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Background: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. Aim: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. Method: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. Results: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. Conclusion: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

BACKGROUND/AIM We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs). MATERIALS AND METHODS Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1high cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined. RESULTS GLO 1high, PKCλhigh, and ALDH1A3high tumors were enriched in stage I/II/III/IV samples, associated with the HER2 and TNBC subtypes according to receptor status, and associated with the HER2-enriched and basal-like subtypes according to PAM50. Inhibition of either GLO 1 (TLSC702) or PKCλ (ANF) suppressed tumor-sphere formation and enhanced death in ALDH1high cells. TLSC702 also effectively inhibited tumor-sphere formation and induced death in PKCλ knockout ALDH1high cells. CONCLUSION GLO 1 and PKCλ are important for the survival of ALDH1-positive breast CSCs, and may represent potential therapeutic targets for the treatment of ALDH1-positive breast CSCs.

Since 2011, pharmaceutical companies in Japan have been required to issue two types of documents regarding severe adverse drug reactions reported post-marketing, namely the Rapid Safety Communication Materials for Patients and the Related Materials. However, the adequacy of these documents has not yet been systematically assessed. The aim of this study was to evaluate the adequacy of these two types of materials. The Rapid Safety Communications for Patients were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Related Materials were obtained from pharmaceutical companies or the PMDA website. Three assessors independently scored the Rapid Safety Communication for Patients and the Related Materials using the Centers for Disease Control and Prevention Clear Communication Index (CCI). In addition, the contents and descriptions of the materials were analyzed. In total, 13 materials for seven drugs were assessed. Almost all materials contained the "main message" and "call to action". However, the average CCI scores for the Rapid Safety Communication for Patients and Related Materials for Patients were 68.8 and 74.3 (out of 100), respectively. Further, none of the evaluated materials were scored above the CCI threshold score (i.e., ≥ 90%). Descriptions regarding "language", "state of science", and "risk" were not adequate. In particular, the terminology used in materials seemed difficult for patients to understand. In conclusion, the Japanese Rapid Communication Materials for Patients require improvement. Furthermore, a system for evaluating these materials prior to publication should be established.

Background/Aim: Radiotherapy is one of the main treatments for estrogen receptor-positive (ER+) breast cancer. However, in some ER+ breast cancer cases, radiotherapy is insufficient to inhibit progression and there is a lack of markers to predict radiotherapy insensitivity. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter, which has been proposed to be a viable prognostic marker for luminal A and B types of ER+ breast cancer. The present study examined the possibility of SLC20A1 as a novel biomarker for the prediction of radiotherapy efficiency. Patients and Methods: The Molecular Taxonomy of Breast Cancer International Consortium dataset was downloaded from cBioportal and the prognosis of patients with high SLC20A1 expression (SLC20A1high) was compared with that of patients with low SLC20A1 expression, without or with radiotherapy and tumor stages I, II, and III, using the Kaplan–Meier method and multivariate Cox regression analyses of disease-specific and relapse-free survival. Results: Patients in the SLC20A1high group with radiotherapy showed poor clinical outcomes in both luminal A and luminal B breast cancers. Furthermore, in luminal A breast cancer at tumor stage I, patients in the SLC20A1high group with radiotherapy also showed poor clinical outcomes. Therefore, these results suggest that radiotherapy is insufficient for patients in the SLC20A1high group for both luminal A and B types, and especially for the luminal A type at tumor stage I. Conclusion: SLC20A1 can be used as a prognostic marker for the prediction of the efficacy of radiotherapy for luminal A and luminal B breast cancers.

p62 (also known as sequestosome 1) is involved in cancer progression, and high expression of p62 indicates poor clinical outcome in several cancer types. However, the association between p62 gene expression and cancer stem cells (CSCs) in breast cancer subtypes remains unclear.In the present study, genomic datasets of primary breast cancer (The Cancer Genome Atlas, n=593; and Molecular Taxonomy of Breast Cancer International Consortium, n=2,509) were downloaded. p62 Expression was then examined in normal and breast cancer tissues derived from the same patients. Kaplan-Meier and multivariate Cox regression analyses were employed to evaluate disease-specific survival. Next, the effect on cell viability and in vitro tumor-sphere formation of p62 knockdown using targeted small interfering RNA was assessed by using cells with high activity of aldehyde dehydrogenase 1 (ALDH1Patients with normal-like, luminal A or luminal B breast cancer with p62p62 is potentially a prognostic marker and therapeutic target for ALDH1-positive luminal B breast CSCs.

