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18 TNF-α IL-1β COX2, IL-β LPS Receptor H2 E2 1.Phospholipid Arachidonic acid COX-2 PGH2, PGG2 2.MAPK cascade Transcription factors (KF-κB, AP-1) COX-2 Berberine Gingerols, Shogaols Wogonin Berberine 26 p.21

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20 Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials Yuki Matsuda, Taro Kishi*, Hiroto Shibayama and Nakao Iwata Hum. Psychopharmacol Clin Exp 2013; 28: Objectives There is currently no meta-analysis of the efficacy and tolerability of Yokukansan in the treatment of behavioral and psycho- logical symptoms of dementia. Method We used information obtained from the PubMed and Cochrane Library databases until October We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing Yokukansan with usual care (UC, i.e., con- trols). Standardized mean difference and weighted mean difference were calculated. All studies used the Neuropsychiatric Inventory (NPI) for the evaluation of behavioral and psychological symptoms of dementia. Results Four relevant studies (total n=236) were identified. Yokukansan was superior to UC in the reduction of total NPI scores (p = , weighted mean difference =7.20, I2 = 0%). In addition, Yokukansan was more efficacious in reducing scores on the NPI sub- scale (delusions, hallucinations, and agitation/aggression) than UC (p < ). Yokukansan treatment also improved activities of daily living scores compared with UC (p = 0.04, standardized mean difference = 0.32, I2 = 0%). Mini-mental state examination scores did not differ between the Yokukansan and UC treatment groups. Yokukansan was not different from UC regarding discontinuation due to any cause. Conclusion Our results suggest that Yokukansan has a beneficial effect on NPI and on ADL scores and that Yokukansan seems to be a well-tolerated treatment. 32

21 33 Hum. Psychopharmacol Clin Exp 2013; 28:

22 CONCLUSION Our results suggest that Yokukansan has a more beneficial effect on Behavioral and Psychological Symptoms of Dementia (BPSD) and Activites of Daily Living (ADL) scores in patients with dementia than do Usual Care (UC), and this treatment seemed to be well-tolerated. However, double-blind, randomized, controlled clinical trials should be conducted to further explore the utility of Yokukansan in dementia patients with BPSD. Hum. Psychopharmacol Clin Exp 2013; 28:

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33 1 L- GERD (NERD, ERD) 2 L- FD, PDS, EPS 3 5-HT2cR Ach FD, PDS, EPS 4 GERD; Gastroesophageal reflux dissease NERD; Non-erosive reflux disease ERD; Erosive reflux disease FD; Functional dyspepsia PDS; Postprandial distress syndorome EPS; Epigastric pain syndorome imazu.org

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