Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease
Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease
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DOI：
10.1001/archneur.1997.00550160091022
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发表时间：
1997-04-01
影响因子：
--
通讯作者：
Paul, SM
中科院分区：
文献类型：
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作者：
Bodick, NC;Offen, WW;Paul, SM
目的：评价酒石酸克诺美林（m1和m4选择性毒蕈碱受体（mAChR）激动剂）选择性胆碱能替代治疗可能患有阿尔茨海默病（AD）的患者的疗效。设计：6个月、随机、双盲、安慰剂对照、平行组试验，随后是1个月、单盲、安慰剂洗脱。设置：美国和加拿大17个中心的门诊患者。参与者：共343名年龄至少60岁的轻度至中度AD男性和女性。干预措施：患者接受75、150或225 mg（低、中、高剂量）的克诺美林或安慰剂治疗6个月。阿尔茨海默病评估量表的认知子量表评分结果：ADAS-Cog、临床医师访谈印象改变量表（CIBIC+）、阿尔茨海默病症状量表（ADSS）和老年患者护士观察量表（NOSGER）治疗效果显著（高剂量与安慰剂; P小于或等于0.05）和CIBIC+（高剂量与安慰剂; P小于或等于0.02）。ADSS的治疗后出现的体征和症状分析（评估AD患者的行为症状）显示，声音爆发、怀疑、妄想、激越和幻觉呈剂量依赖性显著降低（P小于或等于0.002）。在终点分析中，NOSGER评估老年人的记忆力、日常生活工具活动、自我护理、情绪、社会行为和干扰行为，也显示出显著的剂量-反应关系（P小于或等于0.02）。在高损失组中，52%的患者因不良事件而停止治疗;剂量依赖性不良事件主要是胃肠道性质的。晕厥，定义为意识丧失和肌张力，发生在12.6%的患者在高剂量group.Conclusions：观察到的改善ADAS-Cog和CIBIC+以下与咕诺美林治疗提供了第一个证据，从一个大规模的，安慰剂对照的临床试验，直接作用的毒蕈碱受体激动剂可以改善AD患者的认知功能。此外，AD对干扰行为的显著和有利的影响表明了治疗非认知症状的新方法。
Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD).Design: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout.Setting: Outpatients at 17 centers in the United States and Canada.Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD.Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months.Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER).Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P less than or equal to.05), and CIBIC+ (high dose vs placebo; P less than or equal to.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P less than or equal to.002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P less than or equal to.02). In the high-lose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group.Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.