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The case-crossover study design has been proposed as a suitable design for use when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the condition of "brief exposure" is rarely satisfied because medication use is often chronic or successive, which may result in bias due to within-subject exposure dependency. Here we describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios ranging up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by using the case–time-control study design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and we demonstrate how to detect and remove them. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: An administrative database covering a whole population such as the national database in Japan may be used to estimate the nationwide prevalence of diseases including rheumatoid arthritis (RA) when a well-validated definition of the disease is available. In Japan, the record linkage between the administrative database and medical charts in hospitals is strictly prohibited. A "hospital-based" validation study is one of few possible validation studies where claims kept inside the study hospital are rearranged into the database structure.Methods: We selected random samples of 19,734 patients from approximately 1.6 million patients who received medical care between February 2018 and January 2019 in one of the 64 hospitals of the Tokushukai Medical Group. We excluded patients whose observation period was less than 365 days and identified 334 patients who met the definition of "possible cases of RA" whose medical charts were then independently evaluated by two rheumatologists. In a sensitivity analysis, we assessed bias due to misclassifying some patients with RA who did not meet the definition of "possible cases of RA" as a patient with no RA.Results: The kappa coefficient between the two rheumatologists was 0.80. The prevalence of RA in the study population was estimated to be 0.56%. We found that [condition code of RA] and ([any disease-modifying antirheumatic drug] or [oral corticosteroid with no systemic autoimmune diseases (other than RA) and no polymyalgia rheumatica]) had a relatively high sensitivity (approximately 73%) and a high positive predictive value (approximately 80%). In a sensitivity analysis, we found that when some patients with RA who did not meet the definition of "possible cases of RA" were misclassified as a patient with no RA, then this would lead to underestimation of the prevalence of the definition-positive patients and the adjusted prevalence.Conclusions: We recommend using the claims-based definition of RA (found in the current validation study) to estimate the prevalence of RA in Japan. We also suggest estimating the adjusted prevalence using the quantitative bias analysis method, since the prevalence of the disease in the "hospital-based" validation study is different from that in the administrative database.Trial Registration: The current study is not a clinical trial and hence not subject to trial registration. [ABSTRACT FROM AUTHOR]

Background: The number of patients with diabetes is increasing particularly in Asia-Pacific region. Many of them are treated with antidiabetics. As the basis of the studies on the benefit and harm of antidiabetic drugs in the region, the information on patterns of market penetration of new classes of antidiabetic medications is important in providing context for subsequent research and analyzing and interpreting results. Methods: We compared penetration patterns of dipeptidyl peptidase-4 (DPP-4) inhibitors in Taiwan, Hong Kong, Japan, and the United States. We used the Taiwan National Health Insurance Research Database, a random sample of the Hong Kong Clinical Data Analysis and Reporting System, the Japan Medical Data Center database, and a 5% random sample of the US Medicare database converted to the Observational Medical Outcomes Partnership’s Common Data Model to identify new users of oral antidiabetic medications. We standardized prevalence and incidence rates of medication use by age and sex to those in the 2010 Taiwanese population. We compared age, sex, comorbid conditions, and concurrent medications between new users of DPP-4 inhibitors and biguanides. Results: Use of DPP-4 inhibitors 1 year after market entry was highest in Japan and lowest in Hong Kong. New users had more heart failure, hyperlipidemia, and renal failure than biguanide users in Taiwan, Hong Kong, and the United States while the proportions were similar in Japan. In a country with low penetration of DPP-4 inhibitors (eg, Hong Kong), users had diabetes with multiple comorbid conditions compared with biguanidine users. In a country with high penetration (eg, Japan), the proportion of users with comorbid conditions was similar to that of biguanide users. Conclusions: We observed a marked difference of the penetration patterns of newly marketed antidiabetics in different countries in Asia. Those results will provide the basic information useful in the future studies. [ABSTRACT FROM AUTHOR]

