- Email: [email protected]
W1085 Functional Dyspepsia: Are Relapse Rates Influenced By Active Treatment ?
acid-suppressive therapy. These observations suggest that the Rome 3 subdivision of FD is best applied in patients who are not on anti-secretory therapy.
Selected were trials in FD with n > 100 and a follow up period > 1 month reporting outcomes as nominal data on “Responders” and on “Recurrences”. Retained for analysis were the data of 8 trials with a total of 3881 patients with FD or not investigated dyspepsia; 6 trials were Randomized Controlled Trials (RCTs) and 2 were open studies. Shortcomings in the database were the variable definitions of FD employed in the various trials (e.g. the inclusion of patients with symptoms of gastroesophageal reflux disease, GERD), the variable lengths of treatments and of follow-up (1.5 - 12 months). Some of the studies were limited to Hppositive patients or to non-responders/relapses of earlier trials. Results: The main outcomes are shown in the table of pooled data by drug. With the sole exception of the herbal preparation STW5, the Relative Risks of relapse (RR-r) were fairly similar, regardless of the treatment given. There is fair evidence that the RR-r observed with STW5 was lower compared to other treatments of FD, independent of the predictive covariates (i.e. response rate, symptoms of GERD). Longer treatments -also with placebo- in general showed higher response rates while the RR-r remained stable Conclusions: Current data suggest that STW5 might have a better efficacy to prevent relapse of FD than other therapies, but further RCTs are needed. Table: pooled data by drug
AGA Abstracts
W1083 Is Therapeutic Response to Esomeprazole in Patients with Uninvestigated Dyspepsia Sustainable During Sixteen Weeks of Therapy: Its Potential Clinical Implication? Irene Sarosiek, Katherine Roeser, Stanley A. Edlavitch, Richard McCallum, Jerzy Sarosiek Management of uninvestigated dyspepsia remains a challenge for primary care physicians and gastroenterologists. Although antisecretory therapy targeting parietal cell remains one of the first-line therapies, its long-term efficacy in alleviating patient's dyspeptic symptoms remains largely unexplored. Aim: To evaluate the efficacy of esomeprazole (40mg) vs. placebo in providing satisfactory relief of pain/discomfort symptoms in dyspeptic patients during 16 weeks of therapy. Methods: This randomized double-blind trial was conducted in KUMC patients with dyspepsia, diagnosed acc. to Rome II criteria, with at least moderately severe symptoms of pain/discomfort. Patients with heartburn or regurgitation as their predominant symptoms, H. pylori (+) or aspirin-like drugs users were excluded. Patients (mean age of 44.2; 62.2% F) were randomized to placebo (N=36) or esomeprazole regimens (N=38) 40 mg QD. Primary outcome measures were satisfactory relief of pain/discomfort symptoms, measured at four consecutive 4 weeks intervals (16 wks total), a 7-day daily diary preceding each visit, quality of life questionnaire and global overall symptoms assessment. Drug dose was titrated at each visit according to the following schedule: if patient reported relief dose unchanged for 8wks; if no relief - dose doubled to 40 mg BID; if patient reported relief for 2 visits (8 weeks) - dose reduced to 50% of current level and if dose reduction resulted in worsening of symptoms, patients returned to their previous effective dose. Responses were compared using a Chi-Square test with continuity correction. Results: 74% of patients receiving 40 QD esomeprazole reported satisfactory relief of symptoms vs. 30% on placebo (P<0.001) after 4 wks. The rate of satisfactory relief of symptoms increased to 82% when non-responders received dose 40 BID, and the placebo response rate also increased on BID dosing to 56% (P<0.05). During the next 4 wks of therapy (dose in responders reduced to 20 QD), the esomeprazole response rate declined to 69%, compared to placebo response rate 48% (p<0.10). When the dose was increased for non-responders during the last 4 weeks of therapy the response rate in patients on esomeprazole increased to 83% (vs. 57% placebo, P<0.05). Conclusions: 1. The significantly higher rate of satisfactory relief of symptoms in esomeprazole treated patients with uninvestigated dyspepsia compared to placebo indicates that this medication is statistically and clinically superior and its longterm efficacy is clearly demonstrated. 2. An increased response rate with higher dose of esomeprazole implies that some patients may benefit from 40 BID.
