Novel Pharmacological Strategies in Autism

自闭症的新药理学策略

• 批准号: 7070638
• 负责人: Christopher J McDougle
• 金额: $ 31.44万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7070638
• 关键词: adolescence (12-20); aggression; antipsychotic agents; autism; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; drug adverse effect; electrocardiography; extrapyramidal disorder; human subject; human therapy evaluation; hyperprolactinemia; mental disorder chemotherapy; middle childhood (6-11); patient oriented research; self destructive behavior; social behavior; weight gain

DESCRIPTION (provided by applicant): The long-term objective of this application is to improve the pharmacotherapy of autism by developing safer and more efficacious novel drug treatment strategies. Autism is a major public health concern in the U.S. and throughout the world. The cost of the disability is estimated to be in the range of $30 billion annually in the U.S. alone. Despite an improved ability to reduce the aggression, self-injurious behavior (SlB) and irritability that often occur with autism, existing drug treatments are associated with significant adverse effects. These include extrapyramidal symptoms (EPS) and tardive dyskinesia with "typical antipsychotics" and significant weight gain and associated hyperlipidemia, hypertriglyceridemia, diabetes mellitus, hepatic abnormalities, and at times mortality with the "atypical" antipsychotics. The only atypical antipsychotic not linked with significant weight gain, ziprasidone, has been shown to prolong the corrected QT interval on electrocardiogram (ECG); a potentially fatal complication. Both typical and atypical antipsychotics cause hyperprolactinemia. Furthermore, to date, no drug treatment has been developed for the core social impairment of autism. In this application, Study A. Phase I involves an 8-week randomized double blind, placebo-controlled trial of the novel antipsychotic aripiprazole for the short-term treatment of aggression, SlB and irritability in children and adolescents (age 6-17 years) with autism (n=88). Subjects who respond will be eligible to enter a 4-month open-label continuation trial of aripiprazole (Study A. Phase II) designed to determine if ongoing treatment is associated with the maintenance of response. Potential adverse effects of aripiprazole, with particular attention to EPS, weight gain, prolongation of the corrected QT interval on ECG, and hyperprolactinemia, will be monitored throughout both Phases of Study A. Study B. is a pilot combination drug treatment study to determine if adding open-label D-cycloserine, a partial agonist at the N-methyI-D-aspartate (NMDA) subtype of glutamate receptor, to on-going open-label aripiprazole results in improved social behavior in subjects whose aggression, SlB and irritability Iremain stabilized upon completion of Study A. Phase II (following 6 months of aripiprazole monotherapy).

描述（由申请人提供）：本申请的长期目标是通过开发更安全、更有效的新型药物治疗策略来改善自闭症的药物治疗。自闭症是美国和全世界的一个主要公共卫生问题。据估计，仅在美国每年因残疾造成的损失就达 300 亿美元。尽管减少自闭症患者经常出现的攻击性、自残行为（SIB）和烦躁的能力有所提高，但现有的药物治疗仍会产生显着的不良反应。这些包括“典型抗精神病药”引起的锥体外系症状（EPS）和迟发性运动障碍，以及“非典型”抗精神病药引起的体重显着增加和相关的高脂血症、高甘油三酯血症、糖尿病、肝脏异常，有时甚至导致死亡。齐拉西酮是唯一与体重显着增加无关的非典型抗精神病药物，已被证明可以延长心电图 (ECG) 上校正的 QT 间期；潜在致命的并发症。典型和非典型抗精神病药都会引起高催乳素血症。此外，迄今为止，尚未开发出针对自闭症核心社会障碍的药物治疗方法。在本申请中，研究 A. I 期涉及一项为期 8 周的随机双盲、安慰剂对照试验，研究新型抗精神病药物阿立哌唑，用于短期治疗儿童和青少年（6-17 岁）的攻击性、SlB 和易激惹行为患有自闭症（n=88）。做出反应的受试者将有资格参加为期 4 个月的阿立哌唑开放标签持续试验（研究 A. II 期），旨在确定持续治疗是否与维持反应相关。阿立哌唑的潜在不良反应，特别是 EPS、体重增加、心电图校正 QT 间期延长和高催乳素血症，将在研究 A 的两个阶段进行监测。研究 B. 是一项试点联合药物治疗研究，以确定是否将开放标签 D-环丝氨酸（一种谷氨酸受体 N-甲基-D-天冬氨酸 (NMDA) 亚型的部分激动剂）添加到正在进行的开放标签中阿立哌唑可改善受试者的社会行为，在研究 A.II 期完成后（阿立哌唑单药治疗 6 个月后），受试者的攻击性、SlB 和易怒性仍保持稳定。