Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database

BACKGROUND: In March 2007, a regulatory advisory was issued in Japan to restrict oseltamivir use in children aged 10-19 years because of safety concerns over abnormal behavior. The effectiveness and validity of regulatory risk minimization actions remain to be reviewed, despite their significant public health implications. To assess the impact of the regulatory actions on prescribing practices and safety reporting. METHODOLOY/PRINICPAL FINDINGS: In this retrospective review of a nationwide pharmacy database, we analyzed 100,344 dispensation records for oseltamivir and zanamivir for the period from November 2006 to March 2009. The time trend in dispensations for these antiviral agents was presented before and after the regulatory actions, contrasted with intensity of media coverage and the numbers of spontaneous adverse reaction reports with regard to antivirals. The 2007 regulatory actions, together with its intense media coverage, reduced oseltamivir dispensation in targeted patients in fiscal year 2008 to 20.4% of that in fiscal year 2006, although influenza activities were comparable between these fiscal years. In contrast, zanamivir dispensation increased approximately nine-fold across all age groups. The number of abnormal behavior reports associated with oseltamivir in children aged 10-19 years decreased from fiscal year 2006 to 2008 (24 to 9 cases); this decline was offset by the increased number of reports of abnormal behavior in children under age 10 (12 to 28 cases). The number of reports associated with zanamivir increased in proportion to increased dispensation of this drug (11 to 114 cases). CONCLUSIONS/SIGNIFICANCE: The 2007 actions effectively reduced oseltamivir prescriptions and the number of reports of abnormal behavior in the targeted group. The observed increase in abnormal behavior reports in oseltamivir patients under age 10 and in zanamivir patients suggests that these patient groups may also be at risk, calling into question the validity of the current discrimination by age and agent (Abstract translation is available in Japanese: Appendix S1)

Analysis of Radioactive Elements in Testes of Large Japanese Field Mice Using an Electron Probe Micro-Analyser after the Fukushima Accident

The Fukushima Daiichi nuclear power plant (FDNPP) accident drew global attention to the health risks of radiation exposure. The large Japanese field mice (Apodemus speciosus) are rodents endemic to, and distributed throughout, Japan. This wild rodent live in and around the ex-evacuation zone on the ground surface and/or underground. In this study, we evaluated the effect of chronic radiation exposure associated with FDNPP accident on the testes of large Japanese field mice. Morphological analysis and electron-prove X-ray microanalysis (EPMA) was undertaken on the testes. Morphological analysis of testes based on H&E staining showed that the spermatogenesis was observed normally in the breeding season of wild mice in the heavily contaminated area. However, caesium (Cs) was not detected in all testes of wild mice from FDNPP ex-evacuation zone. In conclusion, even if the testes and the process of spermatogenesis are hypersensitive to radiation, we could not detect radiation effects on the spermatogenesis and Cs in the examined large Japanese field mice testes following chronic radiation exposure associated with the FDNPP accident

Intestinal Bacteria as Powerful Trapping Lifeforms for the Elimination of Radioactive Cesium

In March 2011, an accident at the Fukushima Daiichi Nuclear Power Plant led to major problems, including the release of radionuclides such as Cesium (Cs)-137 into the environment. Ever since this accident, Cs-137 in foods has become a serious problem. In this study, we determined the concentration of Cs-137 in the feces, urine, and ruminal contents of cattle and demonstrated the possibility of its elimination from the body by intestinal bacteria. The results revealed a high Cs-137 concentration in the feces; in fact, this concentration was higher than that in skeletal muscles and other samples from several animals. Furthermore, intestinal bacteria were able to trap Cs-137, showing an uptake ratio within the range of 38–81% in vitro. This uptake appeared to be mediated through the sodium–potassium (Na+-K+) ion pump in the bacterial cell membrane. This inference was drawn based on the fact that the uptake ratio of Cs-137 was decreased in media with high potassium concentration. In addition, it was demonstrated that intestinal bacteria hindered the trapping of Cs-137 by the animal. Cattle feces showed high concentration of Cs-137 and intestinal bacteria trapped Cs-137. This study is the first report showing that intestinal bacteria contribute to the elimination of Cs-137 from the body

セイチョウ ホルモン ブンピ フゼン オ ユウスル ニホンジン セイジン カスイタイ キノウ テイカショウ カンジャ ニ オケル セイチョウ ホルモン ホジュウ リョウホウチュウ ノ タイソセイ ヘンカ ニ タイスル Quality of Life ( セイカツ ノ シツ ) ノ オウトウセイ ニ ツイテ ノ ハッショウ ジキ ニ ヨル サイ ニ カンスル ケンキュウ

京都大学0048新制・課程博士博士(社会健康医学)甲第13741号社医博第21号新制||社医||5(附属図書館)UT51-2008-C657京都大学大学院医学研究科社会健康医学系専攻(主査)教授 中山 健夫, 教授 川上 浩司, 教授 小杉 眞司学位規則第4条第1項該当Doctor of Public HealthKyoto UniversityDA

Biased Safety Reporting in Blinded Randomized Clinical Trials: Meta-Analysis of Angiotensin Receptor Blocker Trials

<div><p>Background</p><p>Cough is listed as an adverse drug reaction (ADR) on the labels of angiotensin receptor blockers (ARB). However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI), which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded randomized clinical trials.</p><p>Methods and Findings</p><p>The double-blinded, randomized clinical trials with comparator drugs were identified in the Japanese dossiers for the new drug applications of ARBs. The risk ratios (RR) of reporting cough and headache in ARB arms were calculated for each ARB by comparing trials using ACEIs and trials using non-ACEIs, were then combined with a meta-analysis. 23 trials with a total of 6643 patients were identified, consisting 6 trials using an ACEI comparator including 819 ARB patients and 17 trials using a non-ACEI comparator including 5824 ARB patients. The combined RR of cough reporting was significantly elevated (20.77; 95% confidence interval [CI], 7.47 to 57.76), indicating more frequent reporting of cough in clinical trials using an ACEI comparator. In contrast, the combined RR of headache, a negative control, was insignificant (1.45; 95% CI, 0.34 to 6.22).</p><p>Conclusion</p><p>The use of comparators with well-known ADRs in blinded randomized trials produces potential bias in the reporting frequency of ADRs for investigational drugs. The selection of appropriate comparator drugs should be critical in unbiased safety assessment in double-blinded, randomized clinical trials and thus have relevance in reviewing the safety results from a regulatory point of view.</p></div