG; total akinesia was rare. Most FOG episodes took <10 s and tended to be shorter during ,on' states. Levodopa significantly decreased FOG frequency (P < 0.0001) and the number of episodes with akinesia (P < 0.001). Distinction amongst FOG subtypes enables evaluation of distinctive therapeutic response. Levodopa helps in reducing the frequency and duration of ,off'-related FOG. [source] The symptomatic treatment of multiple system atrophyEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2002C. Colosimo Multiple system atrophy (MSA) is a neurodegenerative disease of undetermined aetiology that occurs sporadically and manifests itself as a combination of parkinsonian, autonomic, cerebellar and pyramidal signs. Despite the lack of any effective therapy to reverse this condition, some of the symptoms may be, at least temporarily, improved with adequate symptomatic therapies. Medical treatment is largely aimed at mitigating the parkinsonian and autonomic features. The therapeutic results of levodopa therapy in cases of MSA are difficult to interpret because of their variability. Nevertheless, the statement that patients with MSA are non or poorly levodopa-responsive is misleading. Clinical and pathologically proven series document about 40,60% levodopa efficacy in patients with MSA presenting with predominant parkinsonian features. Unfortunately, other antiparkinsonian compounds (dopamine agonists, amantadine) are not more effective than levodopa. Orthostatic hypotension (OH) can be suspected from the patient's history and subsequently documented in the clinic by measuring lying and standing blood pressure. The diagnosis ideally should be confirmed in the laboratory with additional tests to determine the cause and evaluate the functional deficit, so as to aid treatment. A variety of pharmacological agents with different mechanisms of action have been used in MSA to reduce OH when this is symptomatic. OH can also be alleviated by avoiding aggravating factors, such as the effects of food, micturition, exposure to a warm environment and physiological diurnal changes and by using other non-pharmacological strategies. The treatment of the very common genito-urinary symptoms (incontinence, retention, impotence) should also be considered in order to improve the quality of life of these patients. [source] The effect of stage of Parkinson's disease at the onset of levodopa therapy on development of motor complicationsEUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2002V. S. Kosti The aim of this study was to ascertain whether the stage of Parkinson's disease (PD) (according to the Hoehn and Yahr staging system) would affect the length of time between the introduction of levodopa therapy and appearance of levodopa-associated motor complications. Forty patients with clinically definite PD were studied. In all, clinical and therapeutic data were collected from the time of diagnosis to the time of levodopa-associated motor complications (i.e. dyskinesia, motor fluctuations). In 17 patients, levodopa could be started in Hoehn and Yahr stage I (H&Y-I; 16.2 months after the onset of PD), whilst in 13 patients levodopa could be started in H&Y-II (19.6 months after the onset of the disease) and in 10 in H&Y-III (45.1 months after the onset of PD). Cox proportional hazard regression model shows that the PD patients in whom the initial levodopa treatment was introduced at stage III develop both dyskinesias and motor fluctuations significantly earlier than the patients whose levodopa started in stage I and II of PD. The median interval to develop dyskinesias was 66, 72 and 24 months for patients in whom levodopa was introduced in stage I, II and III, respectively. These values were 64, 55 and 14 months for motor fluctuations. These findings add to the clinical arguments that favour an essential role of severity of PD at levodopa initiation as a risk factor for the development of levodopa-associated motor complications. [source] A two-fold difference in the age-adjusted prevalences of Parkinson's disease between the island of Als and the Faroe IslandsEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2000L. Wermuth With the aim of comparing the previously found high prevalence of idiopathic Parkinson's disease (PD) in the Faroe Islands with the prevalence of PD in an area of Denmark, we used the same case-finding methods for case ascertainment and the same strict criteria to diagnose PD on the island of Als. During the last year before the prevalence date (1 January 1998), we found in various registries from pharmacies, hospital, private neurologist and general practioners 121 patients with suspected Parkinsonism out of 56 839 inhabitants on the island of Als. After exclusion of those who had other diseases, a total of 79 patients were left for further examinations. Among these we found 58 with PD. The overall prevalence of PD was estimated to be 102.0 and the age-adjusted prevalence to be 98.3 per 100 000 persons compared with 187.6 and 209.0 in the Faroe Islands. Compared with the previous results from the Faroe Islands (prevalence date 1 July 1995) we found an even lower mean age at onset of PD symptoms and at onset of treatment, a lower proportion of definite PD and a lower average dose of levodopa. We therefore conclude that the two-fold higher prevalence in the Faroe Islands than on the island of Als was not due to an early diagnosis and a higher ascertainment of cases with mild PD, which was suggested as being one possible explanation for our previous finding of a high prevalence of PD in the Faroe Islands. [source] How to succeed in using dopamine agonists in Parkinson's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000L. M. Shulman Dopamine receptor agonists are assuming increased importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, tolerability of these drugs can be a problem. Identifying patients who are at increased risk of adverse effects is central to using dopamine agonists in PD. The newer agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side-effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy. [source] Pre-clinical studies of pramipexole: clinical relevanceEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000J. P. Hubble This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal ,2 -adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have ,neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties. [source] Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's diseaseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010David Devos Abstract Gait disorders form one component of the axial disorders observed in Parkinson's disease (PD). Indeed, short steps with a forward-leaning stance are diagnostic criteria for PD in the early stages of the condition. Gait disorders also represent a major source of therapeutic failure in the advanced stages of PD (with the appearance of freezing of gait and falls) because they do not respond optimally to the two hand late-stage therapeutics , levodopa and electrical subthalamic nucleus (STN) stimulation. The late onset of doparesistance in these disorders may be linked to propagation of neurodegeneration to structures directly involved in gait control and to non-dopaminergic neurotransmitter systems. The coeruleus locus (a source of noradrenaline) is rapidly and severely affected, leading to a major motor impact. The pedunculopontine nucleus (PPN) and lateral pontine tegmentum (rich in acetylcholine) are both involved in gait. Degenerative damage to the serotoninergic raphe nuclei appears to be less severe, although serotonin-dopamine interactions are numerous and complex. Lastly, dopaminergic depletion leads to glutamatergic hyperactivity of the efferent pathways from the the STN to the PPN. However, the relationships between the various parkinsonian symptoms (and particularly gait disorders) and these pharmacological targets have yet to be fully elucidated. The goal of this review is to develop the various pathophysiological hypotheses published to date, in order to underpin and justify ongoing fundamental research and clinical trials in this disease area. [source] Rasagiline: defining the role of a novel therapy in the treatment of Parkinson's diseaseINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2 2006F. Stocchi Summary Parkinson's disease (PD) is a therapy area with considerable unmet needs. The current key targets for PD treatment include the slowing of disease progression, improved control of motor fluctuations in advanced disease and the treatment of nonmotor symptoms. In view of such major requirements, it is important to consider how new drug treatments fit into the context of PD therapy, and the practical advantages that they may offer in the management of PD in clinical practice. Rasagiline is a novel, second-generation, irreversible, selective monoamine oxidase type B inhibitor that is indicated for the treatment of idiopathic PD, either as initial monotherapy or as adjunct therapy (with levodopa) for patients experiencing end-of-dose motor fluctuations. This review assesses the outcome from several large-scale clinical studies that have investigated the use of rasagiline in early and advanced PD patient populations and discusses the role of rasagiline within the current scope of PD therapy. [source] | ||||||||||||||||||||||||||||