Madopar HBS in fluctuating parkinsonian patients: two-year treatment

In an open-label study, we substituted conventional levodopa plus benserazide: 100/25 (Madopar) with a controlled-release form (HBS) in 18 fluctuating parkinsonian patients for 24 months. Significantly positive results were obtained in both peak-dose and diphasic dyskinesias up to 12 months of treatment; morning akinesias were also improved up to 6 months. A general trend of deterioration, compared to the first 3-6 months of HBS treatment, was observed in "off" fluctuations after 1 year: akinesias due to a delayed response worsened after 1 year of treatment also when compared with the conventional treatment. Positive results were obtained with new HBS on standard Madopar-related psychiatric disorders.     

多巴丝肼片合用多巴胺受体激动剂治疗帕金森病临床疗效观察

目的 研究多巴丝肼片合用普拉克索或吡贝地尔的疗效与安全性. 方法 选择自2008年8月至2010年1月在福建医科大学附属第一医院神经内科门诊接受治疗的40例PD患者,根据治疗药物的不同分为多巴丝肼片+普拉克索片组(普拉克索组)和多巴丝肼片+泰舒达组(泰舒达组),每组20例.经12周联合用药治疗后,以统一帕金森病评定量表(UPDRS)各部分评分相对于基线(治疗前评分)的变化为指标评估疗效.同时监测血压,观察患者不良反应,比较2组治疗方案的安全性. 结果 经12周治疗后2组UPDRS各项评分相对基线均有下降,差异有统计学意义(P＜0.05).普拉克索组UPDRS-Ⅰ(精神、行为和情感)评分、UPDRS-Ⅳ(治疗的并发症)评分较吡贝地尔组评分下降更多,差异有统计学意义(P＜0.05).普拉克索组临床总有效率为80％,泰舒达组临床总有效率为75％,差异无统计学意义(P＞0.05).2组药品不良反应发生率分别为55％和70％,差异无统计学意义(P＞0.05). 结论 普拉克索或吡贝地尔与多巴丝肼合用治疗PD可获得较显著的近期疗效;在改善PD患者精神、行为和情感及运动波动并发症方面的疗效,普拉克索优于吡贝地尔.     

Clinical and pharmacokinetic evaluation of controlled-release levodopa/carbidopa (CR-4) in parkinsonian patients with severe motor fluctuations: a six month follow-up study

The results of a six month open-label study comparing the efficacy of controlled-release levodopa-carbidopa (Sinemet CR-4 200 mg/50 mg) with standard levodopa/carbidopa (250 mg/25 mg) in 17 patients with idiopathic Parkinson's disease and severe response fluctuations, are reported. Major clinical benefits included; improvement of disability, reduction of the number of ‘off’ periods (predominantly end-of-dose hypokinesia) and a slight increase in ‘on’ time. No improvement was observed in two of our patients. Mean levodopa plasma levels were comparable between the two types of formulations during optimal treatment, however systemic bioavailability was significantly higher with CR-4. Delayed onset of antiparkinsonian effect of CR-4, resulting from an increase of Tmax for levodopa, was one of the major complaints and required additional small amounts of standard levodopa in three patients.     

美多巴单用及与多巴胺受体激动剂合用治疗帕金森病的临床疗效观察

目的　评定单用美多巴 (L dopa) ,L dopa与多巴胺受体激动剂 [溴麦角隐亭碱 (BM)或甲磺酸培高利特 (PM) ]合用治疗帕金森病的疗效和安全性。方法　采用多中心、开放式分组 ,单用L dopa组 4 7例 ,L dopa +BM组 4 3例和L dopa +PM组 4 8例。临床疗效采用改良Webster量表和帕金森病运动功能量表 (MDRSPD)进行治疗前后的评定。同时取血检测肝肾功能 ,血、尿常规 ,测量血压、脉搏和做心电图检查。单用L dopa组平均日用量 (5 2 3 3± 2 35 9)mg;L dopa +BM组平均日用量为L dopa(5 2 6 7± 2 4 1 3)mg ,BM(7 3± 1 5 )mg;L dopa +PM组平均日用量为L dopa(5 5 8 3± 192 9)mg,PM(0 2 35± 0 0 4 5 )mg。结果　Webster量表、MDRSPD量表的临床总有效率 ,单用L dopa组均为74 5 % ,L dopa +BM组分别为 6 9 8%和 79 1% ,L dopa +PM组分别为 77 9%和 81 3%。不良反应发生率单用L dopa组为 2 7 7% ,L dopa +BM组为 39 5 % ,L dopa+PM组为 18 8%。结论　单用L dopa ,L dopa+BM和L dopa +PM治疗帕金森病均有效 ,对于早期帕金森病可以选用单一L dopa治疗 ;对于晚期帕金森病 ,可以选用L dopa与多巴胺受体激动剂联合治疗     

