Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study

IntroductionThe randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).MethodsAll patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.ResultsEighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of −3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).ConclusionsThe safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.     

巨刺疗法联合运动想象对卒中患者肢体功能恢复影响

目的：观察巨刺疗法联合运动想象对卒中患者肢体功能恢复的影响。方法将80例卒中后单侧肢体功能障碍患者随机分为2组。治疗组40例,予巨刺疗法联合运动想象治疗;对照组40例,单纯予巨刺疗法治疗。2组均以4周为1个疗程,连续治疗3个疗程后,采用 Fugl －Meyer 运动功能评分（FMA）评定患者运动功能,改良 Barthel 指数（MBI）评定患者日常生活活动能力,改良爱丁堡斯堪的那维亚评分（MESSS）进行神经功能缺损程度评定,并采用 MESSS 评分进行疗效比较。结果治疗组总有效率95．0％,对照组总有效率82．5％,2组总有效率比较差异有统计学意义（P ＜0．05）;2组治疗后 FMA、MBI 及 MESSS 评分与本组治疗前比较差异均有统计学意义（P ＜0．05）,FMA、MBI 评分升高,MESSS 评分降低,且治疗组改善均优于对照组（P ＜0．05）。结论巨刺疗法联合运动想象可以明显促进卒中后肢体功能障碍患者肢体功能恢复,疗效确切,二者联合相辅相成具有协同作用。     

迟发性运动障碍脑MRI研究进展

迟发性运动障碍(Tardive Dyskinesia,TD)为长期应用抗精神病药后,出现异常不自主运动的综合征[1-2].使用典型抗精神病药治疗10年以上的病例,TD年发生率高达50％,具有明显的致残性和不可逆性[3].随着非典型抗精神病药物的应用,迟发性运动障碍的发生率和流行率似乎相对稳定[4].     

谷氨酸受体在左旋多巴诱导的异动症中的相关研究进展

在帕金森病(PD)患者中,长期使用左旋多巴而诱导的异动症(LID)显著影响着左旋多巴的疗效及患者的生活质量,现有的应对方案效果也均不甚理想,其原因与LID的机制目前尚未完全阐明密切相关。近年来越来越多的研究证实,谷氨酸能系统与多巴胺能系统紧密关联,谷氨酸受体在LID中的作用也日益凸显,特别是代谢型谷氨酸受体(mGluR)4、mGluR5以及部分离子型谷氨酸受体(iGluRs)在LID的机制研究和临床药物研究中更是关注热点。笔者现对各类谷氨酸受体在LID中的变化、作用以及相关的临床研究进展进行综述,以期为PD患者中LID的诊治和机制阐明提供新思路。     

Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease

PurposeIn two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years.MethodsOpen-label rotigotine was titrated to optimal dose (≤16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies.ResultsOf 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered ‘not disabling’ for all occurrences; the worst-case severity was ‘mildly disabling’ for 33/107 (31%), and ‘moderately’ or ‘severely disabling’ for 18/107 (17%; 3% of total participants).ConclusionDuring treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally ‘not disabling’ or ‘mildly disabling’.     

帕金森病运动并发症与ERK磷酸化关系的实验研究

目的观察帕金森病运动并发症模型大鼠纹状体细胞外信号调节激酶(ERK)Thr202/Tyr204位点(ERK1/2)磷酸化水平及表达位点的改变。方法通过脑立体定向仪于大鼠内侧前脑束注射6-羟多巴胺建立帕金森病动物模型,连续腹腔注射左旋多巴(50mg/kg)和苄丝肼(12.50mg/kg)共21 d(2次/d)以诱发运动并发症。通过Western blotting法检测不同处理组大鼠纹状体磷酸化ERK1/2表达水平,免疫荧光双标法观察磷酸化ERK1/2与强啡肽共表达变化,以了解直接通路投射神经元ERK磷酸化修饰情况。结果 Wester·n blotting检测显示,帕金森病组大鼠损伤侧纹状体磷酸化ERK1/2表达水平为(68.28±7.42)%,低于假手术组的(107.05±3.81)%,组间差异具有统计学意义(t=0.109,P=0.018);左旋多巴连续治疗21 d后,表达水平升至(160.37±10.54)%(t=0.109,P=0.000)。免疫荧光双标法检测,帕金森病组大鼠损伤侧纹状体区仅有(35.32±5.03)%的磷酸化ERK1/2与强啡肽共表达;经左旋多巴治疗后,共表达水平显著升至(83.62±1.46)%,高于帕金森病组(t=11.263,P=0.003)。结论长期应用左旋多巴可使帕金森病模型大鼠纹状体磷酸化ERK1/2表达水平明显上调,且ERK磷酸化多发生于直接通路投射神经元,提示黑质-纹状体投射神经元ERK通路的活化可能参与了运动并发症的发生。     

Clinical profile of Parkinson's disease in the Gumei community of Minhang district,Shanghai

OBJECTIVE:

We examined the demographic and clinical profiles of Parkinson''s disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson''s disease prevalence, phenotype, and progression among different regions and ethnic groups.

METHODS:

A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson''s disease patients (104 males, 76 females).

RESULTS:

The average age at onset was 65.16±9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson''s disease (Hoehn-Yahr phase 1–2) was 52.74±45.64 months. Progression from mild to moderate/severe Parkinson''s disease (phase≥3) was significantly slower (87.07±58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83±24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54±7.68 years) compared with the overall mean (p<0.05).

CONCLUSION:

Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ≈4−9 years. Earlier-onset patients experience greater psychiatric dysfunction.     

磁共振动态弥散张量成像对基底节急性脑出血中长期运动功能评估

目的探讨弥散张量成像(Diffusion Tensor Imaging,DTI)预测急性基底节区脑出血(Basal Nuclei cerebralHemorrhage BNCH)后远期运动障碍程度及预后的可行性。方法收集26例首次发病急性BNCH伴有偏瘫体征的病例,分别在发病后3天及2周基于感兴趣区大脑脚锥体束解剖学区域测定各向异性值(Fractional Anisotropy,FA),运动障碍采用美国国立卫生研究所卒中量表(National Institute ofHealth Stroke Scale,NIHSS)的偏瘫分级(Paresis Grading,PG),并分别在入院时及发病后1年的随访时间范围内评定,最后一次随访时评测功能预后(modified Rankin Scale,mRS)。结果受累侧的3天内FA值和2周FA值均明显低于未受累侧(均P<0.01),而同时平均弥散值两侧均没有变化(P>0.05)。2周受累侧和未受累侧的FA比值(Ratio of the FA,rFA),较3天rFA值,与末次PG值、末次NIHSS、末次mRS的相关性更为显著均(P<0.01)。以预测脑卒中后长期运动预后是否良好为目标时,2周rFA值受试者操作特性曲线(ROC)下面积(0.79)大于3天rFA值的ROC下面积(0.77),预测运动预后的2周rFA最佳届值为0.88(敏感度76%,特异度89%)。结论在3天至2周的急性期DTI的改变可以量化评价远期的运动缺损程度、总体预后和功能结局。2周的DTI数据与3天的DTI数据相比更有效的预测基底节区急性脑出血患者的远期总体预后、生活自理能力。     

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose–effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p < 0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p < 0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms.