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研究生:吳秀玲
研究生(外文):Wu,Shiow-Ling
論文名稱:C型肝炎病毒對美沙冬治療成癮的影響
論文名稱(外文):HCV Influences the Methadone Maintenance Treatment for Addiction
指導教授:劉玉麗
指導教授(外文):Liu, Yu-Li
口試委員:陶寶綠鄒小蕙劉玉麗何英剛黃玲玲
口試委員(外文):Tao, Pao-LuhTsou, Hsiao-HuiLiu, Yu-LiHo, Ing-KangHwang, Ling-Ling
口試日期:2013-12-06
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2013
畢業學年度:102
語文別:中文
論文頁數:114
中文關鍵詞:C型肝炎病毒S型美沙冬2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine天門冬胺酸轉胺脢丙氨酸轉胺脢美沙冬支持性替代療法
外文關鍵詞:Hepatitis C VirusS-MethadoneS-EDDPASTALTMMT
相關次數:
  • 被引用被引用:1
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  • 下載下載:45
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背景和目標:海洛因成癮患者有不少的比例因共用針頭而感染C型肝炎(hepatitis C virus; HCV),肝臟是HCV感染的主要器官也是負責藥物代謝的主要器官,美沙冬替代性支持療法(Methadone maintenance treatment;MMT)主要是用於治療鴉片類藥物成癮患者。因HCV的感染而影響美沙冬的代謝之研究很少,本研究首先建立於無鏡像異構物的標準品下量測血漿中美沙冬及其代謝產物的濃度方法,並用以檢視在台灣的MMT族群中HCV病毒可能影響美沙冬的劑量及其代謝產物在血漿中濃度之假說。
方法:利用液態層析法(liquid chromatography-photodiode array)針對對掌性異構物層析分離管柱(chiral analytic column)發展出測量血漿中美沙冬鏡像異構物及其對掌代謝產物EDDP(2-ethylidene-1,5-dimethyl-
3,3-diphenylpyrrolidine )濃度的方法且不需使用R-型美沙冬或S-型美沙冬鏡像異構物標準品。此方法主要是利用重組cytochrome P450 (CYP)同功酶的特性,CYP2C19優先代謝R-型美沙冬,CYP2B6優先代謝S-型美沙冬,應用此分析方法量測366位MMT的收案病人;同時檢測他們血漿中B型肝炎病毒(hepatitis B virus;HBV)、HCV、人類免疫缺乏病毒(human immunodeficiency virus;HIV)的抗體(antibodies;Ab),肝臟天門冬胺酸轉胺脢(aspartate aminotransferase;AST)及丙氨酸轉胺脢(alanine aminotransferase;ALT)的活性、美沙冬及其代謝產物EDDP的濃度,並同時也分析其尿液中嗎啡及安非他命的濃度。
結果:將標準鏡像異構美沙冬混合物與重組cytochrome P450同功酶作用24小時反應後,證實R型及S型美沙冬的滯留時間分別是10.72及14.46分鐘。
另外,在352個案進行HCV抗體檢測的分析,95% 的MMT病人血漿中有HCV的抗體反應。在肝功能的指數AST (Wilcoxon Rank-Sum test, P=0.02)及ALT (Wilcoxon Rank-Sum test, P=0.04)、血漿中的美沙冬濃度(Wilcoxon Rank-Sum test, P=0.043)及R型美沙冬異構物(Wilcoxon Rank-Sum test, P=0.032)這些指標部分,HCV抗體陽性的病人比抗體陰性的病人明顯增高,但S-EDDP/(美沙冬劑量)的比例例外。
由單變項及多變項的回歸分析結果顯示HCV抗體陽性的病人與美沙冬劑量( = 14.65 和14.13; P=0.029 和0.03)及S-EDDP/(美沙冬劑量)( = -0.41 和 -0.40; P=0.00084 和0.002)有統計上的相關性。
結論:初步的研究顯示在MMT的族群,C型肝炎病毒確實可能影響美沙冬的劑量和血漿中S-EDDP/(美沙冬劑量)比值。

Background and Objectives: Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we first established a method to measure the plasma concentrations of methadone and its metabolites under no enantiomer standard circumstances. We then aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.
Methods: A liquid chromatography-photodiode array (LC-PDA) method using a chiral analytical column was developed to determine the plasma levels of enantiomers of methadone and its chiral metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP), without the standard compounds of R-form or S-form enantiomers. This method was established by the characteristics of recombinant cytochrome P-450 (CYP) isozymes; where CYP2C19 prefers to metabolize R-methadone and CYP2B6 prefers to metabolize S-methadone. A total of 366 MMT patients were recruited and measured their plasma methadone and metabolite concentration. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.
Results: We incubated the racemic methadone standard with either enzyme for 24 hours. We identified the retention times of R- and S-methadone to be around 10.72 and 14.46 min, respectively.
Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P=0.02) and ALT (Wilcoxon Rank-Sum test, P=0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P=0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P=0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/ methadone dose ratio.
The HCV levels correlated with the methadone dose ( = 14.65 and 14.13; P=0.029 and 0.03) and the S-EDDP/ methadone dose ratio ( = -0.41 and -0.40; P=0.00084 and 0.002) in both univariate and multivariate regression analyses.
Conclusions: We conclude that HCV may influence the methadone dose and plasma S-EDDP/ methadone dose ratio in MMT patients in this preliminary study.

正文目錄
第一章 緒論 1
第一節 C型肝炎病毒 1
壹、C型肝炎病毒之結構及其功能 1
貳、病毒的生命周期與變異 3
叁、C型肝炎特性及臨床症狀 6
第二節 美沙冬 10
壹、美沙冬的概述 10
貳、美沙冬的藥理作用 11
叁、美沙冬的臨床用途 12
肆、美沙冬的代謝 13
第三節 HCV在成癮病人中之流行病學 14
壹、HCV在成癮病人中之盛行率 14
貳、HCV在成癮病人中之發生率 15
第四節 研究的目的與假說 16
第二章 材料與方法 18
第一節 美沙冬及其代謝產物的定量分析方法建立 18
第二節 研究對象 18
第三節 血清及尿液的檢測 20
第四節 分析血漿中的美沙冬及其代謝產物 20
第五節 CYP2B6即時聚合酶連鎖反應 23
第六節 統計分析 24
第三章 結果 27
第一節 發展液態層析法分析血漿中美沙冬鏡像異構物及其對掌代謝產物EDDP的濃度的方法 27
壹、美沙冬及EDDP的標準層析圖 28
貳、R型美沙冬鏡像異構物及其代謝產物EDDP的確認 28
叁、S型美沙冬鏡像異構物及其代謝產物EDDP的確認 29
肆、回收率評估 30
伍、正確性與精密性 30
陸、鏡像異構物美沙冬與EDDP的再現性 31
第二節C型肝炎病毒感染影響美沙冬劑量及美沙冬血中濃度 33
壹、收案病患的臨床特徵 33
貳、HCV影響美沙冬及其代謝產物血漿中的濃度 34
叁、S-EDDP/Methadone 劑量比率與HCV的感染有關 34
肆、HCV抗體陽性的人具有CYP2B6較高的表現量 35
第四章 討論 36
第五章 結論 41
第六章 未來的研究方向與展望 43
第七章 參考文獻 45


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