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系統識別號 U0007-0108201115150700
論文名稱(中文) 不同粒徑丹參的萃取物在順氯氨鉑引發之腎毒性於純系小鼠的藥效評估
論文名稱(英文) Effects of extracts from different particle sizes of Salvia miltiorrhiza on cisplatin-induced nephrotoxicity in inbred mice
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 99
學期 2
出版年 100
研究生(中文) 黃嘉君
研究生(英文) Chia-chun Huang
學號 M301097008
學位類別 碩士
語文別 中文
口試日期 2011-06-23
論文頁數 85頁
口試委員 委員-黃旭山
委員-李仁愛
指導教授-陳世銘
中文關鍵字 cisplatin 腎毒性      TNF-α  p21  PCNA 
英文關鍵字 cisplatin nephrotoxicity  danshen  TNF-α  p21  PCNA 
學科別分類
中文摘要 癌症是全球導致死亡的主要原因之一。在台灣,癌症更是連續二十九年蟬聯十大死因之首。因此,癌症的預防與治療日漸成為全球醫療發展的重要目標。順氯氨鉑 (cis-diamminedichloroplatinum (II);CDDP) 在臨床上廣泛用於固體癌症的化學治療,對頭頸癌、食道癌、卵巢癌、睪丸癌、膀胱癌、子宮頸癌等癌症的單一或合併治療都有良好的效果,但CDDP 引起的腎毒性卻成為限制其使用的主因之一。丹參 (Salvia miltiorrhiza) 在中醫常作為活血去瘀、調經止痛、養血安神與涼血消廱的用藥。近幾年,丹參被發現有抗氧化與抗發炎等功效,且具有抗癌的活性,故也逐漸在西方醫學中受到重視。
本研究的目的為比較由不同粒徑丹參所抽提的萃取物,探討其對
CDDP 引起腎毒性的預防效果。實驗以六週齡的BALB/c 雌鼠作為實
驗動物,以腹腔注射的方式給予CDDP 5 mg/kg/day,藉以引起腎炎,
並在投予CDDP 前5 天開始經口投予丹參粗粉與細粉的萃取物 (300
mg/kg/day、600 mg/kg/day、900 mg/kg/day),以評估其對於預防CDDP引起腎炎的療效。結果顯示, 丹參粗細粉萃取物對於N-acetyl-β-D-glucosaminidase (NAG)、尿中肌酸酐 (urine creatinine)、
尿蛋白 (urine protein) 與血中尿素氮 (BUN) 皆有不同程度的改善效果;腎組織損傷相較於對照組也有明顯減緩的趨勢。免疫螢光染色也觀察到投予丹參粗細粉萃取物的組別,TNF-α 表現量明顯下降,p21及PCNA 的表現也有不同程度的增加;但在相同劑量下,丹參粗粉
與細粉萃取物間對於各項指標的改善並沒有統計上的差異。
綜合本實驗的結果可推論,經口投予丹參粗細粉萃取物可透過抑
制發炎反應、降低氧化壓力等機制來保護腎臟,減低使用CDDP 對腎臟造成的傷害。但未來仍需更多實驗來佐證不同粒徑丹參的萃取物對於腎臟的保護效果是否會有差異。
英文摘要 Cancer is a global concern because it is a leading cause of death worldwide. In Taiwan, cancer has ranked the number-one cause of death for many years. In recent years, prevention and treatment for cancer become an important issue in the world.
Cisplatin (cis-diamminedichloroplatinum (II);CDDP) is one of the most widely used antineoplastic agents in the treatment of solid tumor and haematological malignancies. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of CDDP. Danshen, the dried root of Salvia miltiorrhiza, is a commonly used traditional Chinese medicine (TCM) for improving body function. In recent years, danshen has been shown to reduce reactive oxygen species (ROS) for antioxidative effect. And it can suppressed the expression of pro-inflammatory cytokines to decrease inflammatory reactions.
The aim of this study is to investigate the kidney damage caused by CDDP administration and to evaluate the effects of treatment with prevention drugs. The prevention drugs were extracted from different particle sizes of danshen. In this animal study, six-week-old female
BALB/c mice were administered with 5 mg/kg/day of CDDP
intraperitoneally (i.p.) for 5 days. Prevention drugs including 300, 600, 900 mg/kg/day extracts from different particle sizes of danshen were given orally once daily from 5 days before CDDP administration, respectively. The result reveals the treatment groups showed improvements in urine N-acetyl-β-D-glucosaminidase (NAG), urine creatinine excretion, urine protein and blood urea nitrogen (BUN) at
different levels. And the treatment groups ameliorated CDDP-induced renal morphological damages, reduced tumor necrosis factor-α (TNF-α) in injury tissues, and increased the expression of p21, proliferating cell nuclear antigen (PCNA) in renal cells as well (p < 0.05). But the efficacy
has no significant differents between the extracts from different particle sizes of danshen.
