Title: BENEFITS OF COMBINING DONEPEZIL PLUS TRADITIONAL JAPANESE HERBAL MEDICINE ON COGNITION AND BRAIN PERFUSION IN ALZHEIMER'S DISEASE: A 12‐WEEK OBSERVER‐BLIND, DONEPEZIL MONOTHERAPY CONTROLLED TRIAL
Abstract: To the Editor: Although many attempts have been made to demonstrate its cognitive benefits in Alzheimer's disease (AD),1 donepezil, one of the cholinesterase (ChE) inhibitors, is still a standard therapeutic agent. Because of a limited benefit of a single drug alone, several clinical trials of combination regimen have been reported.2 One study demonstrated that an inhibition of ChE leads to a marked reduction of choline acetyltransferase (ChAT) levels in the rat brain.3 A negative feedback mechanism may explain this finding, supporting the use of a ChAT activator in combination with donepezil in AD. Kami-Untan-To (KUT), a traditional Japanese herbal medicine, is known to upregulate the expression of ChAT at the messenger ribonucleic acid level.4 It also increases acetylcholine levels and the number of ChAT-positive neurons in aged mice.5 Finally, Suzuki et al. conducted a clinical trial of KUT to evaluate safety and efficacy in patients with mild to moderate AD.6 Therefore, we designed an observer-blind, donepezil monotherapy controlled clinical trial of a combination of donepezil plus KUT. A 12-week, observer-blind, donepezil monotherapy controlled clinical trial was conducted at the Tohoku University hospital outpatient clinic for dementia from October 2003 through January 2005. Thirty-eight eligible AD patients (National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders Association criteria7) were randomly assigned to receive donepezil alone (n=20, mean age±standard deviation 74.6±3.9; men, n=4; women n=16) or a combination of donepezil and KUT (n=18, aged 73.7±5.6; men, n=4; women n=14). In both groups, patients received a 3-mg daily dose of donepezil for the first 14 days followed by an escalation to 5 mg thereafter. The 13 herbs of KUT6 were purchased from Tsumura Co. Ltd, Tokyo, Japan. The quality of the herbs was standardized based on the Good Manufacturing Practice defined by the Ministry of Health and Welfare of Japan. Cognitive function was measured using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)8 and Mini-Mental State Examination (MMSE), as well as regional cerebral blood flow (rCBF) using 123I-IMP-ARG single photon emission computed tomography, with SPM99 software package (Wellcome Department of Imaging Neuroscience, London, UK) implemented in MATLAB 5.3 system (Mathworks Inc., Natick, MA). At baseline, there was no significant difference in age, sex distribution, MMSE score (19.6±4.1 vs 18.9±4.9 points), ADAS-cog score (19.5±6.8 vs 21.0±7.6 points), prevalence of silent brain infarction (38% vs 44%), or grade for deep white matter lesions (0.9±0.6 vs 1.1±0.2) and for periventricular hyperintensity (0.7±0.8 vs 0.7±0.8) (as previously defined9) between the treatment groups (chi-square test, P>.05). Two patients in the donepezil monotherapy group had intractable diarrhea, conceivably due to cholinergic adverse effects by donepezil. No such event was observed in the combination group. Analyses were performed using the last observation carried forward method. Differences in the MMSE and ADAS-cog scores between baseline and posttreatment were analyzed using a paired t test and repeated measure analysis of variance. As shown in Figure 1A, relative to baseline, posttreatment MMSE scores significantly improved only in the combination group (from 18.9±4.9 to 21.6±4.2 points, P=.001; −4.17<95% confidence interval (CI) <−1.28) but not in the donepezil monotherapy group (from 19.6±4.1 to 20.4±4.5). As shown in Figure 1B, ADAS-cog scores also improved significantly in the combination group (from 21.0±7.6 to 16.8±7.1, P<.001; 2.54<95% CI<5.80) but not in the monotherapy group (from 19.5±6.8 to 18.2±7.0). Furthermore, as shown in Figure 1C, the rCBF in frontal regions significantly increased in the combination group alone (P<.05 corrected: Brodmann's area (BA) 9, (x, y, z)=(8, 50, 24), Z=5.19; BA 8, (x, y, z)=(26, 28, 46), Z=5.04; BA 9, (x, y, z)=(8, 54, 36), Z = 4.99; kE=6,029). Mean change from baseline±standard deviation in (A) Mini-Mental State Examination (MMSE) and (B) Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores at the 12-week treatment point in donepezil-treated and donepezil plus KUT (combination)-treated groups. ADAS-cog scores below baseline indicate improvement in cognitive function. (C) Z map of increased regional cerebral blood flow on repeated single photon emission computed tomography examination compared with baseline examination in the combination group. Significant areas are found in prefrontal cortices (P<.05 corrected: Brodmann's area (BA) 9, (x, y, z)=(8, 50, 24), Z=5.19; BA 8, (x, y, z)=(26, 28, 46), Z=5.04; BA 9, (x, y, z)=(8, 54, 36), Z=4.99; kE=6,029). Despite a small sample size and a short observation period, we demonstrated that the combined use of donepezil plus KUT was more beneficial than donepezil alone in cognition and brain perfusion. Although cholinergic-related adverse effects might be expected, such events did not occur in the combination group. Therefore, it is likely that donepezil and KUT worked synergistically in a safe fashion to enhance availability of acetylcholine. In our study, the prevalence of silent brain infarction was 38% in the donepezil monotherapy group and 44% in the combination group. This was comparable with results of studies with serially enrolled autopsy-confirmed AD cases by Heyman et al. (30.2%).10 Therefore, it should be noted that our study was conducted in a mixed population of pure AD and AD with cerebrovascular diseases. In summary, KUT might be used as a complementary regimen to enhance treatment success of current cholinergic therapy for AD. Financial Disclosures: Masahiro Maruyama and Hiroyuki Arai, Japanese patent no. 2004–341921. Author Contributions: Koh Iwasaki and Hiroyuki Arai: study concept and design. Masahiro Maruyama, Naoki Tomita, Mari Ootsuki, Toshifumi Matsui, Miyako Nemoto, and Miho Tsutsui: acquisition of subjects and data. Nobuyuki Okamura, Makoto Higuchi, Tomoko Suzuki, Takashi Seki, and Tomohiro Kaneta: analysis and interpretation of data. Masahiro Maruyama and Koh Iwasaki: preparation of manuscript. Sponsor's Role: None.
Publication Year: 2006
Publication Date: 2006-05-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 41
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