臺灣博碩士論文加值系統

順氯氨鉑 (cis-diamminedichloroplatinum (Ⅱ), CDDP) 是目前廣泛用於治療固體癌的化學治療藥物之一。此藥物的藥效良好，然而藥物引起的腎毒性卻成為臨床上限制其使用的主要原因。本研究目的即為評估人參及水楊酸鈉 (sodium salicylate, S) 於CDDP所引起之腎炎的預防效果，並進一步利用高壓液相層析法 (high performance liquid chromatography, HPLC) 定量所使用之人參中人參皂苷的含量。
實驗以六週齡雌鼠 (BALB/c mice) 為實驗動物，採取腹腔內注射方式連續五天給予CDDP 5 mg/kg/d以引發腎炎。在給予CDDP的前五天開始經口投予人參濃縮劑 (ginseng extract, GE) 250 mg/kg/d、S 100 mg/kg/d或合併GE+S作為預防藥物。在人參含量分析方面，實驗選用Inertsil ODS-2 column (4.6x150 mm, particle size 5 μm)，移動相為acetonitrile : H2O = 20 : 80 (ginsenoside Rg1) 及acetonitrile : H2O = 30 : 70 (ginsenoside Rb1與Rd)，測定波長為203 nm。
實驗結果顯示GE及S對於尿中N-acetyl-β-D-glucosaminidase (NAG)、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減緩的趨勢。在免疫螢光染色方面，TNF-α (tumor necrosis factor-α) 的量明顯減少，而p21及PCNA (proliferating cell nuclear antigen) 的表現則有不同程度的增加。在含量分析部份，實驗中使用之人參濃縮劑中人參皂苷含量經HPLC定量結果依序為Rb1＞Rg1＞Rd。
綜合實驗結果可推論，人參濃縮劑及水楊酸鈉透過其抑制發炎反應，阻止細胞週期的進展並促進DNA修復等作用，因此具有腎臟保護的效果。

Cisplatin (cis-diamminedichloroplatinum (Ⅱ), CDDP) is one of the most commonly used antineoplastic agents in the treatment of various solid tumors. However, the full clinical utility of CDDP is limited because of its dose-related nephrotoxic side effects. The purpose of this study was to evaluate the preventive effects of ginseng extract (GE) and sodium salicylate (S) on CDDP-induced nephrotoxicity in bred mice. Besides, this study also did quantitative analysis by high performance liquid chromatography (HPLC) to comfirm the quantity of ginsenosides in GE.
In this study, six-week-old female BALB/c mice were administered with 5 mg/kg/day of CDDP intraperitoneally for 5 days. Preventive drugs including 250 mg/kg of GE, 100 mg/kg of sodium salicylate, and combination of GE and S were given orally once daily from 5 days before CDDP administration respectively. Besides, in this quantitative analysis, ginsenosides have been separated and identified on an Inertsil ODS-2 column (4.6 x 150 mm, particle size 5 μm) with elution using acetonitrate and water (acetonitrile：H2O = 20 : 80 for ginsenoside Rg1；acetonitrile : H2O = 30 : 70 for ginsenoside Rb1 and Rd) as the mobile phase. The temperature was maintained room temperature, and detection wavelength was 203 nm.
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. Furthermore, the treatment groups ameliorated CDDP-induced renal morphological damages, diminished TNF-α deposited in injury tissues, and increased the expression of p21 and PCNA in renal cells as well. The result of HPLC revealed that GE contained more ginsenoside Rb1 than Rg1 and Rd.
Our findings demonstrated that GE and S attenuate CDDP-induced nephrotoxicity probably by inhibiting TNF-α expression and promoting cell cycle arrest to repair DNA damage.

