臺灣博碩士論文加值系統

人參為臨床上常用在單、複方方劑中的藥材，而中藥藥材面臨許多議題，如品質管制、有效成分分析及潛在中西藥併用產生之交互作用。本研究以人參為主軸，分別探討其人參皂苷活性成分、人參與帕金森氏症常用藥品-selegiline之藥物動力學交互作用以及人參對MPTP誘導產生parkinsonian syndrome之神經性保護作用。第一部分，以建立簡單、選擇性高之高效液相層析串聯式質譜儀分析方法，針對常見人參皂苷：ginsenoside Rb1、ginsenoside Rb2、ginsenoside Rc、ginsenoside Rd、ginsenoside Re及ginsenoside Rg1，應用於12種不同來源人參的有效成分分析，可作為人參品質管制的參考依據。第二部分，為中西藥併用之交互作用探討，使用清醒且能自由移動的大鼠(freely-moving rat)口服人參五天後，再口服給予治療帕金森氏症Monoamine oxidase inhibitor類藥物-司蘭吉林(selegiline)，以藥物動力學之角度討論人參是否會影響selegiline於血中藥物的濃度變化。結果顯示，當服用人參(1 g/kg, p.o.)時，CL上升，伴隨AUC顯著的下降。第三部分，以預防之方式給予口服人參7 天後，利用MPTP誘導小鼠產生parkinsonian syndrome，以動物行為、神經傳導物質層面、免疫組織染色Tyrosine hydroxylase之含量，三方面研究人參對神經性保護作用之潛能，預口服人參組相較於疾病誘導組，能夠增強大鼠行為活動量及增加腦內多巴胺之量，達到神經性保護作用，以上結果可提供臨床中西併用藥參考。

Ginseng is frequently used as clinlical Traditional Chinese Medicine (TCM) prescription; however, traditional herb was confronted with plenties of issue such as quality control, analysis of bioactive components and potential herb-drug interactions.
In this study, three aims were investigated to analysis the active compound ginsenosides, to explore the herb-drug pharmacokinetics interaction between ginseng and Parkinson drug, and to consider the neuroprotective effects of ginseng on MPTP-induced parksonian syndrome. First of all, a rapid and vadilated UPLC-MS/MS method was established for ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rc, ginsenoside Rd, ginsenoside Re and ginsenoside Rg1. The method was successfully applied to analysis different sources of ginseng could be regarded as the reference of ginseng quality control. Second part of this study concerned the potential herb-drug pharmacokinetic interactions, a freely-moving rat model was selected to discuss whether co-administred ginseng and selegiline, a commom Parkinson drug, would affect the Pharmacokinetic parameters of selegiline in rats. The results showed that when ginseng (1 g/kg, p.o.) was taken, CL increased with a significant decrease in AUC of selegiline. The last part of the study is to discuss the neuroprotective effects of ginseg from three aspects: animal behavior, neurotransmitters level, and immunostaing of Tyrosine hydroxylase intensity with pretreating ginseng before MPTP-induced mice parksoniam syndrome. Compared with the disease-inducing group, the pretreatment ginseng group can increase the behavioral activity and the amount of dopamine in the brain in rats to achieve neuroprotective effects. The above results can provide clinical reference while facing the issue of herb-drug interaction.

目錄
誌謝 I
目錄 III
附表目錄 VI
附圖目錄 VIII
摘要 IX
英文摘要 X
第一章 緒論 1
第一節 帕金森氏症 1
一、 帕金森氏症簡介 1
二、 帕金森氏症之機轉 2
三、 帕金森氏症處方用藥 3
四、 帕金森氏症臨床治療方針 4
五、 誘導腦部組織退化的帕金森氏症動物模式 5
第二節 人參 7
一、 人參基原介紹 7
二、 人參之活性成分 7
三、 現代藥理作用 8
第三節 司蘭吉林（selegiline） 9
一、 司蘭吉林（selegiline）介紹 9
第四節 超高效能液相層析串聯質譜儀 11
一、 層析法之概述 11
二、 高效液相層析法(High performance liquid chromatography, HPLC) 11
第五節 分析方法確效 14
一、 選擇性 (selectivity) 14
二、 準確度 (accuracy)及 精確度 (precision) 14
三、 基質效應 (matrix) 及 回收率 (recovery) 15
四、 線性關係與靈敏性 16
五、 安定性 (stability) 16
第六節 藥物動力學 17
一、 藥物動力學之概述 17
二、 藥物動力學之腔室模式 18
三、 藥物動力學之参數 20
四、 線性藥物動力學以及非線性藥物動力學 23
第七節 藥物效力學 24
一、 藥物效力學(Pharmacodynamics, PD)概述 24
二、 神經傳導物質(Neurotransmitters) 24
第三章 研究動機與目的 27
第四章 實驗材料與研究方法 28
第一節 實驗材料 28
一、 化學試藥 28
二、 試劑 28
三、 實驗儀器 29
四、 實驗動物 31
五、 分析軟體 31
第二節 人參皂苷之分析方法開發 32
一、 人參萃取製備 32
二、 人參來源 32
三、 超高效液相層析串聯質譜儀 (UPLC-MS/MS) 32
四、 人參皂苷 ginsenoside標準品儲備溶液及檢量線配置 34
五、 人參含量分析 34
第三節 司蘭吉林之分析方法開發 35
一、 selegiline 標準品儲備溶液配置 35
二、 selegiline於大鼠血漿之檢量線配置 35
三、 超高效液相層析串聯質譜儀 (UPLC-MS/MS)之分析條件 35
第四節 人參對於selegiline 藥物動力學影響 36
一、 實驗動物模式-清醒狀態下動物模式 (Freely-moving rat) 36
二、 實驗動物模式-靜脈注射組別 38
三、 藥物動力學分析 39
第五節 人參對於parkinsonian syndrome 延緩腦部退化之藥效學 39
一、 MPTP 藥物誘導parkinsonian syndrome 之動物模式 39
二、 小鼠動物行為學測試 40
三、 高效液相層析電化學之分析條件(HPLC-ECD) 41
四、 神經傳導物質及其代謝物標準品檢量線製作 41
五、 紋狀體(striatum)內神經傳導物質含量分析 42
六、 免疫組織染-紋狀體(striatum)內tyrosine hydroxylase含量 42
第五章 實驗結果 45
第一節 不同來源之人參皂苷含量分析 45
一、 超高效液相層析串聯式質譜儀(UPLC-MS/MS)之分析條件 45
二、 高效液相層析串聯式質譜儀(UHPLC-MS/MS)之分析方法確效 45
三、 分析方法應用-各人參含量分析 46
第二節 人參對於司蘭吉林之草藥與西藥藥物動力學交互作用 46
一、 超高效液相層析串聯式質譜儀(UPLC-MS/MS)之司蘭吉林分析條件 46
二、 超高效液相層析串聯式質譜儀(UPLC-MS/MS)之分析方法確效 47
三、 人參對司蘭吉林之藥物動力學影響 49
第三節 人參對於parkinsonian syndrome 延緩腦部退化之藥效學 50
一、 小鼠動物行為學測試及評估 50
二、 紋狀體(striatum)內神經傳導物質含量分析 51
三、 紋狀體(striatum)免疫組織染色-tyrosine hydroxylase 52
第六章 討論 54
第一節 不同來源之人參皂苷含量 54
第二節 人參對於selegiline之草藥與西藥藥物動力學交互作用 55
第三節 人參對於parkinsonian syndrome 延緩腦部退化之藥效學 56
第七章 結論 58
第八章 參考資料 59