Background/aim Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. Materials and methods A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1high cell viability and tumor-sphere formation. Results c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Methigh PKCλhigh ALDH1A3high have a poorer prognosis than patients with c-Metlow PKCλlow ALDH1A3low Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. Conclusion c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P

Background Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency exists, conditional logistic regression can be biased. However, this bias has not been well studied. Methods We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia. Results When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression. Conclusion Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders.

// Shoma Tamori 1, 6 , Yuka Nozaki 1, 6 , Hitomi Motomura 1, 6 , Hiromi Nakane 1 , Reika Katayama 1 , Chotaro Onaga 1 , Eriko Kikuchi 1 , Nami Shimada 2 , Yuhei Suzuki 1 , Mei Noike 1 , Yasushi Hara 3 , Keiko Sato 4, 6 , Tsugumichi Sato 2, 6 , Kouji Yamamoto 5, 6 , Takehisa Hanawa 2, 6 , Misa Imai 8, 9 , Ryo Abe 3, 11 , Atsushi Yoshimori 10 , Ryoko Takasawa 2 , Sei-Ichi Tanuma 2, 7 and Kazunori Akimoto 1, 6 1 Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan 2 Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan 3 Research Institute for Biochemical Sciences, Tokyo University of Science, Chiba, Japan 4 Department of Information Sciences, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan 5 Department of Biostatistics, Yokohama City University, School of Medicine, Yokohama, Japan 6 Translational Research Center, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan 7 Laboratory of Genomic Medicinal Science, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan 8 Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan 9 Leading Center for the Development and Research of Cancer Medicine, Juntendo University School of Medicine, Tokyo, Japan 10 Institute for Theoretical Medicine, Inc., Kanagawa, Japan 11 Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan Correspondence to: Kazunori Akimoto, email: akimoto@rs.tus.ac.jp Keywords: cancer stem cell; glyoxalase 1; breast cancer; the Warburg effect; target therapy Received: July 04, 2018 Accepted: November 01, 2018 Published: November 23, 2018 ABSTRACT Glyoxalase 1 (GLO1) is a ubiquitous enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis that induces apoptosis. In this study, we found that GLO1 gene expression correlates with neoplasm histologic grade ( χ 2 test , p = 0.002) and is elevated in human basal-like breast cancer tissues. Approximately 90% of basal-like cancers were grade 3 tumors highly expressing both GLO1 and the cancer stem cell marker ALDH1A3 . ALDH1 high cells derived from the MDA-MB 157 and MDA-MB 468 human basal-like breast cancer cell lines showed elevated GLO1 activity. GLO1 inhibition using TLSC702 suppressed ALDH1 high cell viability as well as the formation of tumor-spheres by ALDH1 high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1 high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1 high cells. These results suggest GLO1 is essential for the survival of ALDH1-positive breast cancer stem cells. We therefore conclude that GLO1 is a potential therapeutic target for treatment of basal-like breast cancers.

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients.

Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers.A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Metc-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.