目錄......................................................I
圖目錄....................................................V
表目錄..................................................VII
縮寫表....................................................i
中文摘要.................................................ii
Abstract.................................................iv
第一章 緒言...............................................1
第二章 文獻回顧...........................................4
第一節 順氯氨鉑 (Cisplatin) 的作用機轉及臨床使用........4
第二節 Cisplatin引起腎毒性的臨床表徵與機轉..............9
第三節 Cisplatin與細胞週期的調控.......................15
第四節 人參及其藥效研究................................23
4.1生藥學的考察.......................................23
4.2人參的藥效研究.....................................25
第五節 人參皂苷Rb1、Rg1及Rd之藥效研究..................30
5.1人參皂苷之結構特性.................................30
5.2人參皂苷Rb1之藥效研究..............................34
5.3人參皂苷Rg1之藥效研究..............................37
5.4人參皂苷Rd之藥效研究...............................39
第六節 水楊酸鈉 Sodium salicylate......................41
第三章 研究目的..........................................44
第四章 材料與方法........................................45
第一節 人參濃縮劑與水楊酸鈉在CDDP引起腎炎模型的藥效評
估..............................................45
1.1實驗動物...........................................45
1.2實驗藥物...........................................45
1.3人參濃縮劑與水楊酸鈉在此腎炎模型之實驗設計.........46
1.4尿液收集...........................................46
1.5動物犧牲法、血液及組織切片製作.....................46
1.6尿中NAG、creatinine及蛋白的含量分析................47
1.7血清中BUN值的含量測定..............................48
1.8 Periodoic acid-Schiff’s (PAS) stain組織染色......48
1.9組織損傷程度的量化.................................49
1.10免疫螢光染色 (Immunofluorescence) ................49
1.11統計方法..........................................50
第二節 人參濃縮劑中GS Rb1、Rg1與Rd含量分析.............52
2.1實驗試藥...........................................52
2.2儀器裝置...........................................52
2.3 HPLC條件..........................................52
2.4標準品配製與檢量線製作.............................53
2.5檢品配製...........................................53
2.6分析方法之精密度與準確度試驗.......................53
第五章 結果..............................................55
第一節 人參濃縮劑與水楊酸鈉在CDDP引起腎炎模型的藥效評
估..............................................55
1.1尿中NAG、creatinine及蛋白的含量分析................55
1.2血清中BUN分析......................................56
1.3組織病理PAS染色....................................57
1.4組織損傷量化分析...................................57
1.5免疫螢光染色.......................................57
第二節 人參濃縮劑中GS Rb1、Rg1與Rd含量分析.............68
2.1人參濃縮劑中GS Rb1、Rg1與Rd含量分析HPLC圖譜........68
2.2線性 (linearity) ..................................68
2.3分析方法之精密度與準確度...........................69
2.4人參濃縮劑中GS Rb1、Rg1與Rd之含量分析..............69
第六章 討論..............................................82
第一節 人參濃縮劑在CDDP引起腎炎模型的藥效評估.........82
第二節 水楊酸鈉在CDDP引起腎炎模型的藥效評估...........87
第三節 人參濃縮劑合併水楊酸鈉在CDDP引起腎炎模型的藥效
估.............................................90
第七章 結論..............................................92
參考文獻.................................................94

1.中華民國行政院衛生署. 中華民國九十六年死因統計. December, 2008.
2.世界衛生組織. Cancer: diet and physical activity''s impact. Accessed February 17th, 2009.
3.Healthcare T. Cisplatin. MICROMEDEX(R) Healthcare Series. Accessed February 17th, 2009.
4.Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: A review. American Journal of the Medical Sciences. 2007;334(2):115-124.
5.Rosenberg B, Van Camp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode [17]. Nature. 1965;205(4972):698-699.
6.Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cellular and Molecular Life Sciences. 2000;57(8-9):1229-1235.
7.Moucheron C. From cisplatin to photoreactive Ru complexes: Targeting DNA for biomedical applications. New Journal of Chemistry. 2009;33(2):235-245.
8.Ahmad S, Isab AA, Ali S. Structural and mechanistic aspects of platinum anticancer agents. Transition Metal Chemistry. 2006;31(8):1003-1016.
9.Zhou H, Kato A, Yasuda H, et al. The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure. Toxicology and Applied Pharmacology. 2004;200(2):111-120.
10.Chu G. Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. Journal of Biological Chemistry. 1994;269(2):787-790.
11.Skeel RT. Handbook of Cancer Chemotherapy. 7th ed; 2007.
12.George R. Aronoff WMB, Jeffrey S. Berns, Michael E. Brier, Nishaminy Kasbekar, Bruce A. Mueller, Deborah A. Pasko, William E. Smoyer. Drug Prescribing in Renal Failure. 5th ed; 2007.
13.Ali BH, Al Moundhri MS. Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: A review of some recent research. Food and Chemical Toxicology. 2006;44(8):1173-1183.
14.Kuhlmann MK, Burkhardt G, Kohler H. Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application. Nephrology Dialysis Transplantation. 1997;12(12):2478-2480.
15.Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: The first selective-target and broad-spectrum radioprotector. Oncologist. 2007;12(6):738-747.
16.Hartmann JT, Knop S, Fels LM, et al. The use of reduced doses of amifostine to ameliorate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anti-Cancer Drugs. 2000;11(1):1-6.
17.Fouladi M, Chintagumpala M, Ashley D, et al. Amifostine Protects Against Cisplatin-Induced Ototoxicity in Children With Average-Risk Medulloblastoma. J Clin Oncol. August 1, 2008 2008;26(22):3749-3755.
18.Healthcare T. Amifostine. MICROMEDEX(R) Healthcare Series. Accessed April 4th, 2009.
19.Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecologic Oncology. 1993;50(2):147-158.
20.Launay-Vacher V, Rey J-B, Isnard-Bagnis C, Deray G, Daouphars M. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemotherapy and Pharmacology. 2008;61(6):903-909.
21.Bachmeyer C, Decroix Y, Medioni J, et al. Hypomagnesemic and hypocalcemic coma, convulsion and eye movement disorders after chemotherapy with platinum compounds. COMA, CRISE CONVULSIVE ET TROUBLES DE L''OCULOMOTRICITE HYPOMAGNESEMIQUES ET HYPOCALCEMIQUES APRES CHIMIOTHERAPIE PAR SELS DE PLATINE. 1996;17(6):467-469.
