DISULFIRAM TREATMENT IN AMYOTROPHIC LATERAL SCLEROSIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肌萎缩侧索硬化症(ALS)是一种神经退行性疾病，导致肢体、呼吸和吞咽肌肉的进行性虚弱和萎缩。死亡通常发生在症状出现后5年内。没有任何治疗方法可以扭转肌萎缩侧索硬化症造成的虚弱。治疗肌萎缩侧索硬化症的理想候选药物是一种能够干扰肌萎缩侧索硬化症中的程序性细胞死亡，可以阻断谷氨酸受体，抑制活性氧物种，并抑制caspase级联的药物。在ALS小鼠模型中，鞘内注射特异性caspase3抑制剂抑制caspase1和caspase3，可使小鼠的生命延长22%(从126天延长到155天)。观察到了剂量依赖性的反应。因此，抑制caspase系统的一个组成部分似乎是一个很有前途的研究方向。不幸的是，除了鞘内给药外，目前还没有已知的药物可以通过任何途径来抑制caspase。双硫兰是Pliva公司的子公司奥德赛制药公司正在开发的一种药物产品，用于根据IND 63,907治疗肌萎缩侧索硬化症(ALS)患者。双硫兰目前由奥德赛制药公司以Antabuse的商标在美国销售，作为对试图保持强制戒酒状态的选定慢性酒精中毒患者的辅助治疗。几十年的临床经验充分证明了本方案中所用剂量的双硫兰的总体安全性和耐受性。最近在组织培养系统中的发现表明，双硫兰可以显著抑制caspase3。然而，双硫兰在细胞死亡途径上还有其他作用。它还能稳定线粒体膜电位，并抑制活性氧。根据这一信息，初步探讨双硫仑治疗ALS的临床效果是合理的。该方案将是一项先导性研究，以进一步探索在ALS特定情况下的安全性和耐受性。本研究将通过对ALS患者使用双硫仑的安全性进行初步的试点评估，为全面的临床计划铺平道路。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive weakness and wasting of limb, breathing, and swallowing muscles. Death usually occurs within 5 years of symptom onset. No treatment reverses the weakness caused by ALS. An ideal candidate for treatment of ALS would be an agent that can interfere with the programmed cell death seen in ALS, could block glutamate receptors, supress reactive oxygen species, and inhibit the caspase cascade. In the mouse model of ALS, inhibition of caspase 1 and 3 by intrathecal injection of specific caspase 3 inhibitors, prolonged life by 22% (from 126 to 155 days). A dose-dependent response was observed. Therefore, inhibition of a component of the caspase system would seem to be a promising line of research to pursue. Unfortunately there are no pharmaceutical agents known to inhibit caspase that can be given by any route other than intrathecally. Disulfiram is a drug product being developed by Odyssey Pharmaceuticals, Inc., a subsidiary of Pliva, Inc., for the treatment of patients with amyotrophic lateral sclerosis (ALS) under IND 63,907. Disulfiram is currently marketed by Odyssey Pharmaceuticals, Inc. in the US under the trade name, Antabuse as an aid in the management of selected chronic alcoholic patients who are attempting to remain in a state of enforced sobriety. The general safety and tolerability of disulfiram in the doses used in this protocol are well established by decades of clinical experience. Recent findings in a tissue culture system have shown that disulfiram can dramatically inhibit caspase 3. However, disulfiram has other effects on the cell death pathway. It also stabilizes mitochondrial membrane potentials as well as suppressing reactive oxygen species. In light of this information, a preliminary exploration of the clinical effects of disulfiram in ALS is justified. This protocol will be a pilot study to futher explore safety and tolerability in the specific context of ALS. The present study will prepare the way for a full clinical program by providing an initial pilot evaluation of the safety of disulfiram in patients with ALS.