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系統識別號 U0007-0408200714594100
論文名稱(中文) Fenofibrate自發性微乳化劑型之口服吸收探討
論文名稱(英文) Study on Oral Absorption of Fenofibrate from Self-Microemulsifying Drug Delivery System
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 蘇育德
學號 M301094012
學位類別 碩士
語文別 中文
口試日期 2007-07-17
論文頁數 109頁
口試委員 指導教授-許明照
委員-林山陽
委員-蔡義弘
委員-吳安邦
關鍵字(中) 自發性微乳化劑型
口服吸收
藥物動力學
關鍵字(英) SMEDDS
oral absorption
pharmacokinetics
fenofibrate
學科別分類
中文摘要 自發性微乳化藥物傳輸系統通常是由油相、界面活性劑系統及藥物以適當比例所組成。此一系統若接觸到水溶液或腸胃道液體,經由消化管壁的蠕動,會自發性乳化形成微乳化透明澄清之液體,因此可以有效的作為難溶性藥物的傳輸載體。在本研究中,選擇一種難溶性藥物Fenofibrate(降血脂藥物)作為模式藥,利用中鏈型三酸甘油脂Myritol 318作為油相及非離子型界面活性劑D-α-Tocopheryl polyethylene glycol 1000 succinate(TPGS)和Polysorbates(Tween系列)製備成自發性微乳化藥物傳輸系統。溶離試驗結果顯示原廠處方在水中幾不溶解;而使用適當的界面活性劑系統在特定的重量比例時,可以得到具適宜溶離速率的配方組成。然而人體試驗結果卻顯示其生體可用率較原廠處方為低。
為了進一步探究影響此配方吸收的可能影響因素,並依據三相圖選擇配方組成,試著開發出提高生體可用率之配方。實驗設計在界面活性劑系統上稍作調整,選出數個不同組成比例之配方,觀察其在pH1.2鹽酸水溶液,10、25以及50 rpm三種轉速下之溶離曲線,藉以模擬藥物於胃中不同收縮張力下釋放的情形;同時紀錄不同配方溶離液外觀及量測粒徑大小,找尋溶離後可形成較小粒徑者,期望可藉改變配方比例組成及提高藥物釋放後總表面積以增加吸收效果。
由體外實驗結果篩選出一組擁有最小平均粒徑、外觀澄清度最高以及適宜溶離速率的配方,分別作成膠囊以及水溶液兩種劑型;另外選定一組平均粒徑較大、外觀較渾濁但也具適宜溶離速率配方做成膠囊劑型,進行人體單向平行試驗。體外實驗結果顯示配方在不同界面活性劑組成下會影響溶離液的顆粒大小與外觀透明澄清度;體內實驗結果顯示溶離液顆粒大小在一定範圍內,降低顆粒大小並無法有效提升生體可用率;而在適當的組成比例下,可得到與原廠對照處方生體可用率相當之配方。最後依據體內及輔以體外實驗結果,針對溶離速率、溶離液粒子大小以及配方組成,在藥物經由口服自發性微乳化劑於人體吸收作相關探討。
由本研究的結果顯示自發性微乳化藥物傳輸系統可有效作為難溶性藥物的載體( Fenofibrate為例),並已初步開發出與市售藥品生體可用率相當之新劑型配方。
英文摘要 Self-microemulsifying drug delivery systems (SMEDDSs), which are self-emulsified into a clear and translucent fluid in aqueous medium under gentle digestive motility in the gastrointestinal tract, usually consisting of a mixture of oils, surfactant systems and drugs, represent a possible alternative to traditional oral formulations of poorly-water soluble. In the present study, a model lipophilic compound, Fenofibrate (an effective agent for the treatment of various types of dyslipidemia), was formulated in a medium chain triglyceride oil (MCT) and nonionic surfactant mixtures of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and polysorbates (Tween 20 and Tween 80). Previous dissolution study showed Fenofibrate was hardly released from reference drug, Tricor®, in water medium (less than 1.5% in 60mins); While using TPGS/Tween 20 as the mixture of surfactant (Smix) at a Km value of 1/4 was found to yield the desired SMEDDSs for Fenofibrate (almost completely released within half hour). However, results of clinical trial showed the bioavailability was lower in SMEDDS formulation than in Tricor®. In order to figure out the reason and with an attempt to develop a formulation that could improve the bioavailability, we change the composition on surfactant system. In vitro dissolution studies from formulations of different compositions under rotation speed of 10, 25 and 50rpm were used to simulate the release of drugs in stomach under different digestive motility. Besides, we looked for formulations that produce small particle size in dissolution medium for their formation of large surface area for absorption. At last, 3 formulations in 2 dosage form were prepared for another clinical trial. In vitro experiments results showed the particle size and the outcome of dissolution medium were influenced by the compositions of surfactant systems. In vivo results revealed that within specific range, lower the particle size of dissolution medium could not efficiently improve the bioavailability. In appropriate formulation composition, the bioavailability could be comparably attained with that of Tricor®. Moreover, several possible factors affecting the absorption of formulations were also in further discussion in the study.
Our study indicated that the potential use of SMEDDS for oral delivery of Fenofibrate can be an alternative to improve its systemic availability. The development of SMEDDS is promising for improving the oral bioavailability of poorly soluble drugs
論文目次 目錄I
中文摘要III
AbstractV
附表目錄VII
附圖目錄IX

第壹章 緒論1

第一節 研究背景介紹1
一、口服劑型簡介1
二、微乳劑系統3
三、自發性微乳劑系統(SMEDDS)7
四、模式藥物:Fenofibrate10

第二節 研究動機18

第貳章 研究材料與實驗方法19

第一節 實驗材料及儀器設備19
一、實驗材料19
二、儀器設備20

第二節 分析方法的確立21
一、Fenofibrate(FFB)之紫外分光光度計之體外分析方法21
二、Fenofibric acid(FFBA)高效液相層析之體內分析方法21

第三節 配方開發及體外試驗25
一、配方開發與製備 25
二、體外溶離試驗28
三、配方粒徑分析28

第四節 臨床人體試驗31
一、臨床人體試驗31
二、血漿檢品之檢測 32
三、藥物動力學數據分析32

第參章 結果與討論33

第一節 分析方法的確立33
一、FFB紫外可見分光光度計之體外分析方法33
二、FFBA高效液相層析之體內分析方法33

第二節 配方開發及體外溶離試驗43
一、配方開發與製備 43
二、體外溶離試驗53
三、配方粒徑分析70

第三節 臨床人體試驗83

第肆章 結論92

參考文獻93
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(Micromedex, 2007)

(Prod Info Tricor®)

柯文庭:以TPGS作為微乳基劑之相圖研究與藥學應用,2005
林怡慧:Nicardipine鹽酸鹽微乳劑型之經皮吸收研究,2005

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系統識別號 U0007-0508200818343800
論文名稱(中文) 應用自行微乳化劑型之溶劑擴散方法配製 高分子PLGA 奈米微粒
論文名稱(英文) Application of self-microemulsification solvent diffusion method for preparation of PLGA nanoparticles
校院名稱 臺北醫學大學
系所名稱(中) 生醫材料暨工程研究所
系所名稱(英) Institute of Biomedicac Materials Engineering
學年度 96
學期 2
出版年 97
研究生(中文) 羅又伶
學號 M212095010
學位類別 碩士
語文別 中文
口試日期 2008-07-29
論文頁數 74頁
口試委員 委員-林山陽
委員-何秀娥
指導教授-許明照
關鍵字(中) 微乳化,聚乳酸與聚甘醇酸,奈
米微小球,藥物載體
關鍵字(英) microemulsion,PLGA,nanoparticles,drug carrier
學科別分類
中文摘要 本研究目標建立一個應用自行微乳化之溶劑擴散方法製備聚乳
酸與聚甘醇酸(PLGA)奈米微粒, PLGA 奈米微粒將由可稀釋性的
自行微乳化型預微乳劑作為模板,預微乳化的模板是由油相、界面活性劑系統及高分子以適當比例組成,此一系統的適當三成份比例可直接稀釋至水相中形成微乳化,稱為可稀釋性的自行微乳化型預微乳劑。以這擬三成分相圖的特性建構為基礎,尋求可自行微乳化之所需的界面活性劑/輔界面活性劑、水相與溶媒的最佳組合種類與比例範圍。
在本研究中二氯甲烷(dichlormethane)將選擇作為PLGA 顆粒溶
劑,在三成份相圖設定為油相,而 Tween (20-80)系列選擇為主要界面活性劑,輔界面活性劑則選自中長鏈型醇類(alcohols)像是乙醇(ethanol)、丁醇(propanol), 以及丙醇(butanol)作為製備之用。建構出的油相與各個界面活性劑/共界面活性劑組合的三成分所形成微乳化的比例,直接稀釋至水相中使得有機溶劑擴散至水相中或揮發去除,使高分子固化。以自行微乳化之溶劑擴散方法製備的奈米級PLGA 顆粒在製程上是簡易的系統,更進一步的探討,由於微乳化具好的熱力學穩定的特性,在PLGA 微/奈米顆粒的發展上可以去克服改善控制PLGA 粒徑大小製作的相關難題。設計出有效的設備作法在複雜且耗時的製程,希望建立自行微乳化之溶劑擴散方法應用在PLGA 微/奈米顆粒技術領域上。
英文摘要 The objectives of this study were to establish a new preparation method for poly (DL-lactide-co-glycolide) (PLGA) nanoparticles by application
the Self-microemulsification solvent diffusion method and to elucidate the mechanism of nanoparticle formation on the basis of the microemulsion principle of PLGA and surfactants、cosurfactants in the preparation system. PLGA nanoparticles were prepared by the utilization of dilutable
Self- microemulsifying systems to form microemulsions as the template for preparing nanoparticles of PLGA.Microemulsion system wes devely with the use of partially water miscible and pharmaceutically acceptable
solvents as the oil phase and the pseudo-ternary phase diagrams was constructed to characterize and optimize surfactants, cosurfactants, and cosolvents for the dichloromethane in the production of nanoparticles.
Tween series (20-80), were selected as surfactants for preparations of nanoparticles. cosurfactants were selected from short-chain alcohols (ethanol, propanol, and butanol) for preparations of nanoparticles. The pseudo-ternary phase diagram were constructed for optimal combinations
of selected solvents for nanoparticles were surfactants/cosurfactants and water/cosolvents. These systems will be examined and process parameters was optimized.
論文目次 目錄............................................... I
中文摘要............................................II
Abstract............................................III
表目錄............................................... IV
圖目錄................................................V
第一章 緒論...................................1
第一節 研究背景介紹................................1
一. 高分子奈米藥物載體........................1
二. 高分子材料聚乳酸與聚甘醇酸(PLGA) ................3
三. 奈米微小球包覆技術..............................5
四. 微乳劑系統...............................14
第二節 研究目標............................................21
第貳章 實驗步驟及材料........................22
第一節 擬三成分相圖實驗方法的建立.....................22
第二節 PLGA 微粒之配製實驗方法的建立...................25
第參章 結果與討論................................31
第一節 擬三成分相圖實驗結果與討論...................31
一. 水為滴定相之擬三成分相圖.....................31
二. 水為滴定相之擬三成分相圖PLGA 固化分析..............44
三. 能自行乳化預微乳系統之擬三成分相圖..............53
四. 能自行乳化預微乳系統之PLGA 固化分析.................61
第四章 結論......................................71
第五章 參考文獻..........................72
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柯文庭:以TPGS 作為微乳基劑之相圖研究與藥學應用,2005
蘇育德:Fenofibrate 自發性微乳化劑型之口服吸收探討,2007

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系統識別號 U0007-0608200715432600
論文名稱(中文) 光敏感性藥物研究 第壹部分 鈣離子阻斷劑光分解反應研究 第貳部分 非固醇類抗發炎藥物光分解產物及其抗發炎活性
論文名稱(英文) Photosensitivity drugs (I) Photodegradation of calcium channel blockers (II) Photoproducts of NSAIDs and their anti-inflammatory activities
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 趙素慧
學號 D301090001
學位類別 博士
語文別 中文
口試日期 2007-07-13
論文頁數 106頁
口試委員 委員-陳朝洋
委員-陳福安
委員-許立人
委員-闕壯卿
委員-張怡怡
共同指導教授-王靜瓊
指導教授-吳安邦
關鍵字(中) 光敏感性藥物
鈣離子阻斷劑
非固醇類抗發炎藥物
光分解產物
關鍵字(英) Photosensitivity drugs
Calcium channel blockers
NSAIDs
Photoproducts
學科別分類
中文摘要 光敏感性是藥物常見的不良影響,本研究第一部份為尼卡迪平的光分解反應,尼卡迪平暴露於汞燈下,以LC/MS鑑定共8個光分解產物,主產物為4-(3'-硝基苯基)吡啶衍生物(NIC-7)。尼卡迪平於照光後進行一系列的硝基還原反應,並提出其可能的反應途徑。

研究第二部份目的是選擇特定之非固醇類抗發炎藥物(氟白普洛芬與吲哚美洒辛)在醇類溶媒中以汞燈照射探討其光解情形,以GC/MS與LC/MS進行其光解產物結構之鑑定,並檢查吲哚美洒辛及其產物一些藥理作用。總計以GC/MS與LC/MS光譜分析氟白普洛芬與吲哚美洒辛於甲醇溶媒中之光分解,各鑑定出10個與4個光解產物,並進而推測其反應途徑。在藥理研究方面,吲哚美洒辛比較其所衍生之光解產物,具有最強的氫氧自由基與黃嘌呤氧化酵素抑制活性,IC50各為 65 µM與86 µM。此外,吲哚美洒辛甲基酯衍生物(IN-3)其在LPS刺激RAW 264.7巨噬細胞誘導發炎的實驗模式中具有優於IN的抑制NO及PGE2生成與iNOS及COX-2蛋白表現的能力,類似一般NSAIDs的作用。對HL-60之細胞毒殺效果是以MTT法檢驗,結果顯示HL-60細胞毒殺IC50為36.9 g/mL,效果強於IN。再者,由生化檢驗發現IN-3會引起HL-60細胞凋亡、DNA 裂解,並增強PARP與pro-caspase 3的裂解作用,以上結果支持光解產物IN-3具有優於母藥吲哚美洒辛的抗發炎(LPS刺激RAW 264.7巨噬細胞)及細胞毒殺(HL-60)效果。
英文摘要 Photosensitivity is a commonly adverse effect of drugs. The purpose of the first part of this study is focus on the photodegradation of nicardipine. When nicardipine was exposed to the Hg lamp, eight photoproducts of nicardipine were identification by LC/MS. The main degraded product was a pyridine analogue (NIC-7). Nicardipine apparently undergoes a series of nitro group photo-reduction pathways under irradiation leading to a complex formation of mainly the reduced products. A reaction scheme of nicardipine was proposed.

The second part, gives a study on the photochemical behavior when NSAIDs (flurbiprofen and indomethacin) in alcoholic solvents are exposed to Hg lamps. GC/MS and LC/MS were applied to determine the structure of photoproducts. In addition, some pharmacological effects were also examined. In total, ten and four photoproducts derived from flurbiprofen and indomethacin methanolic samples, respectively, were identified by GC/MS and LC/MS. Furthermore, the reaction schemes of flurbiprofen and indomethacin in methanol are proposed. As to the study of pharmacological effects, results suggested that among all the related photoproducts, Indomethacin stand out and showed the strongest hydroxyl radical-scavenging effect with an IC50 of 65 µM and the strongest xanthine oxidase inhibitory effect with an IC50 of 86 µM. We also found that the methyl ester derivatives of indomethacin (IN-3) could more-potently inhibit PGE2 and NO production and iNOS and COX 2 protein expression from LPS-stimulated RAW 264.7 cells than indomethacin, similar to the effect of a typical NSAID. The cytotoxic effects of the test samples were measured using the MTT assay. The results showed that IN-3 with an IC50 value maintained at 36.9 ?慊/mL for 12 h that exhibited stronger cytotoxicity than indomethacin in HL-60 cells. Moreover, IN-3 caused apoptotic bodies, DNA fragmentation, and enhanced PARP and pro-caspase 3 degradation in HL-60 cells as determined by a series of biochemical analyses. The above results indicated that the photoproduct, IN-3, had stronger anti-inflammatory in LPS-stimulated RAW 264.7 cells and cytotoxicity effects in HL-60 cells than the parent drug, indomethacin.
論文目次 目 錄
中文摘要.......................................... vii
英文摘要.......................................... viii
縮寫表............................................ ix
緒論.............................................. 1

第壹部份 尼卡迪平光分解反應研究

第一章 研究背景及目的............................ 2
(一) 研究之背景.................................... 2
1.藥物光過敏反應及機轉.......................... 2
2.鈣離子阻斷劑光分解反應研究.................... 4
(二) 研究之動機及目的.............................. 11
第二章 實驗材料及方法............................ 14
(一) 實驗材料...................................... 14
(二) 實驗方法...................................... 14
第三章 實驗結果與討論............................ 16

第貳部份 非固醇類抗發炎藥物光分解產物及其抗發炎活性

第一章 研究背景及目的............................. 22
(一) 研究之背景..................................... 22
1. NSAIDs藥理作用................................. 22
2. NSAIDs的光過敏反應研究......................... 23
3. NSAIDs的光分解與產物結構....................... 25
4. NSAIDs常見的不良反應........................... 26
5. NSAIDs的新適應症與發展方向..................... 27
(二) 研究之動機及目的............................... 28
1. 以GC/MS研究FB光解產物與機轉.................... 28
2. 以LC/MS研究IN光解產物與機轉.................... 30
3. IN光解產物藥理作用探討......................... 34
第二章 實驗材料及方法............................. 43
(一) 以GC/MS研究FB光解產物與機轉.................... 43
(二) 以LC/MS研究IN光解產物與機轉.................... 44
(三) IN光解產物藥理作用探討......................... 45
第三章 實驗結果與討論............................. 50
(一) 以GC/MS研究FB光解產物與機轉.................... 50
(二) 以LC/MS研究IN光解產物與機轉.................... 57
(三) IN光解產物藥理作用探討......................... 60
1. IN光分解產物分離............................... 60
2. IN光分解產物對•OH清除與XO活性抑制之抗氧化效果.. 61
3. IN光分解產物對RAW 264.7以LPS誘導發炎之抑制效果. 63
4. IN光分解產物引發HL-60之細胞凋亡效果............ 64
結論................................................ 69
參考文獻............................................ 70
附錄................................................ 84
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系統識別號 U0007-1007200717350600
論文名稱(中文) 人類有機陰離子運輸器OATP1B1基因型與抗結核藥物治療期間肝損傷之關聯研究
論文名稱(英文) The Correlation between the Genotypes of Human Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and Liver Injury during Antituberculosis Therapy
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 陳香郿
學號 M301094019
學位類別 碩士
語文別 中文
口試日期 2007-06-25
論文頁數 105頁
口試委員 指導教授-陳香吟
委員-高純琇
委員-劉興璟
關鍵字(中) 肝損傷
抗結核藥物
基因
人類有機陰離子運輸器1B1
關鍵字(英) liver injury
antituberculosis drug
gene
OATP1B1
學科別分類
中文摘要 肝損傷是第一線抗結核藥物治療期間最常見的副作用。造成肝損傷的危險因子很多,包括年齡、性別、營養狀態、飲酒、病毒性肝炎以及基因。代謝藥物的酵素發生基因變異已被證實在抗結核藥物治療期間會增加肝損傷的發生率。 然而,最近研究發現在人體內運輸物質的人類有機陰離子運輸器OATP1B1 (Human Organic Anion Transporting Polypeptide 1B1,OATP1B1)和rifampin進入肝臟過程有關。OATP1B1運輸能力根據基因變異而有所不同,被運輸至肝臟的藥量也就因人而異。OATP1B1基因型具有種族差異性,目前在台灣,OATP1B1基因型和抗結核藥物治療期間肝毒性之關聯性則尚未有相關研究。因此,研究OATP1B1基因變異是否會影響rifampin運輸進而導致肝損傷是非常重要的。
本研究主要目的為探討OATP1B1基因型分布在發生肝損傷病患與未發生 肝損傷之對照組中的差異。次要目的為比較肝功能檢驗值於OATP1B1野生型 與變異型之間的差異。本研究共納入97位於台北市立萬芳醫院診斷為結核病之病患,回溯病歷資料並同時收集周邊血液檢體,以PCR-RFLP方式分析檢體,檢測OATP1B1*1b、OATP1B1*5及OATP1B1*15共三個基因變異。研究結果顯示,對偶基因出現頻率以OATP1B1*1b在本研究族群比例最高(64.9%),野生型OATP1B1*1a次之(24.2%),OATP1B1*5最少(0.5%)。OATP1B1*5通常以OATP1B1*15型態出現(10.3%)。然而,對偶基因組合成不同OATP1B1基因型在肝損傷組與對照組之間的比例並無統計上的差異。因此,本研究結果顯示抗結核藥物治療期間肝損傷發生時,OATP1B1*1b、OATP1B1*5及OATP1B1*15並非統計上具有意義的危險因子,需要更進一步研究證實OATP1B1基因型與肝損傷的關聯性。
英文摘要 Liver injury is the most common side effect during the first-line antituberculosis therapy. There are many risk factors of liver injury, such as age, gender, nutrition, alchol, viral hepatitis and gene. It has been proved that the genetic variations of metabolic enzyme increased the incidence rate of liver injury. However, recent studies showed that Human Organic Anion Transporting Polypeptide 1B1(OATP1B1) which transports substrates in human bodies is related to the distribution of rifampin. It is very important to study if the genetic variations of OATP1B1 affect the distribution of rifampin, and lead to liver injury. The transporting ability of OATP1B1 is genetically variant, and consequently influences the amount of drug transported to liver. The distribution of OATP1B1 genotypes are depended on the ethnics. There are no related studies avalible on the correlation between OATP1B1 genotypes and hepatotoxicity during antituberculosis therapy for Taiwanese population.
The primary aim of this study was to discuss the distribution of OATP1B1 genotypes in patients with and without liver injury. The secondary aim was to compare the liver function between the OATP1B1 wild-type and mutant-type. This study included 97 patients whom diagnosed tuberculosis in Taipei Municipal Wan Fang Hospital. The patients’ medical charts were reviewed and their peripheral blood samples were collected. These samples were analysed by PCR-RFLP (polymerase chain reactions- restriction fragment lenth polymorphism) to classify into the genotypes OATP1B1*1b, OATP1B1*5 and OATP1B1*15. This study showed that the allele frequency of the study population, OATP1B1*1b is the highest (64.9%), wild type-OATP1B1*1a is intermediate (24.2%), and OATP1B1*5 is the lowest (0.5%). OATP1B1*5 usually coexisted with OATP1B1*1b, which was classified as OATP1B1*15. However, the distribution of different OATP1B1 genotypes between the groups with and without liver injury are not statistically significant. OATP1B1*1b, OATP1B1*5 and OATP1B1*15 were not statistically significant risk factors of liver injury during antituberculosis therapy . Further studies are warranted to investigate the correlation between the genotypes of OATP1B1 and liver injury during antituberculosis therapy.
論文目次 誌謝 I
中文摘要 II
英文摘要 III
目次 IV
表目錄 VI
圖目錄 VIII
第1章 前言 1
第2章 文獻探討 2
2.1 結核病簡介 2
2.1.1 結核病的流行病學 2
2.1.2 結核病的治療 4
2.2 藥物引起之肝毒性 10
2.2.1 藥物引起之肝毒性的定義及機轉 10
2.2.2 藥物引起之肝毒性種類 11
2.3 第一線抗結核藥物引起之肝毒性 13
2.3.1 Isoniazid 15
2.3.2 Rifampin 18
2.3.3 Pyrazinamide 20
2.3.4 肝毒性之危險因子 21
2.4 人類有機陰離子運輸器1B1(HUMAN ORGANIC ANION TRANSPORTING POLYPEPTIDE-1B1, OATP1B1) 24
2.4.1 OATPs簡介 24
2.4.2 OATP1B1基因之多型性 30
2.4.3 OATP1B1基因之多型性對藥物動力學及藥效學之影響 33
第3章 研究方法 38
3.1 研究設計 38
3.2 研究對象 39
3.2.1 研究納入對象 39
3.2.2 排除標準 39
3.3 資料收集 40
3.4 肝毒性判定與評估 41
3.4.1 肝毒性判定標準 41
3.4.2 肝毒性與抗結核藥物之相關性評估 43
3.4.3 相關名詞定義 44
3.5 基因型檢測方式 45
3.5.1 DNA萃取 47
3.5.2 聚合酶連鎖反應-限制酶切割片段長度多型性 48
3.5.3 基因型判定 53
3.5.4 與OATP1B1基因相關定義 55
3.6 統計分析 56
第4章 研究結果 57
4.1 研究對象初步資料分析 57
4.1.1 本研究納入對象 57
4.1.2 基本資料分析 57
4.1.3 檢驗基準值分析 59
4.2 抗結核藥物治療期間的肝毒性 60
4.2.1 肝毒性發生率 60
4.2.2 肝損傷與藥物不良反應之關聯性 60
4.3 肝損傷組與對照組之結果比較 62
4.3.1 肝損傷組與對照組之基本資料分析 62
4.3.2 肝損傷組與對照組之生化檢驗值分析 64
4.3.3 肝損傷組與對照組之OATP1B1基因型分析 65
4.3.4 肝損傷組與對照組之OATP1B1對偶基因分析 66
4.4 OATP1B1野生型與變異型之比較 67
第5章 討論 69
5.1 研究結果討論 69
5.2 研究限制及改進方向 72
第6章 結論 74
參考文獻 75

