- 學位論文
服用Amantadine會引發角膜水腫: 在台灣一個全國性的人口為基礎的研究
Amantadine use as a risk factor for corneal edema: a nationwide cohort study in Taiwan
摘要
目的： 由一個回朔型國家大型資料庫的研究報告來評估使用amantadine藥物與發生角膜水腫之間的關係 前言: 隨著amantadine在臨床上的使用，過去已有零星的報告指出服用此藥會造成角膜毒性。直到現在，在世界各地已發表越來越多的臨床報告指出服用amantadine引發上述的副作用。特別的是，一旦接受amantadine治療，就有可能在短期內引發嚴重的角膜水腫。這時如果停止amantadine的使用，即有可能在數週後解除角膜水腫並恢復清澈。我們過去曾發表四位案例因為服用amantadine引發角膜水腫並在停藥後恢復，但是部分角膜內皮細胞卻永久失去了。由於上述的發現，我們假設服用amantadine會傷害角膜內皮細胞進而造成角膜水腫。而這種毒性可能與服用藥物的劑量有直接關係。因此，這篇研究使用台灣全民健康保險研究資料庫來分析amantadine與發生角膜水腫是否相關聯，並試著找出服用amantadine引發角膜水腫的致病劑量。 研究材料及方法： 這篇研究使用了台灣健保資料庫自1996.1.1至2010.12.31縱向資料分析了8195位帕金森氏症患者並成為實驗組, 而對照組則根據年齡, 性別, 及Charlson 合併症指標做常態篩選而選擇了同樣數目未患有帕金森氏症的患者。我們運用Kaplan-Meier method計算患角膜水腫隨時間的累積發生率。使用Incident rate ratios 及Cox proportional hazard regressions來分析並比較2組之間的發生率及相對風險值，並進一步比較服用amantadine 及未服藥2組之間發生角膜水腫的差異性。 結果： 帕金森氏症的患者上其角膜水腫的發生率（123 patients; 1.50%）相對於對照組（82 patients; 1.0%）而言呈現有意義的上升（p = 0.004）。以發病率（incidence ratio）來看，帕金森氏症組發生角膜水腫的比例為對照組的5.77倍。在帕金森氏症組中，服用amantadine的人其角膜水腫的危險機率（hazard ratio）為未服藥者的1.79倍。進一步再將實驗組中服用藥物的人根據amantadine累積使用劑量來分組，可以發現，30天內的總累積劑量達到中度，即2000到4000 mg時，其發生角膜水腫的風險比值為2.05倍。如果30天內累積總劑量來到4000 mg以上時，其發生角膜水腫的風險比值將為2.84倍。 結論： 我們的研究發現，持續服用Amantadine，隨著累積的劑量增加，其發生角膜水腫的風險也隨著提高。這篇以台灣全人口基礎的病例對照研究發現使用amantadine藥物治療帕金森氏症患者將顯著增加其發生角膜水腫的風險。我們的研究發現當患者在一個月內服用amantadine累積劑量達到4000毫克，其發生角膜水腫的風險將達到未服藥者的三倍。
並列摘要
Purpose: To evaluate the association between amantadine use and corneal toxicity in a nationwide population. Preface: Few studies have examined the association between the use of amantadine and corneal toxicity. Until now, there are more and more serious studies around the world mentioned this side effect. Specifically, severe corneal edema develops soon after initiation of amantadine therapy and resolves within a few weeks after cessation of amantadine. We previously reported four cases of reversible corneal edema and permanent endothelial loss caused by amantadine use. We hypothesized that use of amantadine may damage the corneal endothelium in a dose-dependent manner. Therefore, this study used the Taiwan Longitudinal Health Insurance Database to investigate the association between amantadine use and corneal edema and to determine the dose that has toxic effects on the endothelium. Design: Retrospective study of nationwide population-based administrative database. Methods: This study analyzed data in the Taiwan Longitudinal Insurance Database for a group of 8195 patients diagnosed with Parkinson's disease during a 15-year period (January 1, 1996 to December 31, 2010). A control group of 8195 patients without Parkinson’s disease was randomly matched with the Parkinson’s group by age, gender, and comorbidity index. The Kaplan-Meier method was used to calculate the cumulative incidence of corneal edema. Incident rate ratios and Cox proportional hazard regressions were estimated to compare the risk of corneal edema. The same methods were then used to compare the risk between patients with and without amantadine treatment. Results : The incidence of corneal edema in the Parkinson’s group (123 patients; 1.50%) was significantly higher than that in the control group (82 patients; 1.0%) (p = 0.004). The incidence ratio for corneal edema in the Parkinson’s group versus the controls was 5.77. When the Parkinson’s group was further subgrouped by use and non-use of amantadine, the hazard ratio for corneal edema was 1.79 times higher in the amantadine subgroup. Analyses of the amantadine subgroup by cumulative dose revealed that, the 30-day hazard ratio for corneal edema was 2.05 times higher in patients given moderate doses (2000-4000mg) of amantadine, and 2.84 times higher in the subgroup of patients given high doses (>4000 mg). Conclusions: Continuous use of Amantadine increases the risk of corneal edema in a dose-dependent manner. This nationwide, case-control study of a Taiwan cohort found that amantadine treatment is a significant risk factor for corneal edema in patients with Parkinson’s disease. Specifically, a high dose (4000mg) of amantadine administered in a short period (1 month) causes a nearly 3-fold increase in the risk of corneal edema.