A Phase I Clinical Trial of Tiopronin, a Putative Neuroprotective Agent, in Aneurysmal Subarachnoid Hemorrhage
A Phase I Clinical Trial of Tiopronin, a Putative Neuroprotective Agent, in Aneurysmal Subarachnoid Hemorrhage
复制标题
DOI：
10.1227/01.neu.0000370919.93259.3c
复制
发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Connolly, E. Sander, Jr.
中科院分区：
文献类型：
--
作者：
Kim, Grace H.;Kellner, Christopher P.;Connolly, E. Sander, Jr.
背景：神经毒性的3-氨基丙醛(3-AP)参与了脑缺血后的脑损伤。硫普罗宁(N-2-硫代丙酰-甘氨酸[N-2-MPG])是美国食品和药物管理局(FDA)批准的治疗胱氨酸尿症的药物，也是一种可能的神经保护剂，已被证明能结合和中和3-AP并减少脑梗塞体积。目的：本试验的目的是建立硫普罗宁治疗动脉瘤性蛛网膜下腔出血(ASAH)患者的安全性，为进一步试验其作为神经保护剂在该疾病过程中的有效性做准备。方法：这项I期剂量递增试验采用常规的“3+3”研究设计，纳入3名患者队列。硫普罗宁剂量从1g/d开始，直到AsaH第14天。随后的每个队列都根据预先确定的指南接受一剂硫普罗宁。选择最大剂量为3g/d，因为这是FDA批准的长期治疗胱氨酸尿症的最大剂量。受试者被监测硫普罗宁的已知副作用。结果：9名患者入选，根据研究设计，这是所需的最小人数。所有患者均未出现硫普罗宁所致的严重副作用，也未发现不能归因于aSAH病理生理学的不良反应。结论：硫普罗宁3g/d在ASAH后持续14d给药似乎是安全的，且没有与长期使用相关的副作用。硫普罗宁用于ASAH后神经保护的随机、安慰剂对照第二阶段试验的计划正在进行中。
BACKGROUND: The neurotoxic aldehyde 3-aminopropanal (3-AP) contributes to brain injury following cerebral ischemia. Tiopronin (N-2-mercaptopropionyl-glycine[N-2-MPG]) is a US Food and Drug Administration (FDA)-approved drug for the treatment of cystinuria and a putative neuroprotective agent that has been shown to bind and neutralize 3-AP and reduce infarct volumes.OBJECTIVE: The objective of this trial was to establish the safety of tiopronin administration in patients with aneurysmal subarachnoid hemorrhage (aSAH) in preparation for further trials of its efficacy as a neuroprotective agent in this disease process.METHODS: This Phase I dose-escalation trial enrolled three-patient cohorts using a conventional "3 + 3" study design. Tiopronin dose began at 1 g/d until aSAH Day 14. Each subsequent cohort received a dose of tiopronin based on predetermined guidelines. A maximum dose of 3 g/d was selected, because this is the maximum FDA-approved dose for long-term cystinuria treatment. Subjects were monitored for known side effects of tiopronin.RESULTS: Nine patients were enrolled, the minimum number required based on the study design. None of these patients experienced serious side effects attributable to tiopronin, and no adverse events were noted that could not be attributed to the pathophysiology of aSAH.CONCLUSION: The administration of 3 g/d of tiopronin following aSAH for up to 14 days appears to be safe and without the side effects associated with long-term use. Plans for a randomized, placebo-controlled Phase II trial of tiopronin for neuroprotection following aSAH are underway.