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系統識別號 U0007-1007200813591600
論文名稱(中文) 多光子顯微鏡系統在皮膚的診斷治療之應用
論文名稱(英文) Multiphoton Microscopy in the Application of Skin Diagnosis and Treatment
校院名稱 臺北醫學大學
系所名稱(中) 醫學科學研究所
系所名稱(英) Graduate Institute of Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 蔡宗樺
學號 M102095023
學位類別 碩士
語文別 中文
口試日期 2008-07-01
論文頁數 58頁
口試委員 指導教授-李婉若
委員-劉漢南
委員-沈杏娟
關鍵字(中) 多光子
自發螢光
二倍頻
雷射
電磁波
紫外光
皮膚
活體實驗
雷射輔助藥物經皮穿透
關鍵字(英) multiphoton
autofluorescence
second harmonic generation
laser
radiofrequency
ultraviolet
skin
in vivo
laser-assisted drug deliver
學科別分類
中文摘要 雷射光療廣泛應用於治療許多種組織包括皮膚的疾病。鉺雅鉻雷射是一種常用的雷射來治療皮膚腫瘤和磨皮;紫外光已知是造成皮膚鬆弛老化的一個重要因子;而電磁波拉皮機器靠著加熱真皮,已被用來做非侵入性的皮膚緊緻治療,治療鬆弛的老化現象。為了找到適合不同個體差異的治療能量,需要評估組織的即時反應和變化。多光子顯微鏡是一種非侵入性的系統,可提供細胞層次的高解析度,近年來被應用於觀測活體生物的研究。此研究目的主要在活體上利用多光子及二倍頻顯微術,做為評估雷射和電磁波對組織作用的系統。鼠皮在使用不同能量的鉺雅鉻雷射、紫外光及電磁波作用後,使用多光子顯微鏡,針對皮膚的自發螢光和二倍頻等非線性光學訊號做型態以及定量分析。二倍頻的量已經被證實和膠原蛋白的量有正相關。鉺雅鉻雷射在低能量下可以把角質層震鬆,而沒有傷害到底下的組織,這個效應可用來進一步研究造成雷射輔助藥物經皮穿透的機轉。鉺雅鉻雷射在高能量下所造成的傷灼現象,以及底下表皮、真皮結締組織的破壞可以清楚得由多光子顯微鏡看到。我們能夠更進一步定量分析二倍頻減少的程度,來評估雷射後剩餘熱傷害的程度。我們利用多光子顯微鏡研究經過紫外光照射後的光老化現象,在紫外光照射的組別其膠原蛋白的二倍頻訊號比起對照組有顯著的降低,而光老化形成的彈性纖維也可在多光子顯微鏡下以自發螢光表現。同時,我們評估電磁波拉皮治療皮膚老化的效果,二倍頻減少的程度和電磁波的強度成正比,表示膠原蛋白因為電磁波加熱的關係而分解。但是在電磁波後的一個月,其二倍頻的強度反而增加到比治療前還要強,表示膠原蛋白在破壞後經過一段時間有增生,這是解釋電磁波能緊緻皮膚的可能機轉。多光子顯微鏡能夠得到細胞層次高解析度的影象,觀察皮膚角質層、表皮層、真皮細胞外間質的變化。由於其非侵入性,可以觀察電波及光線治療後依序的皮膚變化。多光子顯微鏡是一個能應用在活體上評估雷射、紫外光、電磁波對於皮膚組織作用的一個良好工具。此研究將可以使我們更清楚非線性造影術在瞭解電波及光線與組織交互作用的詳細過程的價值,以及進一步應用於臨床研究。
英文摘要 Laser and light is frequently used in treating various diseases, including skin disorders. Erbium:YAG laser is a commonly used laser to treat skin tumors and dermabrasion. Ultraviolet (UV) light is known as a major factor in skin aging and laxity. Radiofrequency have been introduced for nonablative tissue tightening by volumetric heating of the deep dermis to treat redundant skin laxity, which is a major feature of aging. Real-time evaluating tissue reaction is necessary in order to adjust the laser or radiofrequency energy to suit individual. Recently, multiphoton microscopy is an emerging non-invasive technology, which can provide cellular level high resolution images in vivo. The aim of this study was to validate the usefulness of MPM as an imaging modality for monitoring tissue reaction after light, laser and radiofrequency in vivo. Nude mouse skin was irradiated with an Erbium:YAG laser and radiofrequency device at various fluence and the skin was imaged using a MPM. The alterations of cutaneous non-linear optical properties including multiphoton autoflurescence and second harmonic generation (SHG) associated with laser and radiofrequency treatment was evaluated morphologically and quantitatively. SHG intensity has been shown to correlate with the amount of collagen. Out study showed that, at low fluence, Erbium:YAG laser selectively loosened the compact stratum corneum without detectable damage to the viable skin. This effect may contribute to laser-assisted transcutaneous drug delievery. At high fluence, the residual epidermal and dermal structures could be visualized after ablation. Furthermore, the degree of collagen damage in the residual thermal zone was evaluated by quantitative analysis of second harmonic generation signals. UV light induced photodamaged skin was studied with multiphoton microscopy. There was significant decrease of collagen SHG signals in UV-irradiated group compared to control. Solar elastosis was found to emit autofluorescence in MPM. Also, we studied antiaging effects of radiofrequency by MPM. The dermal collagen SHG signals decreased in accordance to energy of irradiation, which means collagen disruption after heating effects of radiofrequency. The SHG signals increased over baseline one month after radiofrequency. The effects displayed collagen regeneration after heat-induced disruption, which could be the mechanism of skin tightening with radiofrequency. Multiphoton imaging with cellular resolution clearly visualized the reaction of the stratum corneum, keratinocytes and dermal extracellular matrix caused by laser, radiofrequency and ultraviolet irradiation. Due to its non-invasiveness, we can obtain serial change of skin. In conclusion, MPM is an ideal tool for monitoring tissue reaction to laser, UV light and radiofrequency in vivo. The study support the usefulness of non-linear optics in studying mechanism of tissue remodeling after laser or radiofrequency treatment, which can be applied in further clinical research.
論文目次 Contents
Acknowledgment -- 1
Chinese abstract -2
English abstract ---4
Contents -- 6
1. Introduction -- 7
1. Lasers in surgery and medicine 7
2. Erbium:YAG laser 8
3. Non-invasive skin tightening 8
4. Multiphoton microscopy 9
5. Motivation of the study 12
2. Materials and Methods 14
3. Results ------- 20
Part 1 MPM and histological examinations after Erbium:YAG laser at various fluence 20
Part 2 Decreased collagen and increased elastic fibers after UV radiation revealed by MPM 32
Part 3 Skin structure alterations immediately after monopolar radiofrequency treatment at different passes 38
Part 4 Collagen remodeling after radiofrequency 44
4. Discussion-----------49
5. Reference----54
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系統識別號 U0007-1108200804174000
論文名稱(中文) 探討玻尿酸-四環黴素膠體經由關節內注射具協同性治療退化性關節炎
論文名稱(英文) THE COMBINED EFFECT OF HYALURONIC ACID AND DOXYCYCLINE VIA INTRA-ARTICULAR INJECTABLE GELS FOR THE TREATMENT OF OSTEOARTHRITIS
校院名稱 臺北醫學大學
系所名稱(中) 醫學科學研究所
系所名稱(英) Graduate Institute of Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 藍絜
學號 M109095011
學位類別 碩士
語文別 英文
口試日期 2008-07-14
論文頁數 108頁
口試委員 指導教授-陳建和
共同指導教授-許明照
共同指導教授-梁有志
委員-宋信文
委員-王德原
關鍵字(中) 關節炎(OA)
減緩關節炎症狀藥物(Disease-modifying osteoarthritis drugs,DMODs)
改善連接組織結構藥物 (connective tissue structure- modifying agents,CTSMAs)
四環黴素(Doxycycline, DC)
基質金屬蛋白?類(MMPS)
第二型膠原蛋白(type II collagen)
玻尿酸Hyaluronic acid (HA)
關鍵字(英) osteoarthritis (OA)
disease-modifying osteoarthritis drugs (DMODs)
connective tissue structure- modifying agents (CTSMAs)
Doxycycline (DC)
type II collagen
matrix metalloproteinases (MMPs)
Hyaluronic acid (HA)
學科別分類
中文摘要 退化性關節炎是一種緩慢漸進式的退化性疾病,目前治療關節炎藥物的研究重點,在於進一步修飾已知傳統藥物之官能基,使其成為具有改善連結組織結構(CTSMAs)以及減緩關節炎症狀之藥物(DMODs)。國外臨床上四環黴素(DC)已普遍使用於治療關節炎,它能抑制第一型介白素B(IL-1B) 和基質金屬蛋白酶類(MMPs)的生合成,也能改善subchondrobone的組織結構,長期使用能有效的治療關節炎。關節腔直接注射玻尿酸(HA)亦是目前臨床上廣泛用於治療關節炎的方式,可抑制MMPs的表現及促進醣胺聚醣(GAG)生成外,亦具備高黏度與黏彈的特性,給予關節物理性的保護並提供止痛的效果。本篇論文是利用鋅離子連結DC及玻尿酸,於外科手術引發關節炎之紐西蘭白兔做關節腔直接注射法來驗證HA-DC膠體是否具備協同之治療效果。本次研究結果顯示,此HA-DC膠體能提供較佳之黏彈性質,並具有止痛功能;此巨型網狀結構使得HA不易被降解,可延緩並增強藥物保護關節軟骨之效果。而關節軟骨染色與切片的結果更顯示,使用HA-DC膠體之組別具有較正常之關節軟骨分佈,只產生少量的磨損裂縫及骨刺,顯示此藥物產生修復與抑制軟骨降解之效果;且相較於單獨使用HA或DC顯示了更佳的治療效果。這些實驗結果符合我們先前一系列的細胞實驗與膠體備製測試,數據皆顯示此HA-DC膠體結構確實能有效減緩關節炎症狀並提供良好之止痛效果。
英文摘要 Osteoarthritis (OA) is a degenerative disease that disunites the extra cellular matrix (ECM) of articular cartilage and is arduous to cure because cartilage is a complex and nonvascular tissue. Treatment of OA has targeted modifiable reagent to be the connective tissue structure-modifying agents (CTSMAs) and disease- modifying osteoarthritis drugs (DMODs), such as hyaluronic acid (HA) or modified tetracycline. However, the aim of this present study was to examine whether intra-articular injection of the HA-DC gel restores the matrix of arthritic knee joints in rabbit model. The injectable HA-DC gel was composed of HA, doxycycline (DC) and zinc chloride. It was administered five times (at days 0, 3, 6, 9 and 12) into the partial meniscectomy and unilateral fibular ligament transected knee joints of 13-week old New Zealand White rabbits, and the effects of HA-DC gel injection were compared with that of DC, HA or normal saline. Evaluation of OA progression was histopathologically by Alcian blue and eosin staining, by the modified grading method and by scanning electron microscopy at day 14. HA-DC gel group showed smoother cartilage surface, no or minimal signs of ulceration, smaller osteophytes, and less fissure formation than the other groups. Normal distribution of chondrocytes or inflammation was noticed in areas of slight OA changes in the HA-DC gel group indicating regenerative ability. HA-DC gel seemed to inhibit the progression of osteoarthritis by protecting the layers of articular cartilage, decreasing the degree of pain and restoring the elasticviscosity. Both macroscopic and histological data of this study supported those biochemical results and gel preparation of previous studies showing the synergistic therapeutic effect of HA-DC gel on osteoarthritis.
論文目次 INDEX I
GRAPHICS INDEX IV
TABLE INDEX VII
I. 摘要 VIII
II. ABSTRACT IX
1 INTRODUCTION 1
2 MATERIALS AND METHODS 5
2.1 PREPARATION OF HYALURONAN–DOXYCYCLINE GELS 5
2.1.1 Materials 5
2.1.2 Confirmation of precipitation- turbidity 5
2.1.3 Gel preparation 5
2.1.4 Viscosity analysis 7
2.1.5 Elastoviscosity evalution 7
2.1.6 Statistical analysis 7
2.2 IN VITRO CELL EXPERIMENTS 8
2.2.1 Cell Lines and Reagents 8
2.2.2 Human bovine chondrocyte isolation and culture 8
2.2.3 Gel preparation 8
2.2.4 WST-1 assay 8
2.2.5 MTT cell viability assay 9
2.2.6 Reverse transcription-coupled PCR (RT–PCR) Analysis 9
2.2.7 Western Blot Analysis 11
2.2.8 Statistical analysis 11
2.3 IN VIVO ANIMAL EXPERIMENTS 12
2.3.1 Reagents 12
2.3.2 Gel preparation 12
2.3.3 Animals 12
2.3.4 Experimental OA model 13
2.3.5 Experimental design 13
2.3.6 Observation of general status and body weight measurement 14
2.3.7 Pain assessment 14
2.3.8 Specimen collection 15
2.3.9 Macroscopic specimen examination 15
2.3.10 Miroscopic specimen examination 15
2.3.11 Statistical analysis 19
3 RESULTS 20
3.1 PREPARATION OF HA-DC GEL 20
3.1.1 Higher concentration of HA accompanied higher viscosity and pH value. 20
3.1.2 Interaction of HA and DC induced precipitation. 20
3.1.3 pH value and DC concentration influenced the extent of precipitation. 21
3.1.4 Temperature and DC concentration influenced the extent of precipitation. 21
3.1.5 Concentration of HA and DC influenced the extent of precipitation. 21
3.1.6 DC consistency influenced the pH value. 22
3.1.7 The effect of different concentration of DC influenced viscosity and turbidity. 22
3.1.8 Zinc/ DC mole ratio influenced viscosity and pH. 22
3.1.9 Formation of gelatinization: the HA-DC gel was formed with a dose dependence manner. 23
3.1.10 Elastoviscosity property of HA-DC gel and HA-DC structure. 24
3.2 CELL EXPERIMENTS 25
3.2.1 Treatment of higher DC concentration induced cell death. 25
3.2.2 Treatment of DC reduced the gene expressions of MMP-1, MMP-3 and MMP-13 in IL-1β induced inflammatory SW1353. 25
3.2.3 Treatment of DC induced no influence on the gene expression of IL-8 in inflammatory SW1353 induced by IL-1β. 26
3.2.4 Treatment of IL-1β induced type II collagen expression but DC decreased that. 26
3.2.5 Treatment of HA (Artz-Dispo) stimulated chondrocyte cell proliferation. 26
3.2.6 Treatment of HA (Artz-Dispo) reduced the gene expression of MMP-1, MMP-3, MMP-13 in SW1353 induced by IL-1β. 28
3.2.7 Treatment of HA (Artz-Dispo) reduced the gene expression of IL-8 in SW1353 induced by IL-1?? 28
3.2.8 Treatment of HA (Artz-Dispo) increased the gene expression of type II collagen in SW1353. 29
3.2.9 Treatment of HA-DC structure induced serious inflammatory reaction 29
3.2.10 Treatment of HA-DC gels influenced cell survival in SW1353. 29
3.2.11 Treatment of HA-DC gel reduced the gene expression of MMP-1, MMP-3, MMP-13 in SW1353 induced by IL-1β. 30
3.2.12 Treatment of HA-DC gels reduced the gene expression of IL-8 in SW1353 induced by IL-1β. 30
3.3 ANIMAL EXPERIMENTS 32
3.3.1 Observation of general status and body weight measurement. 32
3.3.2 Treatment of DC, HA, gel or NS influenced the percentage distribution on left hind paw. 32
3.3.3 Inhibitory effect of reagents on the cartilage degradation and erosion of macroscopical appearances. 32
3.3.4 Inhibitory effect of reagents on the cartilage degradation and erosion of microscopical appearances. 33
4 DISCUSSION 35
5 REFERENCES 47
6 FIGURES 53
6.1 HYALURONAN–DOXYCYCLINE GELS PREPARATION. 53
6.2 IN VITRO CELL EXPERIMENTS 67
6.3 IN VIVO ANIMAL EXPERIMENTS 86
7 APPENDIX 106

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系統識別號 U0007-1307200716101700
論文名稱(中文) 尿苷雙磷酸葡萄糖醛酸基轉移酶1A1 (UGT1A1)基因型與抗結核藥物治療期間肝損傷之關聯研究
論文名稱(英文) The Correlation between the Genotypes of UDP-Glucuronosyl Transferase 1A1 (UGT1A1) and Liver Injury during Antituberculosis Therapy
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 張瑞家
學號 M301094021
學位類別 碩士
語文別 中文
口試日期 2007-06-25
論文頁數 140頁
口試委員 委員-高純琇
委員-陳繼明
指導教授-陳香吟
關鍵字(中) 尿苷
雙磷酸葡萄糖醛酸基轉移酶
1A1
抗結核藥物治療
肝損傷
關鍵字(英) UGT1A1
Antituberculosis Therapy
liver injury
學科別分類
中文摘要 目前已知,第一線抗結核藥物治療期間肝損傷之發生率約為20%。第一線抗結核藥物誘發肝毒性的相關危險因子包括:年齡、性別、營養狀態不良、酗酒、B 型或C 型肝炎感染、HIV感染與基因。尿苷雙磷酸葡萄糖醛酸基轉移酶1A1(UGT1A1)是代謝膽紅素的主要酵素,且其亦參與irinotecan等藥物之代謝。UGT1A1基因變異與未結合型高膽紅素血症,及irinotecan誘發之藥物不良反應有相關,但尚未有UGT1A1基因變異的族群,在接受抗結核藥物治療期間發生肝損傷之研究。
本研究主要目的為:(1)針對UGT1A1 基因變異(UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles)與基因型,分析其在抗結核藥物治療期間,發生肝損傷與未發生肝損傷的結核病病患身上之分布情形;(2)研究年齡、性別與UGT1A1 基因變異是否為抗結核藥物治療期間發生肝損傷之危險因子。次要目的為:比較帶有UGT1A1 野生型與UGT1A1基因變異的病患在臨床表現之差異。
本研究共納入97名於2005年十二月至2007年四月間,在台北市立萬芳醫院接受第一線抗結核藥物治療之病患,參與研究的97名病患中,有16名於抗結核藥物治療期間發生肝損傷。本研究採病患之全血檢體3 mL,利用PCR-RFLP與DHPLC的方式,檢測UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) 共四個alleles,並回溯病患的病歷資料。研究結果發現年齡較大(odds radio:1.043, 95% CI:1.008-1.080)且同時帶有UGT1A1*27 與UGT1A1*28 alleles(odds radio:21.05, 95% CI:1.251-354.2)者,為抗結核藥物治療期間發生肝損傷之高危險族群;UGT1A1*(1091 C to T)allele為台灣族群特有之基因變異,在本研究中出現頻率約為1.0%;UGT1A1基因變異組在肺外結核發生率與治療前total bilirubin檢驗基準值均高於UGT1A1野生型組。因此,UGT1A1基因變異與抗結核藥物治療期間發生肝損傷之間的關聯值得進一步探討研究。
英文摘要 The incidence rate of liver injury for the first-line antituberculosis therapy is about 20%. The relative risk factors of first-line antituberculosis drug-induced hepatotoxicity include age, gender, malnutrition, alcohol abuse, hepatitis B and C, HIV infection and genetics. UDP-Glucuronosyl Transferase 1A1 (UGT1A1) is the major enzyme responsible for the metabolism of bilirubin, as well as irinotecan and other drugs. There are many studies concerning that the genetic variations of UGT1A1 are associated with unconjugated hyperbilirubinemia, and irinotecan-induced adverse drug reactions; however, there is no studies to investigate the association of liver injury during antituberculosis therapy and UGT1A1 genetic variations.
The primary objective of the current study was to analyze the distribution of different UGT1A1 genetic variations(UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles)in tuberculosis patients with or without liver injury during antituberculosis therapy. Risk analysis of patients’ characteristics was also performed. The secondary objective was to determine whether the clinical manifestations differ between subjects with UGT1A1 wild and mutate genotypes .
Ninety-seven subjects on first-line antituberculosis therapy from December 2005 to April 2007 in Taipei Municipal WanFang Hospital were included, sixteen of which were encountered liver injury. Whole blood(3 mL)from each patient were analyzed for UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles by the PCR-RFLP and DHPLC method. Their medical records were also reviewed. The results showed that the elderly(odds radio:1.043, 95% CI:1.008-1.080)with UGT1A1*27 and UGT1A1*28 alleles(odds radio:21.05, 95% CI:1.251-354.2)are susceptible population to liver injury. The frequency of a newly identified allele UGT1A1*(1091 C to T)was about 1% in the study group. The extrapulmonary tuberculosis ratio and pretreatment total bilirubin level were also higher in the UGT1A1 mutate genotype group. Further studies regarding the correlation of UGT1A1 gene variations and liver injury are warranted.
論文目次 誌謝 I
英文摘要 II
中文摘要 III
目次 IV
表目錄 VII
圖目錄 IX
第1章 緒論 1
第2章 文獻探討 2
2.1 結核病概述 2
2.1.1 結核病簡介 2
2.1.2 結核病治療 4
2.2 抗結核藥物誘發的肝毒性 10
2.2.1 藥物誘發之肝毒性 10
2.2.2 第一線抗結核藥物誘發之肝毒性 13
2.2.3 抗結核藥物誘發肝毒性之相關危險因子 21
2.3 尿苷雙磷酸葡萄糖醛酸基轉移酶 (UDP-Glucuronosyl Transferase) 32
2.3.1 UGTs簡介 32
2.3.2 UGT1A1的基因變異 37
第3章 研究目的 55
第4章 研究方法 56
4.1 研究設計 56
4.1.1 本研究之收案標準 57
4.1.2 本研究之排除標準 57
4.1.3 病歷資料收集內容 58
4.1.4 收案日期的定義 58
4.1.5 第一線抗結核藥物治療期間肝毒性之定義 60
4.1.6 第一線抗結核藥物治療期間肝損傷與藥物之相關性評估 61
4.1.7 研究相關定義 62
4.2 UGT1A1基因變異型檢測方式 64
4.2.1 DNA萃取(DNA Extract) 65
4.2.2 聚合酶連鎖反應-限制酶切割片段長度多型性(PCR-RFLP) 65
4.2.3 基因變異型判定 74
4.3 資料統計分析 83
第5章 研究結果 84
5.1 肝損傷組與對照組之資料分析 84
5.1.1 基本資料分析 84
5.1.2 抗結核藥物組合與劑量分析 86
5.1.3 抗結核藥物治療期間之肝毒性類型分析 87
5.1.4 肝功能相關檢驗值之檢測率分析 88
5.1.5 肝功能相關檢驗值分析 89
5.1.6 抗結核藥物治療期間之肝損傷與藥物不良反應之關聯性 90
5.2 肝損傷組與對照組之UGT1A1基因變異分析 91
5.2.1 肝損傷組與對照組之基因型比較 91
5.2.2 肝損傷組與對照組之對偶基因頻率比較 92
5.2.3 抗結核藥物治療期間發生肝損傷之危險因子分析 93
5.3 帶有UGT1A1野生型與基因變異病患之結果比較 94
第6章 討論 97
6.1 研究結果討論 97
6.1.1 UGT1A1基因型與對偶基因頻率分布比較 98
6.1.2 抗結核藥物治療期間發生肝損傷之危險因子分析 100
6.1.3 UGT1A1野生型組與基因變異組病患比較 101
6.2 研究限制及未來改進方向 102
第7章 結論 104
參考文獻 105
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系統識別號 U0007-1307200814553400
論文名稱(中文) 藥物與食物交互作用之資訊化系統
論文名稱(英文) Drug-Food Interactions Information System
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 96
學期 2
出版年 97
研究生(中文) 林卓儀
學號 G158095007
學位類別 碩士
語文別 中文
口試日期 2008-07-11
論文頁數 95頁
口試委員 指導教授-邱泓文
委員-徐建業
委員-張博論
關鍵字(中) 藥物與食物交互作用
飲食
藥物不良反應
電子化病歷
關鍵字(英) Drug-Food Interaction
Diet
Adverse Drug Events
Electronic Health Records
學科別分類
中文摘要 進入這二十一世紀以來台灣人的文明病越來越多,也隨著醫療資源的進步,使用藥物的人有逐年增加的趨勢,人們通常卻只會看醫生、拿藥、吃藥卻往往忽略了,在使用藥物的同時,除了藥物跟藥物之間會產生交互作用,在日常的飲食中所攝取的食物也會造成藥物與食物之間的交互作用,此作用反應有可能會增加藥物的藥效或者產生不可預期的身體傷害。