22.Daugaard G, Abildgaard U. Cisplatin nephrotoxicity. Cancer Chemotherapy and Pharmacology. 1989;25(1):1-9.
23.Lam M, Adelstein DJ. Hypomagnesemia and renal magnesium wasting in patients treated with cisplatin. American Journal of Kidney Diseases. 1986;8(3):164-169.
24.Lee YK, Shin DM. Renal salt wasting in patients treated with high-dose cisplatin, etoposide, and mitomycin in patients with advanced non-small cell lung cancer. Korean Journal of Internal Medicine. 1992;7(2):118-121.
25.Yonezawa A, Masuda S, Nishihara K, Yano I, Katsura T, Inui KI. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochemical Pharmacology. 2005;70(12):1823-1831.
26.Morisaki T, Matsuzaki T, Yokoo K, et al. Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharmaceutical Research. 2008;25(11):2526-2533.
27.Weiner MW, Jacobs C. Mechanism of cisplatin nephrotoxicity. Federation Proceedings. 1983;42(13):2974-2978.
28.Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Experimental and Toxicologic Pathology. 2008.
29.Ramesh G, Reeves WB. Inflammatory cytokines in acute renal failure. Kidney Int. 2004;66(S91):S56-S61.
30.Dong Z, Atherton SS. Tumor necrosis factor-[alpha] in cisplatin nephrotoxicity: A homebred foe? Kidney Int. 2007;72(1):5-7.
31.Leibbrandt MEI, Wolfgang GHI, Metz AL, Ozobia AA, Haskins JR. Critical subcellular targets of cisplatin and related platinum analogs in rat renal proximal tubule cells. Kidney International. 1995;48(3):761-770.
32.Francescato HDC, Costa RS, da Silva CGA, Coimbra TM. Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage. Life Sciences. 2009.
33.Servais H, Ortiz A, Devuyst O, Denamur S, Tulkens P, Mingeot-Leclercq MP. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation. Apoptosis. 2008;13(1):11-32.
34.Rosenberg JM, Sato PH. Cisplatin inhibits in vitro translation by preventing the formation of complete initiation complex. Molecular Pharmacology. 1993;43(3):491-497.
35.Courjault-Gautier F, Le Grimellec C, Giocondi MC, Toutain HJ. Modulation of sodium-coupled uptake and membrane fluidity by cisplatin in renal proximal tubular cells in primary culture and brush-border membrane vesicles. Kidney International. 1995;47(4):1048-1056.
36.Bompart G. Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzyme activities in rat kidney cortex. Toxicology Letters. 1989;48(2):193-199.
37.Mistry P, Merazga Y, Spargo DJ, Riley PA, McBrien DCH. The effects of cisplatin on the concentration of protein thiols and glutathione in the rat kidney. Cancer Chemotherapy and Pharmacology. 1991;28(4):277-282.
38.Galle J. Oxidative stress in chronic renal failure. Nephrology Dialysis Transplantation. 2001;16(11):2135-2137.
39.Ichikawa I, Kiyama S, Yoshioka T. Renal antioxidant enzymes: Their regulation and function. Kidney Int. 1994;45(1):1-9.
40.Halliwell B. The wanderings of a free radical. Free Radical Biology and Medicine. 2009;46(5):531-542.
41.Halliwell B. The role of oxygen radicals in human disease, with particular reference to the vascular system. Haemostasis. 1993;23(SUPPL. 1):118-126.
42.Mladenka P, Simunek T, Hubl M, Hrdina R. The role of reactive oxygen and nitrogen species in cellular iron metabolism. Free Radical Research. 2006;40(3):263-272.
43.Galle J, Wanner C. Oxidative stress and vascular injury - Relevant for atherogenesis in uraemic patients? Nephrology Dialysis Transplantation. 1997;12(12):2480-2483.
44.Klahr S. Oxygen radicals and renal diseases. Mineral and Electrolyte Metabolism. 1997;23(3-6):140-143.
45.Pabla N, Dong Z. Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney International. 2008;73(9):994-1007.
46.Sugiyama S, Hayakawa M, Kato T, Hanaki Y, Shimizu K, Ozawa T. Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: Disturbances in glutathione peroxidase activity. Biochemical and Biophysical Research Communications. 1989;159(3):1121-1127.
47.Barnes PJ, Karin M. Nuclear Factor-{kappa}B -- A Pivotal Transcription Factor in Chronic Inflammatory Diseases. N Engl J Med. April 10, 1997 1997;336(15):1066-1071.
48.Schrier RW. Cancer therapy and renal injury. Journal of Clinical Investigation. 2002;110(6):743-745.
49.Ramesh G, Reeves WB. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. American Journal of Physiology - Renal Physiology. 2003;285:F610-F618.
50.Ramesh G, Brian Reeves W. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. Journal of Clinical Investigation. 2002;110(6):835-842.