In Japan, patients can freely choose medical facilities. Many visit different medical facilities for different diseases, and for convenience, often utilize the pharmacies neighboring these facilities. Accordingly, a "My Pharmacy" model was recommended, in which patients select a single pharmacy using their own judgement to receive proper medication services. A "My Pharmacist" model, in which the pharmacist is constantly involved in the treatment of a patient, was also proposed. However, patients' evaluations of pharmacist/pharmacy services under these models have not been investigated.To examine how a patient's constant involvement with the same pharmacist and pharmacy is associated with their evaluation of the quality of pharmacy services.A cross-sectional survey using a self-administered questionnaire was conducted among patients who used pharmacies periodically. Patients evaluated the pharmacist/pharmacy services and were classified into 4 groups ("My Pharmacy/My Pharmacist," "My Pharmacy/Multiple Pharmacists," "Multiple Pharmacies/My Pharmacist," and "Multiple Pharmacies/Multiple Pharmacists") according to the form of their usage of pharmacies and pharmacists. An intergroup comparison was then performed and correlations within each group analyzed.Data from 3,492 individuals using 147 pharmacies were analyzed. "My Pharmacy" users had significantly higher scores than did "Multiple Pharmacies" users on patient experience of proper medication services (e.g., identifying duplicate medication) (p 0.001). "My Pharmacy/My Pharmacist" users scored higher than the other three groups on four evaluation factors, including "pharmacy/pharmacist's interpersonal services" ("sharing and utilizing patient information," "enhanced health support function," and "consideration towards patients"), "patient satisfaction with the pharmacy," "placing more emphasis on quality of interaction with pharmacist than on waiting time," and "attitude when visiting healthcare facilities" (all p 0.001).The findings indicate that highly tailored, in-person services provided by "My Pharmacists" are associated with not only with the degree of patients' overall satisfaction, but also their evaluation of "the quality of pharmacist services."

Caloric restriction (CR) suppresses age-related pathophysiology and extends lifespan. We recently reported that metabolic remodeling of white adipose tissue (WAT) plays an important role in the beneficial actions of CR; however, the detailed molecular mechanisms of this remodeling remain to be established. In the present study, we aimed to identify CR-induced alterations in the expression of fibroblast growth factor 21 (FGF21), a regulator of lipid and glucose metabolism, and of its downstream signaling mediators in liver and WAT, across the lifespan of rats. We evaluated groups of rats that had been either fed ad libitum or calorie restricted from 3 months of age and were euthanized at 3.5, 9, or 24 months of age, under fed and fasted conditions. The expression of FGF21 mRNA and/or protein increased with age in liver and WAT. Interestingly, in the WAT of 9-month-old fed rats, CR further upregulated FGF21 expression and eliminated the aging-associated reductions in the expression of FGFR1 and beta-klotho (KLB; FGF21 receptor complex). It also enhanced the expression of FGF21 targets, including glucose transporter 1 and peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α. The analysis of transcriptional regulators of Fgf21 suggested that aging and CR might upregulate Fgf21 expression via different mechanisms. In adipocytes in vitro, constitutive FGF21 overexpression upregulated the FGF21 receptor complex and FGF21 targets at the mRNA or protein level. Thus, both aging and CR induced FGF21 expression in rat WAT; however, only CR activated FGF21 signaling. Our results suggest that FGF21 signaling contributes to the CR-induced metabolic remodeling of WAT, likely activating glucose uptake and mitochondrial biogenesis.

Thalidomide was approved for the treatment of multiple myeloma in Japan under a risk management program, named TERMS, in 2008. Since then, we have been conducting a survey of the stakeholders to assess the effectiveness of TERMS. These surveys showed patients had enough knowledge of the risks of thalidomide. In the USA, legislation in 2007 granted its U.S. Food and Drug Administration (FDA) the authority to require Risk Evaluation and Mitigation Strategies (REMS) when necessary to ensure that a drug's benefits outweigh its risks. As of 2015, more than 70 drugs, including thalidomide, have REMS programs. In Germany, in the early 1960s, over 5000 children were born with deformities. Therefore, the safety regulations in Germany go far beyond the European Medicines Agency (EMA) safety regulations at the time of thalidomide re-approval; thalidomide can be prescribed by a special prescribing form, including both proof of the patients' awareness of information about the risks, and participation in a pregnancy prevention program. While Japan has taken similar safety measures, a portion of thalidomide is still privately imported there. By March 2013, 594 patients have been registered to Japan's Safety Management System for Unapproved Drugs (SMUD), which was introduced by the Ministry of Health, Labour and Welfare (MHLW) in 2009. The number of females of child bearing potential (FCBPs) was 33 and the fraction (33/594=5.6%) was higher than that (48/7370=0.7%) in the case of TERMS. Risk management of thalidomide is described in this review.

