DISULFIRAM TREATMENT IN AMYOTROPHIC LATERAL SCLEROSIS

双硫仑治疗肌萎缩侧索硬化症

• 批准号: 7380551
• 负责人: DALE J LANGE
• 金额: $ 0.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-17 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380551
• 关键词: amyotrophic lateral sclerosis; cysteine endopeptidases; disulfiram; oxygen

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，可导致肢体、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发作后5年内。没有治疗可以逆转ALS引起的虚弱。治疗ALS的理想候选物将是可以干扰ALS中所见的程序性细胞死亡、可以阻断谷氨酸受体、抑制活性氧物质并抑制半胱天冬酶级联的药剂。 在ALS小鼠模型中，通过鞘内注射特异性半胱天冬酶3抑制剂抑制半胱天冬酶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路线。不幸的是，除了鞘内给药外，还没有已知的抑制半胱天冬酶的药物。 双硫仑是奥德赛制药公司正在开发的一种药物产品，Pliva公司的子公司，用于治疗IND 63，907下的肌萎缩性侧索硬化症（ALS）患者。双硫仑目前由Odyssey Pharmaceuticals，Inc.销售。在美国，商品名为Antabuse，用于帮助管理选定的试图保持强制清醒状态的慢性酒精中毒患者。根据数十年的临床经验，本方案中所用剂量的双硫仑的一般安全性和耐受性已得到充分确立。 最近在组织培养系统中的发现表明双硫仑可以显著抑制半胱天冬酶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中的临床作用是合理的。该方案将是一项初步研究，旨在进一步探索ALS特定背景下的安全性和耐受性。本研究将通过提供双硫仑在ALS患者中的安全性的初步试点评估，为全面的临床计划做好准备。