Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats

To evaluate the possible involvement of adenosine A(2A) receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of CSC (8-(3-chlorostryryl) caffeine), a selective adenosine A(2A) receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of CSC was 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, i.p.) for 22 days and on day 23 CSC (5 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 CSC (5 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 CSC on day 23 reversed levodopa-induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A(2A) receptor antagonist CSC reverses but does not prevent levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A(2A) receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the antagonism of adenosine A(2A) receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.     

Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice

Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.     

Dopa-induced blood flow responses in nonhuman primates

Initially, treatment with the dopamine precursor levodopa provides substantial symptomatic relief for patients with Parkinson's disease (PD). However, as the disease progresses, side effects such as involuntary movements or psychosis may accompany the response to medication. The mechanisms underlying these actions of levodopa remain unclear. To develop methodology for longitudinal studies of the effects of PD and levodopa treatment in living nonhuman primates, we first studied the effects of an acute dose of levodopa on regional brain activity in sedated baboons using positron emission tomography. We found that levodopa significantly decreased regional cerebral blood flow (rCBF) bilaterally in putamen and right cingulate and increased rCBF in right lateral temporal cortex and bilateral frontal cortex. We then performed similar studies on a nemestrina in awake and sedated states to determine whether these responses were affected by sedation. Interestingly, the directions of the rCBF responses in the putamen and temporal cortex were reversed depending on the presence or absence of sedation. Specifically, responses were decreased in sedated animals, but increased dose-dependently in the awake nemestrina. These findings have important implications for the interpretation of studies that use anesthesia. The responses in the awake nemestrina were most similar to those reported in humans and thus may be the most useful model system. Future imaging studies using selective dopaminergic agents in awake animals may permit the identification of relatively specific agonist-mediated pathways and may help separate the mechanisms that mediate levodopa's benefit from those that produce its unwanted side effects.     

Unilateral pallidotomy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets exhibiting levodopa-induced dyskinesia

Pallidotomy paradoxically reduces the intensity of levodopa-induced dyskinesia without worsening motor symptoms. The reasons for this are not clear and no experimental study has investigated this phenomenon. The objective of this investigation was to evaluate the effects of unilateral pallidotomy on locomotor activity, motor disability and levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated levodopa-primed common marmosets. Animals were primed to exhibit dyskinesia by daily administration of levodopa until stable dyskinesia was evoked by each dose. Locomotor activity, motor disability and dyskinesia were assessed weekly at baseline and following an acute levodopa challenge. Prior to pallidotomies, two distinct groups of animals emerged: poor responders to levodopa with mild dyskinesia (Group 1) and those exhibiting a marked increase in motor activity and pronounced dyskinesia (Group 2). Electrolytic lesions were placed in the left internal segment of the globus pallidus. Pallidotomy had no effect on basal or levodopa-induced motor activity in either group but significantly improved basal motor disability in Group 2. Following pallidotomy, the ability of levodopa to reduce motor disability was significantly increased in both groups. Pallidotomy improved dyskinesia in both Groups 1 and 2 but it was more effective in reducing dystonia compared with chorea. The effect of pallidotomy on dyskinesia in Group 2 was transient, with the intensity of involuntary movements reverting to presurgery levels 4 weeks later. This study shows that in levodopa-primed, parkinsonian marmosets, placement of discrete globus pallidus lesions can ameliorate levodopa-induced dyskinesia but not akinesia. This model allows the evaluation of pallidotomy-induced biochemical changes in dyskinetic primates.     

恩他卡朋添加治疗症状波动的帕金森病的随机、双盲、安慰剂对照临床研究

目的:探讨添加恩他卡朋治疗PD患者剂末现象的疗效和安全性。方法:40例伴有剂末现象的PD患者进行随机、双盲、安慰剂、平行分组临床对照试验。根据患者日记记录的"开"、"关"期时间、UPDRS各部分评分、研究者总体评估变化量表和左旋多巴每日剂量来评定疗效。结果:恩他卡朋治疗12周时能显著延长"开"期时间、缩短"关"期时间,降低UPDRS评分,减少每日左旋多巴用量,研究者主观感觉65%的患者病情好转,与安慰剂组相比差异有显著意义。不良事件的发生率与安慰剂组相比差异无显著意义。结论:添加恩他卡朋治疗伴有剂末现象的PD患者安全、有效。     

Mood fluctuations in Parkinson's disease: a pilot study comparing the effects of intravenous and oral levodopa administration

OBJECTIVES: Parkinson's disease (PD) is associated with motor fluctuations that have been shown to improve when stable plasma levodopa levels are achieved with continuous levodopa infusions. Many patients also develop mood fluctuations. In this pilot study, we gathered preliminary information about the relationship between changing mood states and plasma levodopa levels. METHODS: Six patients with idiopathic PD and histories of motor and mood fluctuations participated in a double-blind levodopa infusion study. Subjects received active oral carbidopa/levodopa and a placebo levodopa infusion on one day and placebo oral carbidopa/levodopa and an active levodopa infusion on the other day, in a randomly determined order. Evaluations included serial plasma levodopa levels and assessments of mood and motor states. RESULTS: Only 4 of the 6 subjects demonstrated mood fluctuations on at least one of the treatment days. All subjects achieved more stable plasma levodopa levels on the active infusion day. Two subjects experienced fewer mood fluctuations on the active infusion day and two experienced fewer on the oral day. Conclusions The results of this pilot study suggest that the relationship between mood state and plasma levodopa level may vary among PD patients.     

