[The effect of PHD inhibitor on tumor microenvironment and tumor immune response].

Since the approval of HIF-PH inhibitors, HIF-PH inhibitors have been used clinically, and many studies and clinical case reports have been reported in Japan. A lot of information has been accumulated on clinical usage. However, HIF-PH inhibitors require careful administration for cancer patients due to their action mechanism through upregulating hypoxia-inducible factors (HIFs) level. In cancer cells, HIFs affect tumor progression and contribute to chemo- and radio-resistance. On the other hand, upregulation of HIFs in immune cells is associated with inflammation and suppress tumor progression. However, these controversial effects are not clear in in vivo model. It is needed to reveal whether upregulating HIFs level is beneficial for cancer therapy or not. We have previously reported that HIF-PH inhibitor treatment in tumor bearing mice model led to reconstitute tumor blood vessel and inhibit tumor growth. In addition, these phenomena were caused by tumor infiltrated macrophages and they altered these phenotypes. In this review, we will describe our findings on the mechanism of tumor growth suppression by HIF-PH inhibitors. We also want to mention the risks and benefits of future HIF-PH inhibitors.

[Devices and attempts to make understand horizontally and vertically for pharmacology education in Osaka Metropolitan University].

As of February 1st, 2023, the Japan Accreditation Council for Medical Education (JACME) has evaluated and certified medical education programs at 70 medical schools as meeting international standards. It is required that medical schools continue to undergo this accreditation process to improve and further develop the quality of medical education. Although many medical schools have received and completed the first round of review, one of the remaining common issues is to change to an integrated curriculum based on an outcome-based education. Osaka Metropolitan University is in the process of reviewing its educational programs, including the establishment of milestones to appropriately assess the level of achievement of the competencies based on the outcome-based education. In addition, the university is continuing to revise the program to promote integrated education and active learning practices toward the set graduation outcomes. This paper introduces the devises and attempts for horizontally and vertically integrated understanding in pharmacology education based on the learning outcome-based educational system promoted by Osaka Metropolitan University.

Partial endothelial-to-mesenchymal transition mediated by HIF-induced CD45 in neointima formation upon carotid artery ligation.

AIMS: Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodelling. However, the precise regulatory mechanism of vascular remodelling during neointima formation and the source of neointima cells are not entirely understood. METHODS AND RESULTS: To investigate the origin of neointima cells and their relevance to vascular wall remodelling, we used an endothelial cell (EC)-specific lineage tracing system [VE-Cadherin (Cdh5)-BAC-CreERT2 mice] and carotid artery ligation model and showed evidence that resident ECs transdifferentiate into neointima cells with the expression of CD45. During the early stages of neointima formation, ECs transiently expressed CD45, a haematopoietic marker, accompanied by a host of EndMT markers, and CD31 and αSMA were prominently expressed in developing neointima. In vitro, CD45-positive EndMT was induced by stabilization of HIF1α with cobalt chloride or with a VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of the ligated artery, and promoted the formation of an integrin α11-shank-associated RH domain-interacting protein (SHARPIN) complex. Notably, a CD45 phosphatase inhibitor disrupted this integrin α11-SHARPIN complex, thereby destabilizing cell-cell junctions. Deletion of Hif1α in ECs suppressed expression of CD45 and EndMT markers and ameliorated neointima formation. CONCLUSION: These results suggest that the HIF-induced CD45 expression is normally required for the retention of an EC fate and cell-cell junctions, CD45-positive EndMT (termed as 'partial EndMT') contributes to neointima formation and vascular wall remodelling.

An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed Mycobacterium smegmatis synergistically or additively in combinations with rifampicin or ethambutol, respectively. The susceptibility to rifampicin and ethambutol was increased by knockdown of inhA, which encodes a target molecule of isoniazid. Additionally, knockdown of rpoB, which encodes a target molecule of rifampicin, increased the susceptibility to isoniazid and ethambutol, which act synergistically with rifampicin in the checkerboard assay. Moreover, CRISPRi could successfully predict the synergistic action of cyclomarin A, a novel TB drug candidate, with isoniazid or rifampicin. These results demonstrate that CRISPRi is a useful tool not only for drug target exploration but also for screening the combinatorial effects of novel combinations of anti-TB drugs. This study provides a rationale for anti-TB drug development using CRISPRi.

Long-term follow-up of insulin autoimmune syndrome in an elderly patient.