本計劃著重整理食物與藥物交互作用的文獻資料,建構食物與藥物交互作用資料庫,並利用衛生署食材資料庫對應食物名稱與特定食物類別,此外更設計可供查詢的網頁方便民眾使用,並利用醫院臨床資料及藥商資料檢視食物與藥物交互作用的發生機率於將食物種類與食物名稱之間設定標準資料格式,以食物名稱提供給民眾查詢。並利用資訊科技協助正在使用藥物者可以適當的攝取日常生活中的食物,以單一食物的輸入、單一藥品之查詢、多筆食物或多筆藥物之查詢、運用病歷號及就診日期之查詢結合電子化的個人藥單上之藥品名稱,隨時可以讓病人選用食物時可以評估此食物是否會與正在服用的藥物產生交互作用加以列表呈現,隨時提供適當的食物選擇資訊,加以提醒。希望可以藉此藥物與食物交互作用評估系統的成效,讓藥物與食物交互作用不良反應避免發生在服用藥物的民眾身上,進而提升用藥的安全性以及藥品藥效能正確在人體釋放。
英文摘要 When medical services become much more convenient in Taiwan, the numbers of medicating patients are raising as well. However, except for drug-drug interactions, there are many drug-food interactions, too. Evan the daily diet may cause the failure of medication therapies, more over, to damage patients’ health.

This thesis is mainly using information technologies to help medicated person to choose appropriate diets for daily lives, by querying both medicines and foods and integrating with electronic health record’s data such as patient identity and prescription lists, the system could easily remind patients when drug-food interaction occurred. By estimating the effectiveness of the system, the author hopes it could improve the efficiency of medication therapies, furthermore, to raise patient safety.

論文目次 標題 i
審定書 ii
上網授權書 iii
誌謝 iv
目錄 iv
表目錄 ivii
圖目錄 iviii
中文摘要 xi
英文摘要 xiii
第一章 緒論 1
1.1研究動機 1
1.2 研究目的 4
第二章 文獻探討 5
2.1食物與營養素的重要性 5
2.2各類營養素介紹 9
2.3 飲食、運動、用藥相互關係 10
2.4 藥物與食物交互作用相互關係 12
2.5 電子病歷及可攜式隨身健康管理系統之探討 22
2.6藥物交互作用網站之探討 24
第三章 系統設備與設計 34
3.1研究設備及軟體 34
3.2 系統之架構 35
3.3 研究架構之設定 38
3.4系統評估 48
第四章 研究結果 50
4.1系統開發介面 50
4.2 系統評估分析 64
第五章 結論與討論 73
5.1結論 73
5.2 討論 74
5.3 研究限制 79
5.4 未來展望 79
參考文獻 82
中文文獻 82
英文文獻 86
電子資料 89
附 錄 90
參考文獻 中文文獻


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電子資料
均衡飲食六大類食物 http://www.mypyramid.gov/ Accessed May,2008

中國醫藥大學附設醫院 藥劑部 http://www.cmuh.org.tw/pharm/ Accessed May,2008

台北榮民總醫院 藥劑部 http://www.vghtpe.gov.tw/~pharm/ Accessed May,2008

衛生署統計資料2006 http://www.doh.gov.tw/statistic/index.htm Accessed May,2008

Health A to Z system http://www.healthatoz.com/healthatoz/Atoz/drugdb/drugSearch.jsp
Accessed May,2008

Drug Digest http://www.drugdigest.org/DD/Interaction/ChooseDrugs/1,4109,,00.html
Accessed May,2008

黃欣怡, 藥物與食物交互作用,花蓮慈濟醫院 藥劑科 藥物安全專欄 Ahttp://www.tzuchi.com.tw/file/DivIntro/drug/med50/7.pdf Accessed May,2008


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系統識別號 U0007-2207200816375300
論文名稱(中文) 建立預測抗結核藥物治療期間肝損傷之評分系統暨評估基因型危險因子之重要性
論文名稱(英文) Development of Risk Scales for Predicting Liver Injury during Antituberculosis Therapy and Evaluation the Importance of Genetic Risk Factors
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 96
學期 2
出版年 97
研究生(中文) 張淑惠
學號 M301095024
學位類別 碩士
語文別 中文
口試日期 2008-07-02
論文頁數 97頁
口試委員 指導教授-陳香吟
委員-黃文鴻
委員-邱弘毅
關鍵字(中) 抗結核藥物
肝損傷
評分系統
關鍵字(英) Antituberculosis drugs
Liver injury
Scoring system
學科別分類
中文摘要 結核病 (Tuberculosis,TB) 在世界各地都是導致死亡率的主要原因之ㄧ,在台灣也是傳染病致死原因的第一位。目前結核病的治療需要合併使用多種藥物且至少需治療六個月以上的時間,而抗結核藥物治療期間最常發生的不良反應即是肝毒性。肝毒性除了會導致病人服藥配合度不高,也間接導致抗結核藥物的抗藥性問題。至目前為止用來預測抗結核藥治療期間肝毒性的危險因子仍尚未有定論,且缺乏能實際應用在臨床上之相關建議。
本研究分為兩大部份,第一部份分析抗結核藥物治療期間肝損傷的流行病學上常見之危險因子,例如:年齡、性別、營養狀況、合併疾病、生活習慣、第一線抗結核藥物使用品項及劑量、併用藥物個數及肝功能檢測基準值;而第二部份則加入NAT2 (N-acetyltransferase 2)、OATP1B1(Human organic anion-transporting polypeptides 1B1)及UGT1A1 (UDP-Glucuronosyl Transferase1A1)等基因型,經logistic regression 校正分析,根據其影響程度分別設計成兩個量表;利用Hosmer and Lemeshow test檢視其配適度,透過AUC of ROC curve檢視量表的鑑別力。
全部研究對象(n=594)的流行病學之危險因子分析及校正後,具有肝臟疾病、rifampin劑量≧12 mg/kg,AST、ALT基準值大於兩倍正常值上限和ALP基準值大於三倍正常值上限為顯著的危險因子,此量表AUC of ROC curve為0.694,在最佳切點3分時,sensitivity和specificity分別為64.2%和67.4%;而包含基因型研究對象的部份(n=97)校正後女性、AST基準值高於正常值、帶有基因型NAT2*7、OATP1B1*1a/*1a和OATP1B1*1a/*15為顯著的危險因子,其量表之AUC of ROC curve為0.862,最適當切點為6分,其sensitivity和specificity分別為81.3%和80.2%。
透過這兩個量表之比較,評估基因型危險因子在預測抗結核藥物治療期間肝傷的重要性,顯示出僅使用一般流行病學之危險因子預測肝毒性時,縱使增加人數依舊無法提高預測的準確性,反之基因型危險因子能大幅增加量表的鑑別力,顯示基因型在預測抗結核藥物治療期間發生肝損傷中扮演很重要的角色。
英文摘要 Tuberculosis (TB), one of the major causes of mortality throughout the world, was the greatest infectious cause of death in Taiwan. The standard therapy of TB requird multiple medications, and patients should be treated for at least 6 months. Hepatotoxicity occured duing anti-TB therapy decreased patients’ adherence and increased the drug resistance. The risk factors in predicting hepatotoxicity were still not clear, and lack of recommendations in clinical practice.
The study was composed of two sections. The traditional risk factors such as age, gender, nutritional status, concomitant diseases, social history, the usage and dosage of first line anti-TB drugs, and baseline liver function were analyzed in section one. Section two, the genotypes of NAT2, OATP1B1 and UGT1A1 were added. The risk factors were adjusted and weighted by logistic regression, and developing two scales. One of the two scales was only traditional risk factors included, and the other was added by genetic risk factors. The goodness of fit was examed by Hosmer and Lemeshow test. The discriminatory power of scale was examed by AUC of ROC curve.
Liver disease, dosage of rifampin≧12 mg/kg, baseline AST and ALT ≧2x ULN (upper limit of normal) and ALP ≧3x ULN were the risk factors in section 1 (n=594). The AUC of ROC curve was 0.694, the sensitivity was 64.2% and specificity was 67.4%. In section 2(n=97), female, AST abnormal, with genotype of NAT2*7, OATP1B1*1a/*1a and OATP1B1*1a/*15 were the significant risk factors. The AUC of ROC curve was 0.862, the sensitivity was 81.3% and specificity was 80.2%.
By comparing the two scales, the genetic risk scale showed better discriminative power in predicting liver injury during anti-TB therapy. Removing the genetic risk factors through the genetic risk scale, the AUC of ROC curve was 0.728 in 97 study population while it was 0.649 in 594. It showed the limitation of traditional risk factors, even increased the study population, it still can’t predict hepatotoxicity precisely. The genetic risk factors play important roles in predicting liver injury during anti-TB therapy.
論文目次 致謝 II
中文摘要 III
英文摘要 IV
目次 V
表目錄 VIII
圖目錄 X
第1章 序論 1
第2章 文獻探討 2
2.1 結核病的流行病學、治療及防治計畫 2
2.1.1 全球結核病流行現狀 2
2.1.2 台灣結核病流行現狀及趨勢 4
2.1.3 結核病的治療及防治計劃 7
2.2 第一線抗結核藥物與肝毒性之關聯 13
2.2.1 Isoniazid 與肝毒性之關聯 13
2.2.2 Rifampin與肝毒性之關聯 16
2.2.3 Pyrazinamide與肝毒性之關聯 17
2.3 抗結核藥物肝毒性之危險因子 18
2.4 第一線抗結核藥物之肝毒性相關基因 20
2.4.1 乙型乙醯轉移酶基因(Arylamine N-Acetyltransferase 2,NAT2) 20
2.4.2 人類有機陰離子運輸器1B1 基因(Human Organic Anion Transporting Polypeptide-1B1, OATP1B1) 23
2.4.3 尿苷雙磷酸葡萄糖醛酸基轉移酶1A1 (UDP-Glucuronosyl Transferase 1A1,UGT1A1) 26
第3章 研究目的 29
第4章 研究方法 30
4.1 研究設計 30
4.2 研究對象 31
4.2.1 本研究之納入對象 31
4.2.2 本研究之排除標準 31
4.3 資料收集 32
4.3.1 資料收集的內容 32
4.3.2 收案日期的定義 35
4.4 肝損傷之定義 36
4.5 統計方法 38
第5章 研究結果 39
5.1 第一部份-全部研究對象之不包含基因型危險因子分析 39
5.1.1 全部研究對象之基本資料分析 39
5.1.2 全部研究對象之抗結核藥物的組合及劑量 39
5.1.3 全部研究對象檢驗基準值分析 41
5.1.4 全部研究對象之肝毒性類型分析 42
5.1.5 全部研究對象-不包含基因型危險因子對肝損傷之分析 43
5.1.6 全部研究對象校正後之危險因子 47
5.1.7 全部研究對象不包含基因型之評分系統建立與評估 48
5.2 第二部份-包含基因型之研究對象分析 52
5.2.1 包含基因型之研究對象基本資料分析 52
5.2.2 包含基因型研究對象之抗結核藥物的組合及劑量 53
5.2.3 包含基因型之研究對象檢測基準值分析 53
5.2.4 研究對象基因型分析 54
5.2.5 研究對象之肝毒性類型分析 58
5.2.6 肝損傷之危險因子分析 58
5.2.7 校正後之危險因子 63
第6章 討論 66
6.1 肝毒性發生率的分析 66
6.2 基因型分佈分析 67
6.2.1 NAT2基因型分析 67
6.2.2 OATP1B1基因型分析 68
6.2.3 UGT1A1基因型與對偶基因頻率分布比較 69
6.3 抗結核藥物治療期間肝損傷之危險因子分析 70
6.3.1 全部研究對象之危險因子討論 70
6.3.2 包含基因型研究對象之危險因子討論 71
6.4 加入基因型危險因子之量表比較 74
6.5 肝損傷發生之時間點評估 78
6.6 研究限制及未來方向 80
第7章 結論 81
參 考 文 獻 82

表目錄
表2.1.1 2006年結核病發生率前五位國家之統計資料 3
表 2.1.2 台灣常用之第一線、第二線抗結核藥物 8
表2.1.3 ATS/CDC/IDSA建議之療程及用藥組合 9
表 2.1.4 台灣行政院衛生署對各類結核病人之分類定義6 10
表 2.1.5 台灣行政院衛生署對各類結核病人的治療建議6 11
表2.3.1 抗結核藥物肝毒性之發生率及危險因子 19
表2.4.1 各種族之NAT2基因型分佈 21
表2.4.2 NAT2基因型及乙醯化速率和ISONIAZID誘發肝毒性之危險性 22
表2.4.3 OATPS之染色體位置、分布器官及受質 24
表2.4.4 OATP1B1在不同地區人種之ALLELE FREQUENCY分布比較 25
表2.4.5 UGT1A家族在人體的分佈位置與代謝受質 27
表4.3.1本研究病患資料收集的時間點定義 35
表4.4.1國際醫學組織學會(THE COUNCIL FOR INTERNATIONAL ORGANIZATION OF MEDICAL SCIENCE, CIOMS)之肝毒性定義 36
表4.4.2 台北市立萬芳醫院肝功能相關生化檢測參考正常值 37
表5.1.1 全部研究對象(594位)之基本資料 40
表5.1.2 全部研究對象之抗結核藥物的組合及劑量 41
表5.1.3 全部研究對象之相關檢測平均基準值 42
表5.1.4 全部研究對象之肝毒性類型分析 42
表5.1.5 全部研究對象肝損傷之危險因子分析-單因子變項分析 44
表5.1.6 全部研究對象之第一線抗結核藥物劑量和併用組合 45
表5.1.7 全部研究對象之肝功能指數基準值分析 46
表5.1.8 全部研究對象校正後之危險因子 47
表5.1.9 全部研究對象不包含基因型危險因子建立預測肝損傷之量表 48
表5.1.10 全部研究對象之簡化後量表 48
表5.1.11 全部研究對象基本資料應用在量表之分布情形 49
表5.2.1 包含基因型之研究對象(97位)基本資料分析 52
表5.2.2 包含基因型研究對象之抗結核藥物組合及劑量 53
表5.2.3 包含基因型之研究對象其相關檢測平均基準值 54
表5.2.4 NAT2基因型及乙醯化代謝程度和對偶基因頻率分析 55
表5.2.5 OATP1B1基因型分佈和對偶基因頻率分析 56
表5.2.6 UGT1A1 基因型和和對偶基因頻率分析 57
表5.2.7 第二部份研究對象之肝毒性類型分析 58
表5.2.8 包含基因型研究對象之肝損傷危險因子分析 59
表5.2.9 肝損傷和對照組之NAT2基因型分析 60
表5.2.10 肝損傷和對照組之OATP1B1基因型分析 61
表5.2.11 肝損傷和對照組之UGT1A1基因型分析 62
表5.2.12 包含基因型研究對象之校正後危險因子 63
表5.2.13 包含基因型研究對象之量表配分比例 64
表5.2.14 包含基因型研究對象基本資料應用在量表之分布情形 64
表6.1.1 肝毒性及肝損傷發生率比較表 66
表6.2.1 本研究第二部份之研究對象其NAT2基因型分佈和比較 67
表6.2.2 OATP1B1基因型與呂文仁研究比較表 68
表6.2.3 OATP1B1對偶基因頻率 (ALLELE FREQUENCY)與過去研究比較表 68
表6.2.4 UGT1A1對偶基因頻率(ALLELE FREQUENCY)比較表 69
表6.3.1 肝臟疾病及病毒性肝炎與抗結核藥治療期間肝毒性之分析研究 70
表6.3.2肝功能指數檢測基準值與抗結核藥物治療期間肝毒性之相關研究 71
表6.3.3 性別與抗結核藥物治療期間肝毒性之相關研究 72
表6.3.4 NAT2基因型或乙醯化代謝型對肝毒性的危險因子 73
表6.4.1 含基因型研究對象去除基因變項之量表 75
表6.4.2 去除基因變項之分佈情形 75
表 6.4.3 僅包含基因變項分析 76
表 6.4.4 僅基因變項總分分佈 76
表6.5.1 肝損傷發生時間點分佈情形 78

圖目錄
圖 2.1.1 2006年全球結核病發生率分布圖 2
圖2.1.2 1996-2006台灣地區結核病每十萬人發生率 4
圖2.1.3 2006年台灣地區結核病每十萬人發生率-依年齡分 5
圖2.1.4 1974~2006台灣地區結核病死亡趨勢 6
圖2.1.5 2006年台灣地區結核病每十萬人死亡率-依年齡分 6
圖2.2.1 抗結核藥物肝毒性之監測與處理 14
圖2.2.2 ISONIAZID代謝途徑 15
圖2.4.1 膽紅素的代謝途徑 28
圖5.1.1 全部研究對象肝損傷組及對照駔其不含基因之量表總分分佈圖 50
圖5.1.2 全部研究對象所建立之量表其ROC CURVE圖形 51
圖5.2.1 包含基因型量表之肝損傷組及對照組之總分分佈圖 65
圖5.2.2 包含基因型研究對象建立之量表其ROC CURVE圖形 65
圖6.4.1 全部研究對象不含基因型及含基因型研究對象之ROC CURVE比較圖 74
圖6.4.2 量表預測程度(ROC CURVE)之比較 77
圖6.5.1 肝損傷發生時間點之圖形 79
圖6.5.2 高危險群及低危險群其肝損傷發生時間點之圖形 79


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系統識別號 U0007-2207200916153500
論文名稱(中文) 建立架構於資訊藥車上之輔助性給藥安全資訊系統
論文名稱(英文) A Drug Information System Constructed on a Computerized Drug Cart to Help Medication Administrating
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 97
學期 2
出版年 98
研究生(中文) 宋浩辰
學號 M110095003
學位類別 碩士
語文別 中文
口試日期 2009-06-23
論文頁數 79頁
口試委員 指導教授-邱泓文
委員-徐建業
委員-劉建財
委員-朱唯勤
委員-蕭嘉宏
關鍵字(中) 資訊藥車
用藥安全
藥物資訊
藥物交互作用
關鍵字(英) Computerized Drug Deliver Cart
Medication Safety
Drug Information
Drug Interaction
學科別分類
中文摘要 前言:


近年來在台灣,臨床藥學的重要性越趨提昇,然而在現行的制度之下,藥師的人力遠不足以去執行藥師法於民國九十六年所增訂的「藥事照顧相關業務」,而為因應現實狀況的限制,許多醫院均運用資訊科技的方式來輔助用藥安全,本研究即是此方面的應用之一,並從不同的關節下手,期望不僅僅是達成「給藥零錯誤」的目標,更能輔助並部份取代目前少有臨床藥師巡房的缺憾,達成近似的功能,並提升病患用藥安全。


系統設計與方法:


本系統主要收集彙整行政院衛生署「藥物辨識資料庫」與「藥事服務整合資料庫」建構藥物資訊資料庫,並收集藥物交互作用資料以及注射用藥相容性資料,計畫在給藥介面中加入住院病患與用藥查詢、藥物資訊查詢與藥物交互作用查詢三項主要功能,用藥查詢功能主要為自所在醫院取得住院病患資訊與處方資訊,藥物資訊與藥物交互作用查詢則為護理人員於發藥時,可立即查詢所交付藥物之藥物資訊與此筆處方是否有藥物交互作用,此功能於注射用藥給藥介面則是查詢此筆處方中注射用藥是否有不相容的問題。本系統主要運用Delphi程式撰寫。


研究結果:


本研究基於建立一個架構於資訊化護理藥車上之輔助性用藥安全資訊系統之研究目的,並依照上述之系統設計與實作,完成此「輔助性給藥安全資訊系統」,其中包涵藥物資訊資料庫內含4,408筆藥物資訊,並在進行藥物資訊資料庫整理時,定立藥物資訊初步標準,我們也完成了注射用藥相容性資料庫內含1,452筆不相容性資訊,以及整合藥物交互作用稽核功能,並在系統建置完成後將醫院病患資料實際帶入,驗證系統及其效益,發現能夠找出約16.3%的住院病患藥物交互作用。


討論與結論:


根據病患資料帶入驗證的結果,我們確立了用藥安全決策支援系統在不同給藥環節之必要性,而藥物交互作用稽核在給藥端的呈現方式及內容與醫囑端之差別,則是日後可繼續研究的方向,另外,注射用藥相容性稽核功能的結果呈現如產生調劑建議表,將可更有利於臨床人員減低工作負擔,對其資料庫之持續建置也是日後可努力的方向。
英文摘要 INTRUDUCTION
In Taiwan, clinical pharmacy has become more and more important these years, and the pharmacy law had revised that medication care should be pharmacists’ obligation in 2007. However, pharmacists could barely practice medication care for patients, especially inpatients in the present system. Therefore, many hospitals use information technology to fix the situation, so as this thesis. In this study, we designed a system constructed on the computerized drug deliver cart to prevent medication errors in many ways, expecting to reach not only “zero omission”, but also play the clinical pharmacists’ role, and raise patient safety.

