Objective: To investigate quantitatively the risk factors of hyperkalaemia or increased blood potassium associated with ACE-inhibitor therapy
Design: Nested case-control study
Methods: We used the antihypertensive drug database(72,379 subjects)developed by the RAD-AR Council, Japan and the Institute of Statistical Mathematics based on the post-marketing surveillance(PMS) data of pharmaceutical companies. Of 37,372 subjects taking ACE-inhibitors, the case group was composed of 64 patients who experienced hyperkalaemia or blood potassium increase while taking ACE-inhibitors, and the control group was composed of 1,280 patients(20 patients per case)randomly selected from patients who did not experience hyperkalaemia or blood potassium increase while taking ACE-inhibitors. The relevant factors that can be extracted from the database were the followings: age, WHO classification of hypertension, complications, antihypertensive drugs used before the PMS survey, and concomitant drugs.
Results: Among the subjects taking antihypertensive agents, 65 patients experienced hyperkalaemia orincreased blood potassium, 64(98.5%)of whom were taking ACE-inhibitors. The factors that were significantly different between two groups(p<0.05)by univariate analysis were WHO classification of hypertension(p=0.005), complications of nephritis/nephrosis(p<0.001), other disorder of urinary system(p<0.001), unclear symptom or diagnosis(p=0.005), taking diuretics as antihypertensive drugs before study(p=0.032), and concomitant treatment with diuretics(p=0.004), vasodilators(p<0.001), and antigout agents(p=0.001). Conditional multivariate logistic analysis of these factors yielded adjusted odds ratio of 21.31 for complications of nephritis/nephrosis(p<0.001), 6.83 for other disorder of urinary system(p<0.001), and 2.30 for concomitant therapy with diuretics(p=0.049).
Conclusion: The risk factors of hyperkalaemia or blood potassium increase associated with taking ACE-inhibitors were nephritis/nephrosis, other disorder of urinary system and concomitant therapy with diuretics.

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Objective: Pharmaceutical manufacturers conduct drug use-results surveys (DUSs) for drug reexamination applications in Japan. However, most DUSs are single-cohort studies to confirm drug safety; therefore little information is obtained from a DUS for safety comparison with other drugs. Integrating DUS data is a novel method to compare drug safety profiles among drugs. This study examined the usefulness of integrating DUS data.
Design: Active surveillance
Methods: We integrated DUS data obtained from two DUSs of antihypertensive drugs-a calcium channel blocker (CCB), azelnidipine (CalblockR), and an angiotensin-receptor blocker (ARB), olmesartan medoxomil (OlmetecR)-with similar study protocols. Both studies were conducted by the same pharmaceuticalcompany. Matching patients using propensity scores, we examined whether the DUS results could be applied to pharmacoepidemiology data resources for hypothesis strengthening. Safety outcomes included vasodilation-related events, which are typical adverse drug reactions (ADRs) to CCB. The incidence of safety outcomes was compared by conditional logistic regression models. Two definitions for safetuoutcomes were employed: definition 1, physician-reported adverse events; and definition 2, physicianreported ADRs.
Results: In a total of 7196 patients included in the analysis, the propensity-matched patients were well balanced. Most safety outcomes were detected in the CCB group including a significant increase in vasodilation-related events (odds ratio for definition 1 versus ARB group, 1.75; 95% confidence interval,1.01-3.03).
Conclusion: Integrated DUS data collated by pharmaceutical manufacturers following clear criteria are potentially useful to commence pharmacoepidemiology studies designed to strengthen hypotheses.

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Objective: The mechanism underlying the development of neuropsychiatric symptoms such as unconsciousness, abnormal behavior, delirium, hallucinations, and convulsions in influenza has not been thoroughly investigated. The relationship between drug administration and neuropsychiatric symptoms during influenza is also poorly understood. This study is the first pharmacoepidemiologic study focused on investigating the relationship between drug administration and neuropsychiatric symptoms.
Design: Cohort study
Methods: Study subjects were patients under 18 years old who had influenza during the 2006/07 season. We prepared two kinds of questionnaires for doctor and for patient's family, and carried out the survey between January and March, 2007. Using data from 9,389 patients, we analyzed the relationship between neuropsychiatric symptoms, such as delirium, unconsciousness and convulsion, and drug administration of acetaminophen and oseltamivir.
Results: Analysis of the relationship between delirium and drug administration provided hazard ratios of 1.55(p=0.061)for acetaminophen and 1.51(p=0.084)for oseltamivir. These hazard ratios, which were adjusted for risk factors by multivariate analysis of the proportional hazard model, showed an increasing tendency of delirium after administration of each drug. In patients who received oseltamivir, a high incidence of delirium was observed between 6 and 12 hours after onset of fever. Furthermore, delirium was found to develop in a shorter time following oseltamivir use than it did after acetaminophen use. There was no relationship between unconsciousness and acetaminophen administration, as demonstrated by a hazard ratio of 1.06(p=0.839). The incidence of unconsciousness increased significantly with oseltamivir use with a hazard ratio of 1.79(p=0.0389), and unconsciousness was found to occur in a short time after oseltamivir use.
Conclusion: The results obtained from this study suggest that there are increased risks of delirium and unconsciousness with drug administration. Further pharmacoepidemiologic studies for hypothesis testing are required to study the relationship between abnormal behavior and drug administration.

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Objective: Standardized clinical data are invaluable for secondary use of medical information. We constructed a standardized database and a data warehouse called D*D, based on the Standardized Structured Medical Information Exchange(SS-MIX)scheme. D*D enables physicians and researchers to perform complex searches with combined conditions, e.g. time to event. It contains data from 1999 for approximately 400,000 individual patients. The objective of this study was to provide an overview of the features of this database system, especially from the perspective of drug safety research.
Methods: Three models of research questions were identified from established drug-risk combinations:1)gatifloxacin and hypoglycemia;2)statins and rhabdomyolysis;and 3)oral 5-fluorouracil S-1 and hepatotoxicity. D*D was searched using predefined keywords and conditions.
Results: 1)A total of 3,635 patients were treated for diabetes. Among 20 diabetic patients prescribed gatifloxacin, hypoglycemia was recorded in one patient(1/38 prescriptions). 2)Among 5,926 patients who had been prescribed any statin within 10 years in our hospital, 6 patients(0.1%)experienced rhabdomyolysis. The incidence was similar to that for fibrate (1/740, 0.1%). The most confounded diagnosis was stiff shoulder. 3)Among 244 patients prescribed S-1, 19 patients(7.8%) experienced hepatotoxicity higher than CTCAE grade3 within 2 months from the prescription.
Conclusion: With limited data items and search keys in standardized data storage, definitions of exposures and outcomes require careful assessment during protocol development. Considering that the system can be implemented at more than half of the hospitals that have already installed ordering systems, D*D can be one of the Japanese models for distributed research network.

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