中华消化病学年度讲坛论文汇编之三(2015).doc

中华消化病学年度讲坛论文汇编之三（2015）2015 Chinese Annual Symposium on Gastroenterology主办机构：北京大学第三医院会议时间：2015年4月24 -26日会议地点：北京国际会议中心一层第三会议厅会场地点：北京市朝阳区北辰东路8号论坛主席：林三仁教授 “2015消化基础及临床新进展学习班暨第八届中华消化病学年度讲坛”于4 月24-26 日在北京国际会议中心隆重召开。此次会议特别邀请了国内外多名知名的消化内、外科专家、学者，针对消化病学的热点问题进行了全方位、深层次、多角度的交流和研讨，使与会者饱飨学科发展的精髓。此次大会的口号是“剖析消化科学新进展，引领消化领域新潮流”。本文主要以文字的形式对2015年4月25日上午13:30至14:45这一时段的精彩内容进行回顾，与读者共同分享学科盛宴。大会日程 13: 30-13: 45 主持专家：林三仁、郑勇、沈锡中、马颖才点评专家：姜慧卿、林琳、李良平、袁伟建13:30-13:50胃粘膜保护剂的药效学研究赵荣生北京大学第三医院13:50-14:10粘膜保护剂辅助治疗的临床疗效评估周丽雅北京大学第三医院14:10-14:30胃粘膜保护剂的临床应用吴小平湖南湘雅第二医院14: 30-14：45 点评讨论 13:30-13:50 胃粘膜保护剂的药效学研究 赵荣生 北京大学第三医院 胃粘膜保护剂的药效学研究赵荣生北京大学第三医院目录1. 胃粘膜损伤的机制2. 常见胃粘膜保护剂3. 粘膜保护剂疗效循证评价消化性溃疡 Peptic Ulcer, PU 消化性溃疡是粘膜发生炎症反应与坏死性疾病，深达粘膜肌层 以胃溃疡（GU）和十二指肠溃疡（DU）最常见，人群中约有10%在其一生中患过此病 PU在我国人群中的发病率尚无确切的流行病学调查资料 占国内胃镜检查人群的10.3%-32.6% 可见于任何年龄，20-50岁居多 男性多于女性（2-5:1） 临床上DU多于GU（3:1）中华消化杂志编委会.消化性溃疡病诊断与治疗规范建议(2008,黄山)J.中华消化杂志,2008,28(7):447-450.胃溃疡伴多种并发症 癌变：胃溃疡癌变率40mm，OR=12.66 2.04， 78.70In addition, the combination therapy was found to be significantly more effective than the use ofPPIsalone for all ESDulcersgreater than 20 mm in size (OR=4.77, 95%CI: 2.22-10.26).Wang J, et al. Efficacy and Safety of Proton Pump Inhibitors (PPIs) Plus Rebamipide for Endoscopic Submucosal Dissection-induced Ulcers: A Meta-analysis. Intern Med. 2014;53(12):1243-8.瑞巴派特-H.Pylori根除率Nishizawa et al. identified six randomized trials (611 patients). Pooled H.pylorieradicationrates by per-protocol analysis were 73.3% and 61.4% for patients with or withoutrebamipide, respectively. The odds ratio was 1.74 (95% confidence interval. 1.19-2.53).瑞巴派特+PPIs vs. PPIs 根除率分别为73.3% and 61.4%OR=1.74 (95% CI, 1.19-2.53)Figure 2 Forest plot displaying the odds ratio and 95% confidence intervals (CIs) of each study for Helicobacter pylori eradication rates by per-protocol analysis.瑞巴派特 vs. 替普瑞酮OR=2.25 0.61，8.22瑞巴派特 vs. 普劳诺托OR=2.53 1.06，6.14Nishizawa T, et al. Effect of supplementation with rebamipide for Helicobacter pylori eradication therapy: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2014;29 Suppl 4:20-4.Proton pump inhibitor alone vs proton pump inhibitor plus mucosal protective agents for endoscopic submucosal dissection-induced ulcer: a systematic review and meta-analysisPPIs vs.PPIs + 胃粘膜保护剂We identified 11 randomized trials for inclusion in our study (1,160 patients).Pooledendoscopicsubmucosaldissection-inducedulcerhealing rates were 45.8% and 34.4% for patients with or withoutmucosalprotectiveagents, respectively. The odds ratio was 2.28 (95% confidence interval, 1.57-3.31) with no significant study heterogeneity.11个RCTs2个韩国，9个日本ESD溃疡整体治愈率OR = 2.28 1.57, 3.31, I2 = 23%治疗4周治愈率OR = 2.19 1.43, 3.34, I2 = 34.9%治疗8周治愈率OR = 3.03 1.42, 6.48, I2 = 0%不同胃粘膜保护剂比较表3 不同胃粘膜保护剂比较胃粘膜保护剂OR值95%Cl研究数目样本量瑞巴派特2.41.68-3.446724依卡倍特2.180.49-9.702131聚普瑞锌1.890.44-7.91样本量较小不足以覆盖差异2208伊索拉啶5.241.08-25.4196研究质量较低Nishizawa T, et al. Proton pump inhibitor alone vs proton pump inhibitor plus mucosal protective agents for endoscopic submucosal dissection-induced ulcer: a systematic review and meta-analysis. J Clin Biochem Nutr 2015; 56(2): 85-90.13 : 50-14：10 粘膜保护剂辅佐治疗的临床疗效评估 周丽雅 北京大学第三医院 粘膜保护剂辅助治疗的临床疗效评估周丽雅北京大学第三医院提纲1. 