Background Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. Methods Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. Results A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47–4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62–0.93) and 0.98 (95%CI 0.85–1.12) for amiodaroneallopurinol and thyroxine-allopurinol, respectively. Conclusion Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events. © 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. key words—prescription symmetry analysis; pharmacovigilance; amiodarone; hyperthyroidism; pharmacoepidemiology

In order for a patient to read a medication guide and develop appropriate behavior regarding use of the medication, the guide should suit patients' needs. In medical care, the primary needs of patients are preventing/curing disease and/or relieving symptoms. Certainly, patients would like knowledge about what can be expected after taking a medication. However, current "Drug Guides for Patients" are based on drug labeling, which is essentially a medically sophisticated instruction manual for medical professionals who have existing knowledge about the medical treatment of the disease. Thus, there seems to be a gap in patients' needs and the contents of existing drug guides. Consequently, this disconnect may be part of the reason Drug Guides for Patients have been underused. If a patient treatment guide, which gives an overview of the disease and possible treatment strategies, is provided in conjunction with a drug guide, this combination may be useful for satisfying patients' needs. In addition, patients generally prefer detailed drug information. Consistently, surveys have revealed that many patients would like to get more information about prescribed medicine than what is frequently provided in medical practice. Furthermore, one survey reported that detailed information about possible side effects resulted in improved compliance. The need to provide patients with drug information can be considered from three points of view: patients' rights, best decision-making by the patient, and minimizing risks. Although in daily practice doctors and pharmacists may have some difficulty providing detailed medication information that includes all possible risks, more effective ways to communicate this information to patients have been suggested.

Michiko Yamamoto,1 Hirohisa Doi,1 Ken Yamamoto,2 Kazuhiro Watanabe,2 Tsugumichi Sato,3 Machi Suka,4 Takeo Nakayama,5 Hiroki Sugimori6 1Department of Drug Informatics, Center for Education & Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan; 2Department of Pharmacy Practice, Center for Education & Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan; 3Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan; 4Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo, Japan; 5Department of Health Informatics, Kyoto University School of Public, Kyoto, Japan; 6Department of Preventive Medicine, Graduate School of Sports and Health Sciences, Daito Bunka University, Saitama, Japan Background: The safe use of drugs relies on providing accurate drug information to patients. In Japan, patient leaflets called Drug Guide for Patients are officially available; however, their utility has never been verified. This is the first attempt to improve Drug Guide for Patients via user testing in Japan.Purpose: To test and improve communication of drug information to minimize risk for patients via user testing of the current and revised versions of Drug Guide for Patients, and to demonstrate that this method is effective for improving Drug Guide for Patients in Japan.Method: We prepared current and revised versions of the Drug Guide for Patients and performed user testing via semi-structured interviews with consumers to compare these versions for two guides for Mercazole and Strattera. We evenly divided 54 participants into two groups with similar distributions of sex, age, and literacy level to test the differing versions of the Mercazole guide. Another group of 30 participants were divided evenly to test the versions of the Strattera guide. After completing user testing, the participants evaluated both guides in terms of amount of information, readability, usefulness of information, and layout and appearance. Participants were also asked for their opinions on the leaflets.Results: Response rates were 100% for both Mercazole and Strattera. The revised versions of both Guides were superior or equal to the current versions in terms of accessibility and understandability. The revised version of the Mercazole guide showed better ratings for readability, usefulness of information, and layout (p

Purpose To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use. Methods Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons). Results Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR)=1.14; 95% Confidence Interval (CI) 1.10–1.17) and Sweden (ASR=1.53; 95% CI 1.13–2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone. Conclusion Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring. Copyright © 2013 John Wiley & Sons, Ltd. key words—Asian Pharmacoepidemiology Network (AsPEN); distributed network model; multi-national collaboration; antipsychotics; hyperglycaemial; prescription sequence symmetry analysis; pharmacoepidemiology