METHODS
Two databases were created to complete the system. The first data source is called “The Integrated Pharmacy Care Database” which was released by the Department of Health (DOH) of Taiwan. The second data source is an “Intravenous Drug Compatibility Database”, the compatibility information were mainly sorted from a textbook called “Handbook on Injectable Drugs” published by American Society of Health-System Pharmacists (ASHP). This database stored information for incompatible drug-drug or drug-solution results. In this study, we constructed three drug-safety information modules, they are drug information module, drug interaction module, and intravenous drug incompatibility module. Delphi language was applied to code the programs of this system.



RESULTS
We completely constructed three drug-safety information modules including drug information module, drug interaction module, and intravenous drug incompatibility module. We completed a drug information database including 4,408 drug information, and a intravenous drug compatibility database including 1,452 incompatible drug combinations. After the system is completed, we used real patients’ drug data to analyze drug interaction rates, and found that 16.3% of inpatients had drug-drug interaction issues.


DISSCUSIONS AND CONCLUSIONS
According to the results, we found that it’s necessary to apply decision support functions in different stage of medication therapy to improve patient safety. In this case, a decision support function could play its role on computerized drug deliver cart, as well as administrating stage. However, the drug alert content should be different from stages to fit the present workflow, and the incompatible drug alert function would be more useful if it could also suggest a proper route or dispensing method. These are issues that could be continuously focused in the future.
論文目次 目錄


審定書 ii
上網授權書 iii
致謝 iv
目錄 vi
圖目錄 ix
表目錄 x
論文摘要 xi
Abstract xiii
第一章 緒論 1
1.1 研究背景 1
1.2 研究動機 2
1.3 研究目的 3
第二章 文獻探討 4
2.1 藥物不良事件 4
2.1.1 藥物不良反應 4
2.1.1.1 第一型藥物不良反應 5
2.1.1.2 第二型藥物不良反應 5
2.1.1.3 藥物不良反應通報系統 6
2.1.2 用藥疏失與潛在藥物不良反應 6
2.1.2.1 用藥疏失種類 6
2.1.2.2 用藥疏失結果及嚴重性分級 8
2.1.2.3 易發生於護理人員端之用藥疏失 9
2.1.2.4 用藥疏失通報系統 9
2.2 臨床醫療資訊系統探討及評估 10
2.2.1 臨床醫療資訊系統簡介 10
2.2.2 臨床醫療資訊系統功能 10
2.2.3 臨床醫療資訊系統於病患安全的角色 12
2.2.4 臨床醫療資訊系統所造成的風險 12
2.2.5 臨床醫療資訊系統的評估方法 14
2.3 行動護理站之探討 16
2.3.1 行動護理站簡介 16
2.3.2 影響醫院接受行動護理站之因素 17
2.3.3 行動護理站與用藥安全之關係 18
2.4 藥物資訊探討 19
2.4.1 國外藥物資訊 19
2.4.1.1 Thomson™ Micromedex® 19
2.4.1.2 AHFS Drug Information 20
2.4.2 國內藥物資訊 20
2.4.2.1 行政院衛生署藥物資訊網 20
2.4.2.2 國內醫院院內藥物資訊 21
2.5 藥物資訊編碼 22
2.5.1 國外常用藥物資訊編碼 22
2.5.2 國內常用藥物資訊編碼 23
2.6 藥袋標示相關規範 23
2.7 藥物-藥物交互作用 25
2.7.1 藥物-藥物交互作用的種類 26
2.7.2 藥物-藥物交互作用分級 26
2.7.2.1 Drug Interaction Facts 27
2.7.2.2 Pocket Guide to Evaluations of Drug Interactions 28
2.8 注射用藥相容性 29
第三章 研究材料與方法 30
3.1 系統需求 30
3.1.1 建構於資訊護理藥車上之系統需求 30
3.1.2 住院病患與用藥資料查詢介面 30
3.1.3 藥物資訊查詢介面 30
3.1.4 藥物交互作用查詢介面 31
3.2 資料收集、前置作業與處理 31
3.2.1 藥物資訊與藥物外觀圖片資料收集 31
3.2.2 藥物交互作用資料收集 31
3.2.3 注射用藥相容性資料收集 32
3.2.4 病患資訊與藥物資訊交換格式 32
3.3 方法 34
3.3.1 系統架構 34
3.3.2 建立藥物資訊資料庫 35
3.3.3 建立注射用藥物相容性資料庫 38
3.3.4 系統實做 40
3.4 系統驗證方法 43
3.5 藥物資訊初步標準 43
第四章 研究結果 45
4.1 系統查詢功能 46
4.1.1 住院病患與用藥資料查詢功能 42
4.1.2 藥物資訊查詢功能 44
4.1.3 藥物交互作用查詢功能 50
4.1.3 注射用藥相容性查詢功能 52
4.2 系統驗證 53
4.2.1 藥物交互作用回溯分析 54
4.2.2 注射用藥物相容性結果回溯分析 57
第五章 討論、結論與未來研究方向 58
5.1 討論 58
5.2 結論 61
5.3 未來研究方向 62
參考資料 63
中文文獻 63
英文文獻 63
電子資料 66
附錄:主程式編碼 67


圖目錄


圖1 護理資訊藥車與用藥安全示意圖 18
圖2 臺北醫學大學附設醫院之院內藥物資訊 22
圖3 資訊護理藥車之實體外觀 30
圖4 系統架構 34
圖5 行政院衛生署「藥事服務整合資料庫」藥物資訊格式 35
圖6 「藥物辨識資料庫」藥物外觀圖片檔案 36
圖7 「注射用藥物相容性資料庫」藥物資訊格式 38
圖8 「注射藥品健保代碼與藥品對應表」示意圖 39
圖9 「住院病患與用藥查詢功能」查詢設計 40
圖10 「藥物資訊查詢功能」介面設計 41
圖11 「藥物交互作用查詢功能」之藥物作用查詢元件介面設計 42
圖12 「系統完成後之整體架構」示意圖 45
圖13 「住院病患查詢功能」示意圖 46
圖14 「病患用藥查詢功能」示意圖 47
圖15 「藥物資訊查詢功能」示意圖 48
圖16 「藥物交互作用查詢功能」示意圖 50
圖17 病患資料庫資料處理示意圖 53
圖18 住院病患分科藥物交互作用之統計圖 55
圖19 藥物交互作用等級分析圖 56


表目錄


表1 理想CPOE系統決策支援應具備的項目 15
表2 各項法令針對藥袋標示事項之比較 25
表3 藥物-藥物交互作用評分表 28
表4 病患資訊交換格式 33
表5 藥物資訊交換格式 33
表6 藥物資訊資料庫可提供之藥物資訊內容整理表 37
表7 藥物資訊格式初步標準 44
表8 藥物資訊查詢功能所提供之藥物資訊內容 49
表9 藥物交互作用警示回溯分析結果 54
表10 注射用藥物不相容結果警示回溯分析結果 57
參考文獻 中文文獻


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莊美華、林俊龍、王昱豐、曹汶龍、梁育彰,〈醫療機構用藥疏失之探討〉,慈濟醫學雜誌15卷4期,民92.08。
陳福基、蕭世榮、陳啟元、杜素珍,〈影響醫院接受行動護理站因素之研究-以南部某區域教學醫院為例〉,資訊管理月報12卷S期 ,民94.03。


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系統識別號 U0007-2301200815371900
論文名稱(中文) 癌症病人之止痛藥服藥遵從性與障礙因子及疼痛處理滿意度的相關探討
論文名稱(英文) Relationships of Analgesics Adherence to Patient-Related Barriers and Satisfaction of Pain Management in Cancer Outpatients
校院名稱 臺北醫學大學
系所名稱(中) 護理學研究所
系所名稱(英) Graduate Institute of Nursing
學年度 96
學期 1
出版年 97
研究生(中文) 鄭允宜
學號 G455091001
學位類別 碩士
語文別 中文
口試日期 2008-01-11
論文頁數 96頁
口試委員 指導教授-林佳靜
委員-張玉坤
委員-張佳琪
關鍵字(中) 服藥遵從性
止痛藥物
服藥障礙
疼痛處理滿意度
關鍵字(英) adherence
analgesics
patient-related Barriers
satisfaction of pain management
學科別分類
中文摘要 疼痛是癌症病人重要的問題,使用止痛劑是緩解癌症疼痛的主要方法,而疼痛處理無效的一個因素正是病人服用止痛劑遵從性差,近年來服藥遵從性漸漸被健康照護者重視,不遵從或不完全遵從,是目前健康照護的一個主要的問題,遵從行為是一種複雜的行為,可能包含病人的人口學變項ヽ疾病的時間ヽ生理功能ヽ病人觀念ヽ態度及病人對治療的滿意度。在國外針對研究服藥遵從性已使用信ヽ效度良好的結構性量表,本研究希望使用台灣版Morisky服藥遵從性敘述量表有效地評估病人的服藥遵從性,並了解門診癌症疼痛病人的服藥遵從性及影響服藥遵從性的相關因素。
研究方法為橫斷式研究設計,採用資料分析法進行分析,資料來源為一大型研究的二次分析,共分析資料100人。資料檔案包含病人之個人及疾病基本資料、台灣版Morisky服藥遵從性量表、病人台灣版障礙量表、家屬台灣版障礙量表、中文版簡明疼痛量表ヽAPS疼痛滿意度量表,及Karnofsky功能評估量表,資料分析採描述性分析、t檢定、F檢定、相關檢定(Pearson correlation)及迴歸分析(regression analyses)。
研究結果顯示門診之癌症疼痛病人服藥遵從性屬低至中度,影響台灣癌症疼痛病人服用止痛藥物遵從性之相關因素,包括病人年齡(r= .211, p= .035)、教育程度(r= .211, p= .035)、病人止痛藥障礙分數(r=- .54, p< .001)、家屬止痛藥障礙分數(r=- .47, p< .001)、病人對疼痛處理的滿意度(r= .49, p< .001)、平均疼痛程度(r=- .20, p = .04)。而病人止痛藥障礙因素及對疼痛處理的滿意度共可解釋37.5%病人服藥遵從性的變異量,此解釋力達統計上的顯著水準(p= .01);加入家屬止痛藥障礙、平均疼痛程度、年齡、教育程度因素,此六個相關因素可預測42.4%病人服藥遵從性的變異量。雖然病人的年齡及教育程度是無法改變的,但是若能降低病人對止痛藥的服藥障礙且增加病人對疼痛處理的滿意度,就可以解決37.5%病人服藥遵從性的問題。故臨床醫護人員應加強癌症疼痛病人止痛藥物服用知識,減少病人錯誤概念,耐心傾聽病人需求增加病人對醫護處理之信任及滿意度,就能增加病人的服藥遵從性,進而減輕病人的疼痛強度。
英文摘要 Pain is one of the major problems faced by cancer patients. Use of analgesics is a major treatment modality in management of cancer pain. Achieving adequate adherence to analgesics regimen is difficult. The most advanced therapeutic regimen with appropriate medicine will fail without patient adherence. Within recent years, non-compliance or the inability to stay in treatment or adhere to a treatment regimen has been recognized as a major health care problem. Lack of adherence may result from patient-related factors, such as barriers to pain management or satisfaction of pain management.
The purpose of the study was to investigate the level of adherence with analgesics regimen and to explore the predicting factors of adherence with analgesics regimen in a sample of Taiwan cancer patients with pain. The study was part of a large study. A total of 100 patients were used in the analysis. Instrument consisted of the Taiwanese Version of Medication Adherence measure, the Barriers Questionnaire--Taiwan Form (BQT), Brief Pain Inventory-Chinese version (BPI-C), Karnofsky Performance Status (KPS), and a demographic questionnaire. Descriptive analysis, t-test, F-test, Pearson correlation, and multiple regression analysis were used for data analysis.
Results from the study show the level of adherence with analgesics regimen was low. The result of multiple regression analysis show that predictors for analgesics adherence in cancer outpatients with pain were patient-related barriers and satisfaction of pain management (p= .01).
The survey may serve the medical personnel and institutions as an important reference for pain management. Decrease of patient-related barriers and improve of satisfaction of pain management will improve analgesics adherence in cancer with pain.
論文目次 致 謝 ……………………………………………………Ⅰ
中文摘要 ……………………………………………………Ⅲ
英文摘要 ……………………………………………………Ⅴ
目 錄 ……………………………………………………Ⅶ
圖表目次 ……………………………………………………Ⅸ

第一章 緒論
第一節 研究動機 ……………………………………1
第二節 研究重要性 ……………………………………3
第三節 研究目的 ……………………………………5
第二章 文獻查證
第一節 癌症疼痛 ……………………………………6
第二節 服藥遵從性 …………………………………7
第三節 癌症病人服用止痛藥的遵從行為 …………10
第三章 研究架構
第一節 研究架構 ……………………………………13
第二節 研究假設 ……………………………………15
第三節 名詞解釋 ……………………………………16
第四章 研究方法
第一節 研究設計 ……………………………………18
第二節 研究場所及對象 ……………………………19
第三節 研究工具 ……………………………………20
第四節 資料收集過程 ………………………………27
第五節 統計分析 ……………………………………28
第五章 分析與結果
第一節 病人人口學特性分析 ……………………30
第二節 癌症病人服藥比率ヽ服藥遵從性分布 ……34
第三節 病人對疼痛處理滿意度之分布 ……………35
第四節 癌症病人疼痛及疼痛干擾日常生活強度之分布36
第五節 癌症病人及家屬止痛藥障礙因子之分布………39
第六節 癌症病人服藥遵從性與各變項之關係 ………43
第七節 癌症病人服藥遵從性與各變項之單一迴歸關係53
第八節 預測影響癌症病人服藥遵從之因素 ………56
第六章 討論
第一節 癌症病人對於服用止痛藥物之服藥遵從性 …58
第二節 癌症病人的疼痛強度及對生活的干擾程度與服藥
遵從性之相關 ………………………………62
第三節 癌症病人對疼痛處理的滿意度與服藥遵從 性之相
關 ……………………………………………65
第四節 癌症病人及家屬對止痛藥物的障礙因子與服藥遵
從性之相關 ………………………………67
第五節 病人服藥遵從性之預測 ……………………71
第七章 結論與建議
第一節 結論 ……………………………………………73
第二節 未來的貢獻 ……………………………………75
第三節 研究限制與建議 ………………………………77

參考文獻
中文部份 …………………………………………………78
英文部份 …………………………………………………79

附錄
附錄一 個人基本資料 …………………………………87
附錄二 台灣版簡明疼痛量表 …………………………88
附錄三 服藥遵從性問卷 ………………………………90
附錄四 台灣版障礙量表 ………………………………91
附錄五 Karnofsky 功能評估量表 ……………………96
參考文獻 參考文獻
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梁淑媛、林佳靜、陳品玲、劉淑娟(2000)•癌症病人及其家屬對癌痛及其影響感受比較•新臺北護理期刊,2(2),17-28。
賴裕和、蔡麗雲、張澤芸、蕭淑代、高靖秋、張淑華、陳淑卿
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系統識別號 U0007-2306200710213300
論文名稱(中文) 醫院藥劑科作業人員抗腫瘤藥劑暴露評估
論文名稱(英文) Occupational Exposure to Antineoplastic Agents of Pharmacy Workers in Hospital
校院名稱 臺北醫學大學
系所名稱(中) 公共衛生學研究所
系所名稱(英) Graduate Institute of Public Health
學年度 95
學期 2
出版年 96
研究生(中文) 曾冠燁
學號 M508094014
學位類別 碩士
語文別 中文
口試日期 2007-05-29
論文頁數 120頁
口試委員 指導教授- 陳叡瑜
委員-陳秋蓉
委員-林佳谷
關鍵字(中) 抗腫瘤藥物
5-Fluorouracil
Cisplatin
藥劑科職業暴露
關鍵字(英) Antineoplastic agents
5-Fluorouraicl
Cisplatin
Occupational exposure assessment
Pharmacy workers
學科別分類
中文摘要 醫院化學治療工作人員,在調配藥物、包裝及傳送藥物等作業流程中,都有可能因洩漏等問題而造成暴露。研究指出,這些職業暴露者會引發細胞毒性,增加致癌風險;致畸胎、異位懷孕或自發性流產等女性生殖危害等;也有引發急性過敏反應的病例報告。國內目前化學治療相關工作人員有數千人之多,人員暴露及健康效應相關研究極少。
本研究以立意取樣的方式,選取台北市一家醫學中心與兩家區域醫院作為樣本醫院。研究設計包括:環境擦拭樣本採集分析以及暴露者問卷調查。環境樣本之採集區域包括:藥劑部門抗腫瘤藥劑調配室及相鄰辦公室區,並以醫院常用的抗腫瘤藥劑5-Fluorouracil以及Cisplatin作為污染指標;問卷調查採結構式自填問卷,對象為三家醫院藥劑科人員所有人員,內容包含:基本人口學資料、工作現況、抗腫瘤藥劑暴露史、健康狀況、個人防護情形與認知等。
環測結果顯示,調劑前後調配室內外皆可測到抗腫瘤藥劑的存在,整天調劑後調配室內5FU污染濃度範圍為N.D.~934.62pg/cm2,Cisplatin濃度範圍為N.D.~24.93pg/cm2,其中又以垃圾桶前地面、transfer box前桌面與氣罩檯面測到濃度較高的污染;調配室外5FU污染濃度範圍為N.D.~825.75pg/cm2,Cisplatin濃度範圍為N.D.~55.46pg/cm2,濃度最高的樣本是儲藥櫃內表面與傳送盒內。除外層手套均可測到兩種抗腫瘤藥劑外,部份內層手套也可測到Cisplatin污染(平均333pg/隻手套)。
個人問卷共回收81份問卷(回收率85.3%),四成受訪藥師為抗腫瘤藥劑暴露者,其中半數懷疑操作時可能有藥劑外洩。六成以上藥劑暴露者認為暴露發生在抽取、混合與包裝藥劑時,暴露途徑為口鼻吸入與皮膚吸收,但不認為會有食入問題。然由於辦公桌面發現抗腫瘤藥劑污染,且人員會於此區進食,顯示藥劑經飲食暴露之可能性值得重視。
各醫院均訂定個人防護具之使用規範,一致要求全面使用手套及隔離衣,而問卷結果顯示,各種防護具實際使用率為手套100%、隔離衣90.5%、髮套80.0%及口罩77.8%。兩家醫院改變管理措施增加鞋套之使用規定,則使地面污染獲得改善。
本研究結果證實調配室內外均存在抗腫瘤藥劑之污染,而個人防護與環境清潔管理仍未臻完善,建議各醫院應強化管理規範並確實執行;同時,鑑於研究對象之潛在暴露風險,建議應進行暴露者生物偵測。
英文摘要 Antineoplastic agents are widely used in hospitals for cancer treatment. Several epidemiological studies found that exposure to antineoplastic agents were associated with reproductive toxic effects, higher rates of advance micronuclei (MN) and sister-chromatic-exchange (SCE), spontaneous abortion, as well as acute allergic reactions. There are thousands of health care workers involving in chemotherapy in Taiwan, but few studies have been conducted to examine the potential health risk related to the use of antineoplastic agents.
One medical center and two area hospitals in Taipei, Taiwan were selected to monitor antineoplastic agent levels and to collect exposure background of hospital workers. Surface wipe samples were collected in the pharmacy units and in their adjacent offices in each study hospital. We examined the concentrations of two commonly used antineoplastic agents, 5-Fluorouracil (5FU) and Cisplatin, in wipe samples and in the disposable protective equipments used in pharmacy units. A self-administered questionnaire was used to collect demographic data, working practices, medical and contact history, and perceived work-related symptoms of staff working in pharmacy units.
According to our results, antineoplastic agents were recovered in all of the sampling pharmacy units, including both inside and outside of the administration rooms (inside: 5FU: N.D.~934.62pg/cm2, Cisplatin: N.D.~24.93 pg/cm2; outside: 5FU: N.D.~825.75pg/cm2, Cisplatin: N.D.~55.46pg/cm2). We detected antineoplastic agents not only on outer gloves (5FU: N.D.~2.87×106 pg/gloves, Cisplatin: N.D.~1.02×105pg/gloves), but also on some of the inner gloves (333pg/gloves). Among the 81 study pharmacy workers, 40% have been exposed to antineoplastic agents. Half of them suspected that the agents leaked during drug preparation. Although gloves and gown must be worn at all time while handling drug in all of the study hospitals, eye protection, mask, and hair cot were not required. Most subjects recognized the potential exposure to antineoplastic agents through inhalation and dermal contact, but not through ingestion. However, we did detect antineoplastic agents on office tables, indicating potential exposure through contaminated hands or food.
In light of extensive antineoplastic agent contamination in pharmacy units, the study hospitals applied improved precaution practices, which resulted in better contamination control. Therefore, better control regulations and procedures should be implemented in hospital pharmacy units to minimize workers’ exposure and health risk.
論文目次 表目錄 iii
圖目錄 v
第一章 前言 1
第一節 研究背景 1
第二節 研究目的 3
第二章 文獻探討 4
第一節 癌症治療 4
第二節 抗腫瘤藥劑 5
第三節 我國常用抗腫瘤藥劑 8
第四節 暴露評估 12
第五節 抗腫瘤藥劑分析方法 16
第六節 健康危害 20
第三章 材料與方法 23
第一節 研究設計 23
第二節 採樣策略 24
第三節 研究工具 26
第四節 實驗流程 30
第四章 結果 44
第一節 樣本醫院描述 44
第二節 藥劑科環境測量 49
第三節 藥劑科手套測量結果 63
第四節 問卷調查 66
第五章 討論 78
第一節 三醫院抗腫瘤藥劑污染狀況與相關文獻之比較 78
第二節 三家醫院防護用具污染狀況與相關文獻之比較 96
第三節 三醫院藥劑部抗腫瘤藥劑管理規範與相關規範之比較 101
第四節 抗腫瘤藥劑之可能暴露途徑 103
第五節 研究限制 104
第六章 結論與建議 105
第一節 結論 105
第二節 建議 106
參考文獻 108
國外文獻 108
國內文獻 112
附錄 113
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系統識別號 U0007-2501200812384600
論文名稱(中文) 精神分裂症病患併用喹硫平之肝功能及血中濃度監測分析
論文名稱(英文) Liver Function Tests and Therapeutic Drug Monitoring in Schizophrenic Patients on Quetiapine Combination Therapy
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 96
學期 1
出版年 97
研究生(中文) 王悅琪
學號 M301094018
學位類別 碩士
語文別 中文
口試日期 2008-01-10
論文頁數 62頁
口試委員 委員-林慧玲
委員-劉興政
委員-盧孟良
委員-邱士娟
指導教授-吳姿樺
關鍵字(中) 精神分裂症
療劑監測