An 84-year-old man was admitted to our hospital. His blood glucose level was 20 mg/dL. Since laboratory tests showed high titers of insulin antibodies, insulin autoimmune syndrome (IAS) was diagnosed. In　order to avoid hypoglycemia, steroids can be effective in the long-term management of IAS in elderly patients.

Relationship between subjective memory complaints and social and leisure activities in community-dwelling older people: Toyoake Integrated Care Study.

AIM: Subjective memory complaints (SMC) have attracted attention in recent years in relation to the early stages of dementia. However, it is not clear whether SMC are related to social and leisure activities. The aim of this study was to evaluate SMC in relation to activities in community-dwelling older adults. METHODS: A questionnaire inquiring about SMC and social and leisure activities was sent to 14 850 people aged ≥65 years residing in Toyoake City, as part of the Toyoake Integrated Care Study. After a preliminary analysis, we targeted respondents aged ≥70 years. Therefore, 6685 people were included in the analysis. Three question items were used detecting SMC: the feeling of a memory problem (SMC-1), memory loss pointed out by others (SMC-2) and difficulty in recalling today's date (SMC-3). Logistic regression was carried out to determine the relationship between SMC and activities. RESULTS: In response to SMC-1, 2 and 3, 45.3%, 13.3% and 23.5% participants, respectively, agreed with the statement. Social and leisure activities were negatively associated with SMC-2 and SMC-3, after controlling for confounding factors (SMC-2: odds ratio 0.76, 95% confidence interval 0.65-0.89; SMC-3: odds ratio 0.79, 95% confidence interval 0.70-0.90). However, a significant increase in participation in social and leisure activities was associated with a positive response to SMC-1 (SMC-1: odds ratio 1.24, 95% confidence interval 1.12-1.38). Conclusion A relationship was observed between SMC and social and leisure activities in community-dwelling older people, although differences in the impact of SMC were seen depending on the question asked. Geriatr Gerontol Int 2020; 20: 867-872.

Prolyl-hydroxylase inhibitors reconstitute tumor blood vessels in mice.

Tumor blood vessels have leaky and low blood flow properties, which lead to hypoxia and low nutrient levels in the tumor tissue area known as the tumor microenvironment (TME). We reported that the prolyl-hydroxylase (PHD) inhibitor Roxadustat normalized tumor blood vessels, improved tumor tissue perfusion, and re-oxygenated the tumor tissue. Recently, several PHD inhibitors including Roxadustat, Daprodustat, Molidustat, and Vadadustat, were evaluated in clinical trials and approved for treating renal anemia. In this study, we showed that PHD inhibitors reconstituted tumor blood vessels and improved the TME, and some agents exhibited differential effects on tumors in a mouse model.

[The effect of PHD inhibitor on tumor microenvironment and tumor immune response].

Tumor tissue environment is generally exposed to low oxygen, nutrition depletion and high interstitial pressure condition. These circumstances are caused by vascular hyper-permeability, irregular vascularization and immature vessels. The blood vessel is important tissue structures to deliver oxygen, nutrition and so on. An abnormal blood vessel formation is a common feature of tumor tissue that were characterized by hyper-permeability, irregular vascularization, immature vessels and intravasation. Therefore, tumor tissue is exposed to low oxygen nutrition depletion and low pH due to hypoperfusion and elevated interstitial pressure. These environments are one of the reasons for chemo- and radio-resistance. Previously, we reported that prolyl hydroxylase (PHD) inhibitor induced tumor blood vessel normalization and improved tumor microenvironment in tumor mouse model. However, effects of PHD inhibitor on tumor progression is controversial. Enhanced hypoxia inducible factors (HIFs) signaling in cancer cells act to promote cancer proliferation and metastases. On the other hand, increasing of HIFs signaling in immune cells may lead to activate inflammation and elicit anti-tumor effect. We describe our study how PHD inhibitor improved tumor microenvironment and focused on tumor infiltrate immune cells were phenotypic alteration after PHD inhibitor treatment in mouse model. Our results implied that PHD inhibitor was possibly beneficial for anti-cancer therapy.

Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model.

