巴金森氏病早期使用amantadine治療與左旋多巴誘發異動症的發病時間相關性探討

Abstract

研究背景 目前認為N-甲基-D-天門冬胺酸受體過激與多巴胺神經逐漸的死亡是造成左旋多巴誘發之異動症的兩項重要病理原因，近期有臨床前研究指出，amantadine除了具有抑制N-甲基-D-天門冬胺酸受體的作用，亦可透過抑制發炎反應達到保護多巴胺神經的作用，故此研究旨在探討巴金森病人早期使用amantadine與其異動症發病時間的相關性。 研究方法 本研究為一回溯性的世代研究，利用台大醫院資料庫2009年7月1日至2016年10月31日作為資料來源，欲納入具有主診斷為巴金森氏症的病患。為評估amantadine是否在不同動作表現型皆具有作用，故Antciholinergics以及MAOBIs將分別在世代一以及世代二作為amantadine的對照組。資料將會以界標分析 (Landmark analysis) 加上意向分析處理，以確保兩個世代有足夠的人數以及減少長期追蹤下的分類錯誤，此外，異動症的風險將會以權重後的Cox比例分險模式去統計。 研究結果 我們分別在世代一中的6個月界標納入741位病人、12個月界標納入641位病人以及18個月界標納入522位病人；世代二中的6個月界標則納入711位病人、12個月界標納入616位病人以及18個月界標納入491位病人。而經過傾向分數 (Propensity score) 加權後，世代一中的兩組其基礎特性相當，然而在世代二仍是存在些許的不平衡。在六個月界標中無事件的病人，amantadine相較於anticholinergics以及MAOBIs其在異動症的風險各別降低了28% (adjusted hazard ratio, 0.72; 95% CI 0.53–0.97)與39% (adjusted hazard ratio,0.61; 95% CI 0.44–0.83); 然而在12個月以及18個月界標中無事件的病人，世代一顯示兩組並無統計上差別，但在世代二amantadine相較於MAOBIs則是在兩個界標分析中皆具有顯著降低異動症風險的作用，其12個月界標分析的風險比為0.52 (95% CI 0.37-0.73)，而在18個月界標分析的風險比則為0.45 (95% 0.31-0.64)。 結論 此為第一個回溯性研究指出早期使用amantadine相較於anticholinergics或是MAOBIs具有降低巴金森病人異動症風險的相關性，然而，amantadine服藥多久與其降低異動症的風險比例則需由未來設計良好的臨床試驗來進一步釐清。

Background Hyperactivity of N-Methyl-D-Aspartate (NMDA) receptor and progressive loss of dopaminergic neuron play crucial role in developing levodopa-induced dyskinesia (LID). Aside from blocking the NMDA receptor, recent preclinical study suggests that amantadine could protect the dopaminergic neurons through modulating the neuroinflammatory response. This study aimed to examine the association between early treatment with amantadine and the onset of LID in patient with idiopathic Parkinson’s disease. Methods We conducted a retrospective cohort study at National Taiwan University Hospital between July 1, 2009 and October 31, 2016. Patients with a primary diagnosis of idiopathic Parkinson’s disease were included in the study. To assess the effect of amantadine across different clinical phenotypes, anticholinergics and monoamine oxidase type B inhibitors (MAOBIs) were respectively selected as the active comparators respectively in the cohort 1 and cohort 2. Landmark analysis plus intention-to-treat approach were applied to ensure adequate sample size and eliminate misclassification in the long-term follow-up. The risk of LID was analyzed by the weighted Cox proportional hazard model. Results We include respectively 741 patients at 6-month landmark, 641 patients at 12-month landmark, and 522 patients at 18-month landmark in the cohort 1, and there were respectively 711 patients at 6-month landmark, 616 patients at 12-month landmark, and 491 patients at 18-month landmark in the cohort 2. After propensity score weighting, baseline characteristics were comparable at each landmark in the cohort 1. However, a few covariates still exist small differences in the cohort 2. Among patients who were event-free at 6-month landmark, amantadine had a respectively 28% (adjusted hazard ratio, 0.72; 95% CI 0.53–0.97) and 39% (adjusted hazard ratio,0.61; 95% CI 0.44–0.83) risk reduction on LID compared to anticholinergics and MAOBIs. No differences were found among patients who were event-free at the 12-month and 18-month landmarks in the cohort 1. However, amantadine significantly reduced the risk of LID among patients who were event-free at the 12-month and 18-month landmarks in the cohort 2, with the adjusted hazard ratios 0.52 (95% CI 0.37-0.73) and 0.45 (95% 0.31-0.64) respectively. Conclusion This is the first retrospective study that showed early treatment with amantadine compared with either anticholinergics or MAOBIs may be associated with a reduced risk for LID. However, well-designed randomized clinical trials are needed to further confirm the study finding and determine the optimal duration of amantadine treatment that would exert the most clinical benefit on delaying the onset of dyskinesia.