SAFETY AND TOLERABILITY OF PYRIMETHAMINE IN SPORADIC ALS

乙胺嘧啶治疗散发性肌萎缩侧索硬化症的安全性和耐受性

• 批准号: 7953720
• 负责人: DALE J LANGE
• 金额: $ 0.07万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953720
• 关键词: Amyotrophic Lateral Sclerosis; Animals; Attenuated; Cell Death; Cerebrospinal Fluid; Clinical Research; Code; Computer Retrieval of Information on Scientific Projects Database; Disease; Disease Progression; Dose; Enzymes; FDA approved; Free Radical Scavenging; Funding; Genes; Grant; Human; In Vitro; Institution; Leg; Life; Lymphocyte; Malaria; Measures; Metabolism; Molecular; Motor; Mus; Mutate; Mutation; Neurodegenerative Disorders; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Process; Proteins; Pyrimethamine; Quality of life; Research; Research Personnel; Resources; Respiratory Muscles; Role; SOD1 gene; Safety; Screening procedure; Source; Speed; System; Toxoplasmosis; United States National Institutes of Health; Upper arm; copper zinc superoxide dismutase; mouse model; multicatalytic endopeptidase complex; mutant; oxidative damage; prevent; programs

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. 1/10/2008 Hypothesis: In patients with sporadic ALS, pyrimethamine will reduce SOD1 levels in lymphocytes and cerebrospinal fluid at doses of 100 mg of less. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS. There is no treatment. The cause is uncertain in most patients. Three percent of patients have a familial form of ALS (FALS) that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). The exact mechanism of how the mutant SOD1 causes the disease is uncertain. However, the SOD1 is definitely integral in the pathogenesis of FALS because inserting the SOD1 mutant gene into mice causes a disease closely resembling ALS; inhibiting expression of the SOD1 gene prevents animals from developing the disease; and increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Reducing SOD1 in the mouse model of FALS attenuates the disease proportionate to the degree of SOD1 reduction. The role that SOD1 plays in sporadic ALS (SALS) is uncertain. However, it is possible that either through mutation, oxidative stress, or some other factor, SOD1 may sustain molecular damage which confers an enhanced propensity to cause oxidative damage, impair processing of the protein through the proteasome and lysosomal system, and alter cellular metabolism eventually causing cell death. Accordingly, lowering of SOD1 levels in sporadic ALS may result in slowing of the disease process. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are now known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. This study's primary objective is to evaluate the safety and tolerability of pyrimethamine in patients with sporadic ALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction. Ten (10) patients with mild to moderate sporadic ALS will receive up to 100mg of pyrimethamine for 44 weeks. Change in Appel ALS score, ALS-FRSr, quality of life and motor unit estimates (MUNE) will also be measured.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 1/10/2008 假设： 在散发性ALS患者中，乙胺嘧啶将降低淋巴细胞和脑脊液中的SOD 1水平，剂量为100 mg或更少。 肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，导致手臂，腿部和呼吸肌的持续进行性无力，这是一致致命的。 大约有30，000名ALS患者。没有治疗方法。大多数患者的病因尚不确定。3%的患者患有家族性ALS（FALS），这是由编码自由基清除酶铜/锌超氧化物歧化酶（SOD 1）的基因突变引起的。突变的SOD 1如何引起疾病的确切机制尚不确定。然而，SOD 1在FALS的发病机制中肯定是不可或缺的，因为将SOD 1突变基因插入小鼠体内会导致与ALS非常相似的疾病;抑制SOD 1基因的表达可以防止动物发展这种疾病;并且增加或减少突变基因的数量会相应地加速或减缓疾病的进展。在小鼠模型中减少SOD 1可减轻与SOD 1减少程度成比例的疾病。 SOD 1在散发性ALS（SALS）中的作用尚不确定。然而，有可能通过突变、氧化应激或一些其他因素，SOD 1可能维持分子损伤，这赋予引起氧化损伤的增强倾向，通过蛋白酶体和溶酶体系统损害蛋白质的加工，并改变细胞代谢，最终导致细胞死亡。因此，散发性ALS中SOD 1水平的降低可能导致疾病过程的减缓。 通过对具有降低SOD 1水平能力的药物的广泛的体外筛选程序，现在已知几种降低SOD 1蛋白水平的分子。最有效的分子之一是乙胺嘧啶，这是FDA批准的用于治疗疟疾和弓形虫病的药物。乙胺嘧啶在小鼠中显著降低了SOD 1水平，我们的初步研究在人类中也显示了类似的发现。 本研究的主要目的是评估乙胺嘧啶在散发性ALS患者中的安全性和耐受性。次要目的是确定最大SOD 1水平降低的剂量优化。10例轻度至中度散发性ALS患者将接受高达100 mg乙胺嘧啶治疗44周。还将测量阿佩尔ALS评分、ALS-FRSr、生活质量和运动单位估计值（MUNE）的变化。