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研究生:吳三源
研究生(外文):San-Yuan Wu
論文名稱:治療尿路結石潛力中藥之探勘
論文名稱(外文):Mining of Potential Chinese Medicines for Urolithiasis
指導教授:陳汶吉
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:中醫學系博士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:115
中文關鍵詞:尿石症補充和替代醫學傳統中醫中藥果蠅模型α受體阻斷劑
外文關鍵詞:UrolithiasisComplementary and Alternative MedicineTraditional Chinese medicineDrosophila melanogaster modelα-blockers
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尿石症是一種古老、常見而又複雜的疾病,具高發病率和復發率;由於成因複雜而且對其病理生理過程,到目前為止仍然所知有限,所以自古以來就一直困擾著人們。在過去的20年裡,過度著重泌尿外科的發展,但內科藥物治療方面卻仍然無明顯的進展;由於缺乏有效的防治藥物,每年用於此一疾病的醫療開銷亦所費不貲。為了尋求更理想的治療方式,世界各國都逐漸地廣泛使用補充和替代醫學做為輔助療法,來解決這個棘手的問題;特別是華人地區以傳統中醫中藥來治療各類疾病已有了數千年的發展,具有深厚的臨床實證基礎。
然而,補充和替代醫學之研究,其成功的關鍵點就在於現代化之科學驗證;以往由於缺乏理想的動物模型以及臨床試驗的種種限制,阻礙了抗結石藥物的開發;因此我們研發了一種利用果蠅模型來快速篩檢抗結石藥物的方法。在該研究中我們驗證了丹參、芍藥、紅花、延胡索、白茅根、杏仁、旱蓮草、艾葉、車前草、車前子、金銀花、虎杖、黃耆、茯苓、黃芩、當歸等16味中藥具抗晶體形成潛能。尤其紅花自古就是活血化瘀良藥,因具活血通經、散瘀止痛功效,也曾被用於治療尿石症;過去的實驗已確認了紅花萃取物在老鼠體內的抗結石效果。此外,為了進一步了解其機轉,我們也用豬的近端輸尿管做了離體實驗;雖然結果與α受體阻斷劑相較不如預期理想,但其對輸尿管的影響,仍對未來中醫藥抗結石機制的研究提供了若干線索。
總之,多年來本研究團隊對於尿石症之研究以及抗結石中藥之探勘不遺餘力,所發表的研究成果都只是開端而並非結束;將來若能廣泛的應用果蠅造模的方法來篩選更多具抗結石淺能的中藥,或許能從中找出理想的防治藥物,來嘉惠尿石症患者,以解決目前的困境。


Urolithiasis is an ancient-common and complicated disease. The incidence and recurrence rates are both high. Since there are multiple related causes, and we have limited understandings of the pathophysiological mechanisms , it is still an annoying problem to humans. Over the past 20 years, there shave been sophisticated improvements and developments in surgical skills and treatment concepts, proper medical treatment is still scanty. Thus the relevant cost burden for the disease is heavy. Considering the economic burden and non-invasiveness perspectives, more people begin to accept the use of Complementary and Alternative Medicine (CAM) all over the world. The history of using Traditional Chinese medicine (TCM) for the treatment of urolithiasis is very long especially in the Chinese communities. However the key-point for successful CAM research is evidence-based medicine. For decades, due to the limitations of human clinical trials regulations as well as the lack of an ideal animal model, the development of effective drugs for prevention and treatment of urinary tract stones. We developed a model, by using a Drosophila melanogaster model, as a rapid screening method to verify herbal drugs with good potential to effectively treat urolithiasis. In our research, we verified 16 herbal drugs( the Salvia, peony, safflower, Corydalis, Imperatae, almonds, Eclipta , leaves, plantain, Plantago, honeysuckle, knotweed, Astragalus, Poria, skullcap, and Angelica ) which were proved to have anti-contraceptive potential and inhibit crystal formation, a key process in the pathogenesis of the disease. In particular, safflower is traditionally famous for promoting blood circulation, analgesics and reducing hemostasis; it was also used for treating urolithiasis. Our screening experiments and animal studies have confirmed the anti-lithogenic effect of the extracts in the body. In addition, in order to further understand the anti-urolithiasis mechanism of the herbal drugs, and to further develop effective treatment of TCM in the future, we conducted in vivo experiments using porcine proximal ureter. Although the inhibitory effect of saffron extract is much weaker than the α-blockers, but the information of its effects on the ureter, still provided valuable clues for following herbal drugs research of anti-urolithiasis sin the future. In short, our team has dedicated ourselves to the exploration of the potential TCM for treating urinary tract stones in the past years. We have some publications, yet it is just the beginning not the end. We found some herbal drugs which had similar level of safety with food. With a traditional concept in Chinese Medicine that food and medicine be homologous, our findings seem to shed light on the potential development of health food with herbal drugs.