This nationwide survey aimed to evaluate reduction of drug and medical costs due to prevention of serious adverse drug reactions through pharmaceutical inquires by community pharmacist, and investigate relation with iyaku bungyo (separation of dispensing from medical practice) rates. Using the national list of pharmacies, 10% of pharmacies were randomly selected by prefecture and asked to participate in an Internet-based survey. The survey period was 7 days, from July 21 to July 27, 2015. Of the 5575 pharmacies queried, 818 responded to the survey (response rate: 14.7%). The proportion of inquiries to total prescriptions was 2.6%. Among these, the proportion of prescriptions changed in response to inquiry was 74.9%. An estimated 103 million yen was saved by reducing drug costs, and 133 million yen was saved by reducing medical costs due to prevention of serious adverse drug reactions. Comparison of prescription change rates between pharmacies with high and low iyaku bungyo rates indicated that the proportion of prescriptions changed was significantly higher in pharmacies with high iyaku bungyo rates than in those with low iyaku bungyo rates (78.2% vs. 69.9%, p

Purpose In order to evaluate the incidence of an adverse event encountered when using a new therapeutic intervention, it is essential to know the background rate of this adverse event in the same patient population. Interstitial lung disease (ILD) often develops in Japanese patients receiving treatment with anti-neoplastic agents or other drugs. In our study, we estimated the background rate of ILD in patients with malignant mesothelioma (MM). Methods We conducted a retrospective cohort study of 328 Japanese patients diagnosed with MM during the period between 1996 and 2006. Results After the diagnosis of MM had been made, 21 (15 new and 6 exacerbation) of the 328 patients developed ILD. The crude baseline rate of ILD was estimated to be 0.023 (95%CI, 0.009–0.054) per patient-year, and the baseline rate using the Poisson regression model was estimated to be 0.032 (95%CI, 0.017–0.059) per patient-year where major therapeutic interventions were incorporated in the model. The risk of ILD was increased by surgical excision (rate ratio, 8.87; 95%CI, 2.39–33.0), pleurodesis with picibanil (rate ratio, 5.14; 95%CI, 1.63–16.3), and systemic chemotherapy using vinorelbine (rate ratio, 5.95; 95%CI, 1.22–29.0). Conclusions Our results have implications for evaluating the safety outcomes of future studies in patients receiving treatment for MM. The development of ILD in such studies at an incidence rate higher than 0.02–0.03 per patient-year might indicate an excess occurrence as a result of a therapeutic intervention. Copyright © 2011 John Wiley & Sons, Ltd.

Objective: To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficile infections across multiple countries Method: National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest. Results: 54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation. Conclusion: Our study confirms the association between PPI initiation and C. difficile infections across countries in the Asia-Pacific region. Refereed/Peer-reviewed

Background Fluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients. Methods Pulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate. Results There were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events. Conclusion The possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.

Objective The primary objective was to estimate the national prevalence of psoriasis and palmoplantar pustulosis (PPP) in Japan. Secondary objectives were to determine (1) whether psoriasis and PPP disease activity varies by season, and (2) whether disease severity is associated with concurrent diabetes mellitus, hyperlipidaemia and hypertension. Settings Patients with a psoriasis or PPP diagnosis code between April 2010 and March 2011 were identified using a Japanese national database. Participants 565 903 patients with psoriasis or PPP were identified. No patient was excluded. Primary and secondary outcome measures National prevalence was calculated using census data. We estimated the difference in the proportion of patients who used healthcare services, as a proxy for disease activity, between the hot and cold seasons and the difference in the standardised prevalence of comorbidities between severe and mild disease. The measures were estimated separately for the two broad disease categories of psoriasis and PPP but not in all patients as planned because the two disease categories had major differences. Results The national prevalence of psoriasis and PPP was 0.34% (95% CI 0.34% to 0.34%) and 0.12% (0.12% to 0.12%), respectively. The difference in the proportion of patients who used healthcare services in the hot compared to the cold season was −0.3% (−0.5% to −0.1%) for psoriasis and 10.0% (9.8% to 10.3%) for PPP. The difference in the standardised prevalence between severe and mild psoriasis was 3.1% (2.7% to 3.4%), 3.2% (2.8% to 3.6%) and 5.1% (4.7% to 5.6%) for concurrent diabetes mellitus, hyperlipidaemia and hypertension, respectively. No significant difference in the prevalence of comorbidity was observed for PPP. Conclusions The national prevalence, seasonal variation in disease activity and prevalence of comorbidities in Japanese patients with psoriasis and PPP estimated in this descriptive study may be used as basic information for future studies.