*) 2 open studies W1086 Metformin Suppresses the Colorectal Carcinogenesis Via Activating AMP Protein Kinase in the Mouse Model Kaori Suzuki, Hiroki Endo, Atsushi Nakajima Background: Metformin is widely used for the treatment of type 2 DM. Previous epidemiological reports suggest metformin reduce the cancer incidence. AMP protein kinase (AMPK) is known to be activated by metformin, and directly inhibit the mTOR (mammalian target of rapamycin) pathway. The mTOR pathway plays an important role for protein translational machinery and cell proliferation. We examined the effect of metformin on colorectal carcinogenesis in the mouse model. Methods: 6 weeks-old Balb/c mice i.p. injected with azoxymethane (AOM, 10mg/kg, twice for ACF and 6 times for polyp formation) was treated with metformin (0, 100, 250 mg/kg) for 24 weeks (for polyp formation), or for 6 weeks (for ACF formation). Colonic epithelial proliferation was evaluated using BrdU index. Activation of AMPK, mTOR pathway was evaluated by western blotting using phosphor-specific antibodies. Results: Treatment with metformin significantly reduced the number of polyp (20 vs. 4.5/ mouse, p<0.001) and ACF formation (15 vs. 4/mouse, p<0.05), and BrdU index in a dose dependent manner in the AOM induced mouse model of colon cancer. Western blot analysis revealed the activation of AMPK (Thr 172) and inactivation of mTOR pathway (S6K, p70S6) in colonic epithelium treated with metformin. AMPK specific activator AICAR and rapamycin (mTOR inhibitor) also reduced the ACF formation and BrdU index in the AOM mice model. Treatment with metformin significantly suppressed the cell proliferation in colon cancer cells (HT-29 and HCT 116) In Vitro, but did not suppress the cell proliferation in the cell transfected with AMPK siRNA. These results indicate that metformin suppresses the epithelial cell proliferation and colon carcinogenesis via activation of AMPK and inhibit the mTOR path way. Conclusion: Metformin is the novel chemopreventive candidate for colorectal cancer.
W1084 Rabeprazole vs. Itopride; a Randomized Multicenter Trial to Determine Efficacy in Functional Dyspepsia in Japan Takeshi Kamiya, Makoto Hirako, Michiko Shikano, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Tsuneya Wada, Hiromi Kataoka, Makoto Sasaki, Takashi Joh Background: Several studies in Western countries show that proton pump inhibitor (PPI) is effective in the treatment of functional dyspepsia (FD). In Japan, prokinetic agents and H2-receptor antagonists are widely used to treat FD patients. Therefore, the efficacy of PPI for FD in Japan, where the level of acid secretion is thought to be lower than Western people, is unknown. Aims: To investigate and compare the therapeutic effects of rabeprazole (RPZ), one of the PPI, and itopride (ITO), dopamine D2 antagonist with acetylcholinesterase effects, in Japanese patients with FD by a randomized open-labeled trial. Methods: 71 FD patients (Age:55.2±17.4yrs, Male/Femal:30/41), diagnosed according to Rome III criteria, were randomly assigned to either 4-week treatment with rabeprazole at a dosage of 10 mg qid; or with itopride 150 mg t.i.d. Dyspeptic symptoms were evaluated with three kinds of questionnaires, Leeds Dyspepsia Questionnaire (LDQ), Frequency Scale for the Symptoms of GERD (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS), at baseline and 1,2 and 4 weeks after the start of treatment. Evaluations using the FSSG used the total score for all 12 questions (FSSG-TS), questions related to acid reflux symptoms (FSSG-RS), and questions related to dysmotility (FSSG-DS). Results: LDQ symptom score in RPZ group decreased significantly after 2 weeks (8.8±2.4 to 7.1±2.6, p<0.05), whereas significant change was observed after 4-week medication in ITO group. After 1 week, FSSG-TS (11.3±2.7 to 7.4±3.0, p<0.05) and FSSG-RS (5.1±1.5 to 2.3±1.3, p<0.05) scores significantly improved in RPZ-treated patients, and these scores were significantly lower compared with those in ITO group (p<0.05). There was no significant difference in dysmotility score between two groups. GSRS total score significantly improved following treatment with RPZ within 1 week (38.4±4.5 to 33.1±3.0, p<0.05). GSRS abdominal pain score also significantly improved after 1-week medication (8.6±1.2 to 6.8±0.7, p<0.05). Furthermore, significant improvement in other GSRS dimensions of gastrointestinal symptoms, reflux, diarrhea and constipation were observed in only RPZ group within 2 weeks (P<0.05). Conclusions: Rabeprazole demonstrated better efficacy in relieving FD symptoms than itopride. These results showed that acid suppressive therapy with PPI for Japanese FD patients is useful like those reported in Western countries.
