第一部份 Celecoxib降低幽門桿菌根除後之殘餘腸化生的效用

研究背景
　　許多研究指出幽門桿菌的感染和胃癌發生有高度的相關性，1994年世界衛生組織將幽門桿菌歸為第一類的致癌因子。根據組織學的研究發現，因幽門桿菌感染而有胃癌前趨病灶的細胞中COX-2酵素有表現增加的現象，而在幽門桿菌根除後COX-2酵素表現雖有降低但腸化生依然存在。近年來許多研究嘗試將COX-2抑制劑用在腫瘤的預防及治療，目前已發現celecoxib能夠治療家族性腺瘤性息肉。Celecoxib是否能降低有腸化生病人胃黏膜細胞中COX-2酵素的表現以及消除腸化生，則有待研究觀察。

研究目的
　　觀察celecoxib是否能夠消除腸化生現象、是否能夠降低胃黏膜細胞中COX-2酵素表現量，並評估使用celecoxib消除腸化生之2個月療程的安全性。

研究對象
幽門桿菌已根除但胃內有殘餘腸化生的患者。

研究方法
　　選取曾於成大醫院胃腸科門診，接受幽門桿菌根除治療發現有腸化生的病人，共22位確定幽門桿菌已根除，但胃黏膜尚有殘餘腸化生的患者納入研究。每位受試者將接受2個月療程的celecoxib治療。為避免可能有腎毒副作用，治療前先評估受試者的BUN/Cr、血壓變化情形，受試者分別於接受治療後第1、4、8週回門診追蹤，同時監測BUN/Cr、血壓變化及併服他藥的情形，來避免藥物副作用的產生。2個月療程後，再經由內視鏡取得病人胃黏膜的組織切片，觀察是否有殘餘腸化生，同時經由免疫組織化學染色法，評估胃黏膜細胞內COX-2酵素的表現程度。

結果
　　本研究共有21位受試者完成治療，在使用celecoxib 200 mg 一天一次，二個月的療程後，有6位腸化生消失，4位腸化生的強度有減弱。整體而言，antrum及body部位的腸化生表現強度平均值均有減弱，而antrum部位的腸化生表現強度減弱有達到統計上顯著的差異性 (p=0.011)。若分析antrum加上body以後的腸化生總表現強度，也發現在二個月celecoxib治療後，腸化生總表現強度減弱，達到統計上顯著的差異性(p=0.007)。二個月celecoxib治療後，並沒有改變胃黏膜COX-2的總表現量，但改變了COX-2在胃的分佈；antrum上皮細胞在治療後COX-2有表現降低的趨勢，antrum及body固有層之COX-2有上升趨勢，而antrum的上皮細胞與固有層之COX-2表現量差距幅度明顯增加 (p=0.03)。

結論
　　celecoxib能夠有意義的降低幽門桿菌根除後的殘餘腸化生的強度，但不會改變胃黏膜COX-2的總表現量，不過COX-2表現量在胃的分佈有所改變。對於使用NSAIDs會造成消化道潰瘍及腎毒性風險的患者，在使用celecoxib時仍應謹慎評估。

第二部份 幽門桿菌患者用藥指導之成效研究

研究背景
　　幽門桿菌根除治療不只可以減少潰瘍的復發，也可能降低胃癌的發生率，其治療的成功與否也就愈形重要。儘管在幽門桿菌根除治療的有效組合下，仍將近有10 ~ 20%的患者無法根除幽門桿菌，菌株、宿主因素、環境因素都會影響根除治療成功的機率，其中又以菌株的抗藥性與患者服藥順從性最為重要。服藥順從性不佳，使得藥物的血中濃度不足，不僅無法發揮抗生素的療效，還可能誘發細菌抗藥性產生。

研究目的
　　提供幽門桿菌根除治療患者的用藥指導與衛教，並進而評估藥師用藥指導對於病患服藥順從性、治療藥物的了解及幽門桿菌根除率之影響。

研究對象
於成大醫院胃腸科門診，接受幽門桿菌根除治療的門診病患。

研究方法
　　對幽門桿菌根除治療的門診病患提供用藥指導與衛教。患者隨機分成實驗組和對照組，實驗組病人以用藥指導、服藥記錄卡及服藥期間的電話訪問，來提高患者的服藥順從性，對照組則在根除治療後進行用藥諮詢。幽門桿菌初次感染者，將進行三合一 (EAC regimen) 根除治療，
若患者之前已使用過三合一治療而仍無法根除幽門桿菌者，則進行四合一 (EBMT regimen) 根除治療。療程結束後以尿素呼氣試驗 (UBT) 或快速尿素酶檢查 (例如CLO test) 來確立是否根除成功。

研究結果
　　在本研究中，用藥指導對服藥順從性及幽門桿菌根除率沒有明顯影響。但幽門桿菌感染患者在接受藥師用藥指導後，對幽門桿菌根除治療及用藥的了解有顯著的增加 (p < 0.001)。

結論
　　用藥指導雖然對服藥順從性及幽門桿菌根除率沒有顯著影響，但確實增加了幽門桿菌感染患者對治療及用藥的認知。持續加強藥師對病患用藥之個人化服務，應是藥師繼續努力的方向。

Part 1. Efficacy of Celecoxib to Reverse Intestinal Metaplasia after Helicobacter pylori Eradication

Background
　　A higher risk of the development of gastric cancer has been reported in subjects with Helicobacter pylori infection. Expression of COX-2 mRNA and proteins was up-regulated in precancerous lesions of subjects with Helicobacter pylori infection. Recent clinical studies have demonstrated the effect of COX-2 inhibitor celecoxib in the treatment of familial adenomatous polyposis. It is worth to evaluate whether gastric COX-2 expression in the precancerous lesion could be reversed by celecoxib and whether celecoxib can regress intestinal metaplasia of stomach after Helicobacter pylori eradication.

