Ph 2 Study of Dextromethorphan in the Treatment of Rett Syndrome

右美沙芬治疗 Rett 综合征的 2 期研究

• 批准号: 8332679
• 负责人: SAKKUBAI R NAIDU
• 金额: $ 39.97万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332679
• 关键词: Ph; Study; Dextromethorphan; Treatment; Rett

Project Summary/Abstract: Our proposal consists of a "Placebo controlled trial of dextromethorphan in Rett syndrome" to be conducted at the Kennedy Krieger Institute (KKI)/Johns Hopkins Medical Institutions (JHMI). RTT is a neurodevelopmental disorder with devastating consequences on both brain and systemic neurons. Girls with RTT have seizures and hyperkinetic movements suggesting excessive excitatory neuronal activity, and the levels of the excitatory neurotransmitter, glutamate, in cerebrospinal fluid are elevated. Brain magnetic resonance spectroscopy (MRS) also shows high levels of glutamate. Neurotransmitter autoradiography of postmortem frontal cortex from girls less than 8 years of age with RTT showed a significant increase in NMDA-type (N-methyl-D-aspartate) glutamate receptors despite a 50% reduction in the number of synapses. Additionally, our in vitro studies of cultured neurons from mice with a mutation in the MECP2 gene show that they are abnormally sensitive to hypoxia and glutamate mediated excitotoxicity. Electrophysiologic studies of these mice show enhanced excitability in the hippocampus and rhythmic discharges in cortex on EEG. As DM competitively blocks NMDA receptor channels, we propose that it will improve the clinical manifestations of RTT (abnormal behaviors, cognitive deficits, neurophysiological abnormalities, and seizures) by reducing excitatory synaptic activity thereby rescuing brain tissue from excitotoxicity. Presently, RTT has no cure. Our objective is to test the efficacy and safety of DM in RTT to improve communication and alleviate behavioral and physical symptoms. Towards this goal, the outcome measures are: Primary outcome: Improvement in the receptive language age equivalent scores on the Mullen scale; Secondary outcomes: a) Improvement in other subscales of the Mullen; b) Improvement in the Socialization and Communication scales of Vineland Adaptive Behavior; c) Improvement in the Ghuman- Folstein Screen for Social Interaction. Exploratory variables are a) Change in the Aberrant Behavior Checklist scores; b) Rett Syndrome Behavior Questionnaire; c) EEG and MisMatch Negativity; d) Quality of Life Questionnaire. A total of 60 subjects who are fast metabolizers of DM, with clinical features of RTT and a known mutation in the MECP2 gene, will be equally randomized in a double-masked trial to placebo or treatment with 5mg dextromethorphan /kg/day for twelve weeks using a blocked and stratified (for age and the presence of seizures) randomization. Analyses will be done on an intention-to-treat basis. Our previous study showing improved alertness and social interaction on neuropsychological and behavioral assessments is encouraging.

项目摘要/摘要： 我们的建议包括一项“右美沙芬治疗雷特综合征的安慰剂对照试验” 在肯尼迪·克里格研究所(KKI)/约翰·霍普金斯医疗机构(JHMI)进行。 RTT是一种神经发育障碍，对大脑和 全身性神经元。患有RTT的女孩有癫痫发作和多动症 过度的兴奋性神经元活动和兴奋性神经递质的水平， 脑脊液中的谷氨酸含量升高。脑磁共振波谱(MRS) 也显示出高水平的谷氨酸。死后额叶神经递质放射自显影 患有RTT的8岁以下女孩大脑皮质中NMDA型显著增加 (N-甲基-D-天冬氨酸)谷氨酸受体，尽管数量减少了50% 突触。此外，我们对培养的小鼠神经元的体外研究发现， MeCP2基因表明它们对低氧和谷氨酸介导的反应异常敏感 兴奋性毒性。对这些小鼠的电生理研究表明，小鼠的兴奋性增强 脑电显示海马区和大脑皮层节律性放电。因为DM竞争性地阻止了NMDA 受体通道，我们认为它将改善RTT(异常)的临床表现 行为、认知缺陷、神经生理异常和癫痫) 兴奋性突触活动，从而将脑组织从兴奋性毒性中拯救出来。目前，RTT已经 没有解药。我们的目标是测试DM在RTT中的有效性和安全性，以改善沟通 并缓解行为和身体症状。为实现这一目标，成果措施包括： 主要结果：接受语言年龄在马伦测验上的等值分数的改善 量表；次级结果：a)马伦其他分量表的改进；b)改进 文兰适应行为的社会化和交际量表；c)改进 在戈曼-福尔斯坦的社交互动屏幕上。探索性变量是)变化 异常行为检查表评分；b)Rett综合征行为问卷；c)EEG和 不匹配的负性；d)生活质量问卷。共有60名受试者的速度很快 具有RTT临床特征和MECP2基因已知突变的DM代谢者将 在双盲试验中随机分为安慰剂或5毫克的治疗 右美沙芬/公斤/天，连续12周，使用阻滞剂和分层(针对年龄和 癫痫的存在)随机化。分析将在意向治疗的基础上进行。我们的 先前的研究表明，提高警觉性和社交互动对神经心理和 行为评估令人鼓舞。