臺灣博碩士論文加值系統

自從幽門螺旋桿菌被發現以來，陸續的研究證實它和多種重要的消化道疾病有關，這些疾病包括慢性活動性B型胃炎、消化性潰瘍、胃癌及胃黏膜組織相關淋巴瘤等。最近10年，含有質子幫浦抑制劑（PPI）的三合一療法被視為清除幽門螺旋桿菌感染首選。然而，服藥順從性不夠和抗藥性菌株的增加常導致除菌的失敗。初步治療失敗後，被推介的二線療法包括他種抗生素的三合一療法或四合一療法，但是這些療法仍然無法克服因抗藥性菌株增加而造成的困擾。因此找出能有效預防和治療幽門螺旋桿菌感染的新成分或混合物，就有迫切的需要。基於以上問題，本研究分為以下三個部分進行臨床及基礎實驗。
第一部分，PPI╱amoxicillin二合一療法因抗藥性盛行率很低，有潛力在抗藥性問題日漸嚴重的環境下，做為除菌治療的良方。但是因之前的一些研究結果認為其除菌效果的變異度很大，所以目前較少被使用。本研究要探討其影響療效的因素，並找出適當的用藥方式。本研究收錄128位幽門螺旋桿菌陽性的十二指腸潰瘍患者。在治療前及治療後4~8週內，以胃鏡和其附屬檢查判定幽門螺旋桿菌存在的狀態。若病患拒做第二次胃鏡則改以碳13呼氣檢查來判定。胃鏡切片後的附屬檢查包括組織學、細菌培養，和CLO test。CYP2C19基因型則以polymerase chain reaction-based restriction fragment length polymorphism （PCR-RFLP）的方法來分析。病患被隨機編入4個治療分組之中接受為期二週的療程，其用藥方式分別為：O2A2組：omeprazole 20 mg bid 加上 amoxicillin 500 mg qid；O2A1組：omeprazole 20 mg bid 加上 amoxicillin 250 mg qid；O1A2組：omeprazole 20 mg qd 加上 amoxicillin 500 mg qid；O1A1組：omeprazole 20 mg qd 加上amoxicillin 250 mg qid。在用藥治療滿1週後（第8天），每組中隨機選取6位病患接受記錄24小時胃內pH值的檢查。所有病患被要求填寫一份問卷，同時在治療期間每天記錄臨床症狀和藥物用量。治療結束後，評估用藥順從度和副作用。結果顯示各組間除菌率的變化從52%至76%。Omeprazole劑量和CYP2C19基因型是影響除菌治療成功率最重要的兩個因素。所有的CYP2C19慢速代謝者都被治療成功，然而對於CYP2C19快速代謝者而言，則僅有44~76%除菌成功。較高劑量omeprazole的組別，有較好的幽菌除菌率（79%對53%）。使用amoxicillin一天4次250 mg或500 mg的療效無差別。由此，我們得到如下結論：使用二合一療法治療幽門螺旋桿菌時，除了CYP2C19慢速代謝的人外，其omeprazole的劑量和amoxicillin的頻率必須要提高，才能達到令人滿意的療效。而革新用法的二合一療法會是一個可以避開抗藥性困擾的第一線或第二線除菌療法。
第二部分，短療程的三合一療法因可增加病患服藥順從度、減少費用和副作用，一些研究用它來清除幽門螺旋桿菌，但是其效果也是變異度很大，因此，我們探討CYP2C19基因多形性對它療效的影響。以幽門螺旋桿菌陽性的消化性潰瘍或慢性胃炎病患為收錄對象。其潰瘍及幽門螺旋桿菌存在的狀態以胃鏡、組織切片、細菌培養及碳13呼氣檢查加以評估。病患被隨機分配為3組用藥方式：A組 rabeprazole 20mg bid 7天＋amoxicillin 1 g 及 clarithromycin 500 mg bid 第1~4天；B組 rabeprazole 20mg bid 7天＋amoxicillin 1 g 及 clarithromycin 500 mg bid 第4~7天；C組 rabeprazole 20mg bid 7天＋amoxicillin 1 g 及 clarithromycin 500 mg bid 第1~7天。CYP2C19基因型則以PCR-RFLP方法來分析。在藥動╱藥效分析上，將病患抽血方式隨機分為4組，除了基礎值外，在0.5, 1, 2, 3, 4, 6, 8, 及10 hr 8個時間點，選取半數來抽血，所以每個時間點，有半數的病患參與採血檢驗。Rabeprazole的消散速度在CYP2C19慢速代謝者明顯低於快速代謝者（平均值各為16.8 L/h和10.7 L/h），導致慢速代謝者有較高的rabeprazole血中濃度。使用多次rabeprazole劑量後會使胃泌素的EC50和keo的數值增加。其中在rabeprazole治療的第一天，CYP2C19慢速代謝者的keo值較低（0.012對0.017×10-4 l/min），但治療第四天，其keo的數值則高於快速代謝者（0.804對0.169×10-4 l/min）。在第四天和第七天，CYP2C19慢速代謝者有較高的胃泌素一時間反應曲線。所有CYP2C19的慢速代謝者，除了一位有clarithromycin抗藥性的病患失敗外，其餘都治療成功。而CYP2C19快速代謝者的除菌率只在58%到85%之間。因此，我們認為短程的三合一療法可用於CYP2C19慢速代謝者。這樣可減少特定病患的費用及副作用。