Objective
1. To determine whether the COX-2 inhibitor
celecoxib can regress the residual precancerous
lesion as intestinal metaplasia of stomach after
Helicobacter pylori eradication.
2. To test whether the gastric COX-2 expression in
the precancerous lesion as intestinal metaplasia
could be reversed by COX-2 inhibition.
3. To assess the safety of celecoxib usage during
the 2-month treatment for intestinal metaplasia.

Subjects
　　Helicobacter pylori infected patients with intestinal metaplasia after eradication therapy.

Methods
　　After granting informed consent, this study proposes to enroll 22 patients with residual precancerous lesion as intestinal metaplasia of stomach after Helicobacter pylori eradication. These eligible patients take celecoxib (celebrex®) 200 mg qd for two months. The patients visit after the start of the therapy will be scheduled on the 1st, 4th, 8th week after therapy. During the returning into the visit on the 1st 4th, 8th week, the drug side effects should be evaluated as well as the drug compliance. After 2-month treatment course, each subject underwent gastric biopsy to assess the intensity of gastric COX-2 expression and the degree of intestinal metaplasia.

Results
　　21 patients had finished 2-month celecoxib 200 mg qd treatment course, 6 of the patients with disappearance of intestinal metaplasia and 4 patients with regression of intestinal metaplasia intensity. After 2-month celecoxib 200 mg qd treatment course, comparisons of the paired samples from the same patient before and after celecoxib treatment revealed reduction of intestinal metaplasia severity (p < 0.05).
　　There was no change in the total COX-2 expression in stomach mucosa, but the distribution of COX-2 expression is different before and after celecoxib treatment. After celecoxib treatment, we observed COX-2 down-regulation in the epithelial cells of antrum (p=0.084) and COX-2 up-regulation in the lamina propria of antrum and body. And we found that the range of difference between COX-2 expression in lamina propria and epithelial cells of antrum is significantly increased (p=0.03).

Conclusion
　　Celecoxib can reverse residual intestinal metaplasia severity after Helicobacter pylori eradication. Celecoxib can not change the total COX-2 expression in stomach mucosa, but it can change the distribution of COX-2 expression after the COX-2 inhibitor celecoxib treatment. Patients with intestinal metaplasia on celecoxib should be carefully followed, especially in high-risk populations such as renal insufficiency and peptic ulcer history.

Part 2. A Patient Counseling Program for
Helicobacter pylori Eradication Regimen

Background
　　Even with the current most effective Helicobacter pylori treatment regimens, approximately 10 ~ 20% of patients do not eradicate the infection. Factors associated with failed eradication include bacterial strain, host factor and socio-economic status. Helicobacter pylori antimicrobial resistance and patient compliance are the most common reasons for eradication failure. Poor compliance to eradication therapy of Helicobacter pylori has serious consequences for Helicobacter pylori-infected patients, including failure to eradicate and increase of the risk to develope antibiotic resistance.

Objective
　　To provide education and counseling for Helicobacter pylori-infected patients and to evaluate the efficacy of counseling program on drug compliance, knowledge of Helicobacter pylori eradication therapy and eradication rate.

Subjects
　　Helicobacter pylori-infected patients in the GI clinic, NCKU hospital

Methods
　　We conducted a randomized, controlled trial to determine the efficacy of patient counseling on the drug compliance, knowledge of anti-Helicobacter
pylori therapy and eradication rate of Helicobacter pylori. Patients were randomly divided into two groups: case group with patient counseling, reminder card at the first visit and follow-up telephone calls to improve adherence, control group with counseling after eradication therapy. Patients was prescribed triple therapy with EAC (esomeprazole + amoxicillin + clarithromycin) regimen. After failure of triple therapy, quadruple therapy with EBMT (esomeprazole + bismuth subcitrate + metronidazole + tetracycline) was administered. The eradication rate was assessed by urea breath test or CLO test.

Results
　　The control group had an eradication rate of 91.3% versus the case group’s rate of 85.7% (p > 0.05). There is no statistically significant difference in drug compliance between different groups. Although the patient counseling did not increase the eradication rate and drug compliance, it resulted in significant improvement in patient’s knowledge of Helicobacter pylori infection and eradication therapy (p < 0.001).

Conclusion
　　In this study, patient counseling by pharmacists did not affect drug compliance and eradication rate, but did increase patient’s knowledge of H. pylori infection and eradication therapy.

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