Introduction: The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of adverse drug events. Objective: The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan. Methods: Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates. Results: Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone [adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14-1.91] and rosiglitazone (ASR 1.65; 95 % CI 1.58-1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93-1.32 and ASR 1.21; 95 % CI 1.01-1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01-3.5 and ASR 1.25; 95 % CI 0.76-2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations. Conclusion: The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use. Refereed/Peer-reviewed

Objective To investigate whether lipid-lowering drugs are associated with new-onset diabetes after adjusting for baseline clinical risk factors for diabetes. Design A retrospective cohort study. Setting Japanese employees of large corporations and their dependents using health insurance claims data linked to clinical and laboratory data for annual health screenings. Participants All persons aged 20 to 74 years with dyslipidaemia between 1 January 2005 and 31 March 2011. We defined the index date as the first date when the person met the criteria for dyslipidaemia. Persons were excluded if they had lipid-lowering drugs, or had a diagnosis, a treatment or a laboratory test result (haemoglobin A1c ≥6.5% or fasting blood glucose ≥126 mg/dL) indicating diabetes during the 6-month period before the index date. Main outcome measures New-onset diabetes. Results We identified 68 620 persons with dyslipidaemia. During the mean follow-up period of 1.96 years, 3674 persons started treatment with a lipid-lowering drug: 979 with a low potency statin, 2208 with a high potency statin and 487 with a fibrate. Of 3674 new users of a lipid-lowering drug, 3621 had a period of non-use of any lipid-lowering drugs before starting a lipid-lowering drug. Among statin users, the incidence rate of new-onset diabetes was 124.6 per 1000 person-years compared with 22.6 per 1000 person-years in non-users. After adjusting for confounding factors including clinical data in health screening using Cox proportional hazards models, the HR was 1.91 (95% CI 1.38 to 2.64) for low potency statins and 2.61 (2.11 to 3.23) for high potency statins. Conclusion The use of statins was associated with a 1.9-fold to 2.6-fold increase in the risk of new-onset diabetes in a Japanese population of working age, despite adjusting for clinical risk factors for diabetes.

PURPOSE: To assess the association between statins and diverse adverse events in Japanese population. METHODS: New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009. RESULTS: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009). CONCLUSIONS: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.

To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use.Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons).Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR) = 1.14; 95% Confidence Interval (CI) 1.10-1.17) and Sweden (ASR = 1.53; 95% CI 1.13-2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone.Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring.

In order to evaluate the incidence of an adverse event encountered when using a new therapeutic intervention, it is essential to know the background rate of this adverse event in the same patient population. Interstitial lung disease (ILD) often develops in Japanese patients receiving treatment with anti-neoplastic agents or other drugs. In our study, we estimated the background rate of ILD in patients with malignant mesothelioma (MM).We conducted a retrospective cohort study of 328 Japanese patients diagnosed with MM during the period between 1996 and 2006.After the diagnosis of MM had been made, 21 (15 new and 6 exacerbation) of the 328 patients developed ILD. The crude baseline rate of ILD was estimated to be 0.023 (95%CI, 0.009-0.054) per patient-year, and the baseline rate using the Poisson regression model was estimated to be 0.032 (95%CI, 0.017-0.059) per patient-year where major therapeutic interventions were incorporated in the model. The risk of ILD was increased by surgical excision (rate ratio, 8.87; 95%CI, 2.39-33.0), pleurodesis with picibanil (rate ratio, 5.14; 95%CI, 1.63-16.3), and systemic chemotherapy using vinorelbine (rate ratio, 5.95; 95%CI, 1.22-29.0).Our results have implications for evaluating the safety outcomes of future studies in patients receiving treatment for MM. The development of ILD in such studies at an incidence rate higher than 0.02-0.03 per patient-year might indicate an excess occurrence as a result of a therapeutic intervention.

