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系統識別號 U0026-0812200910374947
論文名稱(中文) 受磁場與化學反應下微極流體在垂直波形板表面之暫態混合對流熱傳研究
論文名稱(英文) Study on Transient Mixed Convective Heat Transfer of Micropolar Fluid Flow through a Vertical Wavy Plate under Magnetic Field and Chemical Reaction Effects
校院名稱 成功大學
系所名稱(中) 機械工程學系碩博士班
系所名稱(英) Department of Mechanical Engineering
學年度 91
學期 2
出版年 92
研究生(中文) 王怡然
學號 n1690103
學位類別 碩士
語文別 中文
口試日期 2003-05-29
論文頁數 102頁
口試委員 口試委員-蕭世文
口試委員-楊玉姿
指導教授-陳朝光
關鍵字(中) 三次樣線法
微極流體
座標轉換
關鍵字(英) SADI
coordinate transformation
micropolar fluids
學科別分類
中文摘要 本文以座標轉換系統探討磁場及化學反應作用下微極流體通過垂直波形表面之混合對流的暫態行為。統制方程式之推導由完整的Navier-Stokes方程式著手,配合Eringen所推導之微極流體理論將牛頓流體擴展至非牛頓流體的應用。經轉換後之統制方程式可將不規則邊界展開成一規則的計算平面,並配合三次樣線交換方向定置法(SADI;Spline Alternating-Direction Implicit Method) 求解。
研究結果顯示,因微粒懸浮流體具有渦漩黏度、旋轉梯度黏度及微慣量密度等特性,因此造成流動阻力增加及熱傳率、質傳率下降。在加入磁場後,產生的Lorentz力為逆著浮力的方向,抵消了部分浮力效應,促使流體運動趨緩,熱傳、質傳效果因而變差。由於化學反應導致流體中濃度產生變化,流場中濃度梯度不再侷限在單一方向,在質傳率上的影響亦遠比熱傳率強烈。綜合本文實例發現,波形表面所增加的熱傳面積足以抵消因由表面幾何形狀所造成的流動不便所產生之熱阻抗。因此在波形表面的熱傳率皆高於相對應的平板。此外,值得注意的是,通常熱傳、質傳效率的增加亦隱含著板面摩擦係數的增加。
英文摘要 In this study, the coordinate transformation method is used to analyze the transient behavior of the mixed convection in micropolar fluids flow through a vertical wavy surface under magnetic field and chemical raction effect. The governing equations of system are derived from complete Navier-Stokes equations with theories of micropolar fluids, and we can expand the applications from in Newtonian fluids to in non-Newtonian fluids. The transformed governing equations can expand the irregular boundary into a calculable regular plane, and then solve it by using the spline alternating-direction implicit method (SADI).
Numerical results show that, in micropolar fluids, with the velocity of fluid and heat transfer rate and mass transfer rate would decrease since effets of vortex viscosity, spin-gradient viscosity and micro-inertia density. After entering the magnetic field, the produced Lorentz force opposed the
buoyancy effects, and urges the fluid motion into slowing, then the effects
on heat transfer and mass transfer are going to decrease. The chemical reaction induces the concentration change of the fluid, and the concentration gradient in the fluid is not only in one direction. It leads that the effects on mass transfer rate is much stronger than the effects on heat transfer rate.
The synthetic result show that the add quantity of heat transfer area in wavy surfaces is enough to offset the thermal resistance which is due to the geometry surfaces. Therefore, the heat transfer rate of wavy surface is higher than that of the corresponding flat plate in all fluids. Furthermore, it should be noted that the increase in heat transfer rate usually implies the increase in skin-friction coefficient.
論文目次 中文摘要……………………………………………………………Ⅰ
ABSTRACT……………………………………………………………Ⅱ
誌謝…………………………………………………………………Ⅲ
目錄…………………………………………………………………Ⅳ
表目錄………………………………………………………………Ⅴ
圖目錄………………………………………………………………Ⅵ
符號說明……………………………………………………………Ⅶ

第一章、緒論……………………………………………………………1
1-1 研究動機及背景………………………………………………1
1-2 文獻回顧………………………………………………………3
1-3 研究方法………………………………………………………5
1-4 論文結構………………………………………………………5

第二章、理論分析………………………………………………………7
2-1 基本擴散質傳遞理論…………………………………………7
2-2 理論模型的建構與假設………………………………………8
2-2.1 Prandtl 轉換理論……………………………………12
2-3 數值分析………………………………………………………19
2-3.1 解題程序 ………………………………………………20
第三章、結果與討論……………………………………………………22
3-1 混合對流Mixed Convection(Gr/Re2 ≠0、Gc/Re2 ≠ 0)……23
3-1.1 浮力參數Ri與Rd對混合對流的影響………………23
3-1.2 微極流體參數R對混合對流的影響………………26
3-1.3 化學反應參數 對混合對流的影響…………………27
3-1.4 廣義Prandtl數與Schmidt數對混合流體的影響……29
3-1.5 磁場強度Mn對混合流體的影響……………………31
3-1.6 波板振幅 對混合流體的影響………………………32
第四章、總結……………………………………………………………77
4-1 結論……………………………………………………………77
4-2 建議及展望……………………………………………………80

附錄一、三次樣線數值方法……………………………………………81
A-1 三次樣線背景…………………………………………………81
A-2 三次樣線法原理………………………………………………83
A-3 三次樣線法求解微分方程……………………………………86
A-3.1 求解一微二階偏微分方程式…………………………86
A-3.2 求解二微二階偏微分方程式…………………………88
A-4 三次樣線法邊界條件的處理…………………………………90
附錄二、基本磁性流體力學理論………………………………………93

參考文獻…………………………………………………………………96
自述……………………………………………………………………102
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系統識別號 U0026-0812200910394285
論文名稱(中文) 蝴蝶蘭微衛星序列之選殖與特性分析
論文名稱(英文) Isolation and characterization of microsatellites in Phalaenopsis orchids
校院名稱 成功大學
系所名稱(中) 生物學系
系所名稱(英) Department of Biology
學年度 91
學期 2
出版年 92
研究生(中文) 林東杰
學號 l5688106
學位類別 碩士
語文別 中文
口試日期 2003-06-21
論文頁數 75頁
口試委員 指導教授-吳文鑾
召集委員-陳文輝
口試委員-林彩雲
口試委員-高燕玉
關鍵字(中) 小片段插入基因組基因庫
蝴蝶蘭
豐富性微衛星序列基因組基因庫
微衛星序列
關鍵字(英) microsatellite-enriched genomic library
Microsatellites
Phalaenopsis orchids
small-insert genomic library
學科別分類
中文摘要 微衛星序列(microsatellite),又稱簡單重複序列(simple sequence repeat),是一段以2 ~ 6個鹼基對為重複單位的DNA片段。微衛星序列因其共顯性遺傳、多對偶基因、高度多型性、再現性高與易以聚合酵素連鎖反應偵測等優點,成為廣泛應用於分子育種及遺傳多樣性評估的分子標誌。蝴蝶蘭是一種高經濟價值花卉作物且是台灣重要的花卉產業。建立與發展高效率的微衛星標誌系統可有效應用在蝴蝶蘭的品種鑑定與品種專利權的保護。因此,本實驗的目的在於進行蝴蝶蘭微衛星標誌的選殖及特性分析。首先,構築台灣阿媽蝴蝶蘭的小片段插入基因組基因庫及豐富性微衛星序列基因組基因庫,並篩選雙鹼基重複的微衛星序列,總計得到約170個含有微衛星序列的選殖株,目前已完成30個微衛星序列的核酸定序。比較兩種基因庫的微衛星序列選殖效率,發現後者的效率高出10倍左右。分析所選殖出的微衛星序列中,發現連續型微衛星序列佔61.3%;而複合型微衛星序列具有較高的重複次數。根據微衛星序列兩側的游離序列(flanking region)長度,估計有62.5%的微衛星序列可設計引子對。利用6個微衛星基因座引子對檢測不同品系的台灣阿媽蝴蝶蘭,發現這些微衛星基因座之對偶基因數分佈在2 ~ 13之間,平均每一個微衛星基因座會出現7個對偶基因。評估這些微衛星基因座的遺傳變異度後,顯示其範圍分佈在0.47 ~ 0.88之間;而多型性程度則以PIC值(polymorphism information content)表示,分佈在0.19 ~ 0.7之間,而平均值則為0.48。分別將台灣阿媽蝴蝶蘭PaAGS002與PaAGS003基因座之不同對偶基因選殖出並定序,經序列比對分析,發現造成對偶基因大小差異的原因包括重複次數的不同與發生在游離序列的缺失。接著,以聚合酵素連鎖反應偵測6個微衛星基因座在12種原生種蝴蝶蘭與2種同科之蘭花物種的跨物種擴增性,結果顯示微衛星基因座在相近物種間具有高保守性。進一步,由14種原生種蝴蝶蘭與1文心蘭原生種之聚合酵素連鎖反應產物,選殖出PaAGS002相對應的微衛星基因座,並進行核酸定序與親緣演化分析,發現微衛星標誌與傳統型態分類的演化模式大致相同。此外,利用4種蝴蝶蘭商業栽培品種測試5個微衛星基因座的可利用性,初步結果顯示其具有蝴蝶蘭品種鑑定的應用潛力。
英文摘要 Microsatellites, also known as simple sequence repeats (SSRs), are short (2-6 bp) tandemly repeated DNA sequences. Microsatellites are widely used as genetic markers in molecular breeding and genetic diversity assessment because they are codominant, multiallelic, highly polymorphic, high reproducibility and easily scored by PCR. Phalaenopsis orchid is among the most valued ornamentals and considered as an important floriculture industry in Taiwan. The establishment and development of very efficient SSR markers would be very useful for orchid cultivar identification and proprietary variety protection. Therefore, the objectives of this study were to isolate, identify and characterize SSR markers for Phalaenopsis orchids. Firstly, the small-insert genomic library and microsatellite-enriched genomic library of Phalaenopsis amabilis were contructed and screened for dinucleotide, AG/CT or AC/TG- microsatellite sequences. A total of approximate 170 microsatellite-containing clones were obtained. Comparing the efficiency of the two microsatellite isolation strategies, the enrichment approach showed much greater efficiency up to 10-fold. Presently, 30 clones have been sequenced, 61.3% of which are perfect repeats and compound repeats have the higher values of repeat number. According to the length of flanking sequences of microsatellite clones, 62.5% primer pairs could be designed for amplification. Six SSR primer pairs were evaluated for amplification and genetic polymorphism in several Phalaenopsis amabilis cultivars. The number of alleles found per locus varied from 2 to 13 with a mean number of 7. Heterozygosity was ranged from 0.47 to 0.88. The level of polymorphism (polymorphism information content, PIC) ranged from 0.19 to 0.7 with an average of 0.48. Different alleles PaAGS002 and PaAGS003 were cloned from Phalaenopsis amabilis, respectively. These clones were sequenced and aligned, the results revealed that the size differences among the microsatellite alleles are not only due to varization in the numbers of repeats but also due to the occurrence of insertion/ deletion events in the flanking region. Cross-species amplification of six microsatellite loci were tested in 14 orchid species, the results suggested that microsatellite loci were highly conserved in Phalaenopsis species. Furthermore, sequences of PCR products at the homologous microsatellite locus PaAGS002 from 15 orchid species were subjected to phylogenetic analysis, the evolutionary pattern of SSR is highly consistent with that based on morphological characters. In addition, five microsatellite loci were also tested for utility in four commercial orchid varieties. The preliminary results indicated that microsatellites will have potential applications in orchid cultivar identification.
論文目次 目錄
英文摘要i
中文摘要ii
致謝iii
目錄iv
表目錄vii
圖目錄viii
縮寫名詞對照表ix
第一章 前言
一、微衛星序列1
二、微衛星序列的應用2
三、微衛星標誌的發展策略3
四、蝴蝶蘭的簡介4
五、研究策略與目的6
第二章 實驗材料與方法
一、實驗材料8
二、蝴蝶蘭基因組DNA的萃取8
(一) 大量萃取蝴蝶蘭基因組DNA8
(二) 微量萃取蝴蝶蘭基因組DNA9
三、選殖微衛星序列9
(一) 構築小片段插入基因組基因庫9
1. 由瓊脂凝膠中回收DNA片段9
2. 接合作用10
3. 轉型實驗10
3-1. 製備勝任細胞10
3-2. 轉型作用10
3-3. 塗碟10
(二) 構築豐富性微衛星基因組基因庫11
1. 由瓊脂凝膠中回收DNA片段11
2. 製備雙股連接子11
3. 擴增插入DNA11
4. 製備streptavidin磁珠11
5. 雜合反應12
6. 擴增已雜合之插入DNA12
7. 製備microsatellite-enriched之插入DNA13
四、微量製備質體DNA13
(一) 培養細菌13
(二) 微量抽取13
(三) 限制酵素作用測試13
五、菌落雜合反應14
(一) colony lift之製備14
(二) 微衛星序列探針的製備14
(三) 雜合反應14
六、核酸定序及分析15
七、設計微衛星序列基因座之引子15
八、檢測微衛星基因座之擴增性15
(一) 聚合酵素連鎖反應15
(二) 電泳分析15
九、微衛星基因座之特性分析16
(一) 共顯性遺傳分析16
(二) 遺傳變異度評估16
(三) 多型性程度分析16
第三章 結果
一、台灣阿媽基因組基因庫之建構17
二、微衛星序列之選殖與特性分析17
三、微衛星基因座之遺傳變異度與多型性程度評估18
四、微衛星基因座在不同蘭科植物之可擴增性分析20
五、微衛星基因座之共顯性分析20
六、微衛星基因座在不同蘭科植物之序列保守性分析20
七、微衛星分子標誌應用於蝴蝶蘭商業品種之檢測22
第四章 討論
一、台灣阿媽基因組基因庫之特性與比較23
二、微衛星序列的特性分析24
三、微衛星基因座之遺傳變異度與多型性程度25
四、微衛星基因座在蘭科植物之移轉性26
五、比較PaAGS002微衛星基因座在各蘭花物種的核酸序列與演化分析27
六、微衛星標誌在蝴蝶蘭商業品種鑑定的應用29
第五章 未來展望30
參考文獻31
附錄73

表目錄
表一、本實驗所使用的二十七種台灣阿媽品系.................................37
表二、本實驗所使用的十六種蘭花品種..............................................38
表三、本實驗所使用的四種蝴蝶蘭商業品種......................................39
表四、進行蝴蝶蘭微衛星基因座聚合酵素連鎖反應之引子序列......40
表五、微衛星基因座之重複序列總覽......41
表六、微衛星基因座之序列相似度比對結果..43
表七、六個微衛星基因座之聚合酵素連鎖反應資料.45
表八、六個微衛星基因座之對偶基因數偵測與多型性程度評估..46
表九、六個微衛星基因座在不同蘭科植物之可擴增性分析..47
表十、微衛星基因座在蝴蝶蘭商業品種之擴增情形......................48

圖目錄
圖一、本實驗之實驗流程........................................................................49
圖二、確認台灣阿媽之基因組基因庫中有小片段DNA插入之情形..50
圖三、台灣阿媽之小片段插入基因組基因庫以(AG)11探針進行菌落雜合反應之結果.........................................................................51
圖四、PaCTS001微衛星基因座在台灣阿媽不同品系間之多型性分析..52
圖五、PaAGS002微衛星基因座在台灣阿媽不同品系間之多型性分析.......53
圖六、PaGTS004微衛星基因座在台灣阿媽不同品系間之多型性分 析........54
圖七、PaAGD005微衛星基因座在台灣阿媽不同品系間之多型性分析..........................................................55
圖八、PaATS006微衛星基因座在台灣阿媽不同品系間之多型性分析.............................................................................................56
圖九、PaCTS001微衛星基因座在不同蘭花品種之可擴增性分析
...........................................................................................57
圖十、PaAGS002微衛星基因座在不同蘭花品種之可擴增性分析
..............................................................................................58
圖十一、PaGTS004微衛星基因座在不同蘭花品種之可擴增性分析
.........................................................................................59
圖十二、PaAGD005微衛星基因座在不同蘭花品種之可擴增性分析
.......................................................................................60
圖十三、PaATS006微衛星基因座在不同蘭花品種之可擴增性分析
...............................................................................61
圖十四、PaGTS004微衛星基因座在台灣阿媽之共顯性分析..............62
圖十五、台灣阿媽之微衛星基因座(PaAGS002)之對偶基因序列比對結果.....................................................................................63
圖十六、台灣阿媽與Phalaenopsis aphrodite之微衛星基因座(PaAGS002)序列比對結果................................................64
圖十七、台灣阿媽之微衛星基因座(PaAGS003)之對偶基因序列比對結果.....................................................................................65
圖十八、台灣阿媽與Phalaenopsis aphrodite之微衛星基因座(PaAGS003)序列比對結果.........................................................66
圖十九、微衛星基因座(PaAGS002)在十二種蘭花品種中之序列比對結果...........................................................................................67
圖二十、以聚類分析法構築十二種蘭花品種之PaAGS002微衛星基因座核酸序列之親緣演化樹狀圖...................................................71
圖二十一、利用4個微衛星分子標誌檢測蝴蝶蘭商業品種...............72
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系統識別號 U0026-0812200910401173
論文名稱(中文) 微米相變化流體在矩形熱虹迴路內熱傳特性之實驗研究
論文名稱(英文) Experimental Study on Heat Transfer Characteristics of a Rectangular Thermosyphon Loop with Micro Phase Change Fluids
校院名稱 成功大學
系所名稱(中) 機械工程學系碩博士班
系所名稱(英) Department of Mechanical Engineering
學年度 91
學期 2
出版年 92
研究生(中文) 林敬峰
學號 n1690119
學位類別 碩士
語文別 中文
口試日期 2003-06-25
論文頁數 62頁
口試委員 指導教授-何清政
口試委員-謝曉星
口試委員-楊天祥
關鍵字(中) 相變化流體
熱虹迴路
關鍵字(英) phase change fluids
thermosyphon loop
學科別分類
中文摘要 本文主要以實驗方式探討微米相變化流體在矩形熱虹迴路內熱傳特性之研究。實驗迴路模型高度為34.5cm、寬度為34.5cm,迴路材質皆選用不銹鋼(AISI 304,18%Cr,8%Ni)圓管,其外徑為9.5mm 、內徑為8.3mm 。文中考慮迴路加熱段所輸入之熱量及冷卻段外管壁平均溫度對迴路穩態溫度分佈之影響,並同時探討迴路內充填微米相變化流體與純水之間的差異,其相關參數範圍為:加熱段輸入之熱量4~12瓦,冷卻段外管壁之平均溫度10~25度,相變化微粒之質量濃度0~0.15。結果顯示由於過冷效應之影響,導致迴路內微米相變化流體流經冷卻段時無法凝固,其熱傳效果反而比填入純水時為差,當濃度愈大時愈為顯著。另外;將實驗所得之結果與數值模擬相互比較,結果顯示實驗數據與數值模擬之結果相當吻合。
英文摘要 The primary objective of present study is to experimentally heat transfer characteristics of a rectangular thermosyphon loop of phase change material(PCM)suspension. A rectangular loop of 34.5 cm in height and 34.5 cm in width was constructed with a stainless steel(AISI)tube of outer and inner diameters of 9.5 mm and 8.3 mm. Steady state heat transfer experiments of loop were performed for the relevant parameters in the following ranges: the heat input in the heated section q=4~20, the average out surface temperature in the cooled section T=10~25, and the mass fraction of the PCM particles(c=0~0.15). Experimental results obtained show the effectiveness of heat dissipation in the heated section of the circulation loop incorporating the PCM suspension appears inferior to that of pure water(c=0), which may be attributed to occurrence of supercooling of the PCM particles. Corresponding to the experiments, numerical simulations taking the supercooling phenomenon into account were undertaken. Fairly good agreement between the numerical predictions and the experimental data was found for the outer wall temperature distribution along the loop, lending clear evidences of occurrence of supercooling phenomenon in the PCM suspension. The supercooling of PCM particles can thus be detrimental to effectiveness of the suspension as a heat transfer enhancement medium.
論文目次 中文摘要..........................I
英文摘要..........................II
致謝..............................III
目錄..............................IV
圖目錄............................VI
表目錄............................VIII
符號表............................IX
第一章 緒論
1-1 前言..........................1
1-2 文獻回顧......................1
1-3 研究動機與目的................3
1-4 本文架構......................4
第二章 實驗模型與實驗方法
2-1 物理模型......................5
2-2 實驗模型與週邊設備............6
2-3 實驗方法......................13
2-4 實驗步驟......................17
2-5 數據換算及其不準度分析........18
第三章 實驗結果與討論
3-1 迴路外管壁之溫度分佈..........25
3-2 加熱段輸入熱量之影響..........26
3-3 冷卻段壁溫之影響..............28
3-4 相變化微粒質量濃度之影響......28
3-5 實驗結果與數值模擬之比較......34
第四章 結論與建議
4-1 結論..........................45
4-2 對未來研究之建議..............46
參考文獻..........................47
附錄A 相變化流體之物理性質表......50
附錄B 不準度分析之計算............54
附錄C 實驗數據表..................58
自述..............................62
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8. M. Misale, P. Ruffino, and M. Forgheri, ”The Influence of the Wall Thermal Capacity and Axial Conduction Over a Single-Phase Natural Circulation Loop : 2-D Numerical Study,” Heat and Mass Transfer, Vol. 36, pp. 533-539, 2000.
9. P. Charunyakorn, S. Sengupta, and S. K. Roy, ”Forced Convection Heat Transfer in Microencapsulated Phase Change Material Slurries : Flow in Circular Ducts,” Int. J. Heat Mass Transfer, Vol. 34, No. 3, pp. 819-833, 1991.
10. M. Goel, S. K. Roy and S. Sengupta, ”Laminar Forced Convection Heat Transfer in Microcapsulated Phase Change Material Suspensions,” Int. J. Heat Mass Transfer, Vol. 37, No. 4, pp. 593-604, 1994.
11. H. Inaba, M. Kim and A. Horibe, ”Heat Transfer Characteristics of Latent Microcapsule-Water Mixed Slurry Flowing in a Pipe with Constant Wall Heat Flux (Numerical Analysis),” 日本機械學會論文集(B編)68卷665號, pp. 161-168, 2002.
12. H. Inaba, M. Kim and A. Horibe, ”Cold Heat Storage Characteristics of Latent Heat Microcapsule-Water Mixture Flowing in a Pipe with Constant Temperature Wall,” 日本機械學會論文集(B編)68卷673號, pp. 156-163, 2002.
13. 邱勝彥, “ 內含懸浮相變化微粒之矩形熱虹迴路熱傳特性之數值分析,” 國立成功大學機械工程研究所碩士論文, 2002.
14. C. J. Ho,” Solid-Liquid Phase Change Heat Transfer in Enclosure,” Ph. D. Dissertation, Purdue University, 1982.
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18. B. P. Leonard, ‘‘A Stable and Accurate Convective Modeling Procedure Based on Quadratic Upstream Interpolation,’’ Comput. Meth. Appl. Mech. Engng., Vol. 19, pp.59-98, 1979.

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系統識別號 U0026-0812200910413396
論文名稱(中文) 應用薄膜型陰離子交換樹脂暨氣相層析質譜法分析尿中合成除蟲菊農藥生物指標方法之建立
論文名稱(英文) Method Development in the Determination of Metabolites of Pyrethroids in Urine by Strong Anion Exchange Disk Extraction /In-Vail Derivation and Gas Chromatography-Mass Spectrometry
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 91
學期 2
出版年 92
研究生(中文) 陳寶蓮
學號 s7690108
學位類別 碩士
語文別 中文
口試日期 2003-06-27
論文頁數 72頁
口試委員 指導教授-林維炤
口試委員-許憲呈
口試委員-石東生
指導教授-張火炎
關鍵字(中) 生物指標
除蟲菊農藥
強陰離子交換樹脂
分析方法
固相萃取
關鍵字(英) analytical method
SAX
biomarkers
Pyrethroids
solid phase extraction
學科別分類
中文摘要 合成除蟲菊農藥(Pyrethroids)經常使用於農、林、園藝業及一般環境衛生用藥,除蟲菊農藥具有神經毒性,當中毒發生時可能會導致癱瘓甚至死亡,已有相關研究報導指出除蟲菊農藥可能具有基因毒性。隨著合成除蟲菊農藥在一般家庭中使用量及頻率的增加,除蟲菊農藥在一般人口的暴露型態及內在暴露劑量可能較過去增加,如何對人體除蟲菊農藥暴露進行有效的檢測評估已成一重要之課題。過去除蟲菊農藥尿中代謝物分析方法,僅針對部分代謝物進行探討,並未能針對全面性除蟲菊農藥之暴露進行量測,且樣本前處理方式較為繁瑣費時。
本研究利用薄膜型強陰離子交換樹脂 (strong anion exchange, SAX)暨氣相層析質譜儀 (GC/MS)建立一省時且操作簡單並能同時偵測尿中五種除蟲菊農藥生物指標之分析方法。前處理方式為利用薄膜型強陰離子交換樹脂對尿中五種常見除蟲菊代謝物3-(2,2-dimethyl)-2,2-dimethyl-(1-cyclopropane)-carboxylic acid (簡稱ChCA)、3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane)-carboxylic acid (簡稱Cl2CA)、3-(2,2-dibromorovinyl)-2,2-dimethyl-(1-cyclopropane)-carboxylic acid (簡稱Br2CA)、3-phenoxybenzoic acid (簡稱3PBA)及3-(4-hydroxy)-phenoxybenzoic acid (簡稱4OHPBA)進行萃取、過濾、濃縮於一步驟,吹氮後加入CH3I加熱進行線上衍生化,前處理完畢之樣本以氣相層析質譜儀進行分析。
本分析方法可將樣本前處理時間由4-24小時減少為2.5小時,儀器分析時間則由1小時縮短為17分鐘,較以往文獻分析方法大幅減少。大鼠灌食約3mg cypermethrin後尿液檢體測試時,發現加入30μL 10N NaOH(aq)能有效去除代謝酸conjugation,並可降低尿液基值干擾。各代謝酸的方法偵測下限介於0.32~5.52μg/L。以此方法分析除蟲菊農藥噴灑員工(n=22)及無職 業暴露除蟲菊農藥一般民眾(n=20)尿中除蟲菊代謝物含量,經統計分析兩組尿中除蟲菊代謝物含量差異達統計上顯著差異(P<0.05)。
本分析方法不但能有效區別職業性或非職業性暴露除蟲菊農藥其尿中代謝物含量,並且可大幅縮短樣本前處理時間及儀器分析時間,為一經濟、省時且操作簡單並能同時偵測尿中五種除蟲菊農藥代謝物之分析方法。相較於文獻上其他合成除蟲菊農藥之分析方法,本方法更適於例行性大量樣本分析應用,對人體各種除蟲菊農藥暴露進行較為廣泛的檢測評估。

關鍵字:除蟲菊農藥、生物指標、強陰離子交換樹脂、分析方法、固相萃取
英文摘要 Pyrethroids have been extensively used as insecticides in agriculture, forestry, horticulture, and residential hygiene. Pyrethroids have been documented as a neurotoxicant as well as a possible genotoxicant in literature. The exposure profile and total body burden of pyrethroids in population draw more and more attention due to their increasing use. The analytical methods developed in the past, however, only targeted on some metabolites instead of full-spectrum application for widely diversified pyrethroids. Moreover, the procedures in previous methods were considerably complicated and time-consuming.

The purpose of this study is to establish a more timesaving and simpler analytical method incorporating strong anion exchange (SAX) / in-vail derivatization with gas chromatography/mass spectrometry (GC/MS) in the determination of five urinary pyrethroid biomarkers at the same time. SAX was used in extraction, percolation and enrichment in a single step for the following five urinary pyrethroid metabolites: 3-(2,2-dimethyl)-2,2-dimethyl- (1-cyclopropane)-carboxylic acid (ChCA), cis/trans 3-(2,2-dichlorovinyl)-2,2-dimethyl- (1-cyclopropane)-carboxylic acid (cis/trans Cl2CA), 3-(2,2-dibromorovinyl)-2,2-dimethyl- (1-cyclopropane)-carboxylic acid (Br2CA), 3-phenoxybenzoic acid (3PBA), and 3-(4-hydroxy)-phenoxybenzoic acid (4OHPBA). After nitrogen blow, CH3I was added and in-vial derivatization was achieved following by heating prior to GC/MS determination.

We found the method developed in this study reduced the sample preparation time to 2.5 hrs from 4-24 hrs and the chromatographic course to 17 min from 1 hr. The addition of 30μL of NaOH (aq) at 10N to the urine collected from a SD rat after oral exposure to cypermethrin at 3mg was able to effectively improve the recovery rates of biomarkers of interest by possibly breaking down the conjugated forms into free forms as well as eliminate the chromatographic interference. The limits of detection for five pyrethroid metabolites were ranged from 0.32 to 5.52 μg/L. Statistical significance was found in the determination of five pyrethroid metabolites for the urine samples collected from pesticide sprayers (n=22) and from unexposed population (n=20).

This method not only can greatly simplify sample preparation procedure but also significantly reduce the consumption of toxic solvents in sample preparation as well as covering more diversified pyrethroids. This method could be more suitable in routine analysis and for screening purpose in the determination of pyrethroid exposure for general population as well as for occupationally exposed groups.

Key words: Pyrethroids, biomarkers, SAX, analytical method, solid phase extraction
論文目次 摘 要.............................................................I
Abstract............................................................II
誌 謝...........................................................III
目 錄............................................................IV
表 目 錄............................................................VI
圖 目 錄...........................................................VII

第一章 緒 論.....................................................1
1-1 前言.............................................................1
1-2 研究背景.........................................................2
1-2.1 合成除蟲菊農藥之演化...........................................2
1-2.2 合成除蟲菊農藥之使用...........................................2
1-2.3 合成除蟲菊農藥毒性.............................................3
1-2.4 合成除蟲菊農藥之暴露評估.......................................4
1-2.5 合成除蟲菊農藥的生物偵測.......................................4
1-2.6 合成除蟲菊農藥尿中代謝物.......................................5
1-3 研究目的.........................................................6

第二章 文獻回顧...................................................7
2-1 尿中合成除蟲菊農藥代謝物分析方法.................................7
2-2 生物指標的選擇...................................................7
2-3 樣本萃取方式.....................................................8
2-3.1 溶劑萃取 (Liquid-liquid extraction)............................8
2-3.2 固相萃取 (Solid phase extraction, SPE).........................9
2-4 衍生化方式......................................................10
2-5 儀器分析方析....................................................10

第三章 材料與方法................................................12
3-1 實驗材料與設備..................................................12
3-1.1 藥品與材料....................................................12
3-1.2 儀器及設備....................................................12
3-2 實驗室測試分析..................................................14
3-2.1 初步實驗流程..................................................14
3-2.2 前處理與分析條件最佳化測試....................................14
3-2.3 實驗室QA/QC測試...............................................16
3-3 尿液樣本分析....................................................20
3-3.1 研究對象選取..................................................20
3-3.2 尿液檢體收取..................................................20
3-3.3 問卷調查......................................................20
3-3.4 檢體儲存、運送及處理..........................................21

第四章 結果與討論................................................22
4-1 實驗室測試結果..................................................22
4-1.1 實驗流程測試..................................................22
4-1.2 實驗室QA/QC測試...............................................25
4-2 職業與非職業除蟲菊農藥暴露族群之尿液樣本分析結果................27

第五章 結 論....................................................31

第六章 未來工作..................................................32

參考文獻............................................................33

附 錄 一............................................................67
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系統識別號 U0026-0812200910420582
論文名稱(中文) 腎絲球腎炎之藥物治療
論文名稱(英文) Pharmacotherapy in Glomerulonephritis
校院名稱 成功大學
系所名稱(中) 臨床藥學研究所
系所名稱(英) Institute of Clinical Pharmacy
學年度 91
學期 2
出版年 92
研究生(中文) 林婉婷
學號 s6690104
學位類別 碩士
語文別 中文
口試日期 2003-07-10
論文頁數 155頁
口試委員 指導教授-高淑敏
指導教授-黃建鐘
指導教授-高雅慧
口試委員-劉明煇
關鍵字(中) 菌酚嗎碄乙基酯
每日尿蛋白流失量
腎絲球腎炎
類固醇
關鍵字(英) glomerulonephritis
glucocorsteroids
mycophenolate mofetil
daily protein loss
學科別分類
中文摘要 腎絲球腎炎 (Glomerulonephritis, GN) 是造成末期腎病 (end-stage renal disease,ESRD) 的主要原因之一;若早期給予藥物治療,能保留腎功能和減少腎衰竭的發生。目前治療腎絲球腎炎的藥物中,以類固醇 (steroids) 為第一線用藥物;若是治療失敗或容易復發時,可併用其他免疫抑制劑 (immunosuppressants) 作治療,因其具有細胞毒性和引發各種副作用,會造成治療之困難;Mycophenolate mofetil (MMF) 是一新的免疫抑制劑,先應用於腎移植,近年來陸續用來治療器官移植以外疾病,包括:腎絲球腎炎和自體免疫疾病。本研究的主要目的是經由回溯性觀察方式,從2002年10月至2003年4月,分析成大醫院十七位GN患者對MMF治療之反應。他們曾接受過三個月以上MMF之治療且對類固醇有依賴性 (十位) 或抗性 (兩位),曾使用其他免疫抑制劑治療,但反應不佳或復發者有五位。腎臟切片的病理診斷,有七位為膜性腎病變 (membranous nephropathy, MN),五位為微細病變 (minimal change disease, MCD),以及五位其他組,包括:甲型免疫球蛋白腎病變 (IgA nephropathy) 一位,局部節段性腎絲球硬化 (focal segmental glomerulosclerosis, FSGS) 兩位和狼瘡性腎炎 (lupus nephritis) 兩位。男女的比例為9: 8,平均年齡為40.9 �b 14.3 歲。主要評估GN患者接受MMF治療前後的每日尿蛋白流失量 (daily protein loss, DPL) 和血清肌酸酐 (serum creatinine, SCr) 之變化,以中位數 (範圍) 來表示。另外,也評估患者在MMF治療前後的肌酸酐廓清率 (creatinine clearance, CrCl)、血清白蛋白和膽固醇濃度之變化,並觀察MMF治療期間的副作用以及類固醇、ACEI或AIIA和HMG CoA 還原酶抑制劑 (statins) 的併用情形。
MMF治療劑量與療程之中位數 (範圍) 分別為每天1 (0.5-1) 克的和治療14 (3-49) 個月,發現GN患者的DPL在MMF治療前為4.8 (1.7-15) 公克,治療後明顯降低為2.3 (0.3-14.1) 公克 (p = 0.009);治療前後的SCr,則無顯著差異 (1.0 mg/dL vs. 1.0 mg/dL , p > 0.05),而CrCl、血清白蛋白和膽固醇濃度在治療前後的變化,也沒有差異性。其中膜性腎病變的患者對MMF治療的反應最好,DPL由治療前的每天4.8 (1.8-8.6) 公克降低至治療後每天0.4 (0.3-2.3) 公克 (p = 0.018),血清白蛋白由3.3 mg/dL 增加至3.8 mg/dL (p = 0.042),膽固醇由290 mg/dL降低至213 mg/dL (p = 0.028)。MCD患者在MMF治療前後的DPL、SCr、CrCl、血清白蛋白和膽固醇濃度,都不具有顯著差異 (p > 0.05);至於合併FSGS、IgAN和LN患者之「其他組」,接受MMF治療後,DPL由4.8公克下降至3.4公克(p = 0.043)。安全性方面,對MMF的耐受性良好,未出現嚴重的胃腸或白血球降低的副作用。由單變項分析發現,膜性腎病變患者接受MMF治療容易降低其DPL;多變項分析中,併用ACEI/AIIA、未使用過免疫抑制劑治療以及膜性腎病變患者,接受MMF治療容易降低其DPL。
因此,MMF治療對類固醇或其他免疫抑制劑反應不佳的GN患者,可有效地降低DPL,且穩定腎功能。而膜性腎病變患者,除降低DPL,也會改善血中白蛋白和膽固醇值。但微細病變患者接受MMF治療後未有明顯之反應,可考慮提高MMF的治療劑量或以其他免疫抑制劑(如:Cyclosporine)作治療。「其他組」的DPL,呈現有意義下降。未來可增加病人數或作前瞻性的GN研究,以評估MMF之確切療效。
英文摘要 Glomerulonephritis (GN) is a major cause of end-stage renal disease (ESRD). Glucocorsteroids alone or in combination with cytotoxic agents or cyclosporine have been used to treat GN patients with unsuccessful response or having potential toxicities. Mycophenolate mofetil (MMF) is an immunosuppressive agent widely used in transplant recipients. We retrospectively evaluated the effectiveness of MMF as the empirical treatment for refractory GN in Division of Nephrology, National Cheng Kung University Hospital, Tainan, Taiwan.
From October 2002 to April 2003, 17 GN patients with poor response or relapse after steroids or cytotoxic agents had received MMF therapy at least 3 months were enrolled into study. The pathologic findings were grouped into membranous nephropathy (MN, N = 7), minimal change disease (MCD, N = 5), and the other group including: focal segmental glomerulosclerosis (FSGS, N = 2), IgA nephropathy (IgAN, N = 1) and lupus nephritis (LN, N = 2). The median (range) of daily protein loss (DPL), serum creatinine, creatinine clearance, serum albumin and serum cholesterol at the start and the end of MMF therapy were compared using the Wilcoxon signed-ranks test. The use of steroid, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AIIA), and 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) was also analyzed.
The median (range) dose and duration of MMF therapy in these GN patients were 1 (0.5-1.0) g/day and 14 (3.0-14.0) months. The results showed that DPL decreased from 4.8 (1.7g - 15.0) g to 2.3 (0.3- 14.1; p < 0.05) g, but there was no significant change of serum creatinine (1.0 mg/dL vs. 1.0 mg/dL, p > 0.05), creatinine clearance (67.3 mg/dL vs. 78.0 mg/dL, p > 0.05), serum albumin (3.3 mg/dL vs. 3.8 mg/dL, p > 0.05), or serum cholesterol (290.0 mg/dL vs. 224.0 mg/dL, p > 0.05) in all GN patients at the end of MMF therapy. MN patients had better improvement of DPL (4.8 g decreased to 0.8 g, p = 0.018), serum albumin (3.3 g increased to 3.8 g, p = 0.042), and cholesterol (290.0 mg/dL decreased to 213.0 mg/dL, p = 0.028) than other patients at the end of MMF therapy. But MCD patients showed no significant difference of DPL, serum creatinine, creatinine clearance, serum albumin, or serum cholesterol at the end of therapy. The other group only had significant improvement of DPL at the end of therapy (4.8 g vs. 3.4 g, p = 0.043). Side effects of MMF were uncommon and generally mild. In multivavariate analysis,
decrease of DPL correlated with the concomitant use of ACEI/AIIA, no previous treatment of cytocoxic agents and MN patients.
In brief, MMF therapy for patients with refractory GN was well tolerated and can improve DPL and preserve the renal function.
論文目次 中文摘要…………………………………………………………………...I
英文摘要…………………………………………………………………...IV
致謝………………………………………………………………………...VI
縮寫………………………………………………………………………...VII
目錄………………………………………………………………………...VIII
表目錄……………………………………………………………………...XIV
圖目錄……………………………………………………………………...XVI
第一篇 腎絲球腎炎的藥物治療………………………………………….1
第壹章 研究背景………………………………………………………….1
第貳章 文獻回顧………………………………………………………….2
第一節 腎絲球腎炎…………………………………………………….2
1.1 定義………………………………………………………………2
1.2 分類………………………………………………………………2
第二節 致病機轉……………………………………………………….4
第三節 臨床表徵……………………………………………………….6
第四節 評估與診斷…………………………………………………….7
第五節 藥物治療……………………………………………………….10
5.1 膜性腎病變(Membranous nephropathy, MN)的藥物治療……...13
5.1.1 類固醇單ㄧ療法…………………………………………….13
5.1.2.免疫抑制劑療法……..………………………………………16
5.1.2.1 Azathioprine (AZA)……………………………………...16
5.1.2.2 烷基化劑 (alkylating agents)…………………………...16
5.1.2.3 Cyclosporin (CsA)………………………………………..20
5.1.3 結論……………………………..……………………………20
5.2 微細腎病變 (Minimal change disease) MCD的藥物治療……...21
5.2.1 類固醇………………………………………………………...21
5.2.1.1 首次發作的治療…………………………………………21
5.2.1.2 復發性MCD的治療…………………………………….22
5.2.2 免疫調節劑 (Immunmodulator agents)……………………...23
5.2.2.1 Cyclophosphamide (CYC)………………………………..24
5.2.2.2 Chlorambucil……………………………………………...24
5.2.2.3 Cyclosporin A (CsA)……………………………………...24
5.2.2.4 Levamisole………………………………………………..24
5.2.3 結論…………………………………………………………...26
5.3 局部節段性腎絲球硬化 (Focal semential
glomerulosclerosis, FSGS) 的藥物治療………………………...28
5.3.1 類固醇………………………………………………………..28
5.3.2 烷基化劑……………………………………………………..31
5.3.3 Cyclosporin (CsA)…………………………………………….31
5.3.4 結論…………………………………………………………..33
5.4 狼瘡性腎炎 (Lupus nephritis, LN) 的藥物治療………………..34
5.4.1 類固醇………………………………………………………..34
5.4.2 Cyclophosphamide (CYC)……………………………..……..35
5.4.3 Azathiopurine (AZA)…………………………………………36
5.4.4 結論………………………………………………………….36
第六節 Mycophenolate Mofetil (MMF)…………………………………..39
6.1 藥理機轉……………………………………………………………40
6.2 藥動學特性…………………………………………………………43
6.2.1 吸收與分布…………………………………………………….43
6.2.2 代謝與排除…………………………………………………….46
6.3 藥物交互作用………………………………………………………47
6.4 副作用………………………………………………………………47
6.5 MMF用於GN的臨床治療………………………………………...48
6.5.1 背景…………………………………………………………….48
6.5.2 以MMF治療GN的可能機轉………………………………..49
6.5.3 MMF在原發性GN的臨床研究………………………………50
6.5.4 MMF在LN的臨床研究………………………………………54
第參章 研究目的…………………………………………………………….58
第肆章 研究方法…………………………………………………………….59
第一節 研究設計………………………………………………………….59
1.1研究類型……………………………………………...……………..59
1.2研究時間及對象…………………………………………………….59
1.3納入標準…………………………………………………………….59
第二節 研究流程………………………………………………………….60
第三節 評估指標與定義………………………………………………….61
3.1 主要評估指標 (primary endpoint)…………………………………61
3.2 次要評估指標 (secondary endpoint)………………………………61
3.3 評估指標之定義……………………………………………………61
3.4 紀錄方法……………………………………………………………63
第四節 統計方法…………………………………………………………64
4.1 統計模式設定……………………………………………………..64
4.2 資料分析方法……………………………………………………..64
4.3 統計軟體…………………………………………………………..64
第伍章 研究結果……………………………………………………………65
第一節 研究對象…………………………………………………………65
第二節 治療效果…………………………………………………………68
2.1 MN患者的MMF治療效果……………………………………….71
2.2 MCD患者的MMF之治療效果…………………………………..74
2.3 其他患者使用MMF之治療效果…………………………………77
第三節 單變項分析 ……………………………………………………..79
第四節 多變項分析………………………………………………………79
第六章 討論…………………………………………………………………82
第一節 研究對象…………………………………………………………82
第二節 MMF用於頑固性腎絲球腎炎的臨床療效……………………..83
2.1以MMF治療MN的效果…………………………………………84
2.2 以MMF治療MCD的效果………………………………………87
2.3 以MMF治療FSGS、IgAN和LN的效果………...……………89
第三節 以MMF治療GN的劑量與療程……………………………….91
第四節 併用藥品之使用…………………………………………………93
第五節 影響MMF治療後DPL降低的因子…………………………...94
第六節 MMF治療之副作用……………………………………………..96
第七節 研究限制…………………………………………………………97
第八節 未來研究方向……………………………………………………98
第柒章 結語…………………………………………………………………....99
參考文獻………………………………………………………………………100
附錄一 病患紀錄表格………………………………………………………..111
第二篇 臨床藥事服務 (Clinical Service)……………………………………113
一、目的………………………………………………………………………113
二、方法………………………………………………………………………113
三、紀錄方式…………………………………………………………………113
四、結果………………………………………………………………………114
第一節 腎衰竭患者的常見疾病與藥物治療…………………………….114
1.1急性腎衰竭 (Acute renal failure, ARF)…………………………….114
1.1.1 定義……………………………………………………………114
1.1.2 急性腎衰竭相關之危險因子…………………………………115
1.1.3 急性腎衰竭的分類和治療……………………………………116
1.1.4 急性腎衰竭相關檢驗數值的變化 (鑑別診斷)………………116
1.1.5 急性腎衰竭電解質異常的治療……………………………….117
1.1.6 急性腎衰竭的預防…………………………………………….118
1.2慢性腎衰竭 (chronic renal failure, CRF)……………………………119
1.2.1 慢性腎病 (chronic kidney disease, CKD) 之定義……………119
1.2.2 常見併發症與治療…………………………………………….120
1.2.3 慢性腎衰竭患者藥物治療注意事項………………………….124
1.3 血液透析 (Hemodialysis)…………………………………………..125
第二節 藥物諮詢…………………………………………………………..127
2.1 抗生素治療相關問題………………………………………………129
2.1.1腎衰竭患者預防術後感染抗生素之使用……………………..129
2.1.2 Teicoplanin用於CAPD患者腹膜炎的劑量…………………130
2.1.3血液透析患者抗結核藥物的使用……………………………131
2.1.4 Isepamicin 在透析患者的使用……………………………….133
2.2 腎病症候群患者的利尿劑治療…………………………………..135
2.3 腎功能不全患者的降血糖藥物…………………………………..138
第三節 藥物不良反應評估………………………………………………140
五 結語……………………………………………………………………….141
參考文獻……………………………………………………………………... 142

表目錄
第一部分 腎絲球腎炎之藥物治療
表一 原發性腎絲球腎炎之組織學分類…………………………………3
表二 次發性腎絲球腎炎之分類…………………………………………3
表三 腎絲球腎炎以腎病症候群以及腎炎症候群表現的傾向…………8
表四 腎絲球腎炎與診斷之特殊血清免疫學標記………………………9
表五 腎絲球腎炎藥物治療的重大發展………………………………11
表六 研究證據強度之分級 (Level of evidence for studies )…………12
表七 建議等級 (Grades of recommendations)…………………………12
表八 以類固醇 (pednisolone) 治療原發性MN的臨床研究…………15
表九 免疫抑制劑治療MN的控制性試驗……………………………19
表十 以類固醇治療局部節段性腎絲球硬化症(FSGS)患者
(療程大於六個月) 的研究報告…………………………………30
表十一 狼瘡性腎炎 (LN) 的WHO病理分類 …………………………37
表十二 以Cyclophophamide和azathiopurine治療狼瘡性腎炎 (LN)
之隨機控制研 (RCT)……………………………………………38
表十三 一般健康者和器官移植患者的口服MMF藥動學參數 ………44
表十四 口服一公克MMF在特殊族群的藥動學參數 …………………45
表十五 MMF治療原發性GN的非控制性試驗…………………………53
表十六 MMF治療LN的非控制性試驗…………………………………57
表十七 17位接受MMF治療腎絲球腎炎病患之基本資料……………66
表十八 17位病患之基本資料以及MMF使用之療程與劑量…………67
表十九 全部病患以及各組中,接受MMF治療前後每日尿液
流失蛋白量 (DPL)、血清肌酐酸 (SCr)、肌酸酐廓清
率 (creatinine clearance, CrCl)、白蛋白 (albumin) 和
膽固醇 (choletserol) 的變化,以平均值 (�b 標準差)
和中位數 (範圍) 表示。……………………………………………………70
表二十 膜性腎病變 (MN) 患者接受MMF治療之過程…………………73
表二十一 五位微細腎病變 (MCD) 患者接受MMF治療之過程…………76
表二十二 FSGS、IgA和LN患者使用MMF治療之過程…………………78
表二十三 17位GN患者接受MMF治療後,DPL降低與變異
因子之單變項分析…………………………………………………………80
表二十四 17位GN患者接受MMF治療後,DPL降低與變異因子
之多變相分析…………………………………………………………………81
表二十五 復發MN患者以MMF治療和追蹤…………………………………86
第二部分 臨床藥事服務
表一 九十一年十月份至九十二年四月份藥物諮詢項目之統計………127
表二 九十一年十月份至九十二年四月份藥物不良反應評估統計……140
附錄表格…………………………………………………………………………145


圖目錄

圖一 腎絲球腎炎的調控機制…………………………………………………5
圖二 MCD的藥物治療………………………………………………………27
圖三 MMF與MPA的化學結構……………………………………………39
圖四 MMF與其他免疫抑制劑藥理作用位置………………………………41
圖五 MMF作用機轉與嘌呤生合成路徑……………………………………42
圖六 MMF的體內代謝過程…………………………………………………46
圖七 MMF治療GN的可能機轉……………………………………………49
圖八 (A)每日尿液流失蛋白量 (DPL)、(B) 血清肌酐酸 (SCr)、
(B)肌酐酸廓清率 (CCr)、(D) 血清白蛋白 (serum albumin)、
(E) 膽固醇 (choletserol) 在MMF治療前後的變化……………69
圖九 MN病患在MMF治療前後DPL的變化…………………………………72
圖十 MCD病患在MMF治療前後DPL的變化………………………………75
參考文獻 第一篇 腎絲球腎炎的藥物治療

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第二篇 臨床藥事服務(Clinical Service)

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------------------------------------------------------------------------ 第 6 筆 ---------------------------------------------------------------------
系統識別號 U0026-0812200910445348
論文名稱(中文) 超臨界二氧化碳製備微奈米阿司匹靈膠囊粒子及控制釋放之模擬胃液研究
論文名稱(英文) The Preparation and Controlled Release Behavior of Sub-micro Aspirin/Ethyl Cellulose Particles Produced by Supercritical Carbondioxide
校院名稱 成功大學
系所名稱(中) 化學系碩博士班
系所名稱(英) Department of Chemistry
學年度 91
學期 2
出版年 92
研究生(中文) 吳漢鐘
學號 l3690116
學位類別 碩士
語文別 中文
口試日期 2003-07-18
論文頁數 90頁
口試委員 指導教授-黃宏欣
指導教授-黃平志
指導教授-許清雲
指導教授-黃守仁
指導教授-葉茂榮
指導教授-桂椿雄
關鍵字(中) 超臨界流體
藥物控制釋放
微奈米粒子
超臨界流體增大/分散溶液
微膠囊粒子
多孔性微粒子
關鍵字(英) supercritical fluids
microspheres
microcapsules
solution enhanced/dispersion by supercritical fl
controlled-release
micro to nano particle
學科別分類
中文摘要 藥物與人類是密不可分的,不論是醫藥、農藥等產品,都與日常生活息息相關,有些藥物若投藥過量會產生副作用或造成農作及環境的傷害,而藥量太少則失去藥效,因此藥物控制釋放遂成為藥物應用重要的一環;本實驗以超臨界二氧化碳為工具藉以製備藥物控制釋放粒子,一方面減少有機溶劑的使用,一方面則可藉其絕佳的滲透性來去除藥劑中殘留的有機溶劑而避免投藥所造成的傷害。
超臨界流體製造微奈米級粒子技術常被應用在兩個方面:一為製造高表面積比的微粒子,此類粒子多應用在反應的催化;另一為雙物質系統,利用超臨界流體所製備出的多孔性微粒子(microspheres)吸附揮發性物質,或以基質包覆藥物形成微膠囊(microcapsules),以達到控制釋放之效果。
由超臨界製程所製備出的催化劑粒子,具有相當大的孔洞體積,因而增大其表面積以增強催化效果,並能減少用量,降低成本。所製得之多孔性高分子可使藥物均勻分佈在內而緩解釋出。此外,超臨界流體可經由特殊的設計來製造微膠囊;如超臨界流體增大/分散溶液-Solution Enhanced Dispersion by Supercritical fluids (SEDS)所製造出來的微膠囊粒子可應用在藥物遞送元件中,並提供多方面的研究。
本論文主要分為兩部份探討:一為SEDS製程中各變因對製得粒子尺寸的影響,其中包含膨脹槽的壓力及溫度、藥物及基質的質量比以及藥物及基質溶液的流速等;另一則為所製得之阿司匹靈/乙基纖維素粒子在模擬胃液中控制釋放的研究及其釋藥動力模式,其中包括粒子尺寸、藥物基質質量比及其流速快慢對所得粒子在模擬胃液中的釋藥行為及釋藥模式的影響並做一系列的探討。
英文摘要 Medicines are important for human beings. Both medical and chemical products are related as closely as each breath to the daily live. Some drugs would induce side effect or damage the crops and environment by overdosing or cumulating, but lose its effect by not enough dosing. To overcome the situation, controlled-release of drugs becomes an important issue. This study is to producing controlled-release drug by supercritical carbondioxide process which has the benefit of decreasing the consuming of organic solvent.
The techniques of making sub-micro particles by supercritical fluid process are applicated in two territories: one is to make micro particles with high surfacing area to catalyze reactions; the other is composite system for microspheres or microcapsules; the former can absorb vaporous compounds, the latter are medicine-encapsulate by polymeric matrixes. Both of them have controlled release behavior.
Catalytic particles made by supercritical fluids have quite large pore volume to induce its catalytic power, reduce the necessary amounts of catalysis and lower the costs. Drug releasing for microspheres could also be controlled. Besides, microcapsules can be made by supercritical fluid techniques such as solution enhanced/dispersion by supercritical fluids (SEDS).
This thesis contains two parts: one is the studying on each factor in SEDS that could influences on particle size such as the pressure and the temperature of expansion vessel, the ratio of drug/matrix and the flow rate of drug and matrix solution. The other is the controlled-release behaviors of aspirin/ethyl cellulose sub-micro particles in synthetic gastric juice. The factors which affect the conditions and the mode of drug releasing include the particle size, drug/matrix ratio and the flow rate of solutions would be discussed.
論文目次 誌謝……………………………………………………………………..Ⅰ
摘要…………………...…………………………………………...…....Ⅲ
英文摘要……………………………………………………………….Ⅴ
目錄……………………………………………………………………..Ⅶ
表目錄…………………………………………………………………..Ⅹ
圖目錄………………………………………………………….…...ⅩⅠ


第一章 緒論……………………………………………………………1

第二章 控制釋放技術…………………………………………………3
2-1 藥物控制釋放技術…………………………………………….3
2-2 傳統藥劑與控制釋放藥劑釋藥途徑的比較………………….5
2-3 控制釋放微粒釋藥情形……………………………………...10
2-4 藥物控制釋放動力模式……………………………………...16

第三章 微粒包覆技術………………………………………………..20
  3-1 微粒包覆技術…………………………….…………………..20
  3-2 微粒包覆製程簡介……………………….…………………..22
第四章 超臨界流體製備微奈米粒子………………………………..25
  4-1 超臨界流體的定義…………………………………………...25
  4-2 超臨界流體的特性…………………………………………...27
  4-3超臨界二氧化碳………………..…………………………...27
4-4 超臨界流體製備微奈米粒子技術…………………………28

第五章 實驗內容 …………………………………………………….37
  5-1 實驗設備……………………………………………………...37
5-1-1 超臨界流體增大/分散溶液(SEDS)實驗裝置………...37
5-1-2 模擬胃液控制釋放實驗………………………………37
5-1-3 藥品及溶劑……………………………………………...39
  5-2 實驗架構……………………………………………….……..39
5-2-1 膨脹槽壓力與溫度……………………………………...41
5-2-2 藥物基質比及溶液流速………………………………...41
5-3 分析部份……………………………………………………...43
5-3-1 檢量線的配製…………………………………………...43
5-3-2 模擬胃液的組成……...…………………………………43
5-3-3 粒子中的藥物分析...…………………………………44
5-3-4 模擬胃液實驗...…………………………………………44
5-3-5 粒子尺寸分析...…………………………………………45
第六章 結果與討論…………………………………………………..46
6-1溫度與壓力對粒子尺寸之影響………………………………46
6-1-1膨脹槽壓力對粒子尺寸之影響…………………………52
6-1-2膨脹槽溫度對粒子尺寸之影響…………………………52
6-2藥物基質比與溶液流速對粒子尺寸之影響…………………56
6-2-1藥物基質比對粒子尺寸之影響……….…..……………56
6-2-2溶液流速對粒子尺寸之影響…………….……………61
6-3流速與藥物基質比對模擬胃液實驗之影響…………………63
6-4模擬胃液實驗之動力模式探討………………………………69
6-5 膨脹槽內徑大小對粒子尺寸及模擬胃液…………………...79

第七章 結論…………………………………………………………..84

參考文獻………………………………………………………………..85

表 目 錄

表一 氣體、超臨界流體與液體的一般物理性質…………………….27
表二 各種化合物的超臨界性質………………………………………29
表三 藥品列表………………………………………………………....39
表四 實驗設計(1)……………………………………………………...42
表五 實驗設計(2)……………………………………………………...42
表六 各實驗條件所得之粒子尺寸……………………………………51
表七 各製程的粒子尺寸………………………………………………62
表八 不同膨脹槽尺寸所得之粒徑大小………………………………79

圖 目 錄

圖1 一般藥劑釋放的輸送途徑………………………………………..6
圖2 控制釋放劑型的輸送途徑………………………………………..6
圖3 藥物釋放濃度與時間之關係……………………………………11
圖4 儲主式形狀及其藥物釋放速率與時間之關係…………………12
圖5 非儲主式形狀及其藥物釋放速率與時間之關係………………12
圖6 理想的零階釋放動力模式 (a)釋藥速率與時間的關係圖;(b)釋
藥總量與時間的關係圖…………………..……………………14
圖7 時間延遲及突釋效應……………………………………………15
圖8 一般純物質之三相…………………………………………...….26
圖9 RESS製程流程…………………………………………………32
圖10 GAS/SAS製程流程…………………………………….………34
圖11 SEDS製程流程圖……………………………………………...36
圖12 SEDS三套管設計圖…………………………………………...36
圖13 自組SEDS裝置流程圖……………………………………….…38
圖14 實驗架構…………………………………………………………40
圖15 在藥物基質比(D:M = 1:1)及高流速條件下膨脹槽溫度為40 ℃、膨脹槽壓力分別為 (a) 800 psi;(b) 1200 psi;(c) 2000 psi;(d) 3000 psi所製得之粒子…..…………………………………47
圖16 在藥物基質比(D:M = 1:1)及高流速條件下膨脹槽溫度為50 ℃、膨脹槽壓力分別為 (a) 800 psi;(b) 1200 psi;(c) 2000 psi;(d) 3000 psi所製得之粒子……………….….…………………48
圖17 在藥物基質比(D:M = 1:1)及高流速條件下膨脹槽溫度為60 ℃、膨脹槽壓力分別為 (a) 800 psi;(b) 1200 psi;(c) 2000 psi;(d) 3000 psi所製得之粒子………………...….…………………49
圖18 在藥物基質比(D:M = 1:1)及高流速條件下膨脹槽溫度為70 ℃、膨脹槽壓力分別為 (a) 800 psi;(b) 1200 psi;(c) 2000 psi;(d) 3000 psi所製得之粒子………………...….…………………50
圖19 粒子尺寸與膨脹槽壓力之關係圖…….…………….…………..53
圖20 粒子尺寸與膨脹槽溫度之關係圖…………..…………………..55
圖21 D:M=1:2高流速製程製得粒子之光學顯微鏡圖….....……..57
圖22 D:M=1:2低流速製程製得粒子之光學顯微鏡圖….....……..58
圖23 D:M=1:1高流速製程製得粒子之光學顯微鏡圖….....……..59
圖24 D:M=1:1低流速製程製得粒子之光學顯微鏡圖….....……..60
圖25 D:M=1:2中高低流速釋藥總量與時間的關係圖…….……..64
圖26 D:M=1:1中高低流速釋藥總量與時間的關係圖…….……..65
圖27 D:M=2:1中高低流速釋藥總量與時間的關係圖…….……..66
圖28 高流速中不同藥物基質比釋出阿司匹靈總量…………….….67
圖29 低流速中不同藥物基質比釋出阿司匹靈總量…………….….68
圖30 藥物基質比1:2高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..70
圖31 藥物基質比1:1高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..72
圖32 藥物基質比2:1高流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..74
圖33 藥物基質比1:2低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..75
圖34 藥物基質比1:1低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..77
圖35 藥物基質比2:1低流速製程製得粒子之釋藥總量與時間的關係圖……………………………………………………………..78
圖36 D:M = 1:1大槽製程;膨脹槽壓力(P = 1200 psi)、膨脹槽溫度(T = 60 ℃)……………………………………………………....80
圖37 大槽製程製得粒子之阿司匹靈釋放總量與時間的關係圖…..81
圖38 不同膨脹槽尺寸所製得粒子之阿司匹靈釋放總量與時間的關
係圖(◆)5/4 in” id.(▓)1/2 in” id. …..……………………….82
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