W1087 A Selective Cyclooxygenase-2 Inhibitor, Etodolac, Suppresses Stomach Carcinogenesis After Eradication Therapy of Helicobacter pylori in Mongolian Gerbils with Intestinal Metaplasia Hirohito Magari, Kimihiko Yanaoka, Toru Niwa, Hisanobu Deguchi, Takayuki Kanno, Tatsuya Shiraki, Chizu Mukoubayashi, Izumi Inoue, Takao Maekita, Mikitaka Iguchi, Hideyuki Tamai, Kenji Arii, Masashi Oka, Masao Ichinose Purpose:The eradication therapy of Helicobacter pylori(Hp) is considered to be important to control of gastric cancer. However, we often meet up with a patient who develops gastric cancer after eradication therapy of Hp received. Expression of cyclooxygenage-2 (COX-2) in chronic atrophic gastritis (CAG) and intestinal metaplasia is reported recently. CAG including intestinal metaplasia occurs in Hp-infected Mongolian gerbils (MGs). We previously showed that a selective COX-2 inhibitor, etodolac, suppressed stomach carcinogenesis in Hp-infected MGs (B B R C 2005, 334; 606-612).Therefore, in the present study, we investigated the effect of etodolac in succession to the eradication therapy of Hp on Hp-associated stomach carcinogenesis in MGs. Methods: A total of 156 MGs were divided into five groups (groups A-E; n = 23, 40, 37, 40 and 16 respectively). Groups A-D were given MNU in the drinking water at a concentration of 30 ppm for alternate weeks for a total of 5 weeks exposure. MNU was not administered to group E. One week after, animals were inoculated with Hp (3.0×108 CFU/ml, ATCC 43504) or vehicle alone (group E).For the eradicated groups (groups C and D), a triple therapy was performed. The drugs lansoprazole, amoxicillin, clarithromycin were suspended in 0.5% wt/wt carboxymethyl cellulose sodium salt solution and administered intra-gastrically twice a day for successive days at doses of 10, 3 and 30 mg/kg body weight, respectively. In groups B and D, the animals were given the stock Etodolac diet from week 45 until week 65, whereas the animals in groups A, C and E received the control diet. The daily administered dosage of etodolac in groups B and D were30 mg/kg/day. On the 65th experimental week, all animals were sacrificed. Tissues sections were stained with H&E. Results: In all the Hp-infected animals (groups A and B),
W1085 Functional Dyspepsia: Are Relapse Rates Influenced By Active Treatment ? Ulrike von Arnim, Bettina R. Vinson, Peter Malfertheiner Background: Functional dyspepsia (FD) is a chronic relapsing and remitting disorder and studies should provide information about the evolution of the disorder over time and following active treatment. However only few trials evaluated patients' symptoms over a time of six months or more after active treatment. We have tried to examine whether active treatment has an influence on the relapse rates observed during follow up. Methods: Trials were identified through PubMed, Embase, Cochrane Col. databases up to October 07.
