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A Study of the Clinical Efficacy of Ultra-high Dose Methylcobalamin in Amyotrophic Lateral Sclerosis

超高剂量甲钴胺治疗肌萎缩侧索硬化症的临床疗效研究

基本信息

批准号：
13557056
负责人：
KAJI Ryuji
金额：
$ 2.11万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

To develop a method of treating amyotrophic lateral sclerosis (ALS), a typical neurodegenerative disease of unknown etiology, we studied the effect of ultra-high dose methylcobalamin (>1mg/kg/day, I.m.) on clinical symptoms in patients with ALS and survival in an animal model. Ultra-high dose methylcobalamin is known to protect neurons from glutamate-induced excitatory cell death. The study of an animal model using wobbler mouse demonstrated a significantly longer survival of those treated with ultra-high dose methylcobalamin. That of SOD1-transgenic rat is still under way, with a promise of beneficial effects. After having an approval of the institutional review board of the ethics committee of Tokushima University and after obtaining informed consent, we compared the clinical signs and survivals between patients with ALS treated with regimen and those without it. In a long-term follow-up of patients, we demonstrated that this regimen significantly prolonged survivals in ALS. No major adverse effects were noted, and the safety was confirmed to be high. Thus this method may prove useful in larger clinical trials, and may give a therapeutic method for ALS. As a result of the present study, a clinical trial is going to be launched in Europe, starting this year. We also reviewed the pathophysiology of ALS using transcranial magnetic stimulation over the motor cortex, while the subject was minimally contracting the muscle to be tested. The timing of the motor unit discharge was analyzed using a post-stimulus time histograms (PSTHs), and a surge of the firing probability at 20-30 msec after the stimulation corresponds to the EPSP. In patients with early stage of ALS, this surge was significantly enhanced as compared to the normals. This is consistent with neuroexcitatory cell death, and also supports the efficacy of this regimen if given in the early stage of ALS.

为了建立一种治疗肌萎缩侧索硬化症(ALS)的方法，我们研究了超大剂量甲钴胺(&gt；1 mg/kg/day，I.M.)的治疗效果。对肌萎缩侧索硬化症患者的临床症状和动物模型存活的影响。众所周知，超高剂量的甲钴胺可以保护神经元免受谷氨酸诱导的兴奋性细胞死亡。用Wobbler小鼠进行的动物模型研究表明，服用超高剂量甲钴胺的人存活时间明显延长。SOD1转基因大鼠的研究仍在进行中，有望产生有益的效果。在获得德岛大学伦理委员会机构审查委员会的批准并获得知情同意后，我们比较了接受方案治疗的ALS患者和未接受方案治疗的ALS患者的临床体征和生存情况。在对患者的长期随访中，我们证明了该方案显著延长了ALS患者的生存时间。没有发现重大不良反应，安全性被证实是高的。因此，这种方法可能在更大的临床试验中被证明是有用的，并可能为ALS提供一种治疗方法。作为这项研究的结果，一项临床试验将从今年开始在欧洲启动。我们还回顾了ALS的病理生理学，当受试者最小限度地收缩被测试的肌肉时，通过运动皮质进行经颅磁刺激。使用刺激后时间直方图(PSTH)分析运动单位放电的时间，刺激后20-30毫秒的放电概率峰对应于EPSP。在ALS早期患者中，与正常人相比，这一峰明显增强。这与神经兴奋性细胞死亡是一致的，也支持了如果在ALS的早期阶段给予该方案的疗效。