Levodopa-induced dyskinesia: clinical observations

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

The detrimental effect of levodopa on behavioral efficacy of fetal dopamine neuron grafts in rats is reversible following prolonged withdrawal of chronic dosing

In previous studies, we observed that chronic levodopa treatment resulted in impaired morphology and function of grafted dopamine neurons in rats. To begin to better understand how levodopa treatment might influence dopamine neurons, we examined whether subsequent discontinuation of chronic levodopa treatment might allow for recovery of graft efficacy. Function of embryonic mesencephalic tissue grafts was assessed by monitoring rotational behavior elicited by amphetamine in lesioned, grafted rats initially treated for 6 weeks with levodopa followed by a 6 week drug-free period. As observed previously, control grafted animals, but not levodopa treated animals, showed behavioral improvement. However, following a 6 week withdrawal period, the levodopa animals demonstrated a significant reduction in amphetamine rotations which was reminiscent of control animals. This suggests that grafted neurons can recover functionally after levodopa treatment is withdrawn, which may be of significance in clinical transplantation trials.     

Effect of a slow release preparation of levodopa on Parkinson''s disease in combination with a peripheral decarboxylase inhibitor

Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.     

An acute and long-term study with a dispersible formulation of levodopa/benserazide (Madopar®) in Parkinson's disease

The clinical efficacy, tolerability and administration regimens of a dispersible formulation of levodopa/benserazide (DM) were investigated in 30 patients with idiopathic Parkinson's disease, complicated by motor fluctuations. All 30 patients showed delayed- “on” phenomenon after administration of the first morning dose of standard levodopa (SM), and 20 showed delayed- “on” phenomenon after the first afternoon dose. Patients were receiving standard formulations of levodopa as monotherapy or in combination. A double-dose study of the dispersible vs the standard formulation was performed in 30 patients, 24 of whom participated in a 36-month, follow-up clinical study. In the long-term study, SM was replaced with DM by substituting the first morning dose or the first morning and first afternoon doses. In the double-dose study, mean latency to “on” after the first morning dose was significantly shorter with DM than with SM (p < 0.001), whereas the duration of “on” was similar with the two preparations. The post-prandial delayed- “on” in the 14 patients who responded to therapy was significantly shorter for DM than for SM (p < 0.001). In the long-term study, the mean latency to “on” in all patients was significantly shorter than at baseline (p < 0.001). Time spent in “on” during the active day increased significantly, and remained stable during the 36-month study. No changes were apparent in the mean dosage of levodopa/day or the number of doses/day, and no acute or long-term adverse events were reported. In conclusion, these results confirm the long-term safety of the dispersible formulation, and its improved efficacy compared with standard levodopa formulations, as monotherapy and in association with slow-release formulations.     

Levodopa alone and in combination with a peripheral decarboxylase inhibitor benserazide (madopar®) in the treatment of Parkinson's disease

Summary A combination of levodopa and the extracerebrally acting decarboxylase inhibitor benserazide (ratio 4:1) (Madopar^®), was compared with levodopa alone in a controlled double-blind clinical multicenter trial on 94 patients with Parkinson's disease. During 4 months of therapy levodopa + benserazide proved superior to levodopa on several accounts. Nausea and vomiting occurred with statistically significant less severity and frequency. Clinical improvement expressed through improvement in Webster rating occurred sooner and was all together greater.The treatment schedules did not differ with regard to other side effects, in particular involuntary movements and reduction in supine blood pressure. Neither treatment seemed to influence liver function, renal function and hematological parameters.

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Zusammenfassung Levodopa in Kombination mit dem extracerebral wirkenden Dekarboxylasehemmer Benserazid (Dosisverhältnis 4:1) (Madopar^®) wurde mit Levodopa allein in einer kontrollierten, doppelblinden, klinischen Multizenterprüfung an 94 Patienten mit Morbus Parkinson verglichen. Während der viermonatigen Therapie zeigte sich in mehreren Beziehungen Levodopa + Benserazid dem Levodopa überlegen. Übelkeit und Erbrechen waren statistisch signifikant weniger schwerwiegend und traten seltener auf. Klinische Besserung, ausgedrückt durch Reduktion im Webster Rating, trat schneller ein und war im großen und ganzen höher.Andere Nebenerscheinungen, insbesondere unwillkürliche Bewegungen und Reduktion des Blutdruckes im Liegen, verteilen sich gleich über die beiden Gruppen. Bestimmungen von sowohl Leberfunktion und Nierenfunktion als auch hämatologischen Parametern ergaben keine signifikanten Änderungen.

     

Tolcapone added to levodopa in stable parkinsonian patients: A double-blind placebo-controlled study

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose “wearing-off” phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by −35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated “wearing-off” phenomenon.     

Cascade of levodopa dose and weight-related dyskinesia in Parkinson's disease (LD-WD-PD cascade)

We have studied a cohort of 220 Parkinson's disease (PD) patients for risk factors of developing new dyskinesia. Twenty-nine patients were noticed to have developed new dyskinesia at the second assessment. The dyskinetic patients received significantly higher maximum level daily dose of levodopa. These patients had lost weight during the course of the disease from 72±15 to 66±17 kg, p=0.002. The dyskinetic patients received significantly higher daily dose of levodopa per kilogram body weight, 8.4±3.5 mg/kg vs. 6.0±3.9 mg, p=0.003. Weight-losers PD patients developed significantly more dyskinesia than non-weight losers—p=0.002. Logistic regression analysis revealed weight loss and daily levodopa dose per kilogram body weight to be the only significant factors for dyskinesia in addition to disease duration. There was a “dose response to developing dyskinesia” according to the increasing levodopa dose per kilogram body weight.     

Time-dependent effects of levodopa on regional brain dopamine metabolism and lipid peroxidation

Levodopa treatment in Parkinson's disease has been suggested to contribute to disease progression through free radical generation. We compared the time course of levodopa-induced dopamine metabolism, and the resulting oxidative stress, between rat brain regions with varying dopaminergic innervation. At 1, 4, 8, and 12 h after levodopa administration (100 mg/kg), dopamine, dihydroxyphenylacetic acid, and homovanillic acid were measured in striatum and ventral midbrain, regions containing marked dopaminergic innervation, and in prefrontal cortex and cerebellum, which possess little dopaminergic innervation. Malondialdehyde, a marker of oxidative stress, was measured in additional animals. The return of dopamine and its metabolites to control concentrations tended to be slower (by 3-8 h) in cerebellum and prefrontal cortex than in dopaminergic regions. Malondialdehyde concentrations were decreased (p < 0.05) in ventral midbrain 8 h posttreatment, but increased in cerebellum 12 h posttreatment. We concluded that levodopa increases dopamine metabolism in nondopaminergic as well as dopaminergic regions, with delayed clearance of dopamine and its metabolites in nondopaminergic regions. The slower return of dopamine to control levels in nondopaminergic regions may be relevant to some of the side effects of levodopa. No support was found for the hypothesis that levodopa treatment induces oxidative stress.     

3-OMD and homocysteine plasma levels in parkinsonian patients

Summary. One main metabolizing pathway of levodopa is O-methylation to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). Since COMT requires Mg²⁺ and S-adenosylmethionine as methyl donor for this transmethylating process, COMT converts S-adenosylmethionine to S-adenosylhomocysteine and subsequent homocysteine. Objective of this study was to demonstrate relations between plasma levodopa, 3-OMD and total homocysteine in treated parkinsonian subjects. We measured homocysteine, levodopa and 3-OMD by HPLC. We compared plasma homocysteine in two groups of treated parkinsonian subjects subdivided according to their 3-OMD level. Homocysteine was significantly (p = 0.002) elevated in the group with higher 3-OMD concentrations and positively (r = 0.52, p = 0.0006) correlated to 3-OMD. Homocysteine induces vascular disease. Previous studies showed an increase of ischaemic heart- and cerebrovascular disease in treated parkinsonian patients. Received November 20, 2000; accepted September 26, 2001     

Hypothalamo-pituitary function and dopamine dependence in untreated parkinsonian patients

Altered prolactin and thyrotropin responses to the TRH test in parkinsonian patients are held to indicate an impairment of the tubero-infundibular dopaminergic axis (TIDA). We correlated the plasmatic prolactin (PRL), thyrotropin (TSH) and somatotropin (GH) responses to TRH and bromocriptine + TRH of 12 parkinsonian patients, who had never received anti-parkinsonian drugs, with the severity, the duration, the age of onset and the dopamine-dependence of the motor symptomatology as indicated by the therapeutic response to a six-month oral treatment with bromocriptine. Patients with basal motor impairment over 9 on the Webster Rating Scale (WRS), those with duration of the disease over 24 months and those with onset earlier than 55 years of age showed lower PRL responses than the respectively matched subgroups. Patients showing a therapeutic motor improvement over 50% on the WRS (dopamine-dependent or "responder") showed lower PRL and TSH and higher GH responses than the non-responders. These findings suggest that the TIDA impairment described in Parkinson's disease develops along with the progressive course of the extrapyramidal involvement and is strictly correlated with the dopamine-dependence of the motor impairment.     