AGA Abstracts
A-630
Selected were trials in FD with n > 100 and a follow up period > 1 month reporting outcomes as nominal data on “Responders” and on “Recurrences”. Retained for analysis were the data of 8 trials with a total of 3881 patients with FD or not investigated dyspepsia; 6 trials were Randomized Controlled Trials (RCTs) and 2 were open studies. Shortcomings in the database were the variable definitions of FD employed in the various trials (e.g. the inclusion of patients with symptoms of gastroesophageal reflux disease, GERD), the variable lengths of treatments and of follow-up (1.5 - 12 months). Some of the studies were limited to Hppositive patients or to non-responders/relapses of earlier trials. Results: The main outcomes are shown in the table of pooled data by drug. With the sole exception of the herbal preparation STW5, the Relative Risks of relapse (RR-r) were fairly similar, regardless of the treatment given. There is fair evidence that the RR-r observed with STW5 was lower compared to other treatments of FD, independent of the predictive covariates (i.e. response rate, symptoms of GERD). Longer treatments -also with placebo- in general showed higher response rates while the RR-r remained stable Conclusions: Current data suggest that STW5 might have a better efficacy to prevent relapse of FD than other therapies, but further RCTs are needed. Table: pooled data by drug
AGA Abstracts
W1083 Is Therapeutic Response to Esomeprazole in Patients with Uninvestigated Dyspepsia Sustainable During Sixteen Weeks of Therapy: Its Potential Clinical Implication? Irene Sarosiek, Katherine Roeser, Stanley A. Edlavitch, Richard McCallum, Jerzy Sarosiek Management of uninvestigated dyspepsia remains a challenge for primary care physicians and gastroenterologists. Although antisecretory therapy targeting parietal cell remains one of the first-line therapies, its long-term efficacy in alleviating patient's dyspeptic symptoms remains largely unexplored. Aim: To evaluate the efficacy of esomeprazole (40mg) vs. placebo in providing satisfactory relief of pain/discomfort symptoms in dyspeptic patients during 16 weeks of therapy. Methods: This randomized double-blind trial was conducted in KUMC patients with dyspepsia, diagnosed acc. to Rome II criteria, with at least moderately severe symptoms of pain/discomfort. Patients with heartburn or regurgitation as their predominant symptoms, H. pylori (+) or aspirin-like drugs users were excluded. Patients (mean age of 44.2; 62.2% F) were randomized to placebo (N=36) or esomeprazole regimens (N=38) 40 mg QD. Primary outcome measures were satisfactory relief of pain/discomfort symptoms, measured at four consecutive 4 weeks intervals (16 wks total), a 7-day daily diary preceding each visit, quality of life questionnaire and global overall symptoms assessment. Drug dose was titrated at each visit according to the following schedule: if patient reported relief dose unchanged for 8wks; if no relief - dose doubled to 40 mg BID; if patient reported relief for 2 visits (8 weeks) - dose reduced to 50% of current level and if dose reduction resulted in worsening of symptoms, patients returned to their previous effective dose. Responses were compared using a Chi-Square test with continuity correction. Results: 74% of patients receiving 40 QD esomeprazole reported satisfactory relief of symptoms vs. 30% on placebo (P<0.001) after 4 wks. The rate of satisfactory relief of symptoms increased to 82% when non-responders received dose 40 BID, and the placebo response rate also increased on BID dosing to 56% (P<0.05). During the next 4 wks of therapy (dose in responders reduced to 20 QD), the esomeprazole response rate declined to 69%, compared to placebo response rate 48% (p<0.10). When the dose was increased for non-responders during the last 4 weeks of therapy the response rate in patients on esomeprazole increased to 83% (vs. 57% placebo, P<0.05). Conclusions: 1. The significantly higher rate of satisfactory relief of symptoms in esomeprazole treated patients with uninvestigated dyspepsia compared to placebo indicates that this medication is statistically and clinically superior and its longterm efficacy is clearly demonstrated. 2. An increased response rate with higher dose of esomeprazole implies that some patients may benefit from 40 BID.
*) 2 open studies W1086 Metformin Suppresses the Colorectal Carcinogenesis Via Activating AMP Protein Kinase in the Mouse Model Kaori Suzuki, Hiroki Endo, Atsushi Nakajima Background: Metformin is widely used for the treatment of type 2 DM. Previous epidemiological reports suggest metformin reduce the cancer incidence. AMP protein kinase (AMPK) is known to be activated by metformin, and directly inhibit the mTOR (mammalian target of rapamycin) pathway. The mTOR pathway plays an important role for protein translational machinery and cell proliferation. We examined the effect of metformin on colorectal carcinogenesis in the mouse model. Methods: 6 weeks-old Balb/c mice i.p. injected with azoxymethane (AOM, 10mg/kg, twice for ACF and 6 times for polyp formation) was treated with metformin (0, 100, 250 mg/kg) for 24 weeks (for polyp formation), or for 6 weeks (for ACF formation). Colonic epithelial proliferation was evaluated using BrdU index. Activation of AMPK, mTOR pathway was evaluated by western blotting using phosphor-specific antibodies. Results: Treatment with metformin significantly reduced the number of polyp (20 vs. 4.5/ mouse, p<0.001) and ACF formation (15 vs. 4/mouse, p<0.05), and BrdU index in a dose dependent manner in the AOM induced mouse model of colon cancer. Western blot analysis revealed the activation of AMPK (Thr 172) and inactivation of mTOR pathway (S6K, p70S6) in colonic epithelium treated with metformin. AMPK specific activator AICAR and rapamycin (mTOR inhibitor) also reduced the ACF formation and BrdU index in the AOM mice model. Treatment with metformin significantly suppressed the cell proliferation in colon cancer cells (HT-29 and HCT 116) In Vitro, but did not suppress the cell proliferation in the cell transfected with AMPK siRNA. These results indicate that metformin suppresses the epithelial cell proliferation and colon carcinogenesis via activation of AMPK and inhibit the mTOR path way. Conclusion: Metformin is the novel chemopreventive candidate for colorectal cancer.