Effects of levodopa oral bolus on the kinematics of the pointing movements in Parkinson’s disease patients

We studied the time-course of a levodopa oral bolus effects on the kinematics of patients affected by a mild akinetic–rigid form of idiopathic Parkinson’s disease (PD). Eleven PD patients were evaluated: a) in OFF–state, that is before their first medication or after its withdrawal, b) in ON–state, that is at 1/2, 1, 2, 3, 4, 5, 6, 24, 30 and 48 hours after the administration of 250 mg of levodopa plus 25mg of carbidopa. The main kinematics (i. e.movement time, peak of velocity, peak of acceleration and peak of deceleration) of pointing movements to six target–stimuli placed on the horizontal plane of a table were recorded. Clinical conditions were assessed according to the Motor Examination section of the Unified Parkinson’s Disease Rating Scale. The levopoda bolus had stable clinical effects only within the first six hours from its administration. The decline of the clinical response was marked by the changes of peak acceleration whereas other kinematics (i. e. movement time and the peak of velocity) changed also in the late observations (24, 30 and 48 hours after drug intake). The dissociation between the persistent improvement on movement time on peak velocity and the rapid deterioration of levodopa effects on early kinematics (i. e. peak acceleration) could be accounted for by a progressive decline in movement programming.     

Combining entacapone with levodopa/DDCI improves clinical status and quality of life in Parkinson’s Disease (PD) patients experiencing wearing-off,regardless of the dosing frequency: results of a large multicentre open-label study

Summary. The efficacy of entacapone and its impact on patient quality of life (QOL) was investigated in an open-label study of 899 patients with idiopathic Parkinsons Disease (PD) experiencing wearing-off fluctuations. Patients were divided into 3 groups (3, 4 or 5 doses daily) based on their current levodopa dosage frequency. Patients received 200mg entacapone with each levodopa/dopa-decarboxylase inhibitor (DDCI) dose, while continuing their same levodopa/DDCI dosage regimen for 4 weeks. Primary efficacy measure was the Investigators Clinical Global Impression of Change (CGIC). Patient QoL was assessed using the validated 8-item Parkinsons Disease Questionnaire (PDQ-8). Investigators CGIC revealed that 76.5% of entacapone treated patients experienced an improvement in global status after 4 weeks. Treatment with entacapone was also associated with improvement in patient QoL, with a mean reduction (improvement) in PDQ-8 score of 1.8 from baseline. This study confirms and extends the results of earlier studies demonstrating that, independent of dosing frequency, completing levodopa/DDCI therapy with entacapone provides clinically relevant improvements in global status and QoL in PD patients experiencing wearing-off on their current levodopa dosing frequency.     

Repeated rating improves value of diagnostic dopaminergic challenge tests in Parkinson's disease

Summary. Clinicians use acute challenges with levodopa (LD) and/or apomorphine (A) for diagnostic dopaminergic response tests in Parkinson's disease (PD) patients. We consecutively compared the value of both drugs with performance of repeated ratings and adverse effect recording. Oral administration of 200 mg LD was superior to subcutaneous injection of 4 mg A in terms of tolerability and onset of temporary UPDRS motor score decline ([previously untreated PD patients] LD: 4.02 [mean] ± 2.45 [SD] {significant decrease: p = 1.42E-07} vs. A: 1.58 ± 3.38 {not significant decrease: p = 0.14}, p = 0.0009; [treated PD patients] LD: 7.71 ± 4.35 {significant decrease: p = 2.48E-06} vs. A: 5.19 ± 4.32 {significant decrease: p = 7.83E-05}, p = 0.07). We suggest diagnostic acute challenge test performance with LD as first- and A as second choice due to better tolerability and valuation in combination with repeated scoring procedures to improve sensitivity and specifity. Received December 12, 2002; accepted January 20, 2003 Published online April 7, 2003 Authors' address: Prof. Dr. Th. Müller, Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany, e-mail: thomas.mueller@ruhr-uni-bochum.de     

Duodenal levodopa infusion in Parkinson's disease--long-term experience

Motor fluctuations in parkinsonian patients can be reduced by intraduodenal infusion of levodopa. Between 1991 and 1998 continuous daytime administration of levodopa through a transabdominal port has been used in 28 very advanced patients over a total period of 1045 months. A stable suspension of levodopa and carbidopa (Duodopa) has been developed. Patients were characterized by early onset, long history of disease and levodopa therapy. The reason for infusion was in all cases related to on-off fluctuations. All patients experienced a general improvement after the introduction of continuous treatment. There have been no severe complications. Six patients have taken the decision to curtail their treatment. The mean daily levodopa consumption has been slightly reduced on infusion as compared to oral therapy. Nine of the first group of patients participating in the new therapy have been regularly evaluated by means of rating scales and movement analyses. Short-term results have already been published and a follow-up showing continued positive effect after 4-7 years of continuous duodenal infusion is presented.