This study demonstrated that extracts of danshen might attenuated
CDDP-induced nephrotoxicity. But the particle sizes might not be a powerful factor to affect the efficacy. Nevertheless, it may need more future studies to confirm the renoprotective effect between the extracts from different particle sizes of danshen.
論文目次 目錄 ............................................................................................................. I
圖目錄 ........................................................................................................ V
表目錄 ..................................................................................................... VII
縮寫表 ......................................................................................................... i
中文摘要 ................................................................................................... iii
Abstract ...................................................................................................... v
第一章 緒言............................................................................................... 1
第二章 文獻回顧 ...................................................................................... 4
第一節 順氯氨鉑 (cisplatin) 的作用機轉與臨床使用 ....................... 4
第二節 cisplatin 引起腎毒性的機轉 ................................................... 10
2.1 概論 .............................................................................................. 10
2.2 腎臟對CDDP 的吸收與代謝 ..................................................... 10
2.3 氧化壓力 ...................................................................................... 11
2.4 發炎反應 ...................................................................................... 12
2.5 細胞死亡 (cell death) .................................................................. 12
2.6 細胞週期的調控 .......................................................................... 13
2.7 p53、p21 與PCNA 對細胞週期的調控 .................................... 15
第三節 Cisplatin 引起腎毒性的臨床表徵與預防 .............................. 22
第四節 丹參及其藥效研究 ................................................................. 24
4.1 丹參的醫療應用史 ...................................................................... 24
4.2 丹參的藥效研究 .......................................................................... 24
第五節 生藥粒徑與藥效的關係 ......................................................... 28
第三章 研究目的 .................................................................................... 30
第四章 材料與方法 ................................................................................ 31
第一節 丹參粒徑及指標成分的分析研究 ......................................... 31
1.1 實驗試藥 ...................................................................................... 31
1.2 儀器裝置 ...................................................................................... 32
1.3 雷射粒徑分析儀粒徑分析 .......................................................... 33
1.4 掃描式電子顯微鏡粒徑分析 ...................................................... 33
1.5 紅外光光譜分析 .......................................................................... 33
1.6 丹參粗細粉萃取物中丹參酮IIA 與丹參酚酸B 的HPLC 分析
............................................................................................................ 34
第二節 不同粒徑丹參的萃取物在CDDP 引起腎炎模型的藥效評估
............................................................................................................... 36
2.1 實驗動物 ...................................................................................... 36
2.2 實驗藥物 ...................................................................................... 36
2.3 丹參粗細粉萃取物在此腎炎模型的實驗設計 .......................... 36
2.4 尿液收集 ...................................................................................... 37
2.5 動物犧牲法、血液及組織切片製作 .......................................... 37
2.6 尿中NAG、creatinine 及尿蛋白的含量分析 ........................... 38
2.7 血清中BUN 值的含量測定 ........................................................ 39
2.8 Periodoic acid-Schiff’s (PAS) stain 組織染色 ............................ 39
2.9 組織損傷程度的量化 .................................................................. 40
2.10 免疫螢光染色 (Immunofluorescence) ..................................... 40
2.11 統計方法 .................................................................................... 41
第五章 結果............................................................................................. 43
第一節 丹參粒徑及指標成分的分析研究 ......................................... 43
5.1 雷射粒徑分析儀粒徑分析 .......................................................... 43
5.2 掃描式電子顯微鏡粒徑分析 ...................................................... 43
5.3 紅外光光譜分析 .......................................................................... 43
5.4 丹參粗細粉萃取物中丹參酮IIA 與丹參酚酸B 的HPLC 分析
............................................................................................................ 44
第二節 不同粒徑丹參的萃取物在CDDP 引起腎炎模型的藥效評估
............................................................................................................... 54
2.1 尿中NAG、creatinine 及蛋白的含量分析 ............................... 54
2.2 血清BUN 分析 ............................................................................ 56
2.3 組織病理PAS 染色 ..................................................................... 56
2.4 組織損傷量化分析 ...................................................................... 56
2.5 免疫螢光染色 .............................................................................. 57
第六章 討論............................................................................................. 68
第一節 丹參粒徑及指標成分的分析研究 ......................................... 68
第二節 不同粒徑丹參的萃取物在CDDP 引起腎炎模型的藥效評估
............................................................................................................... 71
第七章 結論............................................................................................. 75
參考文獻 ................................................................................................... 77
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