During the post-approval period, hypotheses about potentially new adverse drug reactions (ADR) have traditionally emerged from passive surveillance systems that collect large volumes of spontaneous case reports of suspected adverse drug reactions. With signal detection by traditional (or conventional, or manual) methods, quantitative (or statistical, or automated) methods for spontaneous reporting system (SRS) databases were introduced in the late 1990’s in order to detect serious ADR as early as possible. Most quantitative methods rely on comparisons of relative reporting frequencies, also known as disproportionality analyses. In FY 2009, the Pharmaceuticals and Medical Device Agency (PMDA) plans to introduce the quantitative methods (data mining method) used on Japanese SRS database. This paper introduces the recent situation on signal detection and signal management of adverse drug reactions.

Objective: Databases, such as the Medicaid recipient database in the USA and the General Practice Research Database (GPRD) in the UK, take on an important role as resources for balancing the benefits and risks of medicines in Europe and the United States.
Their record sizes are several ten million and a few million each. They are actually used for epidemiological studies. However, in Japan, a database that can be used for such studies is insufficient. We attempted to create a database of pre-marketing clinical trial data for antihypertensive drugs. These data have been managed by a Controller Committee.
(Design : not applicable )
Methods: The database is made from the data and the documents, including electronic and paper media. The creation process was as follows : computerizing documents, item-name identification, defining the integrated database, protocol review, batch processing, and logical/validation checking.
Results: The database has 13 datasets and consists of 56 trials and 12,389 subjects. Overall, 15 trials involved beta-blockers which is the largest drugs as the investigational drug, and 43 trials compared the same group of antihypertensive drugs.
Conclusion: A database that can be used for quantitative evaluation of various hypotheses has been built. It is possible to completely analyze all of the data in this large-scale database to conduct, for example, individual patient data (IPD) meta-analyses.

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.

Objective : To examine whether drug treatment for hypertension prevents the first occurrence of cerebral hemorrhage, a population-based case-control study was conducted in Hirara-city, Okinawa Prefecture, Japan.
Methods : Cases were 36 hypertensive persons, 45 to 84 years of age, who had experienced cerebral hemorrhage from 1991 to 1994. Twenty of them were ascertained to be hypertensive by residential mass health examinations before the occurrence of cerebral hemorrhage, and other cases were ascertained by stroke register. Controls were 158 hypertensive persons unaffected by stroke and other life-threatening diseases, who were matched with their corresponding case for sex, age and mean blood pressure. All controls were ascertained as hypertensive by health examinations in 1991. Data on antihypertensive treatment, during the two years before the occurrence for cases and between April 1992 and March 1994 for controls, were collected by claims for medical care cost and medical records. Conditional logistic regression was employed for matched analyses.
Results : Regarding treatment, 16 (44.4%) cases and 36 (23.5%) controls did not receive antihypertensive drug treatment, and 13 (36.1%) cases and 30 (19.6%) controls had interrupted treatment. Compared with continuously treated persons, untreated persons and interrupted persons had odds ratios of 6.27 (95% confidence interval : 2.21 to 17.8) and 4.94 (1.79 to 13.6) for cerebral hemorrhage, respectively. Cases were prescribed antihypertensive drugs for fewer months than controls. By subgroup analyses limited to the cases ascertained as hypertensive by mass health examinations and their matched controls, the same relation was observed.
Conclusion : Among hypertensive persons, non-treatment and interruption of antihypertensive drug treatment were associated with a higher risk of cerebral hemorrhage. Long-term continuous treatment with antihypertensive drug (s) prevents the first occurrence of cerebral hemorrhage.

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.

Objective : Carvedilol is a non-selective β blocker with an α blocking activity. Since this drug is highly fat-soluble, it can pass through the blood-brain barrier, and thus may induce depression and lower QOL. In the present study, physicians and pharmacists collaborated to evaluate the antihypertension effect of carvedilol and post-administration changes in QOL. Furthermore, the relationship between QOL and antihypertension effect was analyzed.
Design : Self-controlled study.
Patients and Methods : Subjects were outpatients with hypertension above the age of 70 years who visited one of 42 medical institutions in Japan between April 1995 and March 1996. A total of 243 patients were registered, and 10-20 mg of carvedilol was administered once a day for six months. Pharmacists assessed the QOL of these patients by asking 82 questions on three separate occasions : before administration and one and six months after administration. The antihypertensive effect of this drug was investigated in patients in whom all three QOL questionnaires were collected. The main test items were antihypertensive effect, changes in QOL (subjective QOL with a special emphasis on patient psychology), and the relationship between antihypertensive effect and QOL. The antihypertensive effect of this drug was statistically analyzed by a paired t-test, and changes in QOL were statistically analyzed using generalized estimating equations.
Results : All three QOL questionnaires were collected from a total of 146 patients. Their pre-administration systolic blood pressure was 159.6±1.4 mmHg, and diastolic blood pressure 94.0±0.9 mmHg, and their blood pressure decreased significantly one month after the start of administration. This antihypertensive effect of carvedilol persisted, and the systolic and diastolic blood pressure of these patients six months after the start of administration was 141.1±1.2 and 85.2±0.7 mmHg, respectively (significant decreases when compared to pre-administration levels ; both p<0.05).
Subjective QOL improved significantly after carvedilol administration. And, changes were not seen in sexual function. Changes in the five categories of subjective QOL were as follows : psychological stability, disease-induced inconvenience, and independence improved significantly after carvedilol administration, but changes were not seen in gratification or vitality. However, improvements in subjective QOL did not correlate with improvements in blood pressure.
Conclusions : The results of the present study showed that carvedilol improved QOL without negatively affecting sexual function. Subjective QOL reflects the psychological well-being of patients. In the present study, psychological stability, disease-induced inconvenience, and independence improved significantly, but changes were not seen in gratification or vitality. Since β blockers can suppress the central nervous system, they can reduce psychological stability, gratification and vitality. Even though carvedilol is highly fat-soluble, the results of non-clinical studies have shown that it does not suppress the central nervous system as much as propranolol. The results of the present study showed that carvedilol does not strongly suppress the central nervous system of humans. Moreover, significant changes in QOL were not seen between one and six months after the start of administration of carvedilol, suggesting that it is possible to estimate the QOL of patients on antihypertensive therapy after six months of administration by assessing their QOL one month after administration.