Bias in spontaneous reporting of adverse drug reactions in Japan.

BACKGROUND: Attitudes of healthcare professionals regarding spontaneous reporting of adverse drug reactions (ADRs) in Japan are not well known, and Japan's unique system of surveillance, called early post-marketing phase vigilance (EPPV), may affect these reporting attitudes. Our objectives were to describe potential effects of EPPV and to test whether ADR seriousness, prominence, and frequency are related to changes in reporting over time. METHODS: A manufacturer's database of spontaneous ADR reports was used to extract data from individual case safety reports for 5 drugs subject to EPPV. The trend of reporting and the time lag between ADR onset and reporting to the manufacturer were examined. The following indices for ADRs occurring with each drug were calculated and analyzed to assess reporting trends: Serious:Non-serious ratio, High prominence:Low prominence ratio, and High frequency:Low frequency ratio. RESULTS: For all 5 drugs, the time lag between ADR onset and reporting to the manufacturer was shorter in the EPPV period than in the post-EPPV period. All drugs showed higher Serious:Non-serious ratios in the post-EPPV period. No specific patterns were observed for the High prominence:Low prominence ratio. The High frequency:Low frequency ratio for peginterferon alpha-2a and sevelamer hydrochloride decreased steadily throughout the study period. CONCLUSIONS: Healthcare professionals may be more likely to report serious ADRs than to report non-serious ADRs, but the effect of event prominence on reporting trends is still unclear. Factors associated with ADR reporting attitude in Japan might be different from those in other countries because of EPPV and the involvement of medical representatives in the spontaneous reporting process. Pharmacovigilance specialists should therefore be cautious when comparing data between different time periods or different countries. Further studies are needed to elucidate the underlying mechanism of spontaneous ADR reporting in Japan.

Nitrile anion cyclization with epoxysilanes followed by Brook rearrangement/ring-opening of cyclopropane nitriles/alkylation.

[reactions: see text] The reaction of delta-silyl-gamma,delta-epoxypentanenitrile derivatives 9-12 with a base and an alkylating agent affords (Z)-delta-siloxy-gamma,delta-unsaturated pentanenitrile derivatives via a tandem process that involves the formation of a cyclopropane derivative by epoxy nitrile cyclization followed by Brook rearrangement and an anion-induced cleavage of the cyclopropane ring. Exclusive formation of a (Z)-derivative from trans-epoxides is explained by the reaction pathway that involves a backside displacement of the epoxide by the alpha-nitrile carbanion and the O-Si bond formation followed by concerted processes involving Brook rearrangement and the anti-mode of eliminative ring fission of the cyclopropane from the rotamer 19. The fact that (E)-isomers are exclusively obtained from cis-epoxides and alpha-cyclopropyl-alpha-silylcarbinol derivative 26 provides experimental support for the proposed pathway.

Nitrile anion cyclization with epoxysilanes followed by brook rearrangement/ring opening of cyclopropane nitriles/alkylation.

The reaction of delta-silyl-gamma,delta-epoxypentanenitrile derivatives with a base and an alkylating agent affords delta-siloxy-gamma,delta-unsaturated pentanenitrile derivatives via a tandem process that involves the formation of the cyclopropane derivative by epoxy nitrile cyclization followed by Brook rearrangement and an anion-induced cleavage of the cyclopropane ring.