瑞巴派特作用机制2. 瑞巴派特对上消化道粘膜的保护作用3. 瑞巴派特对ESD术后溃疡愈合的效果4. 瑞巴派特对小肠粘膜损伤的保护作用5. 其他一、瑞巴派特作用机制全面主动双向作用的胃粘膜保护剂促进前列腺素的合成与分泌，增加胃粘膜防御因子清除氧自由基和抑制氧自由基的生成，清除胃粘膜侵袭因子抑制胃粘膜炎症，促进炎症消退；刺激生长因子，加速修复重建瑞巴派特在胃粘膜内及血清中的浓度变化健康人，单次口服给药100mg测胃粘膜、粘液及血清中浓度推移胃粘膜及粘液中瑞巴派特的浓度在服药1小时后达到最高，在0.1mM以上；血清浓度未超过1uMDrug Med, 1997; 17:1527.瑞巴派特的药代动力学 Tmax 1.9h，Cmax: 0.57uM, T1/2: 1.5小时 饭前、饭后服药药效无明显差异 脏器选择性高：在以胃粘膜为中心的消化管高浓度分布 服药后仅有0.1%被代谢 主要经粪便排泄瑞巴派特的药效学特点u 高浓度胃肠道粘膜靶向分布（70%以上）u 多种作用机制（促进PG合成，清除氧自由基，抑制炎症）较好的提高了临床治疗效果瑞巴派特在过度酸分泌大鼠中预防阿司匹林联合氯吡格雷致胃出血及溃疡样反应中的作用研究Low-dose aspirin (acetylsalicylic acid ASA)实验方法METHODS:Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8mg/kg/h), and the stomach was perfused with 25mmol/L ASA at a rate of 0.4mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30mg/kg) was given p.o. 24h before the perfusion. Rebamipide (3-30mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion.ASA外对照组90min0-120min处死 生理盐水+组胺内对照组ASA-24h-120min090min处死-氯吡格雷30mg/Kg p.o.生理盐水+组胺实验组ASA-24h-150min-120min090min处死-l 瑞巴派特l 奥美拉唑l 法莫替丁l 伊索拉唑l 提普瑞特氯吡格雷30mg/Kg p.o.生理盐水+组胺结果组胺刺激可导致大鼠胃酸分泌过多，在此基础上应用阿司匹林加重胃粘膜损伤，而氯吡格雷的重叠应用进一步增加胃出血风险髓过氧化物酶（MPO）PPI，抗酸药及胃粘膜保护剂对于MPO的活性均有显著抑制作用结果瑞巴派特可以预防上述情况导致的胃粘膜损伤及减少胃出血并呈剂量依赖关系，其效果与抗酸分泌药物相似Takeuchi K, et al. Effect of rebamipide on gastric bleeding and ulcerogenic responses induced by aspirin plus clopidogrel under stimulation of acid secretion in rats. J Gastroenterol Hepatol, 2014; 29(Suppl 4): 37-46.瑞巴派特对N-甲基N-硝基N-亚硝酸胍（MNNG）致大鼠胃癌的预防作用方法39只雄性SD大鼠被分为四组Fig. 1. Experimental design. A total of 39 rats were used in the experiment. N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was administered in the drinking water for a period of 30 weeks to rats in both the Control-M and Rebamipide-Mgroups. The rebamipide groups were given rebamipide at 5 mg/kg/day mixed with food (gray bar). All rats were sacrificed 50 weeks after the study commenced.观察指标u 大鼠腺胃的肿瘤发生率u 癌变区域的分型u 瑞巴派特组或瑞巴派特-MNNG组PCNK阳性表达的细胞计数、80HDG、肿瘤细胞凋亡（TUNEL方法）u 血清胃泌素水平结果Fig. 2. Macroscopic and microscopic appearance of a N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric tumor in a rat. Shown is representative of the macroscopic appearance of a typical well-differentiated adenocarcinoma (A) as well as the microscopic appearance of the well-differentiated adenocarcinoma stained with HE (B;10, C; 400).