Background: Anticoagulant therapy is recommended in patients with atrial fibrillation (AF) but remains underused. The proper use of anticoagulants has been encouraged in guidelines frequently published over the past two decades. Materials and methods: In this study, we used insurance claims data collected from 2005 to 2014 to investigate the prevalence and incidence of non-valvular AF (NVAF) patients aged 20 to 74 years standardized to the Japanese population in 2012 and subdivided by stroke prevention drug type. We estimated the frequency of coagulation monitoring in patients with incident NVAF undergoing warfarin therapy in 2011 and later. Results: From 2005 to 2014, the standardized prevalence of NVAF increased from 117/100,000 to 278/100,000 and the proportion of anticoagulant users increased from 38.4% to 58.0%, while that of antiplatelet monotherapy decreased from 32.3% to 12.0%. The standardized incidence of NVAF was stable at ~40/100,000 patient-years. The proportion of those patients who started anticoagulant soon after the initial diagnosis increased from 19.9% to 49.1% from 2006 to 2013. Among patients who started warfarin, switchers to DOAC had more frequent coagulation monitoring than non-switchers. Conclusion: The use of anticoagulant therapy has gradually increased in patients with NVAF in Japan during the study period from 2005 to 2014. [ABSTRACT FROM AUTHOR]

Background/objectives: HMG-CoA reductase inhibitors (statins) reduce ischemic heart disease (IHD) in middle-aged diabetic individuals, and LDL-cholesterol (LDL-C) is a risk factor. However, their preventive effects on cerebrovascular attack (CVA) have not been identified in elderly, especially in elderly ≥ 75 years (late elderly), who account for approximately 30% of diabetic individuals in Japan. Randomized controlled studies of statins for late elderly are difficult to carry out, because many co-morbidities in elderly disrupt randomized controlled conditions. Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up since 2004. A total of 4014 type 2 diabetic patients without previous IHD or CVA (n = 1936 women; age = 67.4 ± 9.5 years; ≥ 75 years: n = 1016) were enrolled, while 405 patients were registered as sub-cohort patients. We recorded detailed information on medications and laboratory data after every change in medication in patients of sub-cohort and suffered from IHD or CVA. We subdivided statin-users into prevalent, new and non-users. Results: A total of 104 CVAs occurred during 5.5-years. Plasma HDL-C level was inversely correlated with CVA in patients ≥ 65 years. In case–control study, among patients who were not prescribed statins, CVA increased in age-dependent manner. CVA incidence was lower in prevalent and new statin-users than in non-users (hazard ratio [HR]:0.46, 0.523), especially in late elderly (HR: 0.51, 0.21). Statins reduced CVAs mainly due to a direct effect and partially due to the effects of HDL-C and glucose metabolism. No significant differences were observed between statins. Conclusion: Statins prevented CVA in middle-aged, elderly and late elderly diabetic patients via a direct effect. This study is the first to demonstrate the usefulness of observational studies for statistically analyzing agents' effects on late elderly. [ABSTRACT FROM AUTHOR]

In prescription-event monitoring in Japan (J-PEM), patients are identified by prescriptions in individual pharmacies where drugs are dispensed. The methodology is somewhat different to that used by the Drug Safety Research Unit in the UK, in that two questionnaires, one to the pharmacist and the other to the doctor are sent for each patient and the method of concurrent control is employed in J-PEM. In the data analysis, the list of events reported as a suspected reaction or a reason for stopping the drug is made to generate a signal. In addition, a signal may be generated for some events with the statistically significant difference of crude rates followed by the regression analysis or a follow-up study. In J-PEM, Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for data entry and data analysis. Lowest level terms (LLTs) in MedDRA are used in data entry while a signal is generated using preferred terms (PTs). However, to generate a signal effectively, some PTs may be grouped as one term. In addition, if two terms are so similar, it may be instructed that one of those two terms is normally selected in data entry to avoid confusion. Many more PEM studies could be undertaken to determine if MedDRA can be used for effective signal generation, but the usefulness of MedDRA in J-PEM is still to be determined. [ABSTRACT FROM AUTHOR]

