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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳燕惠 | |
dc.contributor.author | Meng-Lin Wu | en |
dc.contributor.author | 吳孟霖 | zh_TW |
dc.date.accessioned | 2021-06-13T04:19:44Z | - |
dc.date.available | 2011-08-03 | |
dc.date.copyright | 2006-08-03 | |
dc.date.issued | 2006 | |
dc.date.submitted | 2006-07-24 | |
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Clin Pharmacol Ther 73, 253-263 (2003). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/32943 | - |
dc.description.abstract | 研究背景
Warfarin是臨床上一個常用來治療及預防血液栓塞疾病的藥物。然而使用warfarin來治療有其風險存在,基本上是因為病患間的個體差異,可歸因於:基因變異、環境、疾病種類及嚴重程度所影響,而使得在劑量的調整相當重要,現在臨床上的作法是監測其國際標準凝血時間比值(INR, international normalized ratio)。為達個別化用藥的目的,我們將討論可能的影響因子。 研究方法 本研究共收集94年7月至94年10月台大醫院內科部有使用warfarin之門診病患,於病情穩定後,抗凝血劑warfarin之使用情形,且收集病患之性別、年齡、適應症、病患用藥、INR值,並檢測病患的基因型,包括CYP1A2、CYP2C9、CYP2C19、CYP3A4、凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ、蛋白質C、蛋白質S、EPHX1、GGCX、GSTA1和VKORC1等基因,以及檢測warfarin異構物之血中濃度,研究病患個體化的warfarin用藥與藥物基因體學的相關性。 研究結果 符合受試者條件的病患共計75位,其中73位成功鑑定出所有納入檢測基因之基因型型別。病患處方warfarin之適應症主要為深層靜脈栓塞(deep vein thrombosis)。病患的平均維持劑量為3.9毫克/天,平均之INR值為2.02。基因型與劑量使用之關連性分析發現,VKORC1基因的-1639、1173、2225位置和CYP2C19基因的681位置,與warfarin的維持劑量有高度的相關。且VKORC1基因的-1639、1173、2225三個位置,有鏈鎖不平衡(linkage disequilibrium)現象出現。另外,年齡的因素也和維持劑量的多寡有高度的負相關。 異構物濃度與維持劑量間有顯著的相關性存在,但與療效間卻沒有直接的相關,故無法以監測濃度的方式來調整病患之劑量,仍需採用臨床上使用的INR值(或PT值) 來監測。 結論 Warfarin的維持劑量,是多種因素互相影響所決定的。台灣人的平均維持劑量與西方人不同的原因,可能是因為CYP2C19與VKORC1上SNP位置變異頻率的不同所致。經由迴歸模式的建立,可根據年齡、體重及基因上的變異等因素,計算出適合台灣人所使用的warfarin藥物投與劑量,以減少副作用的產生,增加藥物使用的安全性。 | zh_TW |
dc.description.abstract | Background
Warfarin is an anticoagulant that is prescribed widely for the treatment and prevention of thrombosis. However, risks caused by warfarin vary, depending on the individuals, mainly genetic variations, environment, diseases and the severity of disease. It is important to adjust the dose of warfarin in clinical use based on the International Normalized Ratio (INR) value monitoring. All the possible factors involving dose adjustment will be investigated in this study in order to approach the individualized drug use. Methods Outpatients receiving long-term therapy were enrolled in National Taiwan University Hospital from July to October 2005. We collected the data including sex, age, indication, concomitant agents, INR value and the genotype of certain SNP sites in CYP1A2, CYP2C9, CYP2C19, CYP3A4, coagulation factor II, factor VII, factor IX, factor X, protein C, protein S, EPHX1, GGCX, GSTA1 and VKORC1. Furthermore, we detected the concentration of warfarin enantiomers and studied the association of pharmacogenomics and personalized warfarin doses. Results There were 75 patients enrolled in the study but two were excluded due to the failure of identifying the genotype. Deep vein thrombosis is the main indication in all patients. The mean maintenance dose was 3.9 mg/day and the mean INR value was 2.02. Results showed the variants of the positions -1639, 1173, 2225 in VKORC1 and the position 681 in CYP2C19 were highly related with warfarin maintenance dose. Also, there was negative relationship between age and warfarin maintenance dose in our study. Linkage disequilibrium of factor IX, GGCX and VKORC1 in certain SNP sites occurred in the study. The concentration of enantiomers was positively related to the maintenance dose of warfarin, but not to drug response. It is not applicable to adjustment of the dose by monitoring the concentration of racemic warfarin, or to its enantiomers. Conclusion The maintenance dose of warfarin was determined by multiple factors. The ethnic effect of Taiwanese and Caucasian might be partly caused by the different frequency of SNP sites of VKORC1 and CYP2C19. According to the regression model, we can calculate the warfarin maintenance dose by age and the genotype of these SNP sites so as to decrease the adverse drug effects and increase the safety of the drug. | en |
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dc.description.tableofcontents | 中文摘要………………………………………………………………Ⅰ