51.丁明孝等編著. 細胞分子生物學. 第一版. 台北市: 九州圖書文物有限公司; 2001.
52.Price PM, Megyesi J, Safirstein RL. Cell cycle regulation: Repair and regeneration in acute renal failure. Kidney International. 2004;66(2):509-514.
53.Csikasz-Nagy A. Computational systems biology of the cell cycle. Brief Bioinform. March 6, 2009 2009:bbp005.
54.Blomen VA, Boonstra J. Cell fate determination during G1 phase progression. Cellular and Molecular Life Sciences. 2007;64(23):3084-3104.
55.Ivanchuk SM, Rutka JT, Piepmeier JM, Parsa AT, Boulis N. The Cell Cycle: Accelerators, Brakes, and Checkpoints. Neurosurgery. 2004;54(3):692-700.
56.Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell cycle (Georgetown, Tex.). 2002;1(2):103-110.
57.Shah MA, Schwartz GK. Cyclin dependent kinases as targets for cancer therapy. Update on Cancer Therapeutics. 2006;1(3):311-332.
58.Lin Z, Lim S, Viani MA, Sapp M, Lim MS. Down-regulation of telomerase activity in malignant lymphomas by radiation and chemotherapeutic agents. American Journal of Pathology. 2001;159(2):711-719.
59.Megyesi J, Andrade L, Vieira J.M, Jr., Safirstein RL, Price PM. Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure. Kidney International. 2001;60(6):2164-2172.
60.Megyesi J, Safirstein RL, Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. Journal of Clinical Investigation. Feb 15 1998;101(4):777-782.
61.Megyesi J, Udvarhelyi N, Safirstein RL, Price PM. The p53-independent activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal failure. Am J Physiol Renal Physiol. December 1, 1996 1996;271(6):F1211-1216.
62.Miyaji T, Kato A, Yasuda H, Fujigaki Y, Hishida A. Role of the increase in p21 in cisplatin-induced acute renal failure in rats. Journal of the American Society of Nephrology. 2001;12(5):900-908.
63.Nowak G, Price PM, Schnellmann RG. Lack of a functional p21WAF1/CIP1 gene accelerates caspase-independent apoptosis induced by cisplatin in renal cells. American Journal of Physiology - Renal Physiology. 2003;285:F440-F450.
64.Price PM, Safirstein RL, Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. American Journal of Physiology - Renal Physiology. 2004;286:F378-F384.
65.Shankland SJ, Wolf G. Cell cycle regulatory proteins in renal disease: Role in hypertrophy, proliferation, and apoptosis. American Journal of Physiology - Renal Physiology. 2000;278:F515-F529.
66.Yasuda H, Kato A, Miyaji T, Zhou H, Togawa A, Hishida A. Insulin-like growth factor-I increases p21 expression and attenuates cisplatin-induced acute renal injury in rats. Clinical and Experimental Nephrology. 2004;8(1):27-35.
67.Kelman Z. PCNA: Structure, functions and interactions. Oncogene. 1997;14(6):629-640.
68.Freudenthal BD, Ramaswamy S, Hingorani MM, Washington MT. Structure of a mutant form of proliferating cell nuclear antigen that blocks translesion DNA synthesis. Biochemistry. 2008;47(50):13354-13361.
69.Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): A dancer with many partners. Journal of Cell Science. 2003;116(15):3051-3060.
70.Naryzhny SN. Proliferating cell nuclear antigen: A proteomics view. Cellular and Molecular Life Sciences. 2008;65(23):3789-3808.
71.Miyachi K, Fritzler MJ, Tan EM. Autoantibody to a nuclear antigen in proliferating cells. Journal of Immunology. 1978;121(6):2228-2234.
72.Nakajima T, Miyaji T, Kato A, Ikegaya N, Yamamoto T, Hishida A. Uninephrectomy reduces apoptotic cell death and enhances renal tubular cell regeneration in isch?mic ARF in rats. American Journal of Physiology - Renal Fluid and Electrolyte Physiology. 1996;271:F846-F853.
73.Sano K, Fujigaki Y, Miyaji T, et al. Role of apoptosis in uranyl acetate-induced acute renal failure and acquired resistance to uranyl acetate. Kidney International. 2000;57(4):1560-1570.
74.Celis JE, Madsen P. Increased nuclear cyclin/PCNA antigen staining of non S-phase transformed human amnion cells engaged in nucleotide excision DNA repair. FEBS Letters. 1986;209(2):277-283.
75.McCormick D, Hall PA. The complexities of proliferating cell nuclear antigen. Histopathology. 1992;21(6):591-594.
76.賴榮祥. 原色生藥學. 台中市: 創譯出版社; 2000.
77.Gillis CN. Panax ginseng pharmacology: A nitric oxide link? Biochemical Pharmacology. 1997;54(1):1-8.
78.Yun TK. Panax ginseng - a non-organ-specific cancer preventive? Lancet Oncology. 2001;2(1):49-55.
79.Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomised clinical trials. European Journal of Clinical Pharmacology. 1999;55(8):567-575.
