Apomorfina w zaawansowanej chorobie Parkinsona

Apomorphine is the most potent dopamine receptor agonist and its symptomatic effectiveness is comparable to levodopa. Subcutaneous apomorphine is rapidly and completely absorbed. Plasma peak concentrations are achieved after 5–15 minutes and onset of clinical effect is within 20 minutes. Apomorphine intermittent subcutaneous injections are effective as rescue therapy for unpredictable off periods in advanced Parkinson disease (PD). More often apomorphine is administered as a subcutaneous infusion which secures the continuous dopaminergic stimulation. The benefit on ‘off’ periods is consistent across all studies, but dyskinesia improvement is not so obvious. Two infusion therapies (apomorphine and intraduodenal levodopa) and deep brain stimulation (DBS) are effective in advanced PD patients with untreatable motor complications. Apomorphine infusions should be considered in patients unable to undergo DBS because of cognitive impairment and neurosurgical contraindications.     

Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

Long-term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase gamma-aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14-23; P < 0.05). This effect was more marked during the onset period (0-20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease.     

Continuous dopaminergic stimulation—From theory to clinical practice

Patients with advanced Parkinson's disease (PD) experience worsening motor fluctuations and dyskinesia. Management options include deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) or continuous duodenal levodopa administration. We have used all three therapies at our clinic in Milan and report our experience. Apomorphine infusion reduced daily off time but did not improve dyskinesia; long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioural changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioural changes and allowed patients to discontinue all other PD medications. Duodenal levodopa should be considered in PD patients with advanced disease.     

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.     

Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease.

Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.     

Motor response following repeated apomorphine administration is reduced in Parkinson's disease

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.     

Ropinirole therapy for Parkinson's disease

Ropinirole (Requip, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.     

Motor response to levodopa in patients with parkinsonian motor fluctuations: a follow-up study over three years.

To clarify the way in which the clinical response to levodopa changes with the progression of Parkinson's disease, a longitudinal study was performed to quantify motor response characteristics to single doses of levodopa by mouth over three years in 23 patients with fluctuating motor function. A significant increase in motor disability in "on" (time of peak motor improvement) and "off" (before levodopa dose) phases occurred and "on" phase dyskinesia increased by 24%, though the amplitude of motor response was conserved. There was no evidence of progressive loss of response of certain motor deficits affecting axial muscles and gait. The mean duration of motor response decreased by 17%. Both shortening of response duration and increase in "off" phase disability contribute to the development of motor fluctuations. A short response time to the levodopa test dose was not an invariable finding in patients with severe fluctuations, whereas all had large response amplitudes and high "off" phase disability scores. Patients who have developed motor fluctuations may continue to respond to dopaminergic treatment until late in the disease course, despite the unstable nature of their responses.     

Neuroprotection and pharmacotherapy for motor symptoms in Parkinson's disease

Parkinson's disease leads to major disability that impairs the quality of life of patients and leads to increased health-care costs. While there is no proven neuroprotective treatment, more basic-science research and clinical trials are needed to identify drugs that slow or halt the progression of the disorder. The mainstay of symptomatic treatment is levodopa. With long-term use, levodopa causes motor complications including involuntary movements and response fluctuations. These have lead to more cautious prescribing of levodopa. Dopamine agonists can be used as an alternative initial therapy to delay the onset of motor complications but at the expense of more dopaminergic adverse events, poorer control of motor symptoms, and increased cost. Once motor complications have developed, adjuvant therapy with dopamine agonists or entacapone can reduce off time and levodopa dose. Severe fluctuations that are not controlled by oral combination therapy can be controlled with subcutaneous apomorphine injections or infusions.     

L-deprenyl, levodopa pharmacokinetics, and response fluctuations in Parkinson's disease

Six patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) on levodopa treatment participated in an open-label trial of L-deprenyl (Eldepryl) in conjunction with Sinemet. Deprenyl (10 mg/day) allowed a slight but not statistically significant 22% reduction of total daily levodopa intake after 4 weeks of treatment, with a significant but unsustained reduction in the number of daily "off" periods and an increase in the portion of waking day spent "on." Pharmacokinetic studies revealed no effect of deprenyl on the plasma levodopa concentration vs. time curve, or the coefficient of variation (C.V.) of plasma levodopa levels measured over an 8-h period. Plasma DOPAC levels were unaffected, suggesting that the majority of peripheral DOPAC is generated by action of MAO-A. For most patients, benefit was not maintained. Two patients have continued taking the drug, and both have enjoyed significant reductions in total levodopa dose. Both have mild end-of-dose failure and little dyskinesia. Since no changes in peripheral pharmacokinetics of levodopa could be demonstrated, any therapeutic action of deprenyl in PD would appear to be due to prolongation of dopaminergic activity within the CNS.     

Prevention and treatment of motor fluctuations

The symptoms of Parkinson's disease can become increasingly difficult to control as the disease advances, particularly with the development of motor complications, such as end-of-dose wearing-off and dyskinesias, following long-term therapy. At this stage, the patient is frequently referred to a Parkinson's disease specialist for advice on the management of their disease. In this review we provide an overview of the Parkinson's disease specialist's strategies for coping with such problems. This includes strategy to prevent or delay motor fluctuations and the concept of the long duration response. The paper also includes establishing the optimum and most rational levodopa treatment schedule, improving levodopa absorption, use of COMT-inhibition, the addition of oral dopaminergic agonists, and the use of subcutaneous injections or infusions of apomorphine or lisuride. Finally, we highlight the increasing importance of treatment strategies that stimulate dopamine receptors in a more continuous, less pulsatile manner as a way of reducing the risk of developing treatment-associated motor complications.     

Apomorphine: an underutilized therapy for Parkinson's disease.

Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study. A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings. Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy. In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias. The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.     