The effect of deprenyl (selegiline) on cognition and emotion in parkinsonian patients undergoing long-term levodopa treatment

ABSTRACT — The effects of deprenyl on memory, other cognitive functions, vigilance and emotional processes were investigated in seven parkinsonian patients undergoing long-term levodopa treatment. The patients were selected on the basis of their cognitive impairment, observed during a follow-up study of 8–10 years. Four of the patients had progressive dementia and three did not. After deprenyl treatment lasting 4 weeks, there were two patterns of responses. Patients with slow progressive dementia failed to respond to treatment, whereas patients without progressive impairment tended to show improvement in memory and motor speed; the former group also showed more emotional changes than the latter. Typical responses in all patients treated with deprenyl were: increased arousal, paradoxical spells of tiredness, deterioration in vigilance and in set shifting, but improvement of parkinsonian disability. These preliminary findings indicate that there is a dissociation between pure motor responses and cognitive as well as other behavioural responses to deprenyl. It is probable that although enhanced availability of dopamine by MAO-B inhibition partly explains the present neuropsychological findings, also other brain mechanisms are involved.     

A hospital-based study: risk factors in development of motor complications in 555 Parkinson's patients on levodopa therapy

OBJECTIVES: Although levodopa (LD) is the gold standard therapy for symptomatic treatment of Parkinson's disease (PD), the chronic use of LD leads to the development of motor complications in almost all patients. PATIENTS AND METHODS: We assessed the presence and risk factors for motor complications in PD patients on LD therapy. We examined 555 PD patients on LD for the presence or absence of wearing-off (WO+/-) and dyskinesia (DK+/-). RESULTS: WO was present in 46.3%, and DK in 30.1% of patients. The mean age at onset of symptoms were earlier in WO(+)/DK(+) groups (p<0.001). The duration of PD was longer in WO(+)/DK(+) groups (p<0.001). The time between the first symptom and the occurrence of WO/DK, or LD initiation were not significantly different. The initial LD dose was significantly higher in WO(+) compared to WO(-) (300.1mg/d versus 232.5mg/d, p<0.001), and DK(+) compared to DK(-) groups (291.4 mg/d versus 251.9 mg/d, p=0.001). The time until dopamine agonist (DA) initiation was longer in WO(+)/DK(+) groups (p<0.001). WO (p<0.001) and DK (p=0.002) were more common in patients with H&Y stages 3+4. UPDRS scores were higher in WO(+) and DK(+) patients (p<0.001 and p=0.027). CONCLUSION: Our study showed that the development of motor complications was associated with early onset PD, longer disease duration, advanced disease, higher initial LD dose, longer LD use, and late DA initiation, but not with the timing of LD initiation.     

Semantic activation in Parkinson's disease patients on and off levodopa

Research suggests that dopamine may exert a neuromodulatory influence on automatic spreading activation within semantic networks. In order to investigate the influence of dopamine depletion on semantic activation in Parkinson's disease (PD), nine patients with PD performed a lexical decision task when on and off levodopa medication. Eleven healthy controls matched to the PD patients in terms of sex, age and education also participated in the study. Both directly related word pairs (e.g., tiger - stripe) and indirectly related word pairs (word pairs related via a mediating word, e.g., chalk - black) were used to measure semantic activation across stimulus onset asynchronies (SOAs) of 270 msec, 520 msec and 1020 msec. Analysis of variance statistics revealed that the activation of directly related and indirectly related targets was slower for the PD group relative to the control group. Within group comparisons revealed further changes to semantic activation in PD patients off medication, with no activation of directly or indirectly related target words evident in PD patients off medication. These results further clarify the nature of dopamine's neuromodulatory influence on semantic activation, and suggest that the nature of altered semantic activation in PD may depend on the magnitude of dopamine depletion.     

左旋多巴对帕金森病鼠行为及多巴胺神经纤维的影响

目的 了解左旋多巴对帕金森鼠行为及多巴胺神经纤维的影响。方法采用左旋多巴和生理盐水分别治疗不同程度损伤的帕金森鼠,观察TH阳性神经纤维及神经元的表达和鼠旋转行为。结果 左旋多巴治疗的重度帕金森病鼠出现旋转行为,而中、轻度帕金森病鼠和生理盐水治疗组未出现鼠旋转行为;左旋多巴治疗的中、轻度帕金森病鼠TH阳性神经纤维表达增加。结论 左旋多巴对中、轻度帕金森病鼠有益。     

Effect of hypoglycaemia,TRH and levodopa on plasma growth hormone,prolactin, thyrotropin and cortisol in Parkinson's disease before and during therapy

Summary Thirteen drug-free and not severely affected patients with idiopathic Parkinson's disease underwent an insulin-hypoglycaemia test, a TRH test and a levodopa test. The responses of growth hormone, prolactin, cortisol and thyrotropin were measured, and retested under stable therapy with levodopa and benserazide. Mean basal and stimulated hormonal concentrations were in the normal range before and during therapy. Minor abnormalities were observed in individual cases, but did not indicate a hypothalamic dopamine deficit.