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Abstract：
With the current limited drug therapy for the core symptoms of autism spectrum disorder (ASD), we herein report a randomized, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3-6 years old. A total of 120 children were enrolled into the study and randomly assigned to either 0.5 mg bumetanide or placebo. In the final sample, 119 children received at least one dose of bumetanide (59 children) or placebo (60 children) were included in the final analysis. The primary outcome was a reduction in the Childhood Autism Rating Scale (CARS) score, and the secondary outcomes were the Clinical Global Impressions Scale (CGI) -Global Improvement (CGI-I) score at 3 months and the change from baseline to 3-month in the Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing the severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with a decrease in insular GABA in the bumetanide group. In conclusion, this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD. However, the clinical significance remains uncertain, and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.
摘要：
目前针对自闭症谱系障碍（ASD）核心症状的药物治疗有限，我们在这里报告了一个随机的，双盲,安慰剂对照试验以调查疗效，安全,3～6岁ASD患儿应用布美他尼的潜在神经机制。共有120名儿童被纳入研究，并随机分配给0.5mg布美他尼或安慰剂。在最后的样本中,最终分析包括119名接受至少一剂布美他尼（59名儿童）或安慰剂（60名儿童）的儿童。主要结果是儿童自闭症评定量表（CARS）评分降低，次要结局是3个月时的临床总体印象量表(CGI)-总体改善(CGI-I)评分以及自闭症诊断观察时间表(ADOS)从基线到3个月的变化.磁共振波谱（MRS）用于测量治疗前后岛叶皮层（IC）中γ-氨基丁酸（GABA）和谷氨酸神经递质的浓度。与安慰剂相比，布美他尼治疗在降低严重程度方面明显更好。没有患者因不良事件退出试验。布美他尼在降低岛叶GABA方面优于安慰剂，使用MRS测量，被证明了。临床改善与布美他尼组的岛叶GABA减少有关。总之,这项试验在一大群以中度和重度ASD为主的幼儿中进行,结果表明布美他尼在改善ASD的核心症状方面是安全有效的.然而,临床意义仍不确定，未来的多中心临床试验需要重复这些发现,并使用多种结局指标确认临床意义.