80.Choi KT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacologica Sinica. 2008;29(9):1109-1118.
81.Ki SK, Hyun YK, Yamabe N, Nagai R, Yokozawa T. Protective effect of sun ginseng against diabetic renal damage. Biological and Pharmaceutical Bulletin. 2006;29(8):1678-1684.
82.Shi W, Wang Y, Li J, Zhang H, Ding L. Investigation of ginsenosides in different parts and ages of Panax ginseng. Food Chemistry. 2007;102(3):664-668.
83.Kim SN, Ha YW, Shin H, Son SH, Wu SJ, Kim YS. Simultaneous quantification of 14 ginsenosides in Panax ginseng C.A. Meyer (Korean red ginseng) by HPLC-ELSD and its application to quality control. Journal of Pharmaceutical and Biomedical Analysis. 2007;45(1):164-170.
84.Wu CF, Bi XL, Yang JY, et al. Differential effects of ginsenosides on NO and TNF-α production by LPS-activated N9 microglia. International Immunopharmacology. 2007;7(3):313-320.
85.Kiefer D, Pantuso T. Panax ginseng. American Family Physician. 2003;68(8):1539-1542.
86.Shin HR, Kim JY, Yun TK, Morgan G, Vainio H. The cancer-preventive potential of Panax ginseng: A review of human and experimental evidence. Cancer Causes and Control. 2000;11(6):565-576.
87.Persson IAL, Dong L, Persson K. Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production. Journal of Ethnopharmacology. 2006;105(3):321-325.
88.Chang YS, Seo E-K, Gyllenhaal C, Block KI. Panax ginseng: A Role in Cancer Therapy? Integr Cancer Ther. March 1, 2003 2003;2(1):13-33.
89.Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: Multiple constituents and multiple actions. Biochemical Pharmacology. 1999;58(11):1685-1693.
90.Wang CZ, Aung HH, Ni M, et al. Red American ginseng: Ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots. Planta Medica. 2007;73(7):669-674.
91.Yun TK. Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2003;523-524:63-74.
92.Liu WK, Xu SX, Che CT. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sciences. 2000;67(11):1297-1306.
93.Chen CF, Chiou WF, Zhang JT. Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacologica Sinica. 2008;29(9):1103-1108.
94.Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. Journal of the American Medical Association. 2001;286(2):208-216.
95.Gyllenhaal C, Merritt SL, Peterson SD, Block KI, Gochenour T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Medicine Reviews. 2000;4(3):229-251.
96.Kim SJ, Murthy HN, Hahn EJ, Lee HL, Paek KY. Parameters affecting the extraction of ginsenosides from the adventitious roots of ginseng (Panax ginseng C.A. Meyer). Separation and Purification Technology. 2007;56(3):401-406.
97.Jeon BH, Kim CS, Park KS, et al. Effect of Korea red ginseng on the blood pressure in conscious hypertensive rats. General Pharmacology: The Vascular System. 2000;35(3):135-141.
98.Lee SM, Shon HJ, Choi CS, Hung TM, Min BS, Bae K. Ginsenosides from heat processed ginseng. Chemical and Pharmaceutical Bulletin. 2009;57(1):92-94.
99.Stavro PM, Woo M, Vuksan V. Korean red ginseng lowers blood pressure in individuals with hypertension. Am J. Hypertens. 2004;17:533.
100.Tsang D, Yeung HW, Tso WW, Peck H. Ginseng saponins: Influence on neurotransmitter uptake in rat brain synaptosomes. Planta Medica. 1985;NO. 3:221-224.
101.Nah SY, Park HJ, McCleskey EW. A trace component of ginseng that inhibits Ca2+ channels through a pertussis toxin-sensitive G protein. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(19):8739-8743.
102.Su CF, Cheng JT, Liu IM. Increase of acetylcholine release by Panax ginseng root enhances insulin secretion in Wistar rats. Neuroscience Letters. 2007;412(2):101-104.
103.Vuksan V, Sung MK, Sievenpiper JL, et al. Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled, type 2 diabetes: Results of a randomized, double-blind, placebo-controlled study of efficacy and safety. Nutrition, Metabolism and Cardiovascular Diseases. 2008;18(1):46-56.
104.Sato T, Miyata G. The nutraceutical benefit, part II: Ginseng. Nutrition. 2000;16(5):391-392.
105.Scaglione F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs under Experimental and Clinical Research. 1990;16(10):537-542.
106.Kim JY, Germolec DR, Luster MI. Panax ginseng as a potential immunomodulator: Studies in mice. Immunopharmacology and Immunotoxicology. 1990;12(2):257-276.
107.Yang G. Immunologic effect of traditional Chinese drugs. Chinese Medical Journal. 1996;109(1):59-60.
108.Yun YS, Moon HS, Oh YR, Jo SK, Kim YJ, Yun TK. Effect of red ginseng on natural killer cell activity in mice with lung adenoma induced by urethan and benzo(a)pyrene. Cancer detection and prevention. Supplement : official publication of the International Society for Preventive Oncology, Inc. 1987;1:301-309.