• Newer ASMs are increasingly prescribed owing to their effectiveness and safety. • Caution is advised when prescribing ASMs, particularly to childbearing age women. • Generic drug use indicates a shift toward more economical management of epilepsy. This retrospective study aimed to analyze anti-seizure medication (ASM) prescription trends in Japan, particularly among older adults and women of childbearing age, to inform future treatment strategies and optimize ASM selection criteria. Data were extracted from the National Database Open Data Japan for fiscal years (FY) 2018–2021, covering prescriptions across sex and 5-year age groups. We conducted data imputation for prescriptions under 1,000 units to maintain anonymity, calculated the estimated number of patients using standard adult maintenance doses, and adjusted for pediatric dosing using Augsberger's formula. Our analysis revealed a 7.6% increase in ASM usage, with a notable shift from older to newer ASMs, such as levetiracetam (LEV) and lamotrigine (LTG). LEV and LTG prescriptions increased by 26.7% and 15.0% from FY 2018 to FY 2021, respectively, whereas older ASMs such as phenytoin, declined. Sex-specific analysis showed a higher LTG prescription rate among women, especially in adolescent and young adult cohorts, where the female-to-male prescription ratio increased from 1.65 to 1.85. Valproate (VPA) and LEV accounted for 57.0% of ASM prescriptions in older adults. The number of inpatient LTG prescriptions was notably lower than that of outpatient LTG prescriptions across age groups. Pediatric use of generics was lower than that in other age groups. This study revealed that newer ASMs are being used increasingly, with a significant proportion of VPA continuously prescribed among women of childbearing age. In older adults, VPA and LEV accounted for more than half of the ASM prescriptions. These findings are crucial for developing future treatment strategies and improving the ASM selection criteria. [ABSTRACT FROM AUTHOR]

Press-through packaging (PTP) is the most common type of drug packaging in Japan, and a production procedure for PTP has been established at an acceptable cost. However, unknown problems and new needs with regard to safety among users of various age-groups still need to be examined. Considering accident reports involving children and older adults, the safety and quality of PTP and new forms of PTP, such as child-resistant and senior-friendly (CRSF) packaging, should be evaluated. We conducted an ergonomic study on children and older adults to compare types of commonly used PTP and new varieties of PTP. Opening tests were attempted by children and older adults using a common type of PTP (Type A) and child-resistant (CR) PTP (Types B1 and B2) made from soft aluminum foil. The same opening test was conducted on older patients with rheumatoid arthritis (RA). The results showed that CR PTP was difficult for children to open: only 1 out of 18 children could open Type B1. On the other hand, all eight of the older adults could open Type B1, and eight patients with RA could easily open Types B1 and B2. These findings suggest that the quality of CRSF PTP can be improved with the use of new materials. [ABSTRACT FROM AUTHOR]

Three hundred Japanese patients with benign prostatic hyperplasia (BPH) who started an α1-adrenoceptor blocker, tamsulosin, between 1993 and 1996 were followed for 3.0 ± 3.3 years (mean ± SD) to determine whether an association existed between the disease severities measured prior to the tamsulosin treatment and the timing at which the invasive therapy was implemented. Patients with a lower quality of life (QOL) index or maximum urinary flow rate (Qmax) were transferred for invasive therapy earlier than those with less severe BPH. The International Prostate Symptom Score (I-PSS) was also associated, but apparently to a lesser extent, with the timing of the invasive therapy. Finally, the overall severity evaluated using all of the above three indices, I-PSS, QOL index, and Qmax, in accordance with the ‘Severity Criteria for BPH’ issued by the Japanese Urological Association, was found to be a good measure for predicting the prognosis of patients with BPH treated with tamsulosin. [ABSTRACT FROM AUTHOR]

