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

为了研究一种治疗肌萎缩性侧索硬化症（ALS）的方法，我们在动物模型中研究了超高剂量甲基钴胺素（bbb10 1mg/kg/天，I.m）对ALS患者临床症状和生存的影响。已知超高剂量甲基钴胺可保护神经元免受谷氨酸诱导的兴奋性细胞死亡。动物模型研究表明，使用超高剂量甲基钴胺治疗的小鼠存活时间明显延长。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和未接受方案治疗的ALS患者的临床体征和生存期。在对患者的长期随访中，我们证明了这种治疗方案显著延长了ALS患者的生存期。没有注意到主要的不良反应，安全性被证实是高的。因此，这种方法可能在更大规模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。作为目前研究的结果，一项临床试验将于今年在欧洲启动。我们也回顾了ALS的病理生理学使用经颅磁刺激运动皮层，而受试者是最小限度地收缩肌肉进行测试。使用刺激后时间直方图（pshs）分析运动单元放电的时间，在刺激后20-30毫秒的放电概率激增对应于EPSP。在早期ALS患者中，与正常人相比，这种激增明显增强。这与神经兴奋性细胞死亡是一致的，并且也支持该方案在ALS早期给予的有效性。

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.