硫平
水飛薊
肝功能
藥物交互作用
關鍵字(英) schizophrenia
therapeutic drug monitoring
quetiapine
silymarin
liver function
drug-drug interactions
學科別分類
中文摘要 過去研究指出服用喹硫平(quetiapine;QTP)患者可能發生無症狀肝功能異常現象,並可造成糖尿病的發生。而經比較原始血糖正常或異常之精神分裂症病患族群服用QTP後,兩族群之生化指數變化不同;且同時服用水飛薊(silymarin;SB)與口服降血糖藥物的糖尿病患之血糖控制情形較佳;然尚未有研究報告監測臺灣地區服用QTP之精神疾病患者肝功能及分析QTP血中濃度。故本研究欲了解QTP對肝功能的影響,並分析併用SB一週後對生化代謝指數與QTP血中濃度之影響。研究設計:本臨床試驗為經臺北醫學大學人體試驗委員會核可,於臺北市某私立康復之家依照核可內文執行,並獲得病患簽署之同意書;收錄條件須為經醫師診斷之精神分裂症病患。給藥設計如下:試驗開始的一週期間逐漸調升劑量至QTP 300 mg/day,並維持該劑量一週(第15日)後,再併用SB (70 mg/day) 7日(第22日)。分別於試驗第1、15、22日檢測血液生化值,並於試驗第15、22日抽血進行QTP療劑監測(therapeutic drug monitoring)(服藥後第0至8小時)。共收錄受試者13人,平均年齡為46.6 ± 10.8歲,體重為66.6 ± 9.5公斤;經剔除部份同時服用clozapine之病患後,此受試群(10人)平均年齡、體重為48.9 ± 11.3歲、65.9 ± 9.4公斤;結果顯示:此受試群服用QTP兩週後,飯後胰島素值下降、空腹胰島素值上升、quantitative insulin sensitivity check index (QUICKI)下降、aspartate aminotransferase (AST)或alanine aminotransferase (ALT)上升超過10%者共10人;使用SB一週後,空腹胰島素值、QUICKI數值分別較未併用前之basal值下降、上升,且AST或ALT上升超過10%者剩3人。不論是否有剔除同時服用clozapine之病患,併用SB前後QTP療劑監測與臨床藥物動態學(pharmacokinetics)數值並無顯著差異。再依第1日血糖數值,再將病患區分為原始血糖異常(≧100 mg/dL)或正常二族群;經比較後,原始血糖正常之精神分裂患者在第15日呈現AST或ALT上升超過10%者共4人,但無受試者在第22日AST或ALT上升超過10%。原始血糖異常者之QTP平均最高血中濃度值(Cmax)較原始血糖正常者低(p=0.04),併用SB後則兩組之Cmax無顯著差異。又原始血糖異常者總膽固醇值比未併用SB前高(p=0.04),但未達臨床異常標準;而原始血糖正常者QTP分布體積值比未併用SB以前低(p=0.03),兩者皆達統計上顯著差異。從上述結果推論:(1)併用SB可減少服用QTP後觀察到肝功能異常病患之人數,尤其對原始血糖正常之精神分裂患者較為明顯;(2)血糖正常患者短期併用SB (70 mg/day)與QTP兩藥物無需調整QTP劑量;血糖異常者則建議進行療劑監測,作為QTP劑量調整之參考。
英文摘要 It was reported that quetiapine (QTP)-treated patients presented asymptomatic liver dysfunction and new-onset diabetes mellitus. It was also shown that QTP treatment may change metabolic parameters of schizophrenic patients with or without hyperglycemia differently. Blood glucose controls of oral antidiabetics may be improved while diabetic patients co-medicated with silymarin (SB). The purpose of this study was to monitor the liver function changes and therapeutic drug concentrations after QTP treatments, and after QTP co-medicated with SB treatments in Taiwanese schizophrenic patients. This clinical trial was approved by Taipei Medical University Institutional Review Board and each patient’s informed consent was obtained. This study was conducted in a private long-term care facility in Taipei, Taiwan, and patients diagnosed with schizophrenia were recruited. Study design: QTP dosage was titrated up to 300 mg/day within one week. Patients were maintained on this dose until the end of the study. SB (70 mg/day) was added on from day 15 to day 22. Blood samples were collected from patients at day 1, 15, and 22 to test metabolic parameters and liver function. Samples of day 15 and 22 were further analyzed for QTP therapeutic drug monitoring (TDM) at 0~8 hours postdose. There were thirteen patients recruited, and their average age and body weight were 46.6 ± 10.8 years old and 66.6 ± 9.5 kg, respectively. After three patients co-treated with clozapine were excluded, patients’ (n=10) average age and body weight were 48.9 ± 11.3 years old and 65.9 ± 9.4 kg, respectively. Results: After 2 weeks of QTP treatment (day 15), the patients’ average postprandial insulin levels (PPI) decreased significantly (p=0.03) while number of quantitative insulin sensitivity check index (QUICKI) decreased and fasting insulin concentration increased. There were ten patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increased more than 10% at day 15. Fasting insulin concentration and QUICKI of samples collected at day 22 decreased or increased, respectively, when compared to those collected at day 15. There were only three patients whose AST or ALT increased more than 10% at day 22. There were no significant differences in QTP TDM and pharmacokinetic parameters following QTP treatments with or without SB whether patients using clozapine or not. Furthermore, according to their day-1 fasting plasma glucose (FPG), patients were subgrouped into non-hyperglycemic group or hyperglycemics (FPG≧100 mg/dL). In non-hyperglycemic schizophrenic group, there were four patients whose AST or ALT increased more than 10% at day 15, but there was no one had increased AST or ALT more than 10% at day 22. Average peak QTP concentration (Cmax) of hyperglycemic patients were lower than the non-hyperglycemic patients (p=0.04). However, when patients co-treated QTP and SB, the average Cmax became similar between two groups. Moreover, at day 22, total cholesterol levels were statistical significantly higher (p=0.04), but still within normal ranges, than that of samples collected on day 15 in hyperglycemic patients. Mean volume of distribution of the non-hyperglycemic patients was significantly lower (p=0.03) at day 22 than that of samples collected on day 15. The results suggest that: (1) Number of schizophrenic patients with liver function abnormality observed after QTP treatment may be reduced when SB was co-administered for one week, especially in non-hyperglycemic patients. (2) There was no need to adjust QTP therapeutic dosage in non-hyperglycemic schizophrenic patients when the duration of their combination treatment of QTP (300 mg/day) with SB (70 mg/day) was no longer than one week. But TDM for QTP is suggested in schizophrenic patients with hyperglycemia.
論文目次 目次 I
中文摘要 III
英文摘要 IV
第一章 緒論 1
第一節 研究背景 2
第二節 研究目的 3
第二章 文獻探討 4
第一節 喹硫平介紹 5
第二節 水飛薊介紹 7
第三章 研究材料與方法 10
第一節 材料來源與研究對象條件 11
第二節 試驗設計與進行 11
第三節 血液之前處理 12
第四節 QTP血中濃度之分析方法 12
第五節 標準檢量線之製作 12
第六節、分析方法之確效試驗 13
第七節 統計分析 13
第四章 結果 15
第五章 討論 21
第六章 結論 26
第七章 圖表與附錄說明 28
Table 1. Demographic and Basal Clinical Characteristics of All Patients……………………….29
Table 2. The Effects of QTP and QTP-SB Treatments in All Patients…………………………..30
Table 3. Liver Function Tests Changes in All patients…………………..………………………31
Table 4. The Effects of QTP and QTP-SB Treatments in All Patients…………………………..32
Table 5. The Effects of QTP and QTP-SB Treatments in All Patients…………………………..33
Table 6. Demographic and Basal Clinical Characteristics of Patients not Using Clozapine…….34
Table 7. The Effects of QTP and QTP-SB Treatments in Patients not Using Clozapine………..35
Table 8. Liver Function Tests Change in Patients not Using Clozapine……..…………………..36
Table 9. The Effects of QTP and QTP-SB Treatments in Patients not Using Clozapine………..37
Table 10. The Effects of QTP and QTP-SB Treatments in Patients not Using Clozapine………38
Table 11. Comparison of Demographic and Basal Clinical Characteristics: Subgroups………...39
Table 12. The Effects of QTP and QTP-SB Treatments in HG Group…………………………..40
Table 13. The Effects of QTP and QTP-SB Treatments in Non-HG Group……………………..41
Table 14. Liver Function Tests Enzyme Levels Change in Patients not Using Clozapine:
    Comparisons Within HG or Non-HGgroup...................................................................42
Table 15. Comparisons of QTP Effects Between HG and Non-HG Group……………………...43
Table 16. Comparisons of SB Effects Between HG and Non-HG Group………………………..45
Table 17. The Effects of QTP and QTP-SB Treatments on PK Parameters: Comparisons Within
    HG or Non-HG group………………………………………………………………….47
Table 18. The Influence of QTP or QTP+SB on Two Groups of Patients With Different Basal
    FPG…………………………………….........................................................................48
Table 19. Differential Changes of QTP or QTP+SB on Two Groups of Patients With Different
    Basal FPG.......................................................................................................................49
圖一、研究設計與研究流程……………………………………………………………………50
圖二、精神分裂症病患服用QTP(300 mg/day)兩週後及併用SB(70 mg/day)一週後時間
   與平均血中濃度曲線比較圖……………………………………………………………51
圖三、研究病患分群流程圖……………………………………………………………………52
圖四、分群方法一收錄之精神分裂症病患服用QTP(300 mg/day)兩週後及併用SB(70
   mg/day)一週後時間與平均血中濃度曲線比較圖……………………………………53
圖五、分群方法二收錄之精神分裂症病患服用QTP(300 mg/day)兩週後及併用SB(70
   mg/day)一週後時間與平均血中濃度曲線比較圖……………………………………54
附錄表、確效試驗操作結果…………………………………………………………………….55
參考文獻 56