W1084 Rabeprazole vs. Itopride; a Randomized Multicenter Trial to Determine Efficacy in Functional Dyspepsia in Japan Takeshi Kamiya, Makoto Hirako, Michiko Shikano, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Tsuneya Wada, Hiromi Kataoka, Makoto Sasaki, Takashi Joh Background: Several studies in Western countries show that proton pump inhibitor (PPI) is effective in the treatment of functional dyspepsia (FD). In Japan, prokinetic agents and H2-receptor antagonists are widely used to treat FD patients. Therefore, the efficacy of PPI for FD in Japan, where the level of acid secretion is thought to be lower than Western people, is unknown. Aims: To investigate and compare the therapeutic effects of rabeprazole (RPZ), one of the PPI, and itopride (ITO), dopamine D2 antagonist with acetylcholinesterase effects, in Japanese patients with FD by a randomized open-labeled trial. Methods: 71 FD patients (Age:55.2±17.4yrs, Male/Femal:30/41), diagnosed according to Rome III criteria, were randomly assigned to either 4-week treatment with rabeprazole at a dosage of 10 mg qid; or with itopride 150 mg t.i.d. Dyspeptic symptoms were evaluated with three kinds of questionnaires, Leeds Dyspepsia Questionnaire (LDQ), Frequency Scale for the Symptoms of GERD (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS), at baseline and 1,2 and 4 weeks after the start of treatment. Evaluations using the FSSG used the total score for all 12 questions (FSSG-TS), questions related to acid reflux symptoms (FSSG-RS), and questions related to dysmotility (FSSG-DS). Results: LDQ symptom score in RPZ group decreased significantly after 2 weeks (8.8±2.4 to 7.1±2.6, p<0.05), whereas significant change was observed after 4-week medication in ITO group. After 1 week, FSSG-TS (11.3±2.7 to 7.4±3.0, p<0.05) and FSSG-RS (5.1±1.5 to 2.3±1.3, p<0.05) scores significantly improved in RPZ-treated patients, and these scores were significantly lower compared with those in ITO group (p<0.05). There was no significant difference in dysmotility score between two groups. GSRS total score significantly improved following treatment with RPZ within 1 week (38.4±4.5 to 33.1±3.0, p<0.05). GSRS abdominal pain score also significantly improved after 1-week medication (8.6±1.2 to 6.8±0.7, p<0.05). Furthermore, significant improvement in other GSRS dimensions of gastrointestinal symptoms, reflux, diarrhea and constipation were observed in only RPZ group within 2 weeks (P<0.05). Conclusions: Rabeprazole demonstrated better efficacy in relieving FD symptoms than itopride. These results showed that acid suppressive therapy with PPI for Japanese FD patients is useful like those reported in Western countries.
W1087 A Selective Cyclooxygenase-2 Inhibitor, Etodolac, Suppresses Stomach Carcinogenesis After Eradication Therapy of Helicobacter pylori in Mongolian Gerbils with Intestinal Metaplasia Hirohito Magari, Kimihiko Yanaoka, Toru Niwa, Hisanobu Deguchi, Takayuki Kanno, Tatsuya Shiraki, Chizu Mukoubayashi, Izumi Inoue, Takao Maekita, Mikitaka Iguchi, Hideyuki Tamai, Kenji Arii, Masashi Oka, Masao Ichinose Purpose:The eