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

为探讨肌萎缩侧索硬化症（ALS）的治疗方法，我们研究了超大剂量甲钴胺（> 1 mg/kg/day，I.m.）ALS患者的临床症状和动物模型的存活率。已知超高剂量甲钴胺可保护神经元免受谷氨酸诱导的兴奋性细胞死亡。使用摇摆小鼠进行的动物模型研究表明，接受超高剂量甲钴胺治疗的患者的生存期明显延长。SOD 1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的机构审查委员会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率。在对患者的长期随访中，我们证明了该方案显著延长了ALS患者的生存率。未发现重大不良反应，安全性高。因此，这种方法可能在更大的临床试验中证明是有用的，并可能为ALS提供治疗方法。作为目前研究的结果，从今年开始，将在欧洲启动一项临床试验。我们还回顾了ALS的病理生理学，使用经颅磁刺激运动皮层，而受试者是最低限度地收缩肌肉进行测试。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毫秒的放电概率激增对应于EPSP。在ALS早期患者中，与正常人相比，这种浪涌显著增强。这与神经兴奋性细胞死亡一致，并且如果在ALS的早期阶段给予，也支持该方案的功效。

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.