Disease Modification in Parkinson's Disease
Disease Modification in Parkinson's Disease
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DOI：
10.2165/11591320-000000000-00000
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发表时间：
2011-01-01
期刊：
影响因子：
2.8
通讯作者：
Severt, W. Lawrence
中科院分区：
文献类型：
--
作者：
Henchcliffe, Claire;Severt, W. Lawrence
帕金森病（PD）是一种与年龄相关的进行性多系统神经退行性疾病，导致显著的发病率和死亡率，并在老龄化人口中造成越来越大的社会和经济负担。PD的标志是黑质致密部多巴胺能神经元的丧失，导致运动迟缓、僵硬和震颤。因此，目前的药物治疗以多巴胺替代为主，以减轻症状。然而，两个主要问题使这种方法复杂化：(i)运动症状持续进展，需要增加药物剂量，这导致短期不良反应和中长期运动并发症；（ii）多巴胺替代对治疗非多巴胺能运动和非运动症状几乎没有作用，这些症状是发病率的重要来源，包括痴呆、睡眠障碍、抑郁、体位性低血压和导致跌倒的体位不稳定。因此，开发更广泛和更基本的PD治疗方法至关重要，主要的研究工作集中在开发神经保护干预措施上。尽管许多令人鼓舞的临床前数据表明，通过减缓细胞损失来解决潜在病理生理的可能性，但过去将其转化为临床领域的努力在很大程度上证明是令人失望的。寻找PD的神经保护或疾病改善药物的障碍包括缺乏有效的进展生物标志物，这阻碍了临床试验的设计和解释；候选神经保护疗法的症状和神经保护作用难以区分；可能在一些基本的临床前模型和测试中存在根本缺陷。然而，最近的三个临床试验使用了一种新的延迟启动设计，试图克服这些障碍。虽然没有检查决定神经保护作用的细胞损失和功能标记，但该试验设计实用地测试了早期干预与晚期干预是否有益。如果呈阳性（即早期干预被证明更有效），这表明疾病发生了改变，这可能是神经保护或其他机制造成的。因此，该策略为支持PD的神经保护提供了第一步。在三个延迟启动设计临床试验中，有两个研究了雷沙吉兰（一种特异性不可逆单胺氧化酶B抑制剂）的早期和较晚启动。每一项试验都支持（尽管尚未证实）疾病改善效果。第三个延迟开始设计的临床试验检查普拉克索潜在的疾病改善作用，不幸的是，根据初步报告，据报道是负面的。体外和PD动物模型研究表明，雷沙吉兰具有神经保护作用，这一观点更加令人信服。在这篇综述中，我们研究了迄今为止在PD中证明神经保护作用的努力，描述了正在进行的神经保护试验，并批判性地讨论了最近延迟启动的临床试验的结果，这些试验测试了雷沙吉兰和普拉克索在PD中可能的疾病改善活性。
Parkinson's disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions.Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing.However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects.In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD.