臺灣博碩士論文加值系統

中醫藥在臨床用藥上有許多重要的議題，包括品質管制、多種指標成分分析缺乏臨床上的實證資料以及中西藥合併使用的問題。本研究對常見的黃耆製劑---黃耆桂枝五物湯進行物理性與化學性分析並且，希望能透過基礎實驗，對於黃耆相關製劑有更為完整的了解，以利於臨床應用。研究的第一個部分以高效液相層析串聯式質譜儀同時偵測黃耆桂枝五物湯中活性指標成分astragaloside I、astragaloside IV、formononetin、cinnamic acid、paeoniflorin 和 gingerol含量，並應用於市售科學中藥。為了提高指標成分或使藥品賦形，科學中藥常添加生藥粉末及澱粉，這些添加物可能會使中藥產品品質不穩定。因此利用掃描式電子顯微鏡、以剛果紅及碘化鉀染色後在光學顯微鏡下觀察、粗纖維試驗探討黃耆桂枝五物湯科學中藥添加物。透過物化性質的整合分析，了解黃耆桂枝五物湯及市售產品的特性。研究的第二部分為探討服用中藥黃耆桂枝五物湯後大鼠對於西洛他唑藥物動力學及藥物效力學的影響。西洛他唑有抗血小板凝血及舒張血管作用，跟黃耆桂枝五物湯一樣為治療周邊循環疾病的治療用藥。西洛他唑經由肝酵素CYP3A4、CYP2C19代謝，黃耆桂枝五物湯中的黃耆、生薑被證實可能對肝酵素造成直接或間接的影響，同時服用的情況下有產生藥物交互作用的疑慮。因此，在藥物動力學方面，我們利用高效液相層析結合光二及陣列偵測器來探討西洛他唑與黃耆桂枝五物湯之交互作用。在藥物效力學方面，利用雷射都卜勒血流儀來監測大鼠下肢的血流，評估黃耆桂枝五物湯與西洛他唑在藥物效力學的交互作用。研究結果顯示，黃耆桂枝五物湯並不顯著影響西洛他唑在Sprague-Dawley大鼠體內之藥物動力學與藥物效力學。藉由此動物實驗結果，期望提供臨床中西藥合併用藥安全性的參考依據。

Traditional Chinese medicine has raised many important clinical issues, such as quality of herb, multicomponent analysis, insufficient clinical evidence base, and the potential herb-drug interactions. The study investigated chemical and physical analysis and the potential interaction on the Western medicine for a traditional Chinese prescription, Huangqi-Guizhi-Wuwu decoction (HGW). The first object of study is to develop a validated liquid chromatography-tandem mass spectrometry with electrospray ionization to determine the biomarkers of astragaloside I, astragaloside IV, formononetin, cinnamic acid, paeoniflorin and gingerol in HGW. consistency and standardization for the quality of the herbal medicine are still controversial. Raw herbal powder and starch are also legal to add into the herbal pharmaceutical products to modify their content. It is important to inspect the content of Chinese herbal pharmaceutical products, as various additives may cause the quality of herbal pharmaceutical products to remain unknown. To evaluate the physical quality of HGW, a serious of methods such as scanning electron microscope, light microscopy photographs with Congo red and potassium iodine staining, crude fiber analysis were used to identify the additives in the commercial pharmaceutical products. The results demonstrate deviations in biomarker content and physical properties across different brands, suggesting the importance of the quality assessment for those commercial manufacturers. The second object of the study is evaluating a herb-drug interaction between HGW and cilostazol by pharmacokinetic and pharmacodynamic ways. Cilostazol has been used in clinical for the treatment of peripheral circular disease because of its antiplatelet and vasodilation which is similar to HGW. The liver enzymes of CYP3A4 and CYP2C19 are potentially the major metabolic pathway of cilostazol. Herbal medicine in HGW such as Zingiber officinale and Astragalus membranaceus have direct or indirect effect to those liver enzymes. There is concern about the potential herb-drug interaction if the traditional chinese medicine and western medicine has been co-administration. Therefore, the study evaluated the interaction between cilostazol and HGW by High Performance Liquid Chromatography- Photo Diode Array for pharmacokinetic. For pharmacodynamic, the limbs blood flow will be measured by laser doppler flowmeter. The results suggest that the cilostazol might not have significant interaction with HGW in Sprague-Dawley rats and the animal data can provide information for the clinical practice.