It is known that younger patients treated with antipsychotics are at increased risk of metabolic events; however, it is unknown how this risk varies according to ethnicity, the class of antipsychotic and the specific product used, and by age group. We conducted a multinational sequence symmetry study in Asian populations (Hong Kong, Japan, Korea, Taiwan and Thailand) and non-Asian populations (Australia and Denmark) to evaluate the metabolic events associated with antipsychotics in both Asian and non-Asian populations, for typical and atypical antipsychotics, and by the subgroups of children and adolescents, and young adults. Patients aged 6–30 years newly initiating oral antipsychotic drugs were included. We defined a composite outcome for metabolic events which included dyslipidemia, hypertension and hyperglycemia. We calculated the sequence ratio (SR) by dividing the number of people for whom a medicine for one of the outcome events was initiated within a 12-month period after antipsychotic initiation by the number before antipsychotic initiation. This study included 346,904 antipsychotic initiators across seven countries. Antipsychotic use was associated with an increased risk of composite metabolic events with a pooled adjusted SR (ASR) of 1.22 (95% CI 1.00–1.50). Pooled ASRs were similar between Asian (ASR, 1.22; 95% CI 0.88–1.70) and non-Asian populations (ASR, 1.22; 95% CI 1.04–1.43). The pooled ASR for typical and atypical antipsychotics was 0.98 (95% CI 0.85–1.12) and 1.24 (95% CI 0.97–1.59), respectively. No difference was observed in the relative effect in children and adolescents compared to young adults. The risk of metabolic events associated with antipsychotics use was similar in magnitude in Asian and non-Asian populations despite the marked difference in drug utilization patterns. [ABSTRACT FROM AUTHOR]

Background: Blister packs with paperboard backing, which is useful for displaying instructions and information, are the most popular type of packaging for osteoporosis drugs in Japan. However, the main users of drugs are the aged, who often find blister packs difficult to open or drop their pills during opening. In this study, we compared different types of blister packs in terms of usability and handling. Methods: We conducted a subjective and objective study to compare commonly used blister packs with newly designed ones that have a jagged notch designed to hold a pill temporarily and a perforated line that enables the pack to be held easily in one hand. Regarding subjective data, packaging and sensory tests were performed. The participants in the sensory test were healthy older adults and patients with rheumatoid arthritis (RA). We also measured the pinch power of all participants. Results: A comparison of several items, including opening status, prevention of pill dropping, and understanding of the instructions, using a numerical rating scale revealed no significant differences between ordinary (type A) and newly designed (type B) packaging. However, the scores for type B were the same or better than those for type A for every evaluation item. In addition, more than 85% of the participants reported preferring to use type B. More than 80% of the participants in both groups reported dropping pills using type A, which seemed to be related to their preference for type B. In the evaluation by the examiner (objective study), all participants could successfully remove their pills without dropping using type B, including those in the RA group who had difficulty handling packages. Conclusion: These findings suggest that the new type of blister pack assessed in this study (type B) is preferable among older and shows promise for a universal design. [ABSTRACT FROM AUTHOR]