英文摘要………………………………………………………………Ⅱ 目錄……………………………………………………………………Ⅳ 表目錄……………………………………………………………… Ⅵ 圖目錄…………………………………………………………………Ⅶ 第一章 前言……………………………………………………………1 第二章 文獻探討………………………………………………………3 第一節 Warfarin 總論………………………………………………3 一、化學結構與物化性質……………………………………………3 二、藥理作用機轉………………………………………………………4 三、藥物動力學…………………………………………………………4 四、藥物藥效學…………………………………………………………5 五、適應症、劑量及副作用……………………………………………6 六、藥物交互作用………………………………………………………7 第二節 基因多型性……………………………………………………9 一、單核甘酸多型性(SNP)……………………………………………9 二、Cytochrome P450的基因多型性…………………………………9 三、凝血因子相關的基因多型性……………………………………10 四、與維他命K 循環有關的基因多型性……………………………10 五、基因多型性與warfarin 用藥劑量的關係……………………10 第三章 研究目的………………………………………………………13 第四章 研究方法………………………………………………………14 第一節 試驗設計與流程………………………………………………14 一、研究對象…………………………………………………………14 二、受試者選擇標準…………………………………………………14 三、研究進行流程……………………………………………………14 四、資料來源…………………………………………………………14 第二節 基因型鑑定……………………………………………………15 一、SNPstream 之鑑定……………………………………………15 二、PCR-RFLP 之鑑定………………………………………………17 第三節 Warfarin 異構物的濃度測定:HPLC 分析…………………20 一、檢體處理…………………………………………………………20 二、實驗步驟…………………………………………………………20 三、分析條件…………………………………………………………20 四、標準溶液配製……………………………………………………21 五、標準曲線(Standard curve)製作……………………………… 21 六、校正曲線(Calibration curve)製作……………………………22 七、分析方法之確效…………………………………………………22 八、萃取回收率………………………………………………………22 第四節 試劑配方………………………………………………………24 第五章 研究結果………………………………………………………29 第一節 研究對象的基本資料…………………………………………30 第二節 基因型鑑定……………………………………………………31 第三節 HPLC 異構物濃度分析………………………………………32 一、滯留時間及檢量線水準…………………………………………32 二、萃取回收率………………………………………………………32 三、確效性試驗………………………………………………………32 四、樣本數、異構物平均濃度………………………………………32 第四節 各因子間相關性分析…………………………………………33 一、維持劑量與基因型或其他因子之關聯性………………………34 二、異構物濃度與劑量或其他因子間的關聯性……………………34 第五節 Warfarin 維持劑量投與的模式建立………………………36 一、單變項分析………………………………………………………36 二、多變項分析及迴歸模式的建立…………………………………36 第六章 討論…………………………………………………………50 第一節 研究對象的基本資料…………………………………………50 第二節 基因型鑑定……………………………………………………51 第三節 HPLC 異構物濃度分析………………………………………53 第四節 各因子間相關性分析…………………………………………54 第五節 Warfarin 維持劑量投與的模式建立………………………56 第六節 研究限制………………………………………………………57 第七章 結論及建議……………………………………………………58 第八章 參考文獻………………………………………………………59 附錄一 受試者同意書…………………………………………………65 附錄二 問卷……………………………………………………………69 表目錄 表2-1 維生素K 依賴型蛋白質………………………………………12 表4-1 Primers for polymerase chain reaction-restriction fragment length polymorphism analysis…………………………………28 表5-1 Demographic and clinical characteristics of the enrolled patients……37 表5-2 Selected SNP sites for genotyping………………………………… 38 表5-3 Genetic variants of the enrolled patients…………………………………39 表5-4 人體血漿中warfarin 異構物及diclofenac 的萃取回收率…………………………40 表5-5 偵測人體血中warfarin 異構物之方法確效參數……………40 表5-6 Warfarin daily dose and INR value in various genotypes……………………41 表5-7 Characteristics of patients with higher or lower warfarin dose requirements…43 表5-8 維持劑量與其它因子關係表………………………………………44 表5-9 影響warfarin 維持劑量之單變項迴歸分析…………………………………44 表5-10 Regression equation for modeling warfarin daily dose requirements……….46 表5-11 Regression equation for modeling warfarin weekly dose requirements in desired INR value……………………………………………………46 圖目錄 圖2-1 The structure of racemic warfarin……..………………………….……...3 圖2-2 The vitamin K cycle…………………………………………………..…..12 圖4-1 SNPstream®作用原理之圖解………………………………………..…..26 圖4-2 The strategy of RFLP to genotype CYP2C19*2 and *3…………..….27 圖5-1 Warfarin doses for population study…………………………………….47 圖5-2 INR value of patients receiving warfarin…………….……..…………..47 圖5-3 RFLP analysis of CYP2C19……………………………………….…….48 圖5-4 Calibration curve of warfarin enantiomers……….………………........48 圖5-5 Box plot of mean warfarin doses for different age and genotype.…..49 | |
dc.language.iso | zh-TW | |
dc.title | Warfarin 臨床使用劑量與藥物基因體學之研究 | zh_TW |
dc.title | The Association of Warfarin Dosage in Clinical Use and Pharmacogenomics | en |
dc.type | Thesis | |
dc.date.schoolyear | 94-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 呂紹俊,蔡偉 | |
dc.subject.keyword | 藥物基因體學,抗凝血劑,鏡像異構物, | zh_TW |
dc.subject.keyword | warfarin,VKORC1,CYP2C19,pharmacogenomics,SNPstream,enantiomer, | en |
dc.relation.page | 69 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2006-07-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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