结论瑞巴派特抑制MNNG诱导的大鼠肿瘤发生并且可能抑制癌症进展In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats.Tsukamoto H, et al. Preventive effect of rebamipide on N-methyl-N-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Exp Toxicol Pathol, 2015; 67(3): 211-7.2、 瑞巴派特对上消化道粘膜的保护作用u 6个RCT研究显示对于上消化道粘膜损伤的疗效瑞巴派特优于安慰剂RR=1.55 (95%Cl; 1.02,2.36)Fig. 4 Rebamipide is superior to placebo in preventing shortterm NSAID-induced gastric damage. NSAIDs nonsteroidal anti-inflammatory drugs, CI confidence intervalMeta分析：瑞巴派特 vs. PPIsu 3个RCT对比了瑞巴派特和PPIs的上消化道粘膜损伤的疗效u Kawai等人的研究显示瑞巴派特和奥美拉唑的效果类似u Zhu等人的研究显示两者预防胃十二指肠溃疡的效果相当，但瑞巴派特可以节省51.4%的费用u Suyata等人的研究显示瑞巴派特和奥美拉唑都可以减轻消化不良的症状，瑞巴派特的效果弱于奥美拉唑Meta分析：瑞巴派特 vs. H2 受体拮抗剂u 两个RCT对比了瑞巴派特和H2受体拮抗剂u Naito等人的交叉设计的研究显示瑞巴派特组和法莫替丁组胃病变的发生率相似（17% vs 25%, P=0.50）u Yamao等人纳入112名长期服用NSAIDs且出现出血和糜烂的患者，提示在治疗NSAIDs胃病的方面，瑞巴派特效果比法莫替丁差 结论 u 目前的证据显示： 瑞巴派特在防止NSAID所致的胃十二指肠损伤方面安全有效，但弱于PPI及H2受体拮抗剂。Zhang S, et al. Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. Dig Dis Sci, 2013; 58(7):1991-2000.瑞巴派特联合选择性COX-2抑制剂对于关节炎患者的胃肠道事件的预防作用-GLORIA研究组 方法 u 入组患者：类风湿性关节炎、骨关节炎及腰背痛u 单一疗法组：塞来考昔 100mg, Bidu 联合治疗组：塞来考昔 100mg, Bidu +瑞巴派特 100mg, Tidu 治疗前和治疗后3个月分别行内镜检查，评估胃肠道粘膜损伤情况u 初级终点：内镜下见上消化道溃疡u 不能耐受的胃肠道症状 METHODS l Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. l Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on 100 mg of rebamipide three times a day). l The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. l The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group. 结果-上消化道不良事件的发生率 RESULTS:n Seventy-five patients were enrolled. n Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 13 years). n The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were6/34 (17.6%) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252. 结论 联合瑞巴派特可显著预防上消化道事件的发生，瑞巴派特可作为选择性COX-2抑制剂造成的上胃肠道事件的预防用药。 CONCLUSIONS The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events.Hasegawa M, et al. The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group. Mod Rheumatol, 2013; 23(6): 1172-8. 瑞巴派特对NSAIDs介导的粘膜毒性的预防效果及安全性 随机、双盲、双模拟、多中心、平行对照临床试验 方法 u 受试者：至少服用NSAIDs达12周以上的患者，年龄大于19岁，包括类风湿性关节炎、骨关节炎、强制性脊柱炎或其他关节炎u 治疗组：瑞巴派特 100mg/tidu 对照组：米索前列醇 200ug/tidu NSAIDs药物：醋氯芬酸 100mg/bid；u 美洛昔康 15mg/qd;u 蔡丁美酮 1000mg/qdu 12周后行胃镜检查u 主要终点：胃溃疡u 次要终点：治疗失败、胃肠道症状、抗酸药的使用 METHODS METHODS:We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 mg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy. 结果 Fig. 2. Subject dispositions. *One subject had multiple reasons for screening failure (inclusion/exclu-sion criteria were not respected, and others). 胃溃疡 发生情况 治疗失败率 胃肠道症状严重程度 抗酸药使用量 主要不良反应 结论 u 瑞巴派特可预防NSAIDs引起的胃溃疡，并减少NSAIDs相关的胃肠道不良反应；u 考虑到米索前列醇潜在的不良反应及依从性差，瑞巴派特可作为其临床有效及安全的替代用药。 CONCLUSIONS n Rebamipide can prevent gastric ulcers when used with NSAIDsandcan decrease the gastrointestinal symptoms associated with NSAID administration. n When the possibility of poor complianceandthe potential adverse effects of misoprostol are considered, rebamipide appears to be a clinically effectiveandsafe alternative.Jeong Ho Kim, et al. Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity. Gut and Liver, 2014; 8: 371-379.3、 瑞巴派特对ESD术后溃疡愈合的效果 背景 u PPI预防ESD相关溃疡出血优于H2受体拮抗剂u 胃粘膜保护剂可以提高胃粘膜组织在修复过程中的防御能力u 东亚地区广泛应用的粘膜保护剂：瑞巴派特、依卡倍特钠、聚普瑞锌、硫糖铝、藻酸钠、普劳诺托、索法酮、替普瑞酮、马来酸伊索拉啶、米索前列醇、氢氧化铝镁u Meta分析：对ESD相关溃疡，PPI联合瑞巴派特优于单独PPI Background A recent study showed that proton pump inhibitors (PPIs) more effectively prevented bleeding due to ESD-induced gastric ulcers than histamine H+-receptor antagonists. The generally assumed mechanism underlying the action of these agents involves the up-regulation of gastric mucosal defenses during recovery of mucosal tissue. Mucosal protective agents include drugs such as rebamipide, ecabet sodium, polaprezinc, sucralfate, sodium alginate, plaunotol, sofalcone, teprenone, irsogladine maleate, misoprostol, and aluminum-magnesium hydroxide, which are widely prescribed, in East Asia. A meta-analysis study recently demonstrated that treatment of ESD-induced ulcers with PPIs plus rebamipide results in superior outcomes to PPI monotherapy. 结论 PPI联合粘膜保护剂可促进ESD相关溃疡的愈合治疗ESD相关溃疡，PPI联合粘膜保护剂（尤其是瑞巴派特）优于单独应用PPI CONCLUSIONS In conclusion, the systematic review and meta-analysis showed that the combined therapeutic use of proton pump inhibitors and mucosal protective agents improved healing rates of endoscopic submucosal dissection-induced ulcers compared to treatment with proton pump inhibitor monotherapy.Toshihiro Nishizawa, et al J Clin Biochem Nutr, 2015; 56(2):85-90.胃早癌ESD术后，1周Hp根除治疗联合7周瑞巴派特与8周标准PPI治疗的有效性和安全性分析随机、对照、前瞻、多中心研究Fig. 1 Patient flow chart 方法 胃镜胃镜ESD胃镜A组25807Hp阳性早期胃癌患者IIaI13C-UBT胃镜胃镜胃镜ESDB组8458920IIIIIbII：奥美拉唑 40mg Qd 静脉用药；IIa: 奥美拉唑 20mg Qd 口服IIb: 奥美拉唑 20mg Bid + 阿莫西林 750mg Bid + 克拉霉素 400mg BidIII: 瑞巴派特 100mg Tid Method Patients were randomized to two study groups (group A and B). All patients received intravenous administration of 40 mg omeprazole on the first 2 days after ESD; then, the study drugs were administered. In group A, patients received 20 mg of omeprazole daily for 56 days. In group B, patients received 20 mg of omeprazole, 750 mg of amoxicillin, and 400 mg of clarithromycin twice daily for 7 days, and then 100 mg of rebamipide three times daily for 49 days. Endoscopic examination was performed at day 2, 7, and 58 after ESD, and the artificial ulcer area was calculated. In addition, ulcer stages such as healing and scar stages were evaluated. In group B, the 13C-urea breath test (UBit ; Otsuka, Tokyo, Japan) was performed on day 84 after ESD to confirm the presence or absence of H. pylori. 用药45天后溃疡瘢痕形成情况 A组瘢痕形成率明显高于B组 人工溃疡减少情况 The change in the reduction ratio of the artificial ulcer area at day 7 was 15.2 52.5 % in group A and 38.1 24.0 % in group B, respectively (P = 0.0195). The change in t