背景：儘管草藥產品日益受到歡迎， 中藥所造成肝傷害的潛在危害越來越受到關注。此外，肝毒性案例報告有關新的藥物(nimesulide, celecoxib and rofecoxib)逐漸增加。在台灣病毒肝炎的盛行率是非常高的。台灣健保資料庫提供了一個機會進行藥物的上市後監測。藥物造成肝的不良反應的流行病學過去很少有相關研究，也因為難以進行研究。因此，我們對於中藥及可能造成肝毒性的新藥及台灣國民的肝傷害間的關係的流行病學研究感到興趣。因此，我們進行研究的三個目標：(1) 我們進行了觀察性研究，評估是否病例對照研究和病例交叉研究設計(case-control and case-crossover designs)，利用電腦資料庫，可用於檢測出肝毒性藥物在肝損傷的風險;(2) 研究台灣國民使用中藥與急性肝炎住院的關係;(3) 研究台灣國民使用止痛新藥cyclo­oxygenase­2 (COX-2) selective inhibitors與急性肝炎住院的關係。
方法：第一個研究設計：研究材料是使用大約 2200萬多人參加的，從1997年1月1日至2004年12月31的台灣全民健康保險資料庫。我們採用病例對照研究和病例交叉設計，來對已知的肝毒性藥物isoniazid, rifampicin, erythromycin及 diclofenac所造成的肝傷害進行.風險評估。我們使用上述兩個研究設計，並使用調整其他肝毒性藥物使用及共同疾病的Logistic回歸模型來統計。第二個研究設計：使用1997至2002年20萬隨機抽樣歸人檔的健保研究資料庫，進行病例交叉研究(case-crossover design)。採取在住院前的30及60天期間的所有藥物進行了探討，並與四個控制時期（住院之前及之後的180和360天）。進行在危險期間的中藥處方的勝算比的logistic回歸模型研究。第三個研究設計：研究新藥與傳統肝毒性非固醇類止痛藥造成急性肝炎之間的關係，設計單邊與雙邊的28天暴露期間的病例交叉研究兩種模型，並使用logistic回歸模型統計。
結果和結論：第一，病例對照及病例交叉研究兩種研究設計，所得到肝傷害住院病人在住院前30天的暴露肝毒性藥物的矯正後勝算比是相近且顯著增加的。使用健保資料庫，兩個研究設計都可以使用來評估肝毒性藥物造成的肝傷害風險。第二，在非病毒，非酒精性急性肝炎的族群，在矯正過傳統肝毒性西藥後，中草藥使用顯示略有增加急性肝炎的風險。因此，我們建議對可能肝毒性的中藥使用，進行藥物主動監視。第三，celecoxib, nimesulide, dicofenac, ibuprofen和其他肝毒性非固醇類止痛藥的勝算比是顯著增加的。我們的結果對肝毒性非固醇類止痛藥包括celecoxib使用，造成急性肝炎住院風險增加，提供證據。進一步的機轉研究來證實celecoxib的肝毒性是必要的。

Background: Despite the increase in popularity of herbal products, there is growing concern over potential hepatoxic hazards caused by the Chinese herbal medicines (CHMs). Otherwise, case reports of hepatoxicity about new drugs (nimesulide, celecoxib and rofecoxib) seem to increase. The prevalence rates of viral hepatitis are very high in Taiwan. The reimbursement database of National Health Insurance (NHI) in Taiwan provided an opportunity for post-marketing surveillance. The epidemiology of adverse hepatic reaction remains poorly documented and hard to conduct. Our epidemiologic studies were interested in an attempt to determine the association between the use of CHMs or potential hepatoxic new drug and the risk of liver injury amongst the citizens of Taiwan. Thus, we conducted our study for three objectives; (1) our observational study was conducted to assess if case-control and case-crossover designs could be applied to detect the risk of hepatoxic drugs on liver injury in the automated databases.; (2) to determine the association between the use of CHMs and the risk of hospitalizations related to acute hepatitis amongst the citizens of Taiwan; (3) to determine the association between the use of cyclo­oxygenase­2 (COX-2) selective inhibitors and the increased hospitalizations related to liver injury among the citizens of Taiwan.
Methods: First design: the study was conducted on approximately 22 million people enrolled in Taiwan’s national health insurance database from January 1, 1997 to December 31, 2004. We applied case-control and case-crossover designs to assess the estimated risks of liver injury related to well-known hepatoxic drugs, including isoniazid, rifampicin, erythromycin, and diclofenac. We applied two designs by conditional logistic regression model to adjust for other hepatoxic drugs and co-morbidity. Second design: a case-crossover study was designed on 200,000 randomly selected individuals from the NHI Research Database who were then followed from 1997 to 2002. All medications taken in the 30- and 60-day periods prior to hospitalization were explored and compared with four control periods (the 180- and 360-day periods prior to and after the hospitalization). A conditional logistic regression model was then constructed to determine the odds of CHM being prescribed during these risk periods. Third design: we conducted to determine the association between the use of hepatoxic NSAIDs and increased hospitalizations related to acute hepatitis. We applied two kinds of models to analyze by uni-directional and bi-directional case-crossover designs during the 28 days exposure periods and performed conditional logistic regression models.
Results and conclusions: First, the adjusted odds ratios of hospitalized liver injury patients during the 30-day exposure window showed similar and significant increases for hepatoxic drugs by the case-control and case-crossover designs. The risk of admission with liver injury related to hepatoxic drugs could be assessed by both designs based on automated databases. Second, after adjustment for conventional hepatotoxic drugs, Chinese herbal users revealed a slightly increased risk of acute hepatitis for nonviral, nonalcoholic acute hepatitis. We therefore recommend active surveillance for CHMs suspected with hepatotoxicity. Third, the odds ratios of celecoxib, nimesulide, dicofenac, ibuprofen and other hepatoxic NSAIDs were significantly increased. Our results provide evidence for an increased risk of hospitalization with acute hepatitis among hepatoxic NSAIDs including celecoxib users. Further mechanistic research is warranted in order to document celecoxib’s hepatotoxicity.

口試委員會審定書 ......................................2
誌謝...................................................3
中文摘要 ..............................................4
Abstract.............................................. 7
Chapter Ⅰ background ........................................... 9
Drug-induced liver injury (DILI)................................................ 9
Hepatotoxicity of Chinese herb medicines (CHMs)................................................ 11
Hepatotoxicity of new drugs..................................................12
Viral hepatitis and hepatoxic medicines .............................................13
The database of National Health Insurance .............................................14
Case-crossover design ................................................15
Main objective ........................................17
研究假說形成背景 ....................................................17
Chapter Ⅱ apply case-crossover design to assess the risk of DILI ...............................................18
Objective ............................................ 18
Material and methods ..................................18
Main findings .........................................22
Chapter Ⅲ risk of CHMs-induced liver injury ..........25
Objective ............................................ 25
Material and methods ..................................25
Main findings .........................................29
Chapter Ⅳ risk of COX-2 inhibitors-induced liver injury ............................................... 31
Objective ............................................ 31
Material and methods ..................................31
Main findings .........................................37
Chapter Ⅴ conclusions ................................39
Reference .............................................40
Appendix ..............................................44

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