第三部分，幽門螺旋桿菌進入胃內之後，需附著在胃黏膜細胞上，再引起細胞的氧化壓力，造成上皮細胞的損傷。因此本研究利用體外細胞培養及體內小鼠模式，探討合併使用兒茶素（具抗微生物和抗氧化效果）和唾液酸（具抗黏附效果）兩者對幽門螺旋桿菌感染的預防和治療的效果，並探討其作用機轉。在體外試驗，我們先以agar dilution method和checkerboard method來評估兒茶素或╱唾液酸的抗菌能力。再利用超敏感冷光分析儀、免疫組織化學染色和西方墨點法在AGS胃上皮細胞株的培養系統中，加入和未加入兒茶素或╱和唾液酸，觀察這兩種化合物，是否具有保護AGS cell對抗幽門螺旋桿菌的能力。在體內試驗，我們將不帶有特殊病原菌的小鼠依治療的方式分為四組，包括未受感染控制組、感染控制組、感染前治療組、感染後治療組。治療時依規劃流程給予餵食含有128 mg/L兒茶素和32 mg/L唾液酸的水或葡萄糖溶液。利用組織學和免疫組織化學染色觀察其效果。我們發現兒茶素和唾液酸的抗菌效果有加成或協同作用。同時發現兒茶素和唾液酸併用可以對抗幽門螺旋桿菌對胃上皮細胞造成破壞，減少ROS和細胞凋亡的產生，減少mice胃黏膜的發炎反應，及增加autophagy。對幽門螺旋桿菌感染有100%的預防效果。若在感染後的治療，也可達到60%的根除率。本篇研究的內容及結果為國際上首次發表。此種治療方式成果良好，又可避開對抗生素有抗藥性菌株的困擾，可能開啟幽門螺旋桿菌治療及預防的新方向。

Helicobacter pylori (H. pylori) is strongly associated with chronic active gastritis, peptic ulcers, gastric cancer and gastric MALT lymphoma. Currently, a 1-wk combination therapy of a proton pump inhibitor and antibiotics is used as the first-choice treatment for H. pylori infection. However, poor compliance and the increasing emergence of H. pylori strains resistant to some of these agents can lead to eradication failure. Following failure of the initial treatment, second-line therapies, including alternative triple and quadruple regimens, have been recommended. However, these drugs still cannot solve the problem of the rising trend in antibiotic resistance. An alternative agent or mixture with preventive and therapeutic effects is urgently required to reduce H. pylori infection. Our studies included three parts of results in different aspects of this issue.
【Part I】To explore the factors that may influence H. pylori eradication using omeprazole/amoxicillin dual therapy, 128 patients with H. pylori-positive duodenal ulcer were enrolled and were randomly allocated to four different groups given omeprazole (20 mg bid or qd) and amoxicillin (250 mg or 500 mg qid). The eradication rates varies from 52% to 76%. Omeprazole dose and CYP2C19 genotype were the most important factors influencing the treatment outcome. All CYP2C19 poor metabolizers (PMs) were cured, while the H. pylori eradication rate in CYP2C19 extensive metabolizers varied from 44% to 76% in different treatment groups. Eradication of H. pylori was favored in higher omeprazole dose groups (79% vs. 53%). The eradication rates were comparable for patients receiving 250 mg or 500 mg amoxicillin qid. The dose of PPI and the frequency of amoxicillin in dual therapy should be increased to achieve a satisfactory outcome except in CYP2C19 PMs. The updated dual therapy can be used as an optimal 1st-line and rescue anti-H. pylori therapy.