Orally active hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors that stabilize HIF protein and stimulate the production of erythropoietin have been approved to treat renal anemia. Our previous report suggested that HIF-1α dependent fibrogenic mechanisms are operating at the early onset of renal fibrosis and its contribution declines with the progression in mouse unilateral ureteral obstruction (UUO) model. The aim of the study is to evaluate the renal fibrogenic potential of FG4592, a recently approved orally active HIF prolyl hydroxylase inhibitor in mouse UUO model. Male C57BL/6J mice orally given FG-4592 (12.5 mg/kg/day and 50 mg/kg/day) were subjected to UUO. Neither dose of FG-4592 affected renal fibrosis or macrophage infiltration. FG-4592 had no effects on increased mRNA of collagen I, collagen III or transforming growth factor-ß1. At 3 days after UUO, higher dose of FG-4592 potentiated the increased mRNA expression of profibrogenic molecules, plasminogen activator inhibitor 1 (Pai-1) and connective tissue growth factor (Ctgf) but such potentiation disappeared at 7 days after UUO. It is suggested that FG-4592 used in the present study had little effects on renal fibrosis even though high dose of FG-4592 used in the present study transiently potentiated gene expression of Pai-1 and Ctgf in the UUO kidney.

Increase in direct social care costs of Alzheimer's disease in Japan depending on dementia severity.

AIM: With the aging population, costs of direct social support for patients with Alzheimer's disease have grown and will continue to increase. The purpose of the present study was to estimate the cost of direct social support for Alzheimer's disease under long-term care insurance in Japan. METHODS: This cross-sectional study included 169 patients with Alzheimer's disease or mild cognitive impairment who visited a memory clinic and were followed over time. Dementia severity, use of care services and costs were analyzed. RESULTS: The use of direct social support and costs increased significantly between patients with mild, moderate and severe dementia (P < 0.001). In particular, the use of day services and short stay services increased with the severity of dementia (P < 0.001). Similar findings were obtained when participants were stratified by long-term care insurance care levels. Of 169 participants, 49 had not applied for long-term care insurance, although their dementia severity was not different from support-need level 1 and care-need level 1. Logistic regression analysis of "did not apply" and "applied and certified" groups showed significant differences not only in dementia severity, but also in age (odds ratio 1.112, 95% confidence interval 1.037-1.193, P = 0.003) and living arrangements (odds ratio 0.257, 95% confidence interval 0.076-0.862, P = 0.028). CONCLUSIONS: As the number of patients with Alzheimer's disease increases, direct social costs will increase. The findings of this study might help standardize the type of direct social support provided after diagnosis of Alzheimer's disease and contribute to the development of cost-effective care for these patients. Geriatr Gerontol Int 2019; 19: 1023-1029.

Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model.

The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6Clo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cneg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy.

Efficacy and Safety of Cholinesterase Inhibitors for Mild Cognitive Impairment:A Systematic Review and Meta-Analysis.

BACKGROUND: The clinical benefit of cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) remains inconclusive. OBJECTIVE: We performed a systematic review and meta-analysis of the efficacy/safety of ChEIs on subjects with MCI. METHODS: We included randomized controlled trials (RCTs) of ChEIs in subjects with MCI, using cognitive function scores as a primary outcome measure. RESULTS: Fourteen RCTs (six using donepezil, four using galantamine, and four using rivastigmine) with 5,278 subjects were included. We found no significant difference in cognitive function scores between the ChEIs and placebo groups [standardized mean difference (SMD) = -0.06, p = 0.38, I2 = 76% ]. However, in the secondary outcomes, ChEIs were associated with a lower incidence of progression to dementia compared with placebo (risk ratio = 0.76, the number needed to treat = 20). For safety outcomes, ChEIs were associated with a lower prevalence of fall than placebo. On the other hand, compared with placebo, ChEIs were associated with a higher incidence of discontinuation due to all causes, discontinuation due to adverse events, at least one adverse event, abnormal dreams, diarrhea, dizziness, headache, insomnia, loose stools, muscle cramps, nausea, vomiting, and weight loss. CONCLUSIONS: Although ChEIs have a slight efficacy in the treatment of MCI, there are many safety issues. Therefore, ChEIs are difficult to recommend for MCI. However, the efficacy and safety of ChEIs on MCI with a biomarker-based diagnosis is unclear. Further RCTs are needed to confirm the efficacy and safety of ChEIs when used for individual neuropathological classifications of MCI.

Suvorexant for insomnia in patients with psychiatric disorder: A 1-week, open-label study.

AIM: There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders. METHODS: This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset. RESULTS: The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%). CONCLUSION: Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.

Influx of Tau and Amyloid-ß Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-ß Removal System for Alzheimer's Disease.