Objective: The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan. Methods: Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan–Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors. Results: Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio ¼ 2.17; 95% confidence interval, 1.36 –3 .46), non-epithelioid type (hazard ratio ¼ 1.58; 95% confidence interval, 1.15–2 .18), poor performance status (hazard ratio ¼ 3.22; 95% confidence interval, 1.19–8.74), high white blood cell count (hazard ratio ¼ 1.49; 95% confidence interval, 0.99– 2.26) and high C-reactive protein level (hazard ratio ¼ 1.80; 95% confidence interval, 1.06 –3 .06) were negatively associated with survival, after adjustment for other factors. Conclusions: Some baseline conditions including old age, poor performance status, nonepithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma.

Thalidomide, once withdrawn because of its teratogenicity, has now been re-launched worldwide. In Japan, thalidomide has been imported by individual doctors since around the year 2000. In October 2008, it was approved for the treatment of multiple myeloma (MM) by the Ministry of Health, Labour and Welfare (MHLW) on the condition that the manufacturer implemented a risk management programme termed the Thalidomide Education and Risk Management System (TERMS). It is likely that the imports of thalidomide will be used off-label to treat diseases other than MM. Thus, the MHLW is also planning to introduce a web-based registration system, referred to as the Safety Management System for Unapproved Drugs (SMUD), for thalidomide imported by individual doctors. To evaluate the difference between TERMS and SMUD and establish a way to resolve the 'double standard' for risk management of thalidomide treatment in Japan. The fraction of patients with disorders other than MM was estimated by the volume of annual imports obtained from the MHLW and records of the imports for patients with MM, other oncological diseases (ODs) and non-ODs in 2007 through a major supplier covering 63% of the total imported thalidomide. The information for TERMS was obtained from web pages of the manufacturer and the MHLW. The components of TERMS were compared with those in SMUD. Provided that the distribution of the indication for thalidomide (MM) in 2007, estimated from the records of imports through the major supplier, is representative of the entire nation, it is estimated that on average 866 patients, including 851 (98.3%) with MM, are using thalidomide on any one day. However, if the major supplier's imports, which account for 63% of the total imports, are not representative of the nation as a whole, possibly only half of the patients treated with thalidomide in Japan have MM. This would be the case in a scenario where the remaining 37% of imports are exclusively used to treat disorders other than MM. TERMS consists of tools for education and registration of patients, and has the potential for real-time intervention. SMUD is a system for registration of patients and exchange of safety information between health professionals, but has some mandatory components that encourage patient registration. TERMS and SMUD are different in nature, and they impose different criteria that doctors and patients should satisfy in order to use thalidomide. To eliminate this double standard, implementation of a single system would be desirable. However, improvement of SMUD may be the second best option by developing tools for patient education, enhancing the potential for real-time intervention and monitoring thalidomide usage by each patient. On average, a total of about 1000 patients are estimated to be using thalidomide on any one day in Japan. It is likely that those patients are placed under one of two different risk management programmes. SMUD should be improved so that all patients are monitored in a way that results in a similar level of risk management.

In our recent case-control study on the association between non-steroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB), the risk of UGIB was higher in non-drinkers than in heavy-drinkers. To explore this unexpected finding, we re-analyzed the data to test whether non-drinking represented risk factors for UGIB and also conducted an additional survey to find any disagreement with the original study that might suggest information bias. In the re-analysis, we estimated odds ratios (ORs) of UGIB by classifying 183 non-drinkers in the original study into 39 ex- and 144 never-drinkers. We also measured the prevalence of potential risk factors of UGIB in controls. In the new survey, we sent a self-administered questionnaire on previous alcohol consumption. In the re-analysis, the OR for ex-drinking (5.4) was higher and the OR for never-drinking (2.6) was lower than the OR for non- (ex- plus never-) drinking (3.2) in the original study. Ex-drinkers had higher prevalence of H. pylori infection, history of previous ulcer and use of GI drugs than other types of drinkers. The answers on their previous alcohol consumption were consistent between the original and new surveys both in cases (kappa = 0.74) and controls (kappa = 0.73). Ex-drinking may represent unmeasured risk factors for UGIB such as undiagnosed ulcer. In an observational study of UGIB, ex-drinking may be distinguished from never-drinking as a potential surrogate for UGIB risk. When prescribing an NSAID to an ex-drinker in clinical practice, one may make sure to explore whether an ex-drinker has a history of ulcer.

Studies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics. Cases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls. The odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p