CLINICAL TRIAL OF CEFTRIAXONE IN SUBJECTS WITH ALS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项研究的目的是确定头孢曲松的安全性和有效性，头孢曲松是食品和药物管理局(FDA)批准的半合成第三代头孢菌素，用于治疗肌萎缩侧索硬化症(ALS)。研究假设是静脉注射头孢曲松将延长ALS患者无需气管切开或永久辅助通气(PAV)的生存期。在美国国家神经疾病和中风研究所(NINDS)领导的一个合作小组的体外筛选计划中，FDA批准了29项与各种神经退行性疾病相关的1040种药物，包括头孢曲松在内的几种头孢菌素在ALS相关测试中显示命中。在筛选增加星形细胞谷氨酸转运体EAAT2[1]表达的化合物的模型中以及在超氧化物歧化酶介导的毒性模型中都注意到了有效性。自从最初的NINDS筛查完成以来，已经表明头孢曲松增加了啮齿动物大脑中EAAT2启动子的激活和随后的EAAT2活性。头孢曲松还可保护培养的运动神经元免受兴奋性毒性细胞死亡[2]，并具有抗氧化和抗凋亡活性[3，4]。我们提出了一种新的研究设计策略，通过多个中间分析不间断地进行药物开发，以快速应用有关脑脊液(CSF)渗透和头孢曲松安全性的信息来开展PHSE III疗效研究[5]。这项拟议研究的重要第一步是确定头孢曲松在ALS患者中的脑脊液药代动力学(阶段1)，随后进行为期至少16周的安全性和耐受性研究(阶段2)，然后进行全面疗效试验(阶段3)。

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. The study objective is to determine the safety and efficacy of ceftriaxone, a Food and Drug Administration (FDA) approved semi-synthetic third-generation cephalosporin, in subjects with amyotrophic lateral sclerosis (ALS). The study hypothesis is that intravenous (IV) ceftriaxone will prolong survival free of tracheostomy or permanent assisted ventilation (PAV) in patients with ALS. In a National Institute of Neurological Disorders and Stroke (NINDS)-led cooperative group in-vitro screening program of 1040 FDA approved drugs in 29 assays relevant to various neurodegenerative disorders, several cephalosporins, including ceftriazone, showed hits in ALS relevant assays. Efficacy was noted in models screening for compounds that increased expression of the astrocytic glutamate transporter, EAAT2 [1], and in models of superoxide dismutase mediated toxicity. Since completion of the original NINDS screen, it has been shown that ceftriaxone increases EAAT2 promotor activation and subsequent EAAT2 activity in rodent brains. Ceftriaxone also protects motor neurons in culture from excitotoxic cell death [2], and has antioxidant and anti-apoptotic activity [3,4]. We propose a novel study design strategy of nonstop drug development with multiple intermediate analyses to rapidly apply information on cerebrospinal fluid (CSF) penetration and safety of ceftriazone to the development of a phse III efficacy study [5]. An important first step in the proposed study is to determine the CSF pharmacokinetics of ceftriaxone in subjects with ALS (STAGE 1), followed by a safety and tolerability study for a minimum of 16 weeks (STAGE 2), and then a full efficacy trial (STAGE 3)