Use of National Database of Health Insurance Claims and Specific Health Checkups for examining practical utilization and safety signal of a drug to support regulatory assessment on postmarketing drug safety in Japan.

The Pharmaceuticals and Medical Devices Agency (PMDA) has conducted many pharmacoepidemiological studies for postmarketing drug safety assessments based on real-world data from medical information databases. One of these databases is the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), containing health insurance claims of almost all Japanese individuals (over 100 million) since April 2009. This article describes the PMDA's regulatory experiences in utilizing the NDB for postmarketing drug safety assessment, especially focusing on the recent cases of use of the NDB to examine the practical utilization and safety signal of a drug. The studies helped support regulatory decision-making for postmarketing drug safety, such as considering a revision of prescribing information of a drug, confirming the appropriateness of safety measures, and checking safety signals in real-world situations. Different characteristics between the NDB and the MID-NET® (another database in Japan) were also discussed for appropriate selection of data source for drug safety assessment. Accumulated experiences of pharmacoepidemiological studies based on real-world data for postmarketing drug safety assessment will contribute to evolving regulatory decision-making based on real-world data in Japan.

Effect of an inducer of BiP, a molecular chaperone, on endoplasmic reticulum (ER) stress-induced retinal cell death.

PURPOSE: The effect of a preferential inducer of 78 kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein (BiP; BiP inducer X, BIX) against tunicamycin-induced cell death in RGC-5 (a rat ganglion cell line), and also against tunicamycin- or N-methyl-D-aspartate (NMDA)-induced retinal damage in mice was evaluated. METHODS: In vitro, BiP mRNA was measured after BIX treatment using semi-quantitative RT-PCR or real-time PCR. The effect of BIX on tunicamycin (at 2 microg/mL)-induced damage was evaluated by measuring the cell-death rate and CHOP protein expression. In vivo, BiP protein induction was examined by immunostaining. The retinal cell damage induced by tunicamycin (1 microg) or NMDA (40 nmol) was assessed by examining ganglion cell layer (GCL) cell loss, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, and CHOP protein expression. RESULTS: In vitro, BIX preferentially induced BiP mRNA expression both time- and concentration-dependently in RGC-5 cells. BIX (1 and 5 microM) significantly reduced tunicamycin-induced cell death, and BIX (5 microM) significantly reduced tunicamycin-induced CHOP protein expression. In vivo, intravitreal injection of BIX (5 nmol) significantly induced BiP protein expression in the mouse retina. Co-administration of BIX (5 nmol) significantly reduced both the retinal cell death and the CHOP protein expression in GCL induced by intravitreal injection of tunicamycin or NMDA. CONCLUSIONS: These findings suggest that this BiP inducer may have the potential to be a therapeutic agent for endoplasmic reticulum (ER) stress-induced retinal diseases.

Altered localization of amyloid precursor protein under endoplasmic reticulum stress.

Recent reports have shown that the endoplasmic reticulum (ER) stress is relevant to the pathogenesis of Alzheimer disease. Following the amyloid cascade hypothesis, we therefore attempted to investigate the effects of ER stress on amyloid-beta peptide (Abeta) generation. In this study, we found that ER stress altered the localization of amyloid precursor protein (APP) from late compartments to early compartments of the secretory pathway, and decreased the level of Abeta 40 and Abeta 42 release by beta- and gamma-cutting. Transient transfection with BiP/GRP78 also caused a shift of APP and a reduction in Abeta secretion. It was revealed that the ER stress response facilitated binding of BiP/GRP78 to APP, thereby causing it to be retained in the early compartments apart from a location suitable for the cleavages of Abeta. These findings suggest that induction of BiP/GRP78 during ER stress may be one of the regulatory mechanisms of Abeta generation.