DISULFIRAM TREATMENT IN AMYOTROPHIC LATERAL SCLEROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，会导致进行性无力和肢体、呼吸和吞咽肌肉的萎缩。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逆转由肌萎缩侧索硬化症引起的虚弱。治疗渐冻症的理想候选药物是一种能够干扰渐冻症中所见的程序性细胞死亡的药物，可以阻断谷氨酸受体，抑制活性氧，抑制半胱天冬酶级联反应。在ALS小鼠模型中，鞘内注射特异性caspase 3抑制剂抑制caspase 1和3，使寿命延长22%（从126天延长至155天）。观察到剂量依赖性反应。因此，抑制半胱天冬酶系统的一个组成部分似乎是一个有前途的研究方向。不幸的是，目前还没有已知的药物可以抑制半胱天冬酶，可以通过除鞘内以外的任何途径给予。Disulfiram是由Pliva， Inc.的子公司Odyssey Pharmaceuticals， Inc.开发的一种药物产品，用于治疗肌萎缩侧索硬化症（ALS）患者，IND为63,907。Disulfiram目前由美国奥德赛制药公司（Odyssey Pharmaceuticals, Inc.）以商品名Antabuse在市场上销售，用于帮助管理某些慢性酒精患者，这些患者试图保持强制清醒状态。数十年的临床经验证明，本方案中使用剂量的双硫仑的一般安全性和耐受性得到了很好的证实。最近在组织培养系统中发现，双硫仑可以显著抑制caspase 3。然而，双硫仑对细胞死亡途径有其他影响。它还稳定线粒体膜电位以及抑制活性氧。根据这些信息，初步探索双硫仑在ALS中的临床效果是合理的。该方案将是一项试点研究，以进一步探索ALS特定情况下的安全性和耐受性。目前的研究将通过提供双硫仑对ALS患者安全性的初步试点评估，为完整的临床项目做好准备。

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.