The use of antipsychotic medications (APMs) could be different among countries due to availability, approved indications, characteristics and clinical practice. However, there is limited literature providing comparisons of APMs use among countries. To examine trends in antipsychotic prescribing in Taiwan, Hong Kong, Japan, and the United States, we conducted a cross-national study from 2002 to 2014 b y using the distributed network approach with common data model. We included all patients who had at least a record of antipsychotic prescription in this study, and defined patients without previous exposure of antipsychotics for 6 months before the index date as new users for incidence estimation. We calculated the incidence, prevalence, and prescription rate of each medication by calendar year. Among older patients, sulpiride was the most incident [incidence rate (IR) 11.0–23.3) and prevalent [prevalence rate (PR) 11.9–14.3) APM in Taiwan, and most prevalent (PR 2.5–3.9) in Japan. Quetiapine and haloperidol were most common in the United States (IR 8.1–9.5; PR 18.0–18.4) and Hong Kong (PR 8.8–13.7; PR 10.6–12.7), respectively. The trend of quetiapine use was increasing in Taiwan, Hong Kong and the United States. As compared to older patients, the younger patients had more propensity to be prescribed second-generation APM for treatment in four countries. Trends in antipsychotic prescribing varied among countries. Quetiapine use was most prevalent in the United States and increasing in Taiwan and Hong Kong. The increasing use of quetiapine in the elderly patients might be due to its safety profile compared to other APMs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim The risk factors for ischemic heart disease ( IHD) or cerebrovascular accident ( CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia. Method The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia. Results The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged <65 years, 65-74 years and >75 years ( n = 168, 190 and 104, respectively). High-density lipoprotein cholesterol ( HDL- C) and low-density lipoprotein cholesterol/ HDL- C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years, and HDL- C and diastolic blood pressure was significantly associated with cardiovascular events in patients aged 65-74 years. Non- HDL- C was not significantly associated with the risk of cardiovascular events. Multiple regression analysis showed that lower HDL- C was significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years and 65-74 years. Conclusions Lower HDL- C was an important risk factor for cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <75 years. Geriatr Gerontol Int 2014; 14: 806-810. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: For the pending National Claims Database in Japan, researchers will not have access to death information in the enrollment files. We developed and evaluated a claims-based definition of death. Methodology/Principal Findings: We used healthcare claims and enrollment data between January 2005 and August 2009 for 195,193 beneficiaries aged 20 to 74 in 3 private health insurance unions. We developed claims-based definitions of death using discharge or disease status and Charlson comorbidity index (CCI). We calculated sensitivity, specificity and positive predictive values (PPVs) using the enrollment data as a gold standard in the overall population and subgroups divided by demographic and other factors. We also assessed bias and precision in two example studies where an outcome was death. The definition based on the combination of discharge/disease status and CCI provided moderate sensitivity (around 60%) and high specificity (99.99%) and high PPVs (94.8%). In most subgroups, sensitivity of the preferred definition was also around 60% but varied from 28 to 91%. In an example study comparing death rates between two anticancer drug classes, the claims-based definition provided valid and precise hazard ratios (HRs). In another example study comparing two classes of anti-depressants, the HR with the claims-based definition was biased and had lower precision than that with the gold standard definition. Conclusions/Significance: The claims-based definitions of death developed in this study had high specificity and PPVs while sensitivity was around 60%. The definitions will be useful in future studies when used with attention to the possible fluctuation of sensitivity in some subpopulations. [ABSTRACT FROM AUTHOR]