附表目錄
Figure 1. Structures of ginsenosides. (a) panaxadiol group (b) panaxatriol group 67
Figure 2. Product ion mass spectra of seven marker compounds: (a) ginsenoside Rb1 (b) ginsenoside Rb2 (c) ginsenoside Rc (d) ginsenoside Rd (e) ginsenoside Re(f) ginsenoside Rg1 70
Figure 3. Multiple reaction monitoring (MRM) chromatograms of the analytes. 71
Figure 4. Mass spectra of (A) selegiline m/z 188.12->118.98 (B) noscapine (internal standard) m/z 414.29->220.11 72
Figure 5. Representative MRM chromatograms of (A)blank plasma of selegiline and noscapine (B) blank plasma spiked with selegiline 100 ng/mL ; peak 1 : noscapine (internal standard)/ peak 2 : selegiline (C) plasma sample containing selegiline 99.55 ng/mL collected at 15 min after selegiline administration ( 30 mg/kg, p.o.) + Panax ginseng ( 3 g/kg, p.o., daily, 5 days) ; peak 1 : noscapine (internal standard)/ peak 2 : selegiline 73
Figure 6. Concentration-time curve of selegiline in rat plasma. The groups with selegiline (30 mg/kg, p.o.) administration alone (n=6); pretreatment groups with Panax ginseng (3 g/kg, p.o., for consecutive 5 days) and selegiline (30 mg/kg, p.o.) administration (n=6); pretreatment groups with Panax ginseng (1 g/kg, p.o., for consecutive 5 days) and selegiline (10 mg/kg, i.v.) administration (n=6). Data are expressed as mean ± S.D. 74
Figure 7. Effect of Panasx ginseng on total distance in movement traces in the Open Field Test. (A) The trace movement of each group by TruScan software. (B) The total distance of each group. Data were expressed as mean SD. (n=6) 75
Figure8. Rotarod performance in different experimental group. 76
Figure 9. The HPLC-ECD chromatographs of standard neurotransmitters 50 ng/mL (1) norepinephrine (2) epinephrine (3) dopamine (4) DOPAC (5) 5HIAA (6) 5HT (7) HVA 77
Figure 10. The HPLC-ECD chromatographs of neurotransmitters in striatum 78
Figure 11. (A)Effects of Panax ginseng on the expression level of TH in the striatum, of control and experimental mouse(a) control group (b)MPTP group (c)MPTP +ginseng 2 g/kg group(d) MPTP +ginseng 6 g/kg group 79
附圖目錄
Table 1. Twelve different sources of ginseng were provided for this study, and the average content of ginsenosides was divided by the scientific name and cultivation method. 80
Table 2. Method validation of intra-day (precision and accuracy) for the ten determinations of ginsenosides from standard samples. 81
Table 3. The content of ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rc, ginsenoside Rd, ginsenoside Re, and ginsenoside Rg1 of twelve ginseng sources. The average content of ginsenosides was categorized by the scientific name and cultivation method. 83
Table 4. Intra-assay and Interday-assay precision (%RSD) and accuracy (%Bias) of the LC –MS/MS method for the determination of selegiline in plasma 85
Table 5 86
Table 6. Stability of selegiline in rat plasma 87
Table 7. Pharmacokinetic parameters of selegiline in rat 88
Table 8. Effects of Panax ginseng C.A. Meyer on total distance in movement traces in the Open Field test. 89
Table 9. Rotarod performance in different experimental groups. 90
Table 10. Effect of Panax ginseng C.A. Meyer on MPTP-induced loss of striatal dopamine ,serotonin and its metabolites. 91

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