【Part II】To explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against H. pylori infection. Patients with H. pylori infection were tested for CYP2C19 genotype and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1-4, days 4-7, or days 1-7. A direct link model with an effect compartment was used in the population pharmacokinetic/pharmacodynamic analysis. The status of H. pylori infection was evaluated. Rabeprazole clearance was lower in CYP2C19 PM than in EM, resulting in higher plasma levels in the former group. The values of EC50 and keo of gastrin response increased with multiple doses of rabeprazole. The keo values were lower in CYP2C19 PM than in EM on day 1, and higher than in EM on day 4, of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PM than in EM on days 4 and 7. H. pylori was eradicated in all CYP2C19 PM except in one patient infected by a resistant strain. In contrast, in CYP2C19 EM the eradication rates ranged from 58% to 85%. CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PM for H. pylori eradication.
【Part III】We explored the preventive and therapeutic potential of a combination of catechins and sialic acid on H. pylori-infected human gastric cells in vitro and in mice in vivo. The anti-H. pylori activity of catechins and/or sialic acid was evaluated by the agar dilution and checkerboard methods. The effect of catechins and/or sialic acid on H. pylori infection-induced oxidative stress and apoptosis/autophagy in cell culture was explored using an ultrasensitive chemiluminescence analyzer, immunocytochemistry, and Western blotting. Specific-pathogen-free BALB/c mice were divided into uninfected control, infected control, pretreated, and posttreated groups. The effects of catechins/sialic acid were determined by histology and immunocytochemistry. The combination of catechins and sialic acid showed synergistic or additive anti-H. pylori activity and significantly reduced apoptosis, but enhanced autophagy. All mice infected with H. pylori displayed gastritis, accumulation of 3-nitrotyrosine and 4-hydroxynonenal. Pretreatment with catechins/sialic acid completely prevented H. pylori infection and resulted in normal histology. Posttreatment with catechins/sialic acid decreased the bacterial load and gastritis score, and eradicated up to 60% of H. pylori infections in a dose-dependent manner. This is the first demonstration of a non-probiotic non-antibiotic treatment that is 100% effective in preventing and has promising result in treating H. pylori infection. Further studies are needed to confirm this result in human beings.

口試委員會審定書……………………………………………………..…
誌謝…………………………………………………………………..…… i
中文摘要……………………………………………………………..…… iii
英文摘要...................................................................................................... vii
目錄……………………………………………………………….………. xi
表目錄……………………………………………………………………. xiii
圖目錄……………………………………………………………………. xv
第一章 緒論（introduction）…………………………………………………... 1
1.1 幽門螺旋桿菌感染的流行病學和臨床相關疾病…………………… 2
1.2 幽門螺旋桿菌的致病機轉…………………………………………… 3
1.3 幽門螺旋桿菌感染所引發之宿主反應……………………………… 7
1.4 幽門螺旋桿菌感染的診斷…………………………………………… 10
1.5 幽門螺旋桿菌感染的治療…………………………………………… 11
1.6 抗生素抗藥性之機轉與現況………………………………………… 15
1.7 CYP2C19基因多形性與質子幫浦抑制劑………………………….. 18
第二章 Omeprazole劑量和CYP2C19基因型對以二合一療法清除幽門螺旋桿菌效果之影響…………………………………………………………….. 21
2.1 背景…………………………………………………………………… 21
2.2 目的…………………………………………………………………… 22
2.3 研究方法與材料……………………………………………………… 22
2.4 結果…………………………………………………………………… 24
第三章 質子幫浦抑制劑之CYP2C19代謝多形族群對短療程三合一幽門桿菌治療療效影響之評估……………………………………………………. 29
3.1 背景……………………………………………………………..……. 29
3.2 目的…………………………………………………………………… 30
3.3 研究方法與材料……………………………………………………… 30
3.4 結果…………………………………………………………………… 33
第四章 合併使用兒茶素和唾液酸來預防和治療幽門螺旋桿菌感染……… 37
4.1 背景…………………………………………………………………… 37
4.2 目的…………………………………………………………………… 38
4.3 研究方法與材料……………………………………………………… 38
4.4 結果…………………………………………………………………… 42
第五章 討論（discussion）………………………………………………...… 45
5.1 影響除菌治療效果的因素…………………………………………... 45
5.2 控制幽門螺旋桿菌感染的可能方式和標的……………………….. 48
5.3 Omeprazole劑量和CYP2C19基因型對以二合一療法清除幽門螺旋桿菌效果之影響……………………………………………………….…. 50
5.4 質子幫浦抑制劑之CYP2C19代謝多形族群對短療程三合一幽門桿菌治療療效影響之評估………………………………………………… 54
5.5 合併使用兒茶素和唾液酸來預防和治療幽門螺旋桿菌感染……… 60
第六章 展望（perspectives）………………………………………………… 65
6.1 目前處理幽門螺旋桿菌感染的共識................................................... 65
6.2 對抗藥性增加導致除菌療效降低的因應…………………………… 68
6.3 未來研究的方向……………………………………………………… 74
英文簡述（English summary）…………………………………………………. 75
參考文獻（references）…………………………………………………………. 97
附錄：列出個人在博士班修業期間所發表之相關論文清冊…………………..
