Responder characteristics to a single oral dose of cholinesterase inhibitor:: A double-blind placebo-controlled study with tacrine in Alzheimer patients

被引:59
作者
Almkvist, O
Jelic, V
Amberla, K
Hellström-Lindahl, E
Meurling, L
Nordberg, A
机构
[1] Huddinge Univ Hosp, NEUROTEC, Dept Clin Neurosci Occupat Therapy & Elderly Care, Div Mol Neuropharmacol, S-14186 Huddinge, Sweden
[2] Huddinge Univ Hosp, NEUROTEC, Dept Clin Neurosci Occupat Therapy & Elderly Care, Div Geriatr Med, S-14186 Huddinge, Sweden
[3] Huddinge Univ Hosp, NEUROTEC, Dept Clin Neurosci Occupat Therapy & Elderly Care, Geriatr Clin, S-14186 Huddinge, Sweden
[4] Huddinge Univ Hosp, Karolinska Inst, Dept Clin Pharmacol, S-14186 Huddinge, Sweden
关键词
Alzheimer's disease; acetylcholinesterase activity; cholinesterase inhibitor; tacrine; single dose; responders;
D O I
10.1159/000051232
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
A proportion of Alzheimer's disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean +/- SD: 10.5 +/- 11.8, range: 1.0-51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) epsilon4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE epsilon4 allele. Copyright (C) 2001 S. Karger AG, Basel.
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页码:22 / 32
页数:11
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