目錄....................................................I
附表目錄................................................IV
附圖目錄.... ...........................................IV
Abstract................................................V
中文摘要...............................................VII
第一章 緒論 1
第一節 黃耆製劑 1
一、 黃耆之簡介 1
二、 黃耆桂枝五物湯之簡介 1
三、 黃耆桂枝五物湯之主要活性成分與藥理研究 2
第二節 西洛他唑 (cilostazol) 3
一、 西洛他唑之簡介 3
二、 西洛他唑之臨床研究 3
第三節 整合性物理分析 4
一、 掃描式電子顯微鏡簡介 4
二、 光學顯微鏡與染劑簡介 4
三、 粗纖維試驗簡介 5
第四節 層析法 5
一、 層析法簡介 5
二、 高效能液相層析(High performance liquid chromatography) 5
三、 偵測器 6
第五節 分析方法確效 7
一、 選擇性 (Selectivity) 7
二、 準確度 (Accuracy) 與精確度 (Precision) 7
三、 線性關係 8
四、 回收率 (Recovery) 8
第六節 藥物動力學 8
一、 藥物動力學之概述與模式 8
二、 藥物動力學之參數 10
三、 線性藥物動力學以及非線性藥物動力學 12
第七節 藥物效力學 13
一、 藥物效力學之概述 13
二、 雷射督卜勒血流儀 (Laser doppler flowmetry) 13
第二章 研究動機與目的 14
第三章 實驗材料與研究方法 15
第一節 實驗材料 15
一、 化學試藥 15
二、 實驗儀器 16
三、 實驗動物 17
第二節 黃耆桂枝五物湯之分析方法開發 18
一、 黃耆桂枝五物湯製備與萃取 18
二、 高效液相層析結合串聯式質譜儀之分析方法 18
三、 黃耆桂枝五物湯活性成分定量 19
四、 黃耆桂枝五物湯物理性質分析 19
第三節 黃耆桂枝五物湯對於西洛他唑藥物之藥物交互作用影響 20
一、 高效液相層析儀之分析條件 20
二、 檢量線的配置及高效液相層析儀之方法確效 20
三、 動物模式及實驗設計 21
第四節 統計方法 22
第四章 實驗結果 22
一、 高效液相層析串聯質譜儀之分析結果 22
二、 分析系統之方法確效 23
三、 黃耆桂枝五物湯活性成分之定量結果 23
四、 黃耆桂枝五物湯物理性質 24
第二節 黃耆桂枝五物湯對於西洛他唑在藥物交互作用影響 24
一、 高效液相層析儀之西洛他唑及3,4-去氫西洛他唑分析結果及分析系統之方法確效 24
二、 黃耆桂枝五物湯對西洛他唑及3,4-去氫西洛他唑之藥物動力學影響 25
三、 黃耆桂枝五物湯對西洛他唑及3,4-去氫西洛他唑之藥物效力學影響 25
第五章 討論 26
第一節 黃耆桂枝五物湯活性成份之分析方法 26
第二節 黃耆桂枝五物湯中活性成分之含量分析與應用 26
第三節 黃耆桂枝五物湯物理性質 27
第四節 西洛他唑及3,4-去氫西洛他唑之分析方法 27
第五節 黃耆桂枝五物湯對於西洛他唑在藥物之交互作用 28
第六章 結論 30
第七章 參考文獻 31

附表目錄
Table 1. The LC-MS/MS conditions for the identification of the six active components, two internal standards for positive and negative ion mode. 38
Table 2. Intra-day and inter-day precision and accuracy of the six active components of HGW. 39
Table 3. The content of astragaloside I, astragaloside IV, formononetin, cinnamic acid, paeoniflorin, gingerol in lab-made herbal extract (EX) and five brands (A–E) of HGW herbal pharmaceutical products. 41
Table 4. Intra-day and inter-day precision and accuracy of the cilostazol and 3,4-dehydro-cilostazol 42
Table 5. Pharmacokinetic parameters of cilostazol and 3,4-dehydro-cilostazol in the rat plasma after intravenous administration 20 mg/kg cilostazol. 43
附圖目錄
Figure 1. The mass spectra and structures of six active components in HGW and two internals: (a) astragaloside I; (b) astragaloside IV; (c) formononetin; (d) cinnamic acid; (e) paeoniflorin; (f) gingerol; (g) carvedilol and (h) tolbutamide. 44
Figure 2. Scanning electron microscope images: (a) brand A; (b) brand B; (c) brand C; (d) brand D; (e) brand E; (f) herbal powder; (g) herbal powder: brand A = 1:1; (h) corn starch: herbal powder = 1:1 and (i) corn starch. 45
Figure 3. (a) Light microscopy images of Congo red stained samples: (a) brand A; (b) brand B; (c) brand C; (d) brand D; (e) brand E; (f) herbal powder; (g) herbal powder: brand A = 1:1, (h) corn starch: herbal powder = 1:1 and (i) corn starch. 46
Figure 4. Light microscopy images of iodine-KI stained samples: (a) brand A; (b) brand B; (c) brand C; (d) brand D; (e) brand E; (f) herbal powder; (g) herbal powder: brand A = 1:1; (h) corn starch: herbal powder = 1:1 and (i) corn starch. 47
Figure 5. Chemical structure of (a) cilostazol, (b) 3,4-dehydro-cilostazol, (c) 7-methoxyflavone 48
Figure 6. HPLC chromatograms (a) blank plasma, (b) blank plasma spiked with cilostazol (1 ug/mL) , 3,4-dehydro-cilostazol (1 ug/mL) and IS (1 ug/mL), (c) real plasma at 60 min after intravenous administration 20 mg/kg of cilostazol.*1: 3,4-dehydro-cilostazol, 2: cilostazol, 3: 7-methoxyflavone 49

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蔡翠敏；郭進安；鄭喻仁；沈佳錚；郭桂伶 2007. 藥品鑑定學 第二版: 合記
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