A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson''s disease: a five year follow up.

This pilot study was performed to compare the occurrence of long term motor complications in Parkinson's disease when the introduction of levodopa was delayed by an initial treatment with high doses of bromocriptine alone. The trial was a prospective randomised controlled study comparing 31 previously untreated patients with Parkinson's disease initially given bromocriptine alone to which levodopa was later added (group B/D) and 29 other previously untreated patients with Parkinson's disease immediately given levodopa alone (group D). The end point was the occurrence of the first motor complications (wearing off or dyskinesia). Group B/D patients received bromocriptine (52 (SEM 5) mg/day) for 2.7 years, to which levodopa was later added (471 (SEM 46) mg/day). Group D patients received a comparable dose of levodopa alone (569 (SEM 47) mg/day). Both had similar disability scores at the end of the study. Motor complications were fewer and appeared later in group B/D than in group D (56% after 4.9 (SEM 0.5) years of treatment v 90% after 2.7 (SEM 0.5) years, p < 0.01). Wearing off appeared later (p < 0.01) in group B/D (4.5 (SEM 0.6) years) than in group D (2.9 (SEM 0.6) years). Peak dose dyskinesia occurred less often in group B/D patients (three v 14 cases, p < 0.01). This study showed that a three year initial monotherapy with high doses of bromocriptine followed by addition of levodopa delayed the occurrence of long term motor complications usually found in patients with Parkinson's disease treated with levodopa alone from the beginning.     

Usefulness of pallidotomy in advanced Parkinson's disease.

OBJECTIVE: The combined effect of posteroventral pallidotomy and optimal medical treatment was assessed in 22 patients with levodopa sensitive Parkinson's disease. METHODS: Timed motor tests, video recordings, and computer assisted optoelectronic movement analysis were used for serial hourly assessments performed preoperatively and four and 12 months after operation. Tests were made while patients were on optimal medical therapy. RESULTS: There were no serious adverse events of surgery. Two of the 22 patients could not complete all the tests after operation. The proportion of dyskinesia periods decreased in the 20 patients and there was a proportional increase in normal or fairly normal occasions. "Off" periods were not significantly affected. In 12 of 13 patients with limb dyskinesia this symptom was completely abolished in the contralateral limbs. There was also some degree of improvement axially and ipsilaterally. Tremor was moderately improved contralaterally. Bradykinesia remained unchanged. Results at 12 months follow up were similar to those at four months. CONCLUSION: Pallidotomy produced a pronounced positive effect on dyskinesia and a moderate effect on tremor. Bradykinesia was not affected. Posteroventral pallidotomy may be useful in patients with Parkinson's disease who have severe motor fluctuations and may allow an increase in levodopa dose to alleviate bradykinesia in "off" states.     

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.     

Levodopa consumption reduces dopaminergic receptor responsiveness in Parkinson's disease

In seven patients with Parkinson's disease with daily motor fluctuations, we found that the same subcutaneous apomorphine dose that improved motor function when given in the morning after a normal night without taking levodopa failed to turn patients "on" during afternoon and evening "off" periods, and on a different morning after receiving levodopa during the night. No significant changes in levodopa or 3-O-methyldopa plasma levels that could explain these variations were detected. These findings suggest that increased daily levodopa consumption may reduce striatal responsiveness to dopaminergic stimulation.     

Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation

Background: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. Methods: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS‐III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. Results: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS‐III and taps) and the most frequent off‐states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS‐III or taps. Conclusions: STN DBS provided adequate trade‐off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.     

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.     

恩他卡朋添加治疗帕金森病症状波动的系统评价

目的 系统评价恩他卡朋治疗帕金森病(PD)症状波动的疗效.方法 采用Pubmed、Embase、Cochrane Database及其他互联网公共搜索引擎作为检索工具,检索国内外1966-2007年6月已发表的有关恩他卡朋对照、安慰剂治疗PD症状波动的临床研究资料.由2位研究者独立评价研究质量.使用Revman 4.2.10进行统计学处理.结果 共纳入10项随机对照临床试验(RCT)研究(共2212例患者),结果 表明恩他卡朋治疗PD伴症状波动的患者有延长"开"期、缩短"关"期、减少每日左旋多巴剂量(WMD=-1.41,95%CI-2.09～-0.72)和改善"开"期运动症状及生活质量的趋势,然而与安慰剂比,恩他卡朋可以增加异动症的发生率(OR=2.00,95%CI 1.55～2.58).结论恩他卡朋可以改善PD症状波动,同时也需要更多设有相同判效指标的大样本高质量RCT研究进一步证实.     

帕金森病患者运动并发症的调查分析

目的 调查帕金森病(PD)患者中异动症及症状波动的发生率、分布情况以及影响因素.方法 详细记录患者资料,并进行统一帕会森病评分量表(UPDRS)、Hoehn＆Yahn(H-Y)分级评分.根据UPDRS Ⅳ记录患者有无异动症及症状波动.结果 122例患者接受左旋多巴治疗,疗程至少6个月.其中15例(12.3%)合并异动症,41例(33.6%)合并症状波动.异动症的独立影响因素为:发病年龄(OR=0.907,P<0.01)和左旋多巴总量(95%C/1.000～1.004,OR=1.002,P<0.05);症状波动的独立影响因素为:发病年龄(OR=0.922,P<0.05),接受左旋多巴治疗的时间(OR=1.234,P<0.05),左旋多巴总量(95%CI 1.002～1.008,OR=1.005,P<0.01)和H-Y分级(OR=1.869,P<0.05).结论 本组患者异动症及症状波动的发生率均低于欧洲调查结果,每日左旋多巴总最是异动症及症状波动的独立影响因素.添加其他药物辅助治疗而减少左旋多巴用量,可以减少运动并发症的发生.