Thal L J, Ferguson J M, Mintzer J, Raskin A, Targum S D
Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla 92093-0624, USA.
Neurology. 1999 Apr 12;52(6):1146-52. doi: 10.1212/wnl.52.6.1146.
To evaluate the safety and efficacy of controlled-release physostigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity.
A prospective, 24-week, randomized, multicenter, double-blind, parallel group study of patients was conducted. The study enrolled 475 patients at 24 sites. Patients met criteria for probable AD and were randomized to one of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage was escalated by a forced upward titration during the first 6 to 9 weeks of the trial, then maintained at a constant dose to 24 weeks. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change-Plus with caregiver input (CIBIC+). Secondary outcome measures included the Clinical Global Impression of Change (CGIC), the Geriatric Evaluation by Relatives Rating Instrument, and an Instrumental Activities of Daily Living Scale.
In an intent-to-treat population, the last observation carried forward analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between physostigmine and placebo-treated patients for both dosages, and a 0.26 to 0.31-point difference on the CIBIC+ (p = 0.048). There were no significant differences on the secondary outcome measures except for a difference on the CGIC when analyzed by use of the Cochran-Mantel-Haenszel statistic (p = 0.014). There were significant increases in gastrointestinal side effects including nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain for patients on either dose of physostigmine, resulting in a high dropout rate. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities.
CR physostigmine enhanced cognitive and global function. It is relatively safe for the treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible titration schedule might lead to a more favorable adverse event profile in the clinical arena.
评估乙酰胆碱酯酶抑制剂控释毒扁豆碱治疗轻度至中度可能的阿尔茨海默病（AD）患者的安全性和有效性。
对患者进行了一项前瞻性、为期24周、随机、多中心、双盲、平行组研究。该研究在24个地点招募了475名患者。患者符合可能的AD标准，并被随机分为三组之一：安慰剂、每日30毫克控释（CR）毒扁豆碱或每日36毫克CR毒扁豆碱。在试验的前6至9周通过强制向上滴定增加剂量，然后维持恒定剂量至24周。主要结局指标为阿尔茨海默病评估量表-认知分量表（ADAS-Cog）和基于临床医生访谈的变化印象加照顾者输入（CIBIC+）。次要结局指标包括临床总体变化印象（CGIC）、亲属评定的老年评估工具和日常生活活动量表。
在意向性治疗人群中，末次观察向前结转分析显示，两种剂量的毒扁豆碱治疗患者与安慰剂治疗患者之间在ADAS-Cog上有2.9分的差异（p = 0.002），在CIBIC+上有0.26至0.31分的差异（p = 0.048）。除使用 Cochr an-Mantel-Haenszel统计量分析时CGIC有差异外（p = 0.014），次要结局指标无显著差异。两种剂量毒扁豆碱治疗的患者胃肠道副作用显著增加，包括恶心、呕吐、腹泻、厌食、消化不良和腹痛，导致高脱落率。激越显著降低。没有心律失常或肝功能异常的证据。
CR毒扁豆碱可增强认知和整体功能。它对治疗AD继发的认知功能障碍相对安全。然而，鉴于胃肠道副作用，较低的起始剂量和灵活的滴定方案可能在临床领域导致更有利的不良事件谱。