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系統識別號 U0007-2607200720235900
論文名稱(中文) 口服聚合微膠體包覆pMBP-Lac Z之藥物動力學
論文名稱(英文) Pharmacokinetics of oral administered pMBP-Lac Z with polymeric micelles
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 蔡宜珊
學號 M301094011
學位類別 碩士
語文別 中文
口試日期 2007-06-27
論文頁數 43頁
口試委員 指導教授- 廖嘉鴻
委員-高純琇
委員-張淑芬
關鍵字(中) 藥物動力學
質體DNA
關鍵字(英) pharmacokinetics
plasmid DNA
學科別分類
中文摘要 先前本實驗室曾使用非離子型聚合微膠體當作口服基因的載體,於48小時內投與六個劑量後,發現質體DNA不僅於腸胃道有表現,還能由血液分佈至較遠的組織及器官中,包括腦及脊髓。為了進一步了解質體DNA於體內分佈的情形;合適的藥物劑量與多劑量給藥之間距等因此本實驗分別由靜脈及口服投與單一劑量(40 μg/150μL) pMBP-Lac Z與同劑量經微膠體包覆的pMBP-Lac Z 至裸鼠體內,評估pMBP-Lac Z之分布及其藥物動力學。於不同時間點下採集裸鼠血液及組織(包括十二指腸,肝臟,脊髓,與腦) ,經過萃取得到total DNAs,使用同步定量PCR (Q-PCR)分析檢品中Lac Z的含量。本實驗採用絕對定量方式分析檢品中Lac Z DNA的含量,因此以濃度為10^2 copies/μL到10^8 copies/μL的純的pMBP-Lac Z DNA作為標準曲線。在此濃度範圍內,標準曲線的對數值呈線性關係,並以同日內及異日間的數值來評估本實驗分析方法的精確性與準確性,其變異係數均小於15%。實驗結果顯示,利用靜脈注射方式投與後,於血液檢品中發現,未包覆之pMBP-Lac Z的area under the curve (AUC)為1.37x10^8 (min x pg/mL),而微膠體包覆之pMBP-Lac Z於血AUC為3.88x10^7 (min x pg/mL),兩者間無統計上的差異。但經過微膠體包覆後的pMBP-Lac Z的排除半衰期由54.5分鐘延長為210.5分鐘。另一方面,在口服投與後於血液檢品中未包覆之pMBP-Lac Z其 AUC值為9.29 (min x pg/mL),使用聚合微膠體包覆者為6.09x10^3 (min x pg/mL)。此外可觀察到pMBP-Lac Z在體內的排除半衰期從46.6分鐘延長到257分鐘。由結果計算其不包覆與包覆之相對口服生體可用率時,約增加600倍左右。此外,聚合微膠體包覆pMBP-Lac Z經由靜脈注射後,其AUC於十二指腸、肝臟、脊髓及腦分別為170.6,108.3,1086.6,182.6 (min x pg/g gDNA)。未包覆者於上述四種器官中的AUC分別為127.6,199.0,463.8,187.4 (min x pg/g gDNA)。聚合微膠體包覆之pMBP-Lac Z經由口服投與後,於十二指腸、肝臟、脊髓及腦中的AUC分別為331.5,0.26,22.2,9.93 (min x pg/g gDNA),除了小腸之AUC外,其於組織的AUC均小於靜脈注射之值。口服投與未包覆pMBP-Lac Z於十二指腸,脊髓,與腦中的AUC,分別為57.5,1.39,1.8 (min x pg/g gDNA) ,其AUC值均小於相同投與途徑包覆之pMBP-Lac Z。綜合上述結果,聚合微膠體包覆pMBP-Lac Z能增加pMBP-Lac Z之口服生體可用率。此外,利用口服投與聚合微膠體包覆質體DNA,比未包覆者相比有較高的AUC值。然而,經靜脈投與後,於血液中pMBP-Lac Z 有最高的AUC值。
英文摘要 We have previously used the nonionic polymeric micelles (PM) as a carrier for oral gene delivery given at six doses within 48 hours, and the results showed that the delivered gene expression was detected in GI, plasma, and other tissues and organs, including brain and spinal cord. In order to optimize the ideal dose and dose regimen, we evaluate the distribution and pharmacokinetic profile of pMBP-Lac Z DNA (40 μg/150 μL) delivered with or without polymeric micelles to nude mice orally and intravenously. The plasma and tissue samples (duodenum, liver, spinal cord, and brain) were collected at various time points, and total DNAs were extracted for Lac Z DNA quantitation using real-time quantitative polymerase chain reaction (QPCR). To absolutely quantitate Lac Z DNA in the samples, a standard curve was generated using purified pMBP-Lac Z DNA in a range of 10^2-10^8 copies/μL. Within the log linear range of standard DNA at 10^2 to 10^8 copies/μL, we obtained the CV% of within- and between-day assays were all less than 15%, indicating the precision and accuracy of the method used in this study. After IV administration, the area under the curve (AUC) of pMBP-Lac Z and formulated pMBP-Lac Z in plasma was 1.37x10^8 (min x pg/mL) and 3.88x10^7 (min x pg/mL), respectively, which were no significant different. But the formulated pMBP-Lac Z had prolonged elimination half-lives (from 54.5 to 210.5 min). On the other hand, the area under the curve (AUC) of pMBP-Lac Z and formulated pMBP-Lac Z in plasma was 9.29 (min x pg/mL) and 6.09x10^3 (min x pg/mL), respectively, after orally administration. In addition, the formulated pMBP-Lac Z had prolonged elimination half-lives (from 46.6min to 257min). The results indicated that the relative oral bioavailability of formulated pMBP-Lac Z was 600 folds of that of the naked pMBP-Lac Z. Furthermore, after IV administration, the AUC values of formulated pMBP-Lac Z in duodenum, liver, spinal cord and brain were 170.6, 108.3, 1086.6, 182.6 (min x pg/g gDNA), respectively. For naked pMBP-Lac Z, the AUC values in the above organs were 127.6, 199.0, 463.8, 187.4 (min x pg/g gDNA), respectively. The AUC values of formulated pMBP-Lac Z via oral administration in duodenum, liver, spinal cord, and brain were 331.5, 0.26, 22.2, 9.93 (min x pg/g gDNA). Most of the AUC values were smaller than that detected after IV administration, except that detected in duodenum. For the naked pMBP-Lac Z in duodenum, spinal cord and brain, the AUC values were 57.5, 1.39, 1.8 (min x pg/g gDNA) and were lower than that detected with formulated DNA. Overall, these results indicated that PM formulation enhanced the bioavailability of pMBP-Lac Z. In addition, PM-formulated pMBP-Lac Z shows higher AUC than naked pMBP-Lac Z in all tissues after oral administration. However, the highest AUC level of pMBP-Lac Z was observed in the plasma after IV administration.
論文目次 中文摘要 i
Abstract iii
附表目錄 v
附圖目錄 vii
壹、緒論 1
一、大分子藥物 1
1.1蛋白質藥物 1
1.2核酸藥物 2
二、非病毒型基因載體 3
2.1微脂粒 (Liposome) 4
2.2聚合物 5
2.2.1陽離子性聚合物 (cationic polymer) 5
2.2.2聚合微膠體(Polymeric micelles) 5
三、聚合微膠體在大分子藥物傳遞之運用 7
3.1蛋白質藥物 7
3.2核酸藥物 7
3.3抗癌藥物 7
四、基因藥物投與途徑的選擇 8
五、核酸藥物之藥物動力學 8
貳、研究目的 10
參、研究材料與方法 10
一、質體DNA的製備 10
1.1 pMBP-Lac Z質體之製備與純化 11
二、聚合微膠體之臨界微膠體濃度測定 11
三、質體/聚合微膠體 (plasmid/ polymeric micelles) 製備 (P/PM) 12
四、質體/聚合微膠體溶液之物化性質 12
4.1質體/聚合微膠體粒徑大小測定 12
4.2質體/聚合微膠體表面電位測定 12
五、pMBP-Lac Z之同步定量PCR (Real-time quantitative PCR)分析方法 12
5.1同步定量PCR之實驗流程 13
5.2標準檢量曲線之製作 14
5.3分析方法精確性及準確性試驗 14
5.4PCR 反應產物之確認 14
六、動物實驗 15
6.1裸鼠(BALB/c-nu)15
6.2口服及靜脈注射投與質體DNA/聚合微膠體溶液 (P/PM) 及質體DNA 15
七、血漿檢品中質體DNA之分離 16
八、組織中基因體DNA (genomic DNA, gDNA) 之分離 16
九、藥物動力學參數與統計分析 17
肆、研究結果與討論 18
一、聚合微膠體臨界膠體濃度之測定 18
二、聚合微膠體溶液之物化性質 18
2.1聚合微膠體溶液之粒徑 (Particle size) 18
2.2聚合微膠體溶液之表面電位 18
三、pMBP-Lac Z之QPCR分析方法之確效 18
3.1QPCR之標準檢量線 18
3.2QPCR分析方法之產物專一性確認 19
3.3分析方法精確性及準確性試驗 20
四、動物實驗之結果 20
4.1pMBP-Lac Z於裸鼠血液中之藥物動力學 20
4.2pMBP-Lac Z於裸鼠十二指腸中之藥物動力學 21
4.3pMBP-Lac Z於裸鼠肝臟中之藥物動力學 21
4.4pMBP-Lac Z於裸鼠脊髓中之藥物動力學 22
4.5pMBP-Lac Z於裸鼠腦中之藥物動力學 22
伍、結論 24
參考文獻 40
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系統識別號 U0007-2707200713321100
論文名稱(中文) 台灣1997至2002年高血壓藥物的用藥型態評估及當AIIA導入市場對臨床使用之影響
論文名稱(英文) An evaluation on the pharmaceutical expenditure of antihypertensive agents during 1997 to 2002 and Impact of introduction of Angiotensin II Antagonist on the antihypertensive drug utilization in Taiwan
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 95
學期 2
出版年 96
研究生(中文) 林銅祿
學號 D87010011
學位類別 博士
語文別 中文
口試日期 2007-07-20
論文頁數 145頁
口試委員 指導教授-鄭慧文
指導教授-高雅慧
委員-湯藻薰
委員-邱弘毅
委員-許秀藴
委員-高純綉
委員-康照洲
關鍵字(中) 藥物經濟學
藥物使用量
殘餘值
每日劑量
血管張力素II 拮抗劑
市場佔有率
關鍵字(英) Antihypertensive agent
Defined daily dose (DDD)
Drug utilization
Pharmaceutical expenditure
Angiotensin II antagonist (AIIA)
Angiotensin converting enzyme inhibitor (ACEI)
ß
- blocker (BB)
Calcium channel blocker (CCB)
Market share
學科別分類
中文摘要 利用健保局學術研究資料庫(National Health Insurance Academic Research Database;NHIARD),探討從1997年至2002年台灣高血壓藥物的用藥支付費用及型態,並評估當新的高血壓藥物類別血管張力素II 拮抗劑(Angiotensin II Antagonist;AIIA)導入市場後,對原有高血壓藥物使用行為所造成的影響;特別是針對台灣市場佔有率最高的血管收縮素轉換酶抑制劑(Angiotensin Converting Enzyme Inhibitors;ACEI)、乙型腎上腺素阻斷劑(β- Blockers;BB)、鈣離子阻斷劑(Calcium Channel Blockers;CCB)及其他類別Miscellaneous agents(MIS)等,四大類高血壓藥物。
從健保資料庫(NHIARD)取得1997年至2002年高血壓用藥資料,包括門診病例記錄及用藥處方資料,藥物支付費用可分成5個部份,包括相關的藥物價格、病患人數、每位病患的就醫平均數、每位醫師看診病歷處方中的每日劑量及殘餘值;同時並取得病患的病歷檔案(Medication profile)、醫院看診記錄(Hospital visit record)及藥品申報資料(Drug claim data),執行評估高血壓用藥的申報金額、臨床使用量、處方情形與病患市場佔有率分析等等,藉以瞭解當AIIA導入市場後,對高血壓藥物ACEI、BB和CCB及MIS等類別所造成的影響,本研究將以市場佔有率表示各類別高血壓藥物間的市場相對強度,包括:支付金額市場佔有率、臨床市場佔有率、處方數量市場佔有率、病患人數市場佔有率,同時並探討AIIA對不同層級醫院用藥的滲透時間。
1997年至2002年總高血壓用藥增加102%,主要的成因是混合效應-從病患人數增加34%,醫師看診病歷處方中每位病患的每日劑量增加33%,而高血壓用藥總殘餘值因素僅有7%的影響。此結果與瑞典、西班牙兩國經驗有所不同,其藥物支付費用之增加主要是來自於殘餘值。詳細的殘餘值分析顯示:原廠品牌的類別產品有11%的成長,但一般學名藥卻減少12%。至於醫院的殘餘值:醫學中心成長13%、區域醫院成長17%、地區醫院成長10%,但基層醫療診所卻下降14%。此結果顯示,各層級醫院醫師有不同的處方用藥行為,醫院層級醫師的用藥行為偏向新藥或原開發廠品牌藥,基層醫療醫師則傾向使用一般學名藥。至於,高血壓藥物各類別於支付金額市場佔有率、臨床市場佔有率、處方數市場佔有率、病患人數市場佔有率的分析上,當AIIA導入市場後,對其他高血壓藥物ACEI、BB、CCB和MIS所造成的影響。研究結果顯示,AIIA對ACEI影響最大,這是由於藥理性質相類似所造成的結果,AIIA對BB僅有小部份的影響,對CCB無影響且有正面加分作用,MIS則漸被淡忘。AIIA市場上的成長,最主要的原因是來自於取代ACEI及與其他高血壓藥物一起服用的併服療法,尤其是與CCB和BB併服後讓CCB維持成長BB流失不多。AIIA於各層級醫院以臨床市場佔有率及處方數量市場佔有率的成長強度分析依:醫學中心、區域醫院、地區醫院、基層醫療依序為:4.95:3.77:2.77:1及5.28:4.17:2.94:1。可知,醫學中心>區域醫院>地區醫院>基層醫療。
高血壓藥物支付費用成長的重要原因是病患人數及醫師門診處方中DDDS值的增加所致,各層級醫師有不同的處方用藥行為,醫院層級醫師的用藥行為偏向新藥或原開發產的品牌藥,基層醫療醫醫師則傾向使用一般學名藥。CCB是目前高血壓用藥的主流雖有小成長但再成長有限,AIIA呈現持續成長的趨勢,BB雖微下滑但維持平穩,ACEI有被AIIA取代現象僅以大量價格低廉之學名藥維持其數量上之優勢,MIS已漸被淡忘。由於醫院層級醫師用藥行為偏向新藥及品牌藥,所以醫學中心對AIIA的利用與擴散具有關鍵性之角色。
英文摘要 Background and Purpose
Antihypertensive medications have represented a tremendous financial burden to the health care plan globally. This study examined the utilization pattern of the antihypertensive agents to analyze the underlying reasons responsible for the pharmaceutical expenditure in Taiwan during 1997 to 2002 as well as to evaluate the long term impact of a new pharmacological class antihypertensive medicine- angiotensin II antagonist (AIIA) to the clinical utilization of the existing antihypertensive medications in Taiwan.
Methods
The claims data during 1997 to 2002 were obtained from National Health Insurance Academic Research Database (NHIARD), which include ambulatory service record and prescription data of the entire population. Drug expenditure was decomposed into 5 components: relative drug price, number of patients treated, average physician visit per patient, Defined Daily Dose (DDD) per physician visit and a residual. Gross growth of DDD and prescription numbers, market share analysis including monetary market share (MMS), clinical market share (CMS), prescription market share (PrMS) and patient market share (PtMS), market penetration time and DDDs/ prescription were used to assess AIIA's impact on the angiotensin converting enzyme inhibitors (ACEI), β- Blockers (BB), calcium channel blockers (CCB) and other miscellaneous antihypertensive agents (MIS).
Result
Total antihypertensive drug spending increased 102% during this period, mainly due to the compounding effect from the increment of patients treated (34%) and DDD per physician visit (33%). Residual analysis revealed that the aggregate residual for antihypertensive agents only had a 7% effect; the brand- name product had 11% increment and the generic product had a 12% decrement. It also showed that while hospital sector had a positive 11% residual, primary care clinics had an 11% decrement. Detailed analysis on each sub- group revealed that CCB had the most significant gross growth of DDDs and prescription at 117.1 and 3.4 million increments, respectively. CMS results revealed that the introduction of AIIA had the most significant impact to the clinical utilization of MIS (-5.5%) and a moderate impact to both BB (-4.5%) and ACEI (-4.1%). Whereas PMS demonstrated the most significant impact to MIS (-6.5%), a moderate impact to ACEI (-2.3%) and a very minor impact to BB (-0.9%). AIIA, however, had a positive CMS (+3.9%) and PMS (+2.4%) correlation with CCB. AIIA utilization implicated by relative growth strength for the CMS and PMS at Medical Center, Regional Hospital, District Hospital and Primary Care Clinic were 4.95 : 3.77 : 2.77 : 1 and 5.28 : 4.17 : 2.94 : 1, respectively.
Conclusion
The most important factors that contribute to the expenditure surge of antihypertensive agents are number of treated patients and DDD per physician visit. While physicians at the hospital sector adopted more new and innovative medications, their counterpart at the primary care clinics tended to switch some off- patent products to the generics. The introduction of AIIA did not affect the negative clinical utilization drift of MIS and BB since this depressing trend started before AIIA introduction. On the other hand, the preference of using CCB and AIIA to control hypertension among the physicians in Taiwan was on the ascending side. Medial center was the early leading adaptor for AIIA and furthermore played an important role in the utilization diffusion of AIIA.
論文目次 中文摘要……………………………………………………………1
英文摘要……………………………………………………………3
誌 謝……………………………………………………………5
目 錄……………………………………………………………6
表 目 錄……………………………………………………………8
圖 目 錄……………………………………………………………10
第一章 緒論
第一節 研究背景…………………………………………………12
第二節 研究目的…………………………………………………15
第三節 專有名詞縮寫表…………………………………………16
第二章 文獻探討
第一節 前言………………………………………………………18
第二節 處理高血壓之藥物經濟學分析…………………………19
第三節 高血壓藥物使用基準……………………………………22
第四節 高血壓藥物使用型態及趨勢……………………………31
第五節 影響高血壓處方型態及用藥因素之探討………………32
第三章 研究材料與方法
第一節 研究架構…………………………………………………34
第二節 研究對象及期間…………………………………………35
第三節 研究變項…………………………………………………37
第四節 研究流程…………………………………………………40
第五節 資料整理流程……………………………………………44
第六節 統計分析…………………………………………………45
第四章 以藥物經濟學理論評估台灣1997年至2002年高血壓藥物的用藥型態
第一節 前言………………………………………………………51
第二節 分析方法…………………………………………………53
第三節 研究結果…………………………………………………54
第四節 討論………………………………………………………63
第五章 當AIIA導入市場後對高血壓藥物臨床使用上之影響
第一節 前言………………………………………………………88
第二節 分析方法…………………………………………………90
第三節 研究結果…………………………………………………92
第四節 討論………………………………………………………97
第六章 綜合討論
第一節 年與季之異同……………………………………………112
第二節 高血壓藥物單獨或併服療法的處方型態………………113
第三節 高血壓用藥國內外趨勢之比較…………………………115
第四節 本研究的限制條件………………………………………117
第七章 結論………………………………………………………121
第八章 建議
第一節 對中央主管機關之建議…………………………………123
第二節 對未來研究者之建議……………………………………124
參考文獻……………………………………………………………125
投稿論文……………………………………………………………133
附錄一 門診處方及治療明細檔CD檔……………………………134
附錄二 門診處方醫令明細檔OO檔………………………………139
附錄三 醫事機構基本資料檔HOSB檔……………………………140
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系統識別號 U0007-2907200816345300
論文名稱(中文) Levodopa 與 Caffeic Acid 之藥物交互作用
論文名稱(英文) Drug Interaction of Levodopa with Caffeic Acid
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(博士班)
系所名稱(英)
學年度 96
學期 2
出版年 97
研究生(中文) 王莉萱
學號 D8801003
學位類別 博士
語文別 中文
口試日期 2008-07-07
論文頁數 195頁
口試委員 指導教授-林淑娟
委員-劉正雄
委員-陳國棟
委員-許光陽
委員-廖嘉鴻
關鍵字(中) Caffeic acid
Levodopa
藥物交互作用
藥物動力學
關鍵字(英) Caffeic acid
Levodopa
Drug-interaction
Pharmacokinetics
學科別分類
中文摘要 本研究的目的以家兔為實驗動物,同時以肌肉注射方式給與L-dopa/carbidopa及caffeic acid,以研究它們之間是否會產生交互作用。
首先,將L-dopa以肌肉注射方式投予家兔,探討L-dopa劑量依存性之藥物動力學。先以三種不同劑量的L-dopa/carbidopa (2/0.5, 5/1.25, and 10/2.5 mg•kg-1)經肌肉注射及經靜脈注射一種劑量之L-dopa/carbidopa (2/0.5 mg•kg-1),依交叉試驗方式分別投予六隻雄性兔子,在投藥後採血,取血漿樣品並以高壓液相層析儀分析L-dopa及3-O-methyldopa (L-dopa 之代謝物, 3-OMD)之濃度,再經由所得之數據決定L-dopa與3-OMD之藥物動力學之模式。由結果得知,L-dopa經肌肉注射後會被快速吸收,並於30分鐘內達到最高濃度,但3-OMD的形成則較慢,須於120-180分鐘後才達到最高點。L-Dopa經肌肉注射後之生體可用率為0.70-1.21,而3-OMD 形成之相對比率為 0.79-1.24;另於不同劑量間,L-dopa之肌肉注射生體可用率及3-OMD形成比率並不具統計上的差異。此外,L-dopa與3-OMD於排除半衰期上也不具統計上的差異;而在曲線下面積(AUC)及血漿中最高濃度值(Cmax),L-dopa與3-OMD於L-dopa/carbidopa在2/0.5-10/2.5 mg•kg-1劑量範圍內亦呈現正比增加之現象。由此可知,L-dopa與3-OMD在此劑量範圍內無劑量依存性之藥物動力學現象。
此外,對於caffeic acid 與 L-dopa 之交互作用實驗,首先將六隻家兔以交叉投予方式(crossover),分別以肌肉注射投予單一劑量之L-dopa/carbidopa (5/1.25 mg•kg-1)或caffeic acid (5 mg•kg-1),接著再同時投予 L-dopa/carbidopa (5/1.25 mg•kg-1) 與三種不同劑量之caffeic acid (分別為 2.5, 5 及10 mg•kg-1),而後採血分析血中 L-dopa、3-OMD、caffeic acid 及 ferulic acid 之濃度,並計算其相關之藥物動力學參數,結果得到當投予10 mg•kg-1的caffeic acid時,不僅3-OMD的形成會降低22%,而且3-OMD之Cmax會下降31%;此外L-dopa之代謝率(Metabolic ratio, AUC of 3-OMD/AUC of L-dopa) 也會減少22%。此結果顯示,caffeic acid可有意義的減少3-OMD之形成(p < 0.05),但L-dopa/carbidopa則對caffeic acid 及ferulic acid的藥物動力學參數則沒有影響,因此我們認為L-dopa/carbidopa與10 mg•kg-1的caffeic acid同時投予時會明顯的影響L-dopa經COMT pathway的代謝。
由於當 L-dopa/carbidopa與caffeic acid同時投藥時 L-dopa 的血中濃度雖有增加趨勢,但因變異性太大而未達到統計學上之有意義的差異,因此將 caffeic acid 提高劑量投予,評估能否增加 caffeic acid的影響。之後,再分別投予其他多酚類化合物,包括: dihydrocaffeic acid 與 catechin,評估其是否亦有交互作用的存在。將六隻家兔以交叉投予方式(crossover),分別以肌肉注射投予單一劑量之L-dopa/carbidopa (5/1.25 mg•kg-1),而後再同時投予 L-dopa/carbidopa (5/1.25 mg•kg-1) 與高劑量(50 mg•kg-1)之三種不同化合物,caffeic acid、catechin 與dihydrocaffeic acid (DHCA),而後採血分析血中 L-dopa、3-OMD 與 carbidopa 之濃度,並計算其相關之藥物動力學參數,結果得到當 L-dopa 分別與高劑量的 caffeic acid、dihydrocaffeic acid (DHCA)與 catechin併用後,所得L-dopa 之 AUC0-t、AUC0-?V 與 Cmax 皆比單獨投予 L-dopa/carbidopa 結果高,而除了與 catechin 併用所得之 Cmax 數值外,其餘皆達到統計學上有意義的差異(p < 0.05)。而三種化合物影響 L-dopa 之程度則以 DHCA 最大,其AUC0-t、AUC0-?V 與 Cmax 分別增加 64%、64% 與 68%。每次投藥後,所得3-OMD 之平均AUC0-t、AUC0-?V 與 Cmax之數值皆較單獨投予L-dopa 之數值低,然而,此差異除了與 caffeic acid併用結果外,其餘數值皆達到統計學上有意義的差異 (p < 0.05)。此外,與 catechin 併用下降程度最大,其3-OMD 之AUC0-t、AUC0-?V 與 Cmax 分別減低 65%、64% 與 64%,而且catechin 亦降低 3-OMD平均代謝比率達 76%。
由於 catechin 對L-dopa 經 COMT 途徑代謝的影響程度最大,因此進一步探討投予較低劑量的 catechin時,此影響是否仍然存在。將六隻家兔以交叉投予方式(crossover),分別以肌肉注射投予單一劑量之L-dopa/carbidopa (5/1.25 mg•kg-1),而後再同時分別投予L-dopa/carbidopa (5/1.25 mg•kg-1) 及三種劑量的catechin (10 mg•kg-1、20 mg•kg-1與50 mg•kg-1),經由採血分析血中 L-dopa、3-OMD、carbidopa 與 catechin 之濃度,並計算其相關之藥物動力學參數,結果得到當 L-dopa 分別與三種不同劑量的 catechin 同時投予後,可發現當併用時,所得L-dopa 之 AUC0-t、AUC0-?V 與 Cmax皆比單獨投予 L-dopa/carbidopa 結果高,除了同時給予 50 mg•kg-1 之catechin時所得Cmax 數值以外,其餘皆可達到統計學上有意義的差異(p < 0.05)。而以與 20 mg•kg-1 之catechin 同時投予後,其AUC0-t、AUC0-?V 與 Cmax 分別增加 78%、83% 與 82%,且其增加的程度最大。3-OMD 之AUC0-t、AUC0-?V 與 Cmax所得數值亦皆較單獨投予L-dopa 之數值低,其數值皆達到統計上之有意義的差異。除了併用 10 mg•kg-1 之catechin時所得AUC0-?V 數值以外,其餘數值皆達到統計上之有意義的差異(p < 0.05),但仍以與50 mg•kg-1 之catechin 同時投予後,其AUC0-t、AUC0-?V 與 Cmax 的分別下降程度最大。而三種劑量下降3-OMD平均代謝比率的幅度分別為56%、68% 與 76%,其影響程度與catechin劑量有關。
綜合以上實驗結果可知,若巴金氏症病患在服用 L-dopa 時,也併服含有多酚類 (polyphenols, 包括: caffeic acid、DHCA 或 catechin) 之飲料或水果 (如: 綠茶飲料、咖啡或奇異果等),有可能由於多酚類化合物抑制 COMT 的作用,因此增加 L-dopa 之可用率及降低 3-OMD 之生成,相對也增加 L-dopa 之治療效果。
英文摘要 The purpose of this study was to investigate the drug interaction between caffeic acid and L-dopa. Both caffeic acid and L-dopa/carbidopa were simultaneously administered to rabbits via an intramuscular (IM) injection.
First, the dose-dependent pharmacokinetics of levodopa (L-dopa) was studied in rabbits via an intramuscular administration. Three different doses of L-dopa/carbidopa (2/0.5, 5/1.25, and 10/2.5 mg•kg-1) were administered to six male rabbits via an IM route, and one dose of L-dopa/carbidopa (2/0.5 mg•kg-1) was administered via an intravenous (IV) route with a washout period of 1-week between different doses in a crossover treatment protocol. Plasma samples were collected after each treatment and the concentrations of L-dopa and 3-O-methyldopa (an L-dopa metabolite, 3-OMD) were measured by a sensitive high-performance liquid chromatographic (HPLC) method. Subsequently, these measurements were used to determine the pharmacokinetic behavior of L-dopa and 3-OMD. The results indicated that the absorption of L-dopa was fast with the time to the peak within 30 min, but the formation of 3-OMD was slow with the time to the peak of 120-180 min after IM administration. The IM bioavailability of L-dopa was in the range of 0.70-1.21, and the relative ratios of the formation of 3-OMD at different doses of L-dopa were in the range of 0.79-1.24. No statistically significant difference could be observed for IM bioavailability of L-dopa or for the relative ratios of the formation of 3-OMD in this dose range. The elimination half-lives of L-dopa and 3-OMD also exhibited no significant differences for each dose after IM administration. In addition, both the area under the curve (AUC) and maximum plasma concentration (Cmax) values of L-dopa and 3-OMD increased proportionally over the dose range of 2/0.5–10/2.5 mg•kg-1 for L-dopa/carbidopa, suggesting that L-dopa and 3-OMD obeyed dose-independent pharmacokinetics.
The impacts of caffeic acid on the pharmacokinetics of L-dopa were studied in rabbits. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or was co-administered with three different doses of caffeic acid (2.5, 5, and 10 mg•kg-1), or a single dose of 5 mg•kg-1 caffeic acid was administered alone via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-O-methyldopa (3-OMD), caffeic acid, and ferulic acid were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that caffeic acid administered at a dose of 10 mg•kg-1 decreased about 22% of the peripheral formation of 3-OMD and about 31% of the Cmax of 3-OMD. In addition, the metabolic ratios (MR, AUC of 3-OMD/AUC of L-dopa) decreased by about 22%. Results also indicated that caffeic acid significantly decreased the proportion of 3-OMD (p < 0.05). In contrast, the parameters of neither caffeic acid nor ferulic acid were significantly affected by L-dopa/carbidopa. In conclusion, caffeic acid at a dose of 10 mg•kg-1 can significantly affect the COMT metabolic pathway of L-dopa.
When L-dopa/carbidopa and caffeic acid were simultaneously administered, plasma level of L-dopa was increased. Due to large variance, the value did not show statistically significant differences. Therefore, to evaluate the effect of caffeic acid in higher dose with L-dopa, the investigation was carried out. In addition, L-dopa/carbidopa was simultaneously administered with other polyphenols including dihydrocaffeic acid and catechin to evaluate the drug interactions between L-dopa and dihydrocaffeic acid or catechin. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or L-dopa/carbidopa was co-administered with high dose (50 mg•kg-1) of three different compounds including caffeic acid, dihydrocaffeic acid (DHCA) and catechin via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-O-methyldopa (3-OMD), and carbidopa were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that AUC0-t, AUC0-?V and Cmax values of L-dopa were more than the values of L-dopa after administered L-dopa alone. These data were all show statistically significant differences (p < 0.05) except the Cmax values of L-dopa for co-administered with catechin. DHCA affected L-dopa availability the most among these compounds. The AUC0-t, AUC0-?V and Cmax values of L-dopa were all increased 64%, 64% and 68%, respectively. After all treatments, AUC0-t, AUC0-?V and Cmax values of 3-OMD were less than the values of 3-OMD after administered L-dopa alone. These difference were all show statistically significant differences (p < 0.05) except the AUC0-t, AUC0-?V and Cmax values of 3-OMD for co-administered with caffeic acid. Catechin affected 3-OMD data the most among these compounds. The AUC0-t , AUC0-?V and Cmax values of 3-OMD were all decreased 65%, 64% and 64%, respectively. Besides, catechin reduced metabolic ratio of 3-OMD to 76%.
Because catechin affects L-dopa metabolism by COMT pathway the most among these compounds, it intrigues us to advance investigation whether still exists drug interaction between the lower dose of catechin and L-dopa. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or L-dopa/carbidopa was co-administered with three different doses of catechin (10, 20, and 50 mg•kg-1) via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-OMD, carbidopa and catechin were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that L-dopa was co-administered with three different doses, AUC0-t , AUC0-?V and Cmax values of L-dopa were more than the values of L-dopa after administered L-dopa alone. These data were show statistically significant differences (p < 0.05) except the Cmax values of L-dopa for co-administered with catechin (50 mg•kg-1). Catechin (20 mg•kg-1) affected L-dopa availability the most among these compounds. The AUC0-t , AUC0-?V and Cmax values of L-dopa were increased 78%, 83% and 82%, respectively. After all treatments, AUC0-t, AUC0-?V and Cmax values of 3-OMD were less than the values of 3-OMD after administered L-dopa alone. These differences all were show statistically significant differences (p < 0.05). 50 mg•kg-1 of catechin affected 3-OMD data the most among these doses. After co-administered with 10, 20 and 50 mg•kg-1 of catechin, the metabolic ratio mean of 3-OMD was decreased 56%, 68% and 76%, respectively. The effects were dependent on catechin doses.
From the above studies, we inferred that PD patients simultaneously received L-dopa and beverage or fruits containing polyphenols, the polyphenols would inhibit L-dopa metabolism by COMT pathway. Therefore, polyphenols would enhance L-dopa bioavailability and reduce 3-OMD formation, and then increased L-dopa response for PD treatment.
論文目次 目錄
Figures…………………………………………………………………... v
Tables……………………………………………………………………. xiv
中文摘要………………………………………………………………… xxv
英文摘要……………………………………………………………….... xxix
壹. 緒論…………………………………………………………………. 1
貳. 實驗材料與方法……………………………………………………. 19
一. 試藥與材料…………………………………………………… 19
二. 儀器…………………………………………………………… 20
三. 試藥配製……………………………………………………… 21
1. Caffeic acid (CA) 溶液之配製…………………………… 21
2. Ferulic acid (FA) 溶液之配製…………………………… 21
3. Isoferulic acid (IFA) 溶液之配製………………………… 21
4. L-Dopa 溶液之配製………………………………………. 21
5. Carbidopa 溶液之配製(LC/MS/MS 分析)……………… 22
6. 3-O-Methyldopa (3-OMD) 溶液之配製.......................... 22
7. Acebutolol 溶液之配製(HPLC 同時分析CA、FA 及
IFA 時所使用之內標化合物)…………………………….. 23
8. Trifluoroacetic acid (TFA) 溶液之配製........................... 23
9. Nicotinuric acid 溶液之配製(LC/MS/MS 同時分析
L-dopa 及3-OMD 時所使用之內標化合物)…………... 23
四. 分析條件………………………………………………………. 25
1. HPLC 同時定量血漿中caffeic acid, ferulic acid 與
isoferulic acid 濃度的分析條件..………………………... 25
2. HPLC 同時定量血漿中L-dopa 與3-O-methyldopa
(3-OMD)濃度的分析條..…..……………………………… 25
3. LC/MS/MS 同時定量血漿中L-dopa、3-O-methyldopa
(3-OMD)與carbidopa 濃度的分析條件......................... 26
五. 檢品的製備方法(Sample Preparation) …………………… 34
ii
1. Caffeic acid, ferulic acid 與isoferulic acid 血漿檢品........ 34
2. L-Dopa 與3-O-methyldopa (3-OMD) 血漿檢品............. 34
六. 動物試驗…………………………..…………………………... 35
1. 試驗動物選擇……………………………………………... 35
2. 試驗所需用具的準備……………………………………... 35
3. Caffeic acid (7.5 mg/mL、15 mg/mL、30 mg/mL 與
150 mg/mL) 試驗溶液之配備…………………………… 35
4. L-Dopa/carbidopa (二者以4:1 之比例製備,6/1.5
mg/mL, 15/3.75 mg/mL 與30/7.5 mg/mL) 試驗溶液
之配備……………………………………………………… 35
5. (+)-Catechin (150 mg/mL) 試驗溶液之配備……………. 35
6. Dihydrocaffeic acid (150 mg/mL) 試驗溶液之配備……. 36
7. 靜脈注射給藥(Intravenous injection, IV)……………… 36
8. 肌肉注射給藥(Intramuscular injection, IM)…………… 36
七. 實驗數據之處理.................................................................. 37
1. 藥物動力學參數的計算…………………………………... 37
2. 統計分析…………………………..………………………. 38
參. 結果與討論…………………………..……………………………... 39
一. HPLC同時分析血液中caffeic acid、ferulic acid 與isoferulic
acid 分析方法之確效………………………………………… 39
1. 檢體製備………………………….. ……………………… 39
2. 標準曲線(calibration curve) 與線性(linearity)………. 40
3. 精密度(precision) 與準確度(accuracy)……………… 40
4. 最低可定量濃度(lower limitation of quantification,
LLOQ) …………………………………………………….. 41
5. 回收率(recovery) ……………………………………….. 41
6. 冰凍與解凍之安定性(freeze and thaw stability)……… 45
7. 檢體製備後安定性(post-preparation stability)………... 45
二. HPLC 同時分析血液中L-dopa 與3-O-methyldopa 分析方
法…………………………..………………………………...... 48
iii
1. 檢體製備………………………….. ……………………… 48
2. 標準曲線(calibration curve) 與線性(linearity)………. 49
3. 精密度(precision) 與準確度(accuracy)……………… 49
4. 最低可定量濃度(lower limitation of quantification,
LLOQ) …………………………..………………………… 50
5. 回收率(recovery) ……………………………………….. 50
三. LC/MS/MS 同時分析血液中L-dopa、3-O-methyldopa 與
carbidopa 分析方法………………………………………….. 54
1. 檢體製備………………………….. ……………………… 54
2. 標準曲線(calibration curve) 與線性(linearity)………. 55
3. 精密度(precision) 與準確度(accuracy)……………… 55
4. 最低可定量濃度(lower limitation of quantification,
LLOQ) …………………………..………………………… 56
四. L-Dopa/carbidopa 單一劑量(2/0.5 mg·kg-1) 靜脈投予家兔
與以不同劑量之L-dopa/carbidopa (2/0.5、5/1.25 及10/2.5
mg·kg-1) 以肌肉注射投予家兔之藥物動力學及生體可用率
研究……………………………………………………………. 59
1. 家兔血漿中L-dopa 濃度所得的藥物動力學參數.......... 59
2. 家兔血漿中3-OMD 濃度所得的藥物動力學參數.......... 60
五. L-Dopa/carbidopa 單一劑量(5/1.25 mg·kg-1)、caffeic acid
單一劑量(5 mg·kg-1) 及L-dopa/carbidopa (5/1.25
mg·kg-1) 與不同劑量caffeic acid (2.5、5 與10 mg·kg-1)
同時肌肉注射家兔之藥物動力學及藥物交互作用之影響…. 74
1. 家兔血漿中L-dopa 濃度所得的藥物動力學參數.......... 74
2. 家兔血漿中3-OMD 濃度所得的藥物動力學參數.......... 75
3. 家兔血漿中caffeic acid 與ferulic acid 濃度所得的藥
物動力學參數.............................................................. 76
4. 家兔血漿中3-OMD/L-dopa 與ferulic acid/caffeic acid
之代謝比率(metabolic ratio) 的探討………………….. 77
六. Caffeic acid 單一劑量(10 mg·kg-1) 肌肉注射投予家兔
iv
後,caffeic acid 之藥物動力學及其代謝之研究.................... 105
1. 家兔血漿中caffeic acid、ferulic acid 與isoferulic acid
濃度所得的藥物動力學參數……………………………… 107
2. 家兔血漿中ferulic acid 與isoferulic acid 的代謝比率
(metabolic ratio) 的探討…………………………………. 107
七. L-Dopa/carbidopa (5/1.25 mg·kg-1)分別與高劑量(50
mg·kg-1) 的caffeic acid、dihydrocaffeic acid (DHCA) 或
catechin 同時肌肉注射家兔之藥物動力學及藥物交互作用
之影響…………………………..…………………………….. 115
1. 家兔血漿中L-dopa濃度所得的藥物動力學參數............ 115
2. 家兔血漿中3-OMD 濃度所得的藥物動力學參數........... 116
3. 家兔血漿中carbidopa 濃度所得的藥物動力學參數........ 117
4. 家兔血漿中3-OMD/L-dopa 之代謝比率(metabolic
ratio) 的探討…………………………..………………….. 118
八. L-Dopa/carbidopa (5/1.25 mg·kg-1) 與不同劑量catechin
(10, 20 與50 mg·kg-1) 同時肌肉注射家兔之藥物動力學及
藥物交互作用之影響…………………………………………. 140
1. 家兔血漿中L-dopa 濃度所得的藥物動力學參數........... 140
2. 家兔血漿中3-OMD 濃度所得的藥物動力學參數........... 141
3. 家兔血漿中carbidopa 濃度所得的藥物動力學參數........ 142
4. 家兔血漿中catechin 濃度所得的藥物動力學參數........... 143
5. 家兔血漿中3-OMD/L-dopa 之代謝比率(metabolic
ratio) 的探討................................................................. 144
肆. 結論........................................................................................... 174
伍. 參考文獻....................................................................................
陸. 發表論文....................................................................................
178
195
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系統識別號 U0007-2907200819361900
論文名稱(中文) 以台灣全民健保資料庫分析門診新癲癇個案診斷率與藥物處方趨勢
論文名稱(英文) Newly-Diagnosed Rates of Epilepsy and Trends of Antiepileptic Drug Prescribing Pattern in Outpatient Setting in Taiwan
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 96
學期 2
出版年 97
研究生(中文) 姜采玲
學號 M301095021
學位類別 碩士
語文別 中文
口試日期 2008-07-04
論文頁數 140頁
口試委員 委員-高雅慧
委員-薛玉梅
指導教授-簡淑真
關鍵字(中) 癲癇
新診斷病人
抗癲癇藥物處方趨勢
健保資料庫
關鍵字(英) Epilepsy
newly diagnosed patients
antiepileptic drugs prescribing pattern
National Health Insurance Research Database
學科別分類
中文摘要 研究目的: 研究台灣2002年至2005年門診新癲癇個案診斷率及抗癲癇藥物使用趨勢。
研究方法: 以台灣國家衛生研究院所提供的健保資料庫歸人檔(200,432人, 約1%台閩人口)及基本資料檔作為研究材料。擷取診斷碼為345.xx之新診斷病人以估算2002年至2005年新癲癇個案診斷率,並估算每年新診斷病人於初診斷時各種抗癲癇藥物及各種藥物組合的處方率,進而評估2002年至2005年初診斷抗癲癇藥物使用趨勢。追蹤2002年新發生並於初診斷開始用藥病人,估算從2002年至2005年各種抗癲癇藥物及各種藥物組合的處方率並評估藥物使用趨勢、估算自初診斷至停藥的中位時間;針對2002年新診斷但未於初診斷用藥的病人,於2005年12月31日前有用藥者,估算第一次用藥的中位時間。
研究結果: 新癲癇個案診斷率自2002年的131.8/每十萬人年降至2005年的110.0/每十萬人年。大於等於65歲的族群發生率最高,46至64歲的族群次之,19至45歲的族群最低;整體而言,男性高於女性。每年約有50%新診斷病人於初診斷時即開始用藥,多以傳統型抗癲癇藥物為優先選擇(開立率>90%),且以單方使用為主;傳統抗癲癇藥物的使用趨勢逐年遞減(p<0.05)、新型抗癲癇藥物逐年遞增(p<0.05)。從2002年至2004年,phenytoin、carbamazepine和 valproic acid是最常於初診斷時開立;但至2005年clonazepam則取代carbamazepine成為最優先使用之前三項藥物之ㄧ;clonazepam的處方趨勢往上(p<0.05)、carbamazepine則是往下(p<0.05)。追蹤用藥的型態中,4年來仍是以單方傳統抗癲癇藥物的使用為主,其中以phenytoin、carbamazepine和valproic acid為最常開立的藥物;各種成分及處方的使用趨勢皆無統計上的顯著性。32.4%新診斷病人在被診斷為癲癇之後至少3年仍未使用抗癲癇藥物,而在初診斷未用藥病人中,於觀察期間有用藥者,半數於4.5個月開始用藥(95% 信賴區間為0.0-14.7個月)。新診斷且在初診斷開始用藥者,半數於6.8個月後停藥(95% 信賴區間為2.2-11.3個月),16.8%的病人會持續使用藥物至少達3年。
結論: 新癲癇個案診斷率約為104.6~133.9/每十萬人年。雖然傳統抗癲癇藥物的使用趨勢逐年遞減、新型抗癲癇藥物逐年遞增,但是多以單方傳統型抗癲癇藥物為優先選擇,新型抗癲癇藥物多以輔助性的方式給予。在初診斷未用藥病人中,於觀察期間有用藥者,半數於4.5個月開始用藥。新診斷且在初診斷開始用藥者,半數的病人約於7個月後停藥。
英文摘要 Objective: To estimate the newly-diagnosed rates of epilepsy in outpatient setting from 2002 to 2005 in Taiwan. The trends of initial and followup antiepileptic drugs (AEDs) prescribing pattern were also evaluated.
Method: Data set of a randomly sampled cohort with 200,432 people from the registry for beneficiaries in Taiwan, about 1% of the population, was provided by the National Health Research Institutes. The data set consisted of outpatient and inpatient visit, diagnosis, and prescription drug records. Newly-diagnosed epilepsy patients were identified by the ICD-9-CM diagnostic criteria 345.xx coding. The newly-diagnosed rates of epilepsy were estimated and adjusted by coverage rate (about 97.0%). The trends of AEDs prescribing pattern of newly-diagnosed patients each year from 2002 to 2005 were evaluated and compared if they also were prescribed AED in the same visit. In addition, the newly-diagnosed patients in 2002 were followed as a fixed cohort to evaluate the trends of AEDs prescribing pattern over time. The median time of initiation and withdrawing AEDs therapy of this fixed cohort were evaluated as well.
Result: The newly-diagnosed rates of epilepsy decreased gradually from 131.8 per 100,000 person-years in 2002 to 110.0 per 100,000 person-years in 2005. The highest age-specific newly-diagnosed rate was found in the group aged 65 years or older and the lowest in the group aged 19 to 45 years. Overall, the male patients had higher rate of diagnosis than the female patients. Each year, between 47.5% and 56.0% of newly-diagnosed patients were prescribed AEDs at first visit. Contrary to the downward trend found in the prescribing pattern of conventional AEDs (p< 0.05), there was a significant increase in prescribing newer AEDs in these new cases of epilepsy (p< 0.05). However, there were more than 90% of the newly-diagnosed patients prescribed with conventional AEDs as monotherapy at first visit in 2005. The top three prescribed AEDs consistently included phenytoin, carbamazepine and valproic acid from 2002 to 2004, whereas carbamazepine was replaced by clonazepam in the top three list in 2005. The trend of clonazepam prescribing pattern increased (p< 0.05), whereas the trend of carbamazepine prescribing pattern decreased (p< 0.05). Concerning the newly-diagnosed patients in 2002, conventional AEDs as monotherapy was most prescribed. The top three prescribed AEDs consistently included phenytoin, carbamazepine and valproic acid from 2002 to 2005. The median time to start AEDs therapy was 4.5 (95% CI=0.0-14.7) months. The median time of withdrawing AEDs therapy was 6.8 (95% CI=2.2-11.3) months.
Conclusion: The newly-diagnosed rates of epilepsy patients were in the range of 104.6 to 133.9 per 100,000 person-years. At first visit, the trend of conventional AEDs prescribing pattern decreased while the trend of newer AEDs prescribing pattern increased. However, conventional AEDs as monotherapy was prescribed most frequently from 2002 to 2005. The median time of starting AEDs therapy was 4.5 months. The median time of withdrawing AEDs therapy was about 7 months.
論文目次 致謝………………………………………………………………….. I
中文摘要…………………………………………………………….. II
英文摘要…………………………………………………………….. IV
內容目錄…………………………………………………………….. VI
表目錄………………………………………………………………. VIII
圖目錄………………………………………………………………. XI
第一章 前言………………………………………………………… 1
第二章 文獻回顧…………………………………………………… 3
第一節 名詞解釋………………………………………………… 3
第二節 分類……………………………………………………… 5
第三節 癲癇流行病學…………………………………………… 8
第四節 癲癇機轉及病因學……………………………………… 10
第五節 癲癇診斷及評估………………………………………… 13
第六節 癲癇治療………………………………………………… 15
第七節 抗癲癇藥物治療………………………………………… 16
第八節 以automated database之抗癲癇藥物使用研究………… 35
第九節 台灣全民健康保險研究資料庫簡介…………………… 47
第三章 研究目的…………………………………………………… 49
第四章 研究方法…………………………………………………… 50
第一節 研究設計………………………………………………… 50
第二節 研究對象………………………………………………… 50
第三節 研究參數定義…………………………………………… 51
第四節 研究資料收集…………………………………………… 52
第五節 統計分析………………………………………………… 57
第五章 研究結果…………………………………………………… 58
第一節 新診斷率………………………………………………… 58
第二節 初診斷用藥率、藥物使用處方率及趨勢……………… 63
第三節 2002年新發生癲癇病人追蹤…………………………… 110
第六章 討論……………………………………………………….. 124
第一節 新診斷率………………………………………………… 124
第二節 初診斷用藥率、藥物使用處方率及趨勢……………… 126
第三節 2002年新發生癲癇病人追蹤…………………………… 129
第七章 研究限制…………………………………………………… 133
第八章 結論………………………………………………………… 134
第九章 未來展望………………………………………………….. 135
第十章 參考文獻…………………………………………………… 136

表目錄
表2-1 局部發作……………………………………………………... 6
表2-2 癲癇或癲癇發作病因(依年齡分)…………………………… 12
表2-3 台灣抗癲癇藥物的健保給付日期…………………………... 18
表2-4 抗癲癇藥物機轉……………………………………………... 19
表2-5 抗癲癇藥物對各種癲癇發作之臨床療效…………………... 21
表2-6 抗癲癇藥物的重要藥物動力學性質………………………... 24
表2-7 抗癲癇藥物和相關cytochrome P450 isoenzyme的關係…… 25
表2-8 抗癲癇藥物之間有臨床意義的交互作用…………………... 27
表2-9 初診斷藥物選擇建議(成人)………………………………… 30
表2-10 初診斷藥物選擇建議(孩童和青少年)……………………… 31
表2-11 Refractory epilepsy之新型AEDs藥物選擇建議…………… 32
表2-12 接受治療的癲癇病患之盛行率和發生率的研究-英國…….. 36
表2-13 以抗癲癇藥物的使用進行癲癇盛行和發生的研究-荷蘭...... 37
表2-14 抗癲癇藥物使用情形的研究-傳統和新型AEDs-義大利...... 39
表2-15 抗癲癇藥物使用情形的研究-傳統和新型AEDs-英國…...... 40
表2-16 抗癲癇藥物使用情形的橫斷面研究-丹麥……….................. 41
表2-17 抗癲癇藥物使用情形的縱貫性研究-丹麥……..…………… 42
表2-18 台灣癲癇盛行率和抗癲癇藥物使用的研究………………... 43
表2-19 以automated database之抗癲癇藥物使用研究比較表 -盛行個案…………………………………………………….. 45
表2-20 以automated database之抗癲癇藥物使用研究比較表 -新發生個案………………………………………………….. 46
表2-21 台灣全民健康保險研究資料庫之優缺點…………………... 48
表5-1 新診斷率…………………….……………………………….. 59
表5-2 詳細診斷碼的人數分佈…..…………………………………. 59
表5-3 新診斷率-不分組和性別分組…………….............................. 60
表5-4 新診斷率-不分組和年齡分組…………….............................. 61
表5-5 初診斷用藥率………………………………………………... 63
表5-6 初診斷用藥率-性別分組…………………………………….. 64
表5-7 初診斷用藥率-年齡分組…………………………………….. 65
表5-8 初診斷用藥率-醫療層級分組……………………………….. 66
表5-9 初診斷用藥率-地區分組…………………………………….. 67
表5-10 初診斷用藥率-科別分組…………………………………….. 68
表5-11 初診斷藥品成分處方率……………………………………... 71
表5-12 傳統AEDs初診斷處方率-性別分組....................................... 73
表5-13 傳統AEDs初診斷處方率-年齡分組....................................... 74
表5-14 傳統AEDs初診斷處方率-醫療層級分組………………...... 76
表5-15 新型AEDs初診斷處方率-醫療層級分組………………….. 78
表5-16 傳統AEDs初診斷處方率-地區分組...................................... 80
表5-17 新型AEDs初診斷處方率-地區分組....................................... 83
表5-18 傳統AEDs初診斷處方率-科別分組....................................... 85
表5-19 不分組及次分組初診斷藥品成分使用趨勢關係表………... 88
表5-20 初診斷藥物組合型態處方率………………………………... 89
表5-21 初診斷藥物組合型態處方率-性別分組…………………….. 91
表5-22 初診斷藥物組合型態處方率-年齡分組…………………….. 92
表5-23 初診斷藥物組合型態處方率-醫療層級分組……………….. 94
表5-24 初診斷藥物組合型態處方率-地區分組…………………….. 96
表5-25 初診斷常見藥物組合處方率………………………………... 99
表5-26 初診斷常見藥物組合處方率-性別分組…………………….. 101
表5-27 初診斷常見藥物組合處方率-年齡分組………...................... 103
表5-28 初診斷常見藥物組合處方率-醫療層級分組……………….. 105
表5-29 初診斷常見藥物組合處方率-科別分組…………………….. 107
表5-30 不分組及次分組之初診斷藥物組合型態及常見藥物組合使用趨勢關係表……………………………………………... 109
表5-31 用藥追蹤:藥品成分處方率……............................................ 112
表5-32 用藥追蹤:藥物組合型態處方率……………………............ 114
表5-33 用藥追蹤:常見藥物組合處方率……………….................... 116
表5-34 何時停藥-性別分組………………………………………….. 119
表5-35 何時停藥-年齡分組………………………………………….. 120
表5-36 何時開始用藥-性別分組…………………………………….. 122
表5-37 何時開始用藥-年齡分組…………………………………….. 123
表6-1 癲癇發生率/新診斷率.............................................................. 125
表6-2 新使用AEDs病人之處方趨勢............................................... 128

圖目錄
圖2-1 癲癇診斷及評估…………………………………………... 14
圖2-2 抗癲癇藥物發展時間序…………………………………... 17
圖4-1 新診斷率、初診斷用藥之資料處理流程圖……………… 55
圖4-2 2002新診斷癲癇病人追蹤之資料處理流程圖………….. 56
圖5-1 新診斷率-不分組和性別分組…………………………….. 60
圖5-2 新診斷率-年齡分組……………………………………….. 62
圖5-3 2002年新發生癲癇病人追蹤…………………………….. 110
圖5-4 何時停藥…………………………………………………... 118
圖5-5 何時停藥-性別分組……………………………………….. 119
圖5-6 何時停藥-年齡分組……………………………………….. 120
圖5-7 何時開始用藥……………………………………………... 121
圖5-8 何時開始用藥-性別分組………………………………….. 122
圖5-9 何時開始用藥-年齡分組………………………………….. 123
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50. Commission on Antiepileptic Drugs, International League Against Epilepsy. Guidelines for thrapeutic monitoring on antiepileptic drugs. Epilepsia. 1993; 34(4): 585-7
51. Patsalos PN, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008 Apr 3. (Epub ahead of print)
52. Berg AT, et al. Relapse following discontinuation of antiepileptic drugs-a meta-analysis. Neurology. 1994; 44: 601-608
53. Britton JW. Antiepileptic drug withdrawal: literature review. Mayo Clin Proc. 2002; 77(12): 1378-88
54. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet. 1991; 337(8751): 1175-80
55. Sirven JI, Sperling M and Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database Syst Rev. 2001(3): CD001902
56. Report of the Quality Standards Subcommittee of the American Academy of Neurology. A guideline for discontinuing antiepileptic drugs in seizure-free patients-summary statement. Neurology. 1996; 47: 600-2
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58. Wallace H, Shorvon S and Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet. 1998; 352(9145): 1970-3
59. Shackleton DP et al. Dispensing epilepsy medication: a method of determining the frequency of symptomatic individuals with seizures. J Clin Epidemiol. 1997; 50(9): 1061-8
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62. Hsiao FU, et al. Using Taiwan’s National Health Insurance Research Databases for Pharmacoepidemiology Research. Journal of Food and Drug Analysis. 2007; 15: 99-108
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系統識別號 U0007-3007200909060100
論文名稱(中文) 肺結核用藥異常檢核決策支援系統
論文名稱(英文) A Decision Support System for Screening Prescription Errors in Treatment for Pulmonary Tuberculosis
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 97
學期 2
出版年 98
研究生(中文) 劉宇倫
學號 G158094006
學位類別 碩士
語文別 中文
口試日期 2009-06-20
論文頁數 91頁
口試委員 指導教授-徐建業
共同指導教授-邱泓文
委員-莊人祥
委員-張博論
委員-施崇鴻
關鍵字(中) 結核病
藥物處方
知識工程
臨床指引
決策支援系統
關鍵字(英) tuberculosis
prescription
medication
knowledge engineering
clinical practice guideline
decision support system
學科別分類
中文摘要 疾病管制局在幾次抽查結核病用藥處方的計畫中,發現不正確或是不依循現行結核病治療指引處方的比例並不低,因結核病治療指引內容較為複雜,衛生所公衛護士或是結核病承辦人在評估處方的適切性時,亦不易僅靠閱讀指引即可完成。緣此,本研究目的在依用藥指引建立一結核病用藥處方異常之電腦決策支援系統,以方便查核工作的進行。

在本研究中,我們採用疾管局於2008年出版之結核病診治指引第三版,開發了一個針對公衛人員進行處方異常查核使用之Web-based的決策支援系統。透過知識工程的方法,先將標準化的處方指引,轉化成決策表及IF-THEN邏輯,同時設計一輸入介面以便取得分析所需參數,輸入完畢,使用者即可取得決策支援系統的處方異常分析結果。系統也內含一警示模組,可將嚴重錯誤的處方即時回報給相關人員。

我們使用18本特意挑選之健保抽審後疑似有問題之住院病例,共62個處方以評估系統的表現,合計開立200種不同的藥。本系統找出48%的藥物組合、21%的藥物劑量及6%的藥物頻次的異常,其中,藥物組合檢核的敏感度為0.93,特異度為0.59;藥物劑量檢核的敏感度為0.95,特異度為0.91,藥物頻次的檢核的敏感度為1.00,特異度為0.98。
因本用藥查核系統具有高敏感度,對結核病防治公衛人員在進行處方異常查核工作將是一有用的輔助工具,而藥物組合檢核特異度偏低的情形,因所選擇抽樣病歷之處方多於特殊情況時開立,將可在補足特殊情況使用之開藥規則後改善。本決策系統著眼於處方異常的查核,並希望經由本系統減少非標準的處方,能達到增加結核病的治癒率,並提昇病人安全。
英文摘要 High prevalence of prescription errors in treatment of pulmonary tuberculosis (TB) in Taiwan has been reported in previous studies. Due to the complexity of treatment guideline for TB, frontline health workers for TB control often find difficulties in determining the appropriateness of anti-TB regimens. The aim of this study was to build a guideline-based computerized decision support system (DSS) for screening prescription errors in anti-TB regimens.

To facilitate the screening work for prescription errors, we’ve created a web-based DSS implementing the paper-based “Taiwan Guidelines for TB Diagnosis & Treatment, 3rd edition”. By means of knowledge engineering, standardized prescription guidelines were transformed into computerized decision table and if-then rules. An ease-to-use user interface was designed for collecting required parameters. With a single click, users are allowed to obtain the analytic results by the DSS immediately. An alert module for reporting severe or harmful errors to relevant medical officers was also embedded.

For system performance test, we used 62 regimens with 200 different drugs prescribed from 18 pre-selected in-patient medical charts. This DSS detected errors in 48% of drug combination, 21% in dosages and 6% in frequencies. Sensitivity and specificity were, respectively, 0.93 and 0.59 in combination check, 0.95 and 0.91 in dosage check, and 1.00 and 0.98 in frequency check.

