Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study
Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study
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DOI：
10.3233/jad-2012-120805
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Leon, Teresa
中科院分区：
文献类型：
--
作者：
del Ser, Teodoro;Steinwachs, Klaus C.;Leon, Teresa
这项先导性、双盲、安慰剂对照、随机、剂量递增试验探讨了糖原合成酶激酶-3抑制剂tideglusib在阿尔茨海默病（AD）患者中的安全性和有效性。30例接受胆碱酯酶抑制剂治疗的轻度-中度AD患者分别接受递增剂量（400、600、800、1，000 mg）的tideglusib或安慰剂（比例2：1）给药4、4、6和6周。主要目的是根据药物递增或停药的严格标准，评价tideglusib的安全性和耐受性。将简易精神状态检查（MMSE）、阿尔茨海默病评估量表-认知子量表（ADAS-cog+）、文字流畅性、老年抑郁量表（GDS）和最终总体临床评估（GCA）作为次要目标进行评估。治疗耐受性良好。活性药物组和安慰剂组的不良事件同样频繁，除了6例活性药物病例中血清转氨酶的一些中度、无症状和完全可逆的升高（>2.5 × ULN）（p = 0.001）。Tideglusib在MMSE、ADAS-cog、GDS和GCA方面产生了积极趋势，在该小样本中无统计学显著性。活动组的MMSE应答者显著较高（p = 0.05）。与安慰剂相比，剂量递增至1000 mg/天的患者的MMSE获益为1.68分，ADAS-cog+获益为4.72分。这项小型初步研究为替德格鲁西治疗AD患者提供了有价值的安全性和疗效估计，目前正在一项更大规模的临床试验中得到证实。由于剂量递增和样本量小，该试验提供的证据不足以支持或拒绝tideglusib在AD中的获益。
This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 x ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.