109.Wu X, Zhu D. Influence of ginseng upon the development of liver cancer induced by diethylnitrosamine in rats. Journal of Tongji Medical University. 1990;10(3).
110.Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: A prospective study in Korea. International Journal of Epidemiology. 1998;27(3):359-364.
111.Rimar S, Lee-Mengel M, Gillis CN. Pulmonary protective and vasodilator effects of a standardized Panax ginseng preparation following artifical gastric digestion. Pulmonary Pharmacology. 1996;9(4):205-209.
112.Voces J, Alvarez AI, Vila L, Ferrando A, Cabral De Oliveira C, Prieto JG. Effects of administration of the standardized Panax ginseng extract G115 on hepatic antioxidant function after exhaustive exercise. Comparative Biochemistry and Physiology - C Pharmacology Toxicology and Endocrinology. 1999;123(2):175-184.
113.Jeong TC, Kim HJ, Park JI, et al. Protective effects of red ginseng saponins against carbon tetrachloride-induced hepatotoxicity in Sprague Dawley rats. Planta Medica. 1997;63(2):136-140.
114.Han HJ, Yoon BC, Park SH, et al. Ginsenosides protect apical transporters of cultured proximal tubule cells from dysfunctions induced by H2O2. Kidney and Blood Pressure Research. 2002;25(5):308-314.
115.Kennedy DO, Scholey AB. Ginseng: Potential for the enhancement of cognitive performance and mood. Pharmacology Biochemistry and Behavior. 2003;75(3):687-700.
116.Park JD, Rhee DK, Lee YH. Biological activities and chemistry of saponins from Panax ginseng C. A. Meyer. Phytochemistry Reviews. 2005;4(2-3):159-175.
117.Liu ZQ, Luo XY, Liu GZ, Chen YP, Wang ZC, Sun YX. In vitro study of the relationship between the structure of ginsenoside and its antioxidative or prooxidative activity in free radical induced hemolysis of human erythrocytes. Journal of Agricultural and Food Chemistry. 2003;51(9):2555-2558.
118.Lee J, Lee E, Kim D, Yoo J, Koh B. Studies on absorption, distribution and metabolism of ginseng in humans after oral administration. Journal of Ethnopharmacology. 2009;122:143-148.
119.Zhou W, Li J, Li X, Yan Q, Zhou P. Development and validation of a reversed-phase HPLC method for quantitative determination of ginsenosides Rb1, Rd, F2, and compound K during the process of biotransformation of ginsenoside Rb1. Journal of Separation Science. 2008;31(6-7):921-925.
120.Zhou W, Zhou P. Advances in the study of ginsenoside compound K. Yaoxue Xuebao. 2007;42(9):917-923.
121.Paek IB, Moon Y, Kim J, et al. Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharmaceutics and Drug Disposition. 2006;27(1):39-45.
122.Lee HU, Bae EA, Han MJ, Kim NJ, Kim DH. Hepatoprotective effect of ginsenoside Rb1 and compound K on tert-butyl hydroperoxide-induced liver injury. Liver International. 2005;25(5):1069-1073.
123.Shin YW, Bae EA, Kim SS, Lee YC, Kim DH. Effect of ginsenoside Rb1 and compound K in chronic oxazolone-induced mouse dermatitis. International Immunopharmacology. 2005;5(7-8):1183-1191.
124.Choi K, Kim M, Ryu J, Choi C. Ginsenosides compound K and Rh2 inhibit tumor necrosis factor-α-induced activation of the NF-κB and JNK pathways in human astroglial cells. Neuroscience Letters. 2007;421(1):37-41.
125.Jae Youl C, Eun Sook Y, Kyong Up B, Myung Hwan P, Byung Hoon H. In vitro inhibitory effect of protopanaxadiol ginsenosides on tumor necrosis factor (TNF)-α production and its modulation by known TNF-α antagonists. Planta Medica. 2001;67(3):213-218.
126.Kim HA, Kim S, Chang SH, Hwang HJ, Choi Yn. Anti-arthritic effect of ginsenoside Rb1 on collagen induced arthritis in mice. International Immunopharmacology. 2007;7(10):1286-1291.
127.Zhou W, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Ginsenoside Rb1 blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries. Journal of Vascular Surgery. 2005;41(5):861-868.
128.Scott GI, Colligan PB, Ren BH, Ren J. Ginsenosides Rb1 and Re decrease cardiac contraction in adult rat ventricular myocytes: Role of nitric oxide. British Journal of Pharmacology. 2001;134(6):1159-1165.
129.Jiang XY, Zhang JT, Shi CZ. Mechanism of action of ginsenoside Rb1 in decreasing intracellular Ca2+. Yaoxue Xuebao. 1996;31(5):321-326.
130.Liu M, Zhang J. Effects of ginsenoside Rb1 and Rg1 on synaptosomal free calcium level, ATPase and calmodulin in rat hippocampus. Chinese Medical Journal. 1995;108(7):544-547.