With the characteristics of high sensitivity of this DSS, frontline health workers for TB control may find it useful as a screening tool for anti-TB prescription errors. The low specificity in drug combination check can be improved after amending rules used in special considerations. Aside from the purpose of surveillance for non-standardized prescriptions, this system may have the potential for increasing TB treatment success rate and improving patient safety by improving the compliance to TB treatment guidelines.
論文目次 第一章 緒論
1.1 台灣結核病流行現況 1
1.2 台灣結核病處方異常現況 1
1.3 研究目的及主要目標 2
第二章 文獻查證
2.1 用藥錯誤之分類 3
2.2 知識工程 3
2.2.1 知識分類 4
2.2.2 以知識分基礎的系統 4
2.2.3 專家系統的組成 5
2.3 決策支援系統 5
2.4 決策支援系統 6
第三章 研究材料與方法
3.1 系統開發環境 8
3.1.1 系統介面程式 8
3.1.2 後端分析程式 8
3.2 系統檢核資料來源 8
3.3 系統架構 14
3.3.1 知識工程 14
3.3.1.1 用藥組合知識 14
3.3.1.2 用藥劑量知識 34
3.3.1.3 用藥頻次知識 44
3.3.1.4 程式開發過程知識 46
3.3.2 系統運作流程 47
3.3.3 結核病用藥查核輔助系統 47
3.3.3.1 事實庫與知識庫 47
3.3.3.2 推論引擎 47
3.3.4 系統功能與介面 55
3.3.4.1 基本資料 56
3.3.4.2 就診表單 58
3.3.4.3 就診歷程分析 58
3.3.4.4 修正功能 60
3.3.4.5 二線用藥病患查(含SM)及異常用藥快速查詢清單 60
3.3.4.6 E-mail 警示 72
第四章 分析與結果
4.1 中央傳染病追蹤管理系統串接評估測試 73
4.1.1 轉檔方法 73
4.2 中央傳染病追蹤管理系統TB用藥組合評估 77
4.2.1 快速列表清單的統計 79
4.2.2 知識庫藥物組合規則分析 79

第五章 討論
5.1 臨床指引使用的困難與改善方式 85
5.2 研究進行方式 85
5.3 系統評估討論 86
5.4 電子病歷整合 87
5.5 系統限制 87
第六章 結論與建議
6.1 結論結論 88
6.2 研究建議 88
參考資料
中文文獻 89
英文文獻 89
電子資料 91

表1、病患基本資訊表單資料欄位 9
表2、病患用藥組合表單資料欄位 9
表3、藥物感受性試驗表單資料欄位 11
表4、藥物副作用表單資料欄位 11
表5、相關醫事檢查表單資料欄位 12
表6、中央傳染病追蹤管理系統系統總紀錄表 77
表7、中央傳染病追蹤管理系統系統無用藥日誌紀錄 77
表8、中央傳染病追蹤管理系統系統有用藥日誌紀錄 77
表9、各項有用藥日誌紀錄快進選單統計表 78
表10、開藥紀錄與有無藥敏結果統計表 79
表11、藥物服用頻率異常偵測敏感度及特異度分析 82
表12、藥物劑量異常偵測敏感度及特異度分析 82
表13、藥物組合異常偵測敏感度及特異度分析 83

圖1、系統架構圖 14
圖2、決策表範例圖 29
圖3、藥物劑量及頻次知識整理範例 35
圖4、結核病治療用藥查核輔助系統運作意示圖 47
圖5、系統程式流程圖圖 47
圖6、TB就診手冊 55
圖7、中央傳染病監視系統表單輸入畫面 56
圖8、結核病患用藥查核輔助系統功能 56
圖9、系統帳號登錄畫面 57
圖10、基本資料參數輸入介面 57
圖11、就診資料參數輸入介面 58
圖12、藥物組合檢核結果 59
圖13、藥物劑量、頻次檢核結果 59
圖14、修正檢核參數介面 60
圖15、本系統使用到「中央傳染病監視系統資料庫」之資料表欄位關聯圖 61
圖16、二線藥物使用情況快速統計功能 63
圖17、二線藥物使用統計圖 64
圖18、在案非多重抗藥性結核病人使用二線藥物列表 65
圖19、同類藥物併用之病人列表 66
圖20、PAS及CS併用之病人列表 67
圖21、Levofloxacin及moxifloxacin併用之病人列表 68
圖22、Rifater及rifinah併用之病人列表 69
圖23、新病人但未使用一線藥物之病人列表 70
圖24、新病人使用二線藥fluoroquinolone之病人列表 71
圖25、用藥劑量填寫情況查核選單 72
圖26、E-mail警示功能 72
圖27、用藥記錄與藥敏報告藥物品項關聯圖 74
圖28、藥物組合異常(不考慮藥物敏感紀錄) 80
圖29、藥物組合異常(考慮藥物敏感紀錄) 81
參考文獻 中文文獻

1. 陸坤泰等,結核病診治指引 第三版,台北:衛生署疾病管制局,民97.5。
英文文獻
2. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd ed. World Health Organization Document 2003;WHO/CDS/TB/2003.313:1-108.
3. American Thoracic Society, Centers for Disease Control and Prevention, Infectious Disease Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62.
4. Morris, Decision support and safety of clinical environment. Qual. Saf. Health Care 2002;11;69-75
5. Uchiyma Y, Mao TE, Okada K, Chay S, Kou Soum M, Leng C. An assessment survey of anti-tuberculosis drug management in Cambodia. Int J Tuberc Lung Dis 2006 ;10(2):153-159
6. Kenneth HG, International Journal of Risk & Safety in Medicine; 2006; 18 181-186
7. Koppel R, Role of Computerized Physician Order Entry Systems in Facilitating Medication Errors. JAMA, 2005;293:1197-1203
8. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tubercolosis care. Lancet Infect. Dis. 2006; 6(11), 710-725
9. Diop AH, Gakiria G, Pande SB, P. Malla, H.L. Rieder. Dosages of anti-tuberculosis medications in the national tuberculosis programs of Kenya, Nepal, and Senegal. Int J Tuberc Lung Dis 2002; 6(3):215-221
10. Harries AD, Gausi F, Salaniponi FM. Prescriptions and dosages of anti-tuberculosis drugs in the National Tuberculosis Control Programme of Malawi, Int J Tuberc Lung Dis 2004; 8(6):724-729
11. Pollock M, Bazaldua OV, Dobbie AE. Am Fam Physician 2007;75:231-6, 239-40.
12. Kaushal R, Bates DW. Information technology and medication safety: what is the benefit. Qual Saf Health Care 2002;11:261-265
13. Locatelli F, Andrulli S, Del Vecchio L. Difficulties of implementing clinical guidelines in medical practice 2000; Nephrol Dial Transplant15:1284–1287.
14. Montgomery LA, Budreau GK. Implementing a clinical practice guideline to improve pediatric intravenous infiltration outcomes. AACN clinical issues 1996; 7 (3), 411-424.
15. Miller PL, Frawley SJ, Sayward FG, Yasnoff WA, Duncan L, Fleming DW. Combining tabular, rule-based, and procedural knowledge in computer- based guidelines for childhood immunization., Computers and Biomedical Research 1997, 30 (3), 211-231.
16. Wang D, Peleg M, Tu S, Boxwala A, Ogunyemi O, Zeng Q et al. Design and implementation of the GLIF3 guideline execution engine, J. Biomed. Inform. 2004; 37, 305–318.
17. Boxwala AA, Peleg M, Tu S, Ogunyemi, Q. Zeng, D. Wang et al. GLIF3: a representation format for sharable computer-interpretable clinical practice guidelines, J. Biomed. Inform. 2004; 37 , 147–161.
18. Choi J, Currie LM, Wang D, Bakken S. Encoding a clinical practice guideline using guideline interchange format: A case study of a depression screening and management guideline. International Journal of Medical Informatics 2007; 76 (SUPPL. 2)
19. Miller PL. Tools for immunization guideline knowledge maintenance I. Automated generation of the logic 'kernel' for immunization forecasting. Computers and Biomedical Research 1998; 31 (3), pp. 172-189.
20. Miller PL, Frawley SJ, Brandt C, Sayward FG. Tools for immunization guideline knowledge maintenance II. Automated web-based generation of user-customized test cases Computers and Biomedical Research 1998; 31 (3), 190-208.
21. Hripcsak G. The arden syntax for medical logic modules: Introduction, Computers in Biology and Medicine, 1994 ; 24 (5), 329-330.
22. Boxwala AA, Peleg M, Tu S, Ogunyemi O, Zeng QT, Wang D, Patel VL, Shortliffe EH. GLIF3: A representation format for sharable computer-interpretable clinical practice guidelines, Journal of Biomedical Informatics 2004; 37 (3), 147-161.
23. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006
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電子資料
29. 台灣電子病歷交換基本格式. Available at http://emr.doh.gov.tw/. Accessed Mar 20, 2009
30. TB Treatment Guidelines in PDA Format. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/tb/pubs/PDA_TBGuidelines/. Accessed Mar 20, 2009
31. Stanford Medical Informatics. Stanford University. Available at http://protege.stanford.edu/ Accessed Mar 20, 2009.

------------------------------------------------------------------------ 第 19 筆 ---------------------------------------------------------------------
系統識別號 U0007-3107200811314500
論文名稱(中文) 利用HPLC分析方法預測中草藥與藥物之交互作用:探討furanocoumarins對肝臟代謝酵素CYP3A4所引起交互作用之研究
論文名稱(英文) Predicting Herb-drug Interactions by HPLC Analysis: Furanocoumarin-based Metabolic Interactions with CYP3A4
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(博士班)
系所名稱(英)
學年度 96
學期 2
出版年 97
研究生(中文) 林盈谷
學號 D301091001
學位類別 博士
語文別 中文
口試日期 2008-07-09
論文頁數 90頁
口試委員 指導教授-何秀娥
委員-蔡義弘
委員-林山陽
委員-鍾次文
委員-吳安邦
委員-李文森
委員-許明照
關鍵字(中) 中草藥與藥物交互作用
代謝酵素CYP3A4
層析分析
關鍵字(英) Herb-drug Interactions
CYP3A4
Chromatographic analysis
學科別分類
中文摘要 本研究以逆相高效液相層析 (RP-HPLC) 方法預測中草藥與藥物因代謝而發生交互作用之可能性。以二十九種結構相關且已知會抑制藥物代謝phase-I細胞色素P450 3A4 (CYP3A4) 的furanocoumarins為模式藥物利用RP-HPLC進行預測中草藥與藥物之交互作用。將其中五個furanocoumarins標準品利用已經確效的RP-HPLC系統分析,將所得的容量因子 (capacity factor) 值與用Molsuite 2000 molecular modeling pro plus software (ChemSW®) 軟體計算出的furanocoumarins分配係數 (log P) 進行關聯分析。利用此關聯曲線可求得這系列furanocoumarins之容量因子。結果顯示絕大部分的furanocoumarins其容量因子介於1.65和10.57之間 (滯留時間10到40分鐘),也就是相當於RP-HPLC分析時分離層3到8 (fraction 3~8) 之間。每一個分離層利用對nifedipine氧化反應的抑制之程度來表示酵素CYP3A4受抑制之程度。在定量性預測中草藥與藥物交互作用時,Ru 被定義為層析反應單位的總合,可利用方程式Ru = R / 7.79 ?e 105表示,其中R代表每一個層析峰或是任一個分離層內所有層析峰其面積的總合 (sum of the peak area)。結果顯示,CYP3A4酵素抑制百分比 (y) 與層析反應單位的總合 (Ru,x) 呈乙狀 (sigmoidal) 的關係,方程式為 y = 85.36 x (14.86 + x)-1其相關係數為0.63。這乙狀的曲線可以分為低、中和高風險三個範圍,用來代表中草藥或複方濃縮中草藥粉與藥物發生代謝交互作用的風險程度。經由本研究"風險類別"的預測分類結果,可以提供有用的資訊來評估中草藥與藥物之交互作用。
英文摘要 An attempt made in this study was to predict the potential for metabolic interactions of herbal extracts of drugs based on their chromatographic profiles in reverse-phase high-performance liquid chromatography (RP-HPLC) analysis. Twenty-nine structurally related furanocoumarin compounds with known effect on cytochrome P450 3A4 (CYP3A4), which is important for phase-I drug metabolism, were selected as a model system, and analyzed using an RP-HPLC system developed for this study. Log values of the partition coefficients (log P) of these furanocoumarin derivatives calculated using Molsuite 2000 molecular modeling pro plus software (ChemSW®) were used to interpolate the capacity factors from a validated correlation curve constructed using five standard references that covered the elution time range in the RP-HPLC analysis system developed in the lab. The obtained correlations were then used to estimate the capacity factor for all of the furanocoumarin derivatives collected from the literatures with reported herb-drug interaction activity in CYP3A4. The capacity factors for most of the furanocoumarins were between 1.65 and 10.57 (with retention times of 10~40 min), a range approximately equivalent to fractions 3 to 8 (Fr3~8) in the RP-HPLC fraction analysis. Each fraction was examined for its inhibition of microsomal nifedipine oxidation represented as the CYP3A4 inhibitory potency. Ru was designated the total response unit and expressed as Ru = R / 7.79 ?e 105; this was calculated for each single peak or each fraction in terms of the sum of the peak area (R) for all chromatographic peaks appearing in the chromatographic analysis. A sigmoidal relationship was established between the CYP3A4 inhibitory potency (y) and the RP-HPLC peak response unit (Ru,x) as y = 85.36 x (14.86 + x)-1 with a correlation coefficient of 0.63. The sigmoidal curve could be divided into three ranges designated low, medium, and high risk that were used to indicate the relative inhibitory potency of the metabolic interactions of herbs or traditional Chinese herb medicines with CYP3A4. These predictive classifications provide information and might be useful for “risk category” decisions concerning herb-drug interactions.
論文目次 附表目錄 IV
附圖目錄 VI
中文摘要 VIII
ABSTRACT IX
壹、緒論 1
第一節 研究背景介紹 1
一、藥物交互作用的機制 2
二、藥物與藥物的交互作用 (drug-drug interaction) 6
三、食物與藥物的交互作用 (food-drug interaction) 11
四、中草藥與藥物的交互作用 (herb-drug interaction) 15
五、中草藥與藥物發生交互作用的預測方法 22
第二節 研究動機 27
貳、實驗材料與方法 28
第一節 實驗材料 28
第二節 儀器設備 30
第三節 實驗方法 32
一、中草藥萃取液之製備 34
二、中草藥萃取液之RP-HPLC分析 36
三、老鼠肝臟微粒體 (rat liver microsomes) 製備 37
四、CYP3A4代謝模式之建立 38
五、Log P值計算 40
六、RP-HPLC容量因子 (capacity factor、k'g) 的計算 45
七、層析反應單位的總合 (total response unit、Ru) 的計算 46
八、定量性預測酵素抑制百分比 47
參、結果與討論 49
第一節、藥物代謝交互作用評估模式之建立 49
第二節、中草藥萃取液層析分離與其對代謝酵素CYP3A4之影響 51
第三節、建立模式模式成分furanocoumarins之log P 值與RP-HPLC容量因子 (k’g) 之關聯性 63
第四節、定量性預測中草藥對酵素CYP3A4抑制的百分比 72
肆、 結論 82
陸、參考文獻 83
五年內著作 90

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系統識別號 U0007-3107200819135400
論文名稱(中文) 快速取藥器應用於化療調劑作業之成效分析
論文名稱(英文) Impact of a New Medical Device for Chemotherapy in Pharmacy Dispensing Process
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 96
學期 2
出版年 97
研究生(中文) 陳奇良
學號 M301095023
學位類別 碩士
語文別 中文
口試日期 2008-07-17
論文頁數 65頁
口試委員 委員-林山陽
委員-周月卿
指導教授-吳姿樺
關鍵字(中) 化療藥物調劑作業
快速取藥器
調劑時間
痠痛程度
哥本哈根疲勞量表
工作相關疲勞
關鍵字(英) chemotherapy dispensing process
medical device-spike
dispensing time
muscle soreness
Copenhagen Burnout Inventory
work-related burnout
學科別分類
中文摘要 癌症長期是國人十大死因之首,隨著各種治療標準陸續建立,大幅提升存活時間,但癌症發生率卻未因而下降,也因此化療藥物的耗量與藥師調劑工作量居高不下;為提供藥師省力、快速且安全的優良工作環境,並在考量縮短病患等待用藥時間的前提下,本研究首先研究化療調劑工作量之特質以及快速取藥器之物理特質,繼而將其試用來替代傳統針頭於調劑操作量最高的兩藥劑fluorouracil (5-FU)、cisplatin,來進行評估此措施之實施,對北部某醫學中心化療調劑作業效率、調劑藥師本身之身、心之改善與管理效益等指標之改變情形。首先,統計北部某醫學中心96年抗癌針劑藥物調配處方數及化療藥品耗量分析並統計化療藥局藥品耗量,結果顯示門診每月平均處方數為822 ± 86張,住院平均處方數為2267 ± 224張,以抽取藥液之體積來排名則5-FU(平均每日使用瓶數67.5)、cisplatin(平均每日使用瓶數22.7)分別為抽取耗量前2名之藥品。第二部分研究則使用拉力機測試藥品使用傳統針頭抽取時所需最大拉力,並與快速取藥器進行比較,來模擬抽取藥品所需最大拉力。第三部分則由參與試驗的藥師(12人;男5人/女7人;平均年齡為34.1 ± 7.8歲;平均工作年資20.8 ± 37.2個月)測量使用傳統針頭每次抽取30 mL 5-FU藥液量或40 mL cisplatin藥液量,連續12次所需時間,並分別與快速取藥器進行比較;繼而再對受試藥師詢問其上肢酸痛之主觀知覺,評量分數從沒感覺至非常酸痛無法忍耐分別為0~10分,並紀錄其酸痛程度。第四部份則以哥本哈根疲勞量表比較改變取藥器材之對藥師疲勞感知影響。第五部份進行經濟管理效應的推論。結果顯示:以40 cc針筒加上18G針頭抽取5-FU所需最大拉力3.82 ± 0.04 Kg,以快速取藥器抽取藥液則所需最大拉力為0.73 ± 0.20 Kg,具顯著省力效果(p<0.001);以50 cc針筒加上18G針頭抽取cisplatin藥液所需最大拉力5.96 ± 0.12 Kg,以快速取藥器進行拉力測試則所需最大拉力為1.43 ± 0.37 Kg,具顯著省力效果 (p<0.001)。使用快速取藥器連續抽取12支5-FU較使用傳統針頭節省212.3 ± 95.3秒,同樣抽取cisplatin則可節省375.4 ± 125.4秒,抽取兩藥劑累積時間皆具統計上顯著差異(p<0.001);進行測試藥師自覺使用快速取藥器抽取5-FU可改善手指及手掌痠痛程度;抽取cisplatin測試組藥師自覺可同時改善手指、手掌、手腕與上臂及肩之痠痛程度。經使用中文版「哥本哈根疲勞量表」(Copenhagen Burnout Inventory,CBI) 檢測「工作相關疲勞」(work-related burnout)指數,結果顯示針頭、快速取藥器CBI分數分別為67.9 ± 19.0 vs 50.4 ± 27.8,具顯著差異(p=0.019)。分析結果顯示使用快速取藥器與傳統純針頭抽取藥液,在愛睏及無力自覺症狀方面眼睛疲勞(p=0.004),身體局部異常感自覺症狀方面手-肩痛(p=0.008)呈現有意義差異,但在注意力集中困難自覺症狀方面沒有差異。再以計算每日取5-FU或cisplatin兩藥劑調劑瓶數來推算使用快速取藥器可分別節省13.2、29.6分鐘。整體研究結果顯示快速取藥器應用於耗用量高或所需拉力較大之兩藥劑5-FU與cisplatin可縮短藥師調配時間、減少藥師生理疲勞情形;預期可提升整體調劑化療藥物作業流程效率,繼而減少病患候藥時間。
英文摘要 Malignancy is the leading cause of death in Taiwan. The uses and the dispensing of the chemotherapy medicines were also increased. In order to provide energy-saving, efficient and safe working environments and minimize patient waiting time, this study analyze the drug dispensing patterns and characterize the physics of the the tested dispensing device (S; spike®) in the beginning. The impact of this dispensing device application in dispensing anti-neoplastic drugs on the time saving and the physical-psychological parameters of enrolled pharmacists were determined. Results showed that the average number of prescriptions per month was 2267 ± 224 for inpatients and 822 ± 86 for outpatients. According to the consumption volume of anti-neoplasm drugs, fluorouracil (5-FU; 67.5 vials/day) and cisplatin (22.7 vials/day) were the highest-dispensing agents. Well-trained dispensing pharmacists (n=12, M/F=5/7, average age: 34.1 ± 7.8, work experience 20.8 ± 37.2 months) was included. Soreness of upper limb muscle soreness of upper limb muscle with visual analog pain scale (0 is none, 10 cannot endure), and physical fatigue state from the “work-related burnout” of the Chinese version of Copenhagen Burnout Inventory (C-CBI) was also measured for pharmacists (n=10). The results reveal that pulling force required for 5-FU or cisplatin withdrawl by using syringe-needle (18G) is 3.82+/-0.04 Kg, 5.96+/-0.12 Kg and only 0.73+/-0.2 Kg, 1.43+/-0.37 Kg is needed when using new medical device-S significantly decreased the accumulated dispensing time in withdrawing 30 mL 5-FU or 40 mL cisplatin repetitively twelve times by 212.3 ± 95.3 seconds, 375.4 ± 125.4 seconds, compared to the ones using traditional needle (p<0.001). The soreness of muscle of upper limb reported by pharmacists especially in finger and palm regions were also improved for 5-FU and in finger, palm, wrists and shoulder. Results of reported burnout score showed that replacing the needle by the new medical device-S significantly improved the score from 67.86 ± 19.05 to 50.36 ± 27.84 (p=0.019). Compared to using needle in dispensing agents, application of the medical device significantly improved eyestrain (p=0.004) and musculoskeletal discomfort (p= 0.008). Overall time-saving for 5-FU or cisplatin was 13.2 and 29.6 mins per day. Conclusions: Application of a new medical device (spike®) in 5-FU or cisplatin dispensing process shortened the dispensing time and improved efficiency of filling chemotherapy prescriptions, scores of muscle soreness and working-burnout indicators. The goal of improving pharmacy dispensing procesure may be optimized and further decrease patient’s waiting time.
論文目次 目次 I
中文摘要 Ⅲ
英文摘要 Ⅳ
第一章、緒論 1
第一節、研究背景 2
第一項、抗癌藥物調劑作業準則 2
第二項、國內相關法規 2
第二節、研究目的 3
第三節、選擇研究對象及理由 4
第二章、文獻探討 5
第一節、癌症流行病學與疾病治療 6
第二節、調劑化療藥物面臨問題 7
第三節、改善化療藥物調劑流程之相關研究 8
第四節、肌肉酸痛 9
第五節、疲勞測定 10
第三章、研究設計 11
第一節、研究材料來源與研究對象條件 12
第二節、試驗步驟及方法 13
第三節、資料分析與統計分析 15
第四章、結果 16
第五章、討論 23
第六章、結論 29
第七章、圖表及附錄說明 31
Table 1. Demographic and basal characteristics of pharmacists 32
Table 2. Demographic and basal characteristics of pharmacists for fatigue trial. 33
Table 3. Maximum pulling forces required for withdrawing Cisplatin & Fluorouracil by using Spike® or needle. 34
Table 4. Time spent in dispensing 5-FU、cisplatin using Spike® or needle 35
Table 5. Muscle soreness test 36
Table 6. CBI-work related burnout questionnaire test 37
Table 7. Fatigue syndromes reported by pharmacists using Spike or
needles for chemotherapy dispensing 38
圖一、試驗藥品5-FU 39
圖二、試驗藥品cisplatin 40
圖三、快速取藥器 41
圖四、試驗用18G針頭 42
圖五、試驗用針筒 43
圖六、拉力機 44
圖七、96年化療藥局門住診處方數/總筆數
45
圖八、96年化療藥局藥品耗量統計圖 46
圖九、使用傳統18 G針頭抽取Cisplatin藥液所
需拉力之曲線圖 47
圖十、使用快速取藥器抽取Cisplatin藥液所需拉力之曲線圖 48
圖十一、使用傳統18 G針頭抽取5-FU藥液所需拉力之曲線 49
圖十二、使用快速取藥器抽取5-FU藥液所需拉力之曲線圖 50
圖十三、分別使用快速取藥器與傳統針頭18 G連續抽取
12支30毫升之Cisplatin所累積的時間 51
圖十四、分別使用快速取藥器與傳統針頭18G連續抽取
12支40毫升之5-FU所累積的時間 52
圖十五、快速取藥器外加軟管圖 53
附表一、哥本哈根疲勞量表Copenhagen Burnout Inventory CBI)之工
作疲累測試問卷 54
附表二、自覺疲勞症狀調查表 55
參考文獻 56
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