表目錄
表 2-1 Demographic data for the patients in each treatment group……………… 149
表 2-2 Impact of CYP2C19 genotype and the dose of omeprazole on the H. pylori eradication rate…………………………………………………………… 150
表 2-3 Factors that might influence the H. pylori eradication rate in the univariate and multiple logistic regression analysis……………………………………… 151
表 2-4 Impacts of the dose of omeprazole or amoxicillin on the H. pylori eradication rate in relation to different CYP2C19 genotypes…………………………. 152
表 2-5 Factors that might influence the percentage of the time the intragastric pH was > 4 in the univariate analysis……………………………………………… 153
表 2-6 Adverse effects of each treatment regimen……………………………….. 154
表 3-1 Parameters used in the population PK/PD analysis for rabeprazole............. 155
表 3-2 Demographic data for the patients on the different treatment protocols….. 156
表 3-3 Demographic data for the patients categorized according to rabeprazole treatment day………………………………………………………………. 157
表 3-4 Estimated pharmacokinetic parameters for the patients categorized by rabeprazole treatment day…………………………………………………. 158
表 3-5 Estimated pharmacodynamic parameters for the patients categorized by rabeprazole treatment day…………………………………………………. 159
表 3-6 Effects of CYP2C19 genotype and clarithromycin resistance on the eradication rate………………………………………………………………………… 160
表 3-7 Adverse effects in each treatment group………………………………….. 161
表 4-1 In vitro antimicrobial activities of catechins or sialic acid against twenty H. pylori strains………………………………………………………………. 162
表 4-2 Combined effects of catechins and sialic acid against H. pylori strains……………………………………………………………………... 163
表 4-3 Effects of the catechins/sialic acid combination on gastric lesions in H. pylori-inoculated BALB/c mice…………………………………………... 164


圖目錄
圖 2-1 Correlation between the percentage of the time the intragastric pH was > 4 and the mean 24-hr gastric pH………………………………………………… 165
圖 2-2 Effect of the percentage of the time the intragastric pH was >4 on H. pylori eradication (A) and its relationship to the omeprazole regimen (qd vs bid) (B) or CYP2C19 genotype (C)………………………………………………… 166
圖 2-3 Effects of the omeprazole regimen (qd vs. bid) on the percentage of the time the intragastric pH was >4 in (A) homozygous extensive metabolizers, (B) heterozygous extensive metabolizers, and (C) poor metabolizers………… 167
圖 3-1 Changes in the plasma gastrin concentration in CYP2C19 PMs and EMs on different days of rabeprazole treatment. The plots were generated from the PK/PD parameters predicted by NONMEM……………………………… 168
圖 4-1 Effect of catechins and/or sialic acid on O2-, H2O2, and NO production and iNOS expression in AGS cells at 4 h after infection with H. pylori……… 169
圖 4-2 Effect of catechins and/or sialic acid on apoptosis in AGS cells at 4 h after infection with H. pylori…………………………………………………… 170
圖 4-3 Effect of catechins and/or sialic acid on autophagy in AGS cells at 4 h after infection with H. pylori.…………………………………………………… 171
圖 4-4 Effects of catechins and/or sialic acid on morphology, apoptosis, and autophagy in AGS cells at 4 h after H. pylori infection……………………………… 172
圖 4-5 Pathological analysis of gastric tissue in each group of BALB/c mice at 4 weeks after H. pylori inoculation…………………………………………. 173

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