131.Jiang QS, Huang XN, Dai ZK, et al. Inhibitory effect of ginsenoside Rb1 on cardiac hypertrophy induced by monocrotaline in rat. Journal of Ethnopharmacology. 2007;111(3):567-572.
132.Jiang QS, Huang XN, Yang GZ, Jiang XY, Zhou QX. Inhibitory effect of ginsenoside Rb1 on calcineurin signal pathway in cardiomyocyte hypertrophy induced by prostaglandin F2α. Acta Pharmacologica Sinica. 2007;28(8):1149-1154.
133.Ohashi R, Yan S, Mu H, et al. Effects of Homocysteine and Ginsenoside Rb1 on Endothelial Proliferation and Superoxide Anion Production. Journal of Surgical Research. 2006;133(2):89-94.
134.Park JK, Namgung U, Lee CJ, et al. Calcium-independent CaMKII activity is involved in ginsenoside Rb1-mediated neuronal recovery after hypoxic damage. Life Sciences. 2005;76(9):1013-1025.
135.L JP, Ma ZC, Yang J, Huang J, Wang SR, Wang SQ. Ginsenoside Rg1-induced alterations in gene expression in TNF-α stimulated endothelial cells. Chinese Medical Journal. 2004;117(6):871-876.
136.Wang YT, Huang XN, Wang FA. Ginsenoside Rg1 inhabits cardiomyocyte hypertrophy induced by prostaglandin F2α. Chinese Pharmacological Bulletin. 2008;24(5):611-615.
137.Ma ZC, Gao Y, Wang YG, Tan HL, Xiao CR, Wang SQ. Ginsenoside Rg1 inhibits proliferation of vascular smooth muscle cells stimulated by tumor necrosis factor-α. Acta Pharmacologica Sinica. 2006;27(8):1000-1006.
138.Zhang HS, Wang SQ. Ginsenoside Rg1 inhibits tumor necrosis factor-α (TNF-α)- induced human arterial smooth muscle cells (HASMCs) proliferation. Journal of Cellular Biochemistry. 2006;98(6):1471-1481.
139.Cheng Y, Shen LH, Zhang JT. Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacologica Sinica. 2005;26(2):143-149.
140.Chen XC, Fang F, Zhu YG, Chen LM, Zhou YC, Chen Y. Protective effect of ginsenoside Rg1 on MPP+-induced apoptosis in SHSY5Y cells. Journal of Neural Transmission. 2003;110(8):835-845.
141.Wang J, Xu HM, Yang HD, Du XX, Jiang H, Xie JX. Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins. Neurochemistry International. 2009;54(1):43-48.
142.Lee Y, Chung E, Youl Lee K, Hee Lee Y, Huh B, Lee SK. Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor. Molecular and Cellular Endocrinology. 1997;133(2):135-140.
143.Zhang YF, Fan XJ, Li X, et al. Ginsenoside Rg1 protects neurons from hypoxic-ischemic injury possibly by inhibiting Ca2+ influx through NMDA receptors and L-type voltage-dependent Ca2+ channels. European Journal of Pharmacology. 2008;586(1-3):90-99.
144.Kenarova B, Neychev H, Hadjiivanova C, Petkov VD. Immunomodulating activity of ginsenoside Rg1 from Panax ginseng. Japanese Journal of Pharmacology. 1990;54(4):447-454.
145.Ye R, Han J, Kong X, et al. Protective effects of ginsenoside Rd on PC12 cells against hydrogen peroxide. Biological and Pharmaceutical Bulletin. 2008;31(10):1923-1927.
146.Dong E. A study of ginsenoside-Rd in a renal ischemia-reperfusion model. Nephron. 1998;78(2):201-206.
147.Yokozawa T, Owada S. Effect of ginsenoside-Rd in cephaloridine-induced renal disorder. Nephron. 1999;81(2):200-207.
148.Yokozawa T, Liu ZW. The role of ginsenoside-Rd in cisplatin-induced acute renal failure. Renal Failure. 2000;22(2):115-127.
149.Yokozawa T, Dong E. Role of ginsenoside-Rd in cisplatin-induced renal injury: Special reference to DNA fragmentation. Nephron. 2001;89(4):433-438.
150.Tamura T, Cui X, Sakaguchi N, Akashi M. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food and Chemical Toxicology. 2008;46(9):3080-3089.
151.Chang TL, Ding HY, Kao YW. Role of ginsenoside Rd in inhibiting 26S proteasome activity. Journal of Agricultural and Food Chemistry. 2008;56(24):12011-12015.
152.Healthcare T. Sodium salicylate. MICROMEDEX(R) Healthcare Series. Accessed March 9th, 2009.
153.Li G, Sha SH, Zotova E, Arezzo J, Van De Water TR, Schacht J. Salicylate protects hearing and kidney function from cisplatin toxicity without compromising its oncolytic action. Laboratory Investigation. 2002;82(5):585-596.
