Hu Ziheng, Wang Lirong, Ma Shifan, Kirisci Levent, Feng Zhiwei, Xue Ying, Klunk William E, Kamboh M Ilyas, Sweet Robert A, Becker James, Lv Qianzhou, Lopez Oscar L, Xie Xiang-Qun
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
Alzheimers Dement (N Y). 2018 Oct 14;4:542-555. doi: 10.1016/j.trci.2018.09.001. eCollection 2018.
We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping.
We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects.
The combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δβ = +1.46, < .0001). aHTN medications slow down cognitive decline in ChEI users (Δβ = +0.56, = .006), but not in non-ChEI users (Δβ = -0.31, = .53).
aHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin-angiotensin-aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology-identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.
我们研究了抗高血压（aHTN）药物和胆碱酯酶抑制剂（ChEIs）对阿尔茨海默病（AD）患者认知功能衰退的影响，并通过化学基因组学系统药理学图谱分析了协同作用。
我们比较了aHTN药物对617例患有高血压的AD患者简易精神状态检查表得分的影响，并研究了协同效应。
与其他aHTN组相比，利尿剂、钙通道阻滞剂和肾素 - 血管紧张素 - 醛固酮系统阻滞剂联合使用时认知功能衰退较慢（Δβ = +1.46，< .0001）。aHTN药物可减缓ChEI使用者的认知功能衰退（Δβ = +0.56， = .006），但对非ChEI使用者则无此作用（Δβ = -0.31， = .53）。
aHTN和ChEI药物显示出协同效应。利尿剂、肾素 - 血管紧张素 - 醛固酮系统阻滞剂和钙通道阻滞剂联合使用时认知功能衰退最慢。化学基因组学系统药理学确定的分子靶点为临床药物协同作用提供了系统药理学解释。结果表明改善血管健康对AD治疗至关重要，并为AD药物开发提供了新方向。
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