Background: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age. Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and = 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model. Results: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients =75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients =75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients =75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels. Conclusions: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Background: Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions.Objective: The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG.Methods: Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs.Results: Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively.Conclusions: Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Two pilot studies for prescription-event monitoring in Japan (J-PEM) were launched in 1997 and 1998. Here we present data regarding adverse events that were reported in the second pilot J-PEM study where losartan was compared with ACE inhibitors and dihydropyridine calcium channel antagonists.Study Design: We conducted a cohort study with a concurrent control. METHODS/PATIENT GROUP: Study subjects prescribed losartan, an ACE inhibitor or a calcium channel antagonist were identified from prescriptions in hospital or community pharmacies. Events and other information were collected from doctors and pharmacists by mailed questionnaires. Events were coded and analysed using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Crude event rates were calculated and compared between patients treated with losartan and those receiving control drugs. When the difference was statistically significant, the event was further examined in several ways, including follow-up studies and by comparison with the data of the UK PEM study on losartan.Results: Pharmacists were sent 4344 questionnaires and returned 3591 (83%), while doctors were sent 3517 questionnaires and returned 1380 (39%). In the doctors' data, the adverse event rate for losartan treatment was greater than that for ACE inhibitors and/or calcium channel antagonists for the following seven events: headache, palpitations, anaemia, insomnia, feeling abnormal, increased blood pressure and asthma. Most of these are known adverse drug reactions (ADRs) of losartan except for two events: increased blood pressure and asthma. In pharmacists' data, the event rate for losartan was significantly greater than that for control drugs for the following ten events: hot flushes, abnormal hepatic function, oedema, peripheral swelling, decreased blood pressure, increased blood pressure, rhinitis, contact dermatitis, dry skin and heat rash. The first five events were known ADRs of losartan but the other five were not. When the two sets of data were combined, the rate of an additional event, increased blood creatinine phosphokinase, which is a known ADR of losartan, was significantly greater than that for the control drugs. The six events that were not documented as ADRs for losartan were not judged to be ADRs based on the results of follow-up studies and comparison with the UK PEM study on losartan. The crude rate of cough with losartan treatment was similar to that with calcium channel antagonists, but was significantly less than that with ACE inhibitors.Conclusion: No novel safety problems were found in this observational cohort study on losartan. The rates of some known ADRs differed significantly between patients treated with losartan and those in the control groups. [ABSTRACT FROM AUTHOR]

The safety of new drugs introduced into clinical practice in Britain is assessed by Prescription-Event Monitoring, a system complimentary to that of the Committee on Safety of Medicines. It is independent of studies carried out by the pharmaceutical industry. Data on 12692 patients treated with fluoxetine under the National Health Service were obtained from family practitioners throughout England. The main outcome measures were the rate of recorded events per 1000 patients during the first month of treatment and the mean rate of events during the following 5 months. The rates were compared with those for other selective serotonin reuptake inhibitors elicited by Prescription-Event Monitoring. Individual events, documented in the literature as unwanted effects of fluoxetine and other antidepressants and reported in the present study, were assessed with the help of information provided by the practitioners. All pregnancies were followed up to determine their outcome. Causes of death were established from patients' medical records and death certificates. Neuropsychiatric symptoms were the most frequently reported events, while the most commonly reported individual event was nausea. The rate of several events increased with increasing age. No hitherto unrecognized severe adverse drug-related events were reported. Fluoxetine was considered to be a safe drug, even when prescribed in family practice for a wide range of patients, many of them treated with other drugs for concomitant diseases. © 1997 by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BSTRACT Rheological properties were studied with a tube viscometer. Emulsifying agents were soy lecithin and Tween 20. The volume concentration of dispersed phase, φ, ranged from 0.32-0.62. The emulsions behaved as pseudoplastic fluids. The flow behavior index, n, of the lecithin emulsions increased slightly with increasing φ and concentration of emulsifying agent, Ce. However, the n values of Tween 20 emulsions were nearly constant. Apparent viscosity of the emulsions increased with increase of φ and Ce. With φ constant the apparent viscosity was still strongly affected by Ce. [ABSTRACT FROM AUTHOR]

Agar gel spheres (diameter = 4.0, 7.2 and 12.5 cm) were dried in desiccated air flow at low temperatures near freezing point (from - 9.3 to 10.7°C) at atmospheric pressure. Air velocities ranged from 0.05 to 0.32 m/sec. The drying rates during the constant drying rate period were directly proportional to the moisture vapor pressure at the sample surface. A linear relationship between the drying rate and the square root of the air velocity was obtained at each air temperature. Further, the film coefficients of heat transfer were evaluated and arranged as a semi-empirical dimensionless equation. [ABSTRACT FROM AUTHOR]

Background: In Japan, several large healthcare databases have become available for research since the early 2000's. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims.Methods: We selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI.Results: In a random sample of 200 patients, the average age was 67.7 years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%.Conclusion: The PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke. [ABSTRACT FROM AUTHOR]