陳保中臺灣大學:職業醫學與工業衛生研究所詹毓哲Tsan, Yu-TseYu-TseTsan2010-05-112018-06-292010-05-112018-06-292007U0001-0312200722364500http://ntur.lib.ntu.edu.tw//handle/246246/182255簡介：隨著安眠藥於全世界廣泛使用，其安全性備受重視，除常見中樞神經副作用外，安眠藥引起的肝毒性亦不容忽視。大部分安眠藥需經過肝臟代謝，而安眠藥引起之肝毒性均為病例報告，沒有大型流行病學研究。因此，我們研究目的試圖驗證苯二酚和新一代安眠藥與急性肝炎住院間的關聯。法：從1997年至2004年的健保資料庫連結，依研究定義找出個案與前後各兩組對照組，然後去分析不同暴露時段，同時將個案分成乙型、丙型、酒精、非病毒非酒精性肝炎等組別，接著利用個案交叉研究方法算出因急性肝炎住院的勝算比。果：45,626個案因急性肝炎住院，連結門診檔分析後發現於急性肝炎住院前一週接受Zolpidem處方之勝算比為2.4 (95％信賴區間 1.9, 3.0)。而Zopiclone位第一週暴露時間，其勝算比為1.5 (95％信賴區間 1.0, 2.4)。對於傳統苯二酚，亦以住院前一週勝算比最明顯。此外，根據調整過之勝算比趨勢，另一高峰呈現於前三至六週。論：Zolpidem、zopiclone還有傳統苯二酚安眠藥處方時，會增加急性肝炎住院的風險應特別注意，且常見反應為非特異性與非線性劑量。臨床醫師使用這類潛在風險之安眠藥時，需定期監測肝功能。Introduction: With extensive use of hypnosedatives worldwide, in addition to the most commonly reported side effects of sedation, liver injury induced by benzodiazepines (BZDs) has been reported and should be monitored. BZDs, zolpidem and zopiclone all undergo hepatic metabolism. Hepatoxicity has been suspected so the aim of this study was to determine the association between the use of BZDs, zolpidem, zopiclone and the risk of hospitalization related to acute hepatitis.ethods: The study cohort dataset was obtained from the National Health Insurance (NHI) research database in Taiwan from 1997-2004. We separated the groups of patients diagnosed before selected admission of outpatient visits or hospitalization as viral hepatitis B, C, non-viral, non-alcoholic hepatitis, alcoholic hepatitis. Since there were so many determinants, or potential confounders for acute hepatitis, we applied case-crossover design as a means of controlling factors within subjects.esults: 45,626 cases of hospitalization relating to acute hepatitis were obtained. The odds ratio for the first week was the largest and most significant for these medicines. Conditional logistic regression analysis showed a significant adjusted odds ratio of 2.4 (95% confidence interval 1.9, 3.0) for zolpidem during the 7-day risk period. The adjusted odds ratio of zopiclone was 1.5 (95% confidence interval 1.0, 2.4) during the 7-day exposure period. In BZDs, the results were similar to the previous two drugs. In addition, based on the trend of the adjusted odds ratios, another peak was found during the 3 to 6-week period.iscussion: There is an increased risk of hospitalization for acute hepatitis in patients treated with zolpidem, zopiclone and benzodiazepines, and most severe drug induced liver injuries can be idiosyncratic and dose-independent. Thus, physicians and clinical pharmacists should take such potential into consideration and monitor the liver function of patients taking hypnosedatives suspected to be hepatotoxic.Table of Contents要 5bstract 6ntroduction 8ntroduction of benzodiazepines, zolpidem and zopiclone 8iver injury induced by zolpidem, zopiclone and BZDs 8ith and without pre-existing liver diseases 9ethods 11ata Sources 11tudy Subjects 11ase-crossover Design 13ase and Control Exposure Windows and Washout Periods 14ovariates for Adjustment 16tatistical Analysis 16esults 18emographic results 18ncreased risk of hospitalization for acute hepatitis in patients treated with zolpidem, zopiclone, BZDs 18he risks of hospitalization for acute hepatitis in patients treated with zolpidem, zopiclone, BZDs between different hepatitis groups 19he risks of hospitalization for acute hepatitis treated with zolpidem, zopiclone, BZDs by age, sex and dose 20iscussion 21ncreased risk of hospitalization for acute hepatitis in patients treated with zolpidem, zopiclone, BZDs 21he advantage of National Health Insurance in Taiwan 22ncreased risk of hospitalization for acute hepatitis in an individual hypnosedative 22he risks of hospitalization for acute hepatitis in patients treated with zolpidem, zopiclone, BZDs between different hepatitis groups 23he risks of hospitalization for acute hepatitis treated with zolpidem, zopiclone, BZDs by age, sex and dose 25otential limitations 26onclusion 28eference 29igure 1. Subjects selection process. 32igure 2. Timeline of the risk and four control periods 33able 1. Characteristics of study subjects with initial admission diagnosis of acute hepatitis, 1997-2004 34able 2. Odds ratios between hospitalizations and zolpidem, zopiclone, BZDs, by first week and 3 to 6-week risk periods in hepatitis groups 35able 3. Odds ratios between hospitalizations and zolpidem, zopiclone, BZDs, by risk period, age, sex and dose in hepatitis groups. 36ppendix 1. Comparison the latency time and dosage between sedative hypnotics induced liver injury in Micromedex® and NHI databases 37ppendix 2 Comparison between case reports of sedative hypnotics induced liver injury 39ppendix 3. Hepatoxic Drugs (Generic Name) Identified in the Micromedex® Database 54ppendix 4. The trend of adjusted odds ratio between hospitalizations and zolpidem, zopiclone, BZDs by the 1,2,3,4,5,6,7,8,9,10,11,12,13-weeks weekly exposure periods, and acute hepatitis groups. 56ppendix 5. Categories of acute hepatitis according to the International Classification of Diseases, 9th Revision (ICD-9) code. 66ppendix 6. Odds ratios of symmetrical bi-directional versus uni-directional cross-over design between hospitalizations and zolpidem, zopiclone, BZDs, by 3 to 6-week risk period in hepatitis groups 68application/pdf440322 bytesapplication/pdfen-US藥物流行病學健保資料庫苯二酚安眠藥pharmacoepidemialogy, National Health Insurance File and NHI Major Disease Filebenzodiazepinezolpidemzopiclonehepatotoxicityhypnosedative.[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/182255/1/ntu-96-R93841001-1.pdf