154.Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. European Journal of Pharmacology. 2002;447(1):1-9.
155.Chung YM, Bae YS, Lee SY. Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis. Free Radical Biology and Medicine. 2003;34(4):434-442.
156.Ramesh G, Reeves WB. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α. Kidney International. 2004;65(2):490-498.
157.Kiss K, Kiss J, Rudolf E, ervinka M, Szeberenyi J. Sodium salicylate inhibits NF-κB and induces apoptosis in PC12 cells. Journal of Biochemical and Biophysical Methods. 2004;61(1-2):229-240.
158.Vale A. Salicylates. Medicine. 2007;35(12):654-655.
159.Powell SR. Commentary: Salicylate trapping of •OH as a tool for studying post-ischemic oxidative injury in the isolated rat heart. Free Radical Research. 1994;21(6):355-370.
160.Mohanakumar KP, Muralikrishnan D, Thomas B. Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Brain Research. 2000;864(2):281-290.
161.Dinis-Oliveira RJ, Sousa C, Remiao F, et al. Full survival of paraquat-exposed rats after treatment with sodium salicylate. Free Radical Biology & Medicine. April 1 2007;42(7):1017-1028.
162.Kopp E, Ghosh S. Inhibition of NF-κB by sodium salicylate and aspirin. Science. 1994;265:956-959.
163.Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature. 1998;396(6706):77-80.
164.Perugini RA, McDade TP, Vittimberga Jr FJ, Duffy AJ, Callery MP. Sodium Salicylate Inhibits Proliferation and Induces G1 Cell Cycle Arrest in Human Pancreatic Cancer Cell Lines. Journal of Gastrointestinal Surgery. 2000;4(1):24-32.
165.Shim H, Yang SH, Bak SM, Jeong ET. Sodium salicylate(NaSaL) induces apoptosis of NCI-H1299 lung carcinoma cells via activation caspase-3 protease. Tuberculosis and Respiratory Diseases. 2002;53(5):485-496.
166.Klampfer L, Cammenga J, Wisniewski HG, Nimer SD. Sodium salicylate activates caspases and induces apoptosis of myeloid leukemia cell lines. Blood. 1999;93(7):2386-2394.
167.Lee EJ, Park HG, Kang HS. Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. International journal of oncology. 2003;23(2):503-508.
168.Kim YW, Song DK, Kim WH, et al. Long-term oral administration of ginseng extract decreases serum gamma-globulin and IgG1 isotype in mice. Journal of Ethnopharmacology. 1997;58(1):55-58.
169.Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Analytical Biochemistry. 1976;72(1-2):248-254.
170.Soldati F, Sticher O. HPLC separation and quantitative determination of ginsenosides from Panax ginseng, Panax quinquefolium and from ginseng drug preparations. 2nd communication. Planta Medica. 1980;39(4):348-357.
171.張惠婷. 順氯氨鉑引發的腎毒性在純系小鼠的確立與柴胡在此腎炎模型的藥效評估. 台北市: 藥學系碩士班, 台北醫學大學; 2005.
172.邱芷瑩. 人參與人參皂苷在順氯氨鉑引發的腎毒性於純系小鼠的藥效評估. 台北市: 藥學系碩士班, 台北醫學大學; 2007.
173.Hultberg B, Ravnskov U. The excretion of N-acetyl-β-glucosaminidase in glomerulonephritis. Clinical Nephrology. 1981;15(1):33-38.
174.Yokyzawa T, Zhou JJ, Hattori M, Inaba S, Okada T, Oura H. Effects of ginseng in nephrectomized rats. Biological and Pharmaceutical Bulletin. 1994;17(11):1485-1489.
175.Han SW, Kim H. Ginsenosides stimulate endogenous production of nitric oxide in rat kidney. International Journal of Biochemistry and Cell Biology. 1996;28(5):573-580.
176.Park EK, Choo MK, Han MJ, Kim DH. Ginsenoside Rh1 Possesses Antiallergic and Anti-Inflammatory Activities. International Archives of Allergy and Immunology. 2004;133(2):113-120.
177.Wang Y, Wang BX, Liu TH, Minami M, Nagata T, Ikejima T. Metabolism of ginsenoside Rg1 by intestinal bacteria II. Immunological activity of ginsenoside Rg1 and Rh1. Acta Pharmacologica Sinica. 2000;21(9):792-796.
178.黃致云. 人參及人參皂苷Rg1與N-乙醯半胱胺酸在順氯氨鉑引發的腎毒性於純系小鼠的藥效評估. 台北市: 藥學系碩士班, 台北醫學大學; 2008.
179.Shibata S TO, Shoji J, Saito H. . Chemistry and pharmacology of Panax. Economic and Medicinal Plant Research. 1985;1:217-284.
180.Tsuruya K, Ninomiya T, Tokumoto M, et al. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney International. 2003;63(1):72-82.
181.Marra DE, Simoncini T, Liao JK. Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21Waf1 and p27Kip1. Circulation. October 24, 2000 2000;102(17):2124-2130.