目 錄

第一章 前言
第一節 研究之背景……………………………..…………………2
第二節 研究之目的……………………………..…………………6
第二章 文獻探討
第一節 尿路結石的流行病學……………………………………10
第二節 尿路結石的臨床表徵……………………………………14
第三節 尿路結石之分類…………………………………………16
第四節 尿路結石分析的方法……………………………………20
第五節 尿路結石的成因…………………………………………32
第六節 尿路結石的病理機轉……………………………………42
第七節 尿路結石的診斷…………………………………………46
第八節 尿路結石的治療…………………………………………50
第九節 傳統中醫對尿路結石之探討……………………………56
第三章 材料與方法
Part I 〈果蠅模式〉
第一節 理想的成石動物模型……………………………………61
第二節 潛在抗結石藥用植物的篩選……………………………62
第三節 草酸?s(CaOx)晶體形成的觀察…………………………63
Part II 〈輸尿管模式〉
第四節 實驗之豬的輸尿管………………………………………64
第五節 輸尿管蠕動之測量………………………………………65
第六節 實驗藥品之準備…………………………………………68
第七節 統計分析…………………………………………………70
第四章 結果
Part I 〈果蠅模式〉
第一節 草酸鈣晶體形成率………………………………………71
Part II 〈輸尿管模式〉
第二節 α1-腎上腺素受體阻斷劑的效果………………………75
第三節 紅花萃取物的影響效果………………………...………77
第五章 討論
Part I 〈果蠅模式〉
第一節 運用果蠅模式可發展治療尿石症之藥物………..…..…79
第二節 中西醫結合治療尿石症露曙光……………….....…...…81
第三節 小結……………………………………………….…...…84
Part II 〈輸尿管模式〉
第四節 α1-腎上腺素受體阻斷劑的效果…...……………….…86
第六章 結論
Part I 〈果蠅模式〉
第一節 果蠅造模篩選中藥是CAM發展研究成功的案例……91
Part II 〈輸尿管模式〉
第二節 紅花萃取物之抗結石機轉異於α受體阻滯劑…………92

參考文獻………………….. …………………..…………………………..93








圖目錄

圖3-1 紅花對豬近端輸尿管蠕動抑制測試之實驗室示意圖..……...…65
圖4-1 偏光顯微鏡下對照組之果蠅的馬氏管…… ………...………….71
圖4-2 偏光顯微鏡下以致石劑誘導產生結晶之果蠅的馬氏管.…...…71
圖4-3 Doxazosin對豬近端輸尿管蠕動抑制之濃度-效力曲線圖….…76
圖4-4 Tamsulosin對豬近端輸尿管蠕動抑制之濃度-效力曲線圖….…76
圖4-5 Terazosin對豬近端輸尿管蠕動抑制之濃度-效力曲線圖………77
圖4-6 紅花萃取物對豬近端輸尿管蠕動抑制之濃度-效力曲線圖.….. 78
圖5-1 果蠅實像照片………...…….. ……….. ……...….. ……...……...80
圖5-2 果蠅排泄道之卡通示意圖……. ...…… . …....…. ...…...….……80









表目錄

表2-1 尿路結石依結構組成分類及其佔率..………………………...…19
表2-2 尿路結石所在部位的相關症狀..……………………………...…46
表3-1 80種可能具抗結石潛力之中藥(方) ..………….…….……...….62
表4-1 80種篩選中藥在果蠅馬氏管內的草酸鈣結晶形成率………….72
表4-2 豬近端輸尿管蠕動測試劑之50%抑制濃度(IC50)….…..…...…78


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