The accumulation of amyloid-ß protein (Aß) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aß Removal Systems (E-BARS) as a method for enhancing Aß clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aß and evoke large Aß influxes into the blood, resulting in a decrease in brain Aß accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aß accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aß but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aß. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aß migration into the blood. However, as a therapeutic strategy for Alzheimer's disease, it may only be effective for removing Aß from the brain.

Efficacy and Safety of Glycogen Synthase Kinase 3 Inhibitors for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer's disease (AD) is unknown. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients. METHODS: We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure. RESULTS: Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = -0.25, p = 0.11, I2 = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = -0.41, p = 0.04; tideglusib subgroup: SMD = -0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, -0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments. CONCLUSION: Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed.

A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4.

Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg-1·day-1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-ß1 (TGF-ß1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-ß1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.

Efficacy and safety of idalopirdine for Alzheimer's disease: a systematic review and meta-analysis.

OBJECTIVE: The efficacy and tolerability of idalopirdine, a selective 5-hydroxytryptamine6 receptor antagonist, in patients with Alzheimer's disease (AD) is uncertain. A systematic review and meta-analysis of randomized controlled trials (RCTs) testing idalopirdine for patients with AD was performed. METHODS: We included RCTs of idalopirdine for patients with AD and used Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores as a primary measure. RESULTS: Four RCTs with 2,803 patients with AD were included. There was no significant difference in ADAS-cog between the idalopirdine and placebo groups [mean difference (MD) = -0.41, P = 0.32, I2 = 62%]. However, significant heterogeneity remained. Sensitivity analysis revealed that idalopirdine was more effective than placebo for ADAS-cog in the high dose and moderate AD subgroups (high dose subgroup: MD = -2.15, P = 0.005, moderate AD subgroup: MD = -2.15, P = 0.005). Moreover, meta-regression analysis showed that idalopirdine effect size for ADAS-cog was associated with mean dose (coefficient, -0.0289), ADAS-cog at baseline (coefficient, -0.9519), and proportion of male participants (coefficient, 0.2214). For safety outcomes, idalopirdine was associated with a higher incidence of at least one adverse event and increased γ-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, and vomiting than placebo. There were no significant differences in other secondary outcomes between both treatments. CONCLUSIONS: Idalopirdine is not effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small and may be limited.

Efficacy, Acceptability, and Safety of Intravenous Immunoglobulin Administration for Mild-To-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.

A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer's disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate AD.

Memantine treatment for Japanese patients with moderate to severe Alzheimer's disease: a meta-analysis of double-blind, randomized, placebo-controlled trials.

PURPOSE: Although previous meta-analyses of randomized trials in the world literature have provided strong evidence that supports the efficacy and safety of memantine for the treatment of patients with Alzheimer's disease (AD), it is unclear whether the drug is beneficial in the treatment of Japanese patients with moderate to severe AD because of differences in the formulation and regimen of memantine and the cholinesterase inhibitor (ChEI) used in combination with memantine between the drugs made in Japan and those made in other countries. To address this issue, we conducted a meta-analysis on the efficacy and safety of memantine using data from only double-blind, randomized, placebo-controlled trials (DBRPCTs) in Japan on Japanese patients with moderate to severe AD. PATIENTS AND METHODS: Our primary analysis was conducted using data from both memantine monotherapy (memantine vs placebo) and memantine combination therapy (memantine+ChEI vs ChEI+placebo) studies. The primary outcomes measured were cognitive function and behavioral disturbances. The secondary outcomes measured were the subscale scores of Behavioral Pathology in Alzheimer's Disease (Behave-AD), discontinuation rate, and individual adverse events. RESULTS: Four DBRPCTs (n=1,328) were detected. Memantine was superior to the control in cognitive functions (standardized mean difference [SMD]=-0.31, 95% CI=-0.53, -0.10) and behavioral disturbances (SMD=-0.16, 95% CI=-0.28, -0.05). Only memantine monotherapy was superior in both outcomes. It was also superior to the control in delusions, aggression, and diurnal rhythm disturbances based on the Behave-AD subscale scores. Although memantine was associated with a lower incidence of AD progression than that of the control, the incidence of somnolence was higher with memantine. There were no significant differences in other safety outcomes, including all-cause discontinuation, between the groups. CONCLUSION: Our results suggest that memantine is useful for the treatment of patients in Japan with moderate to severe AD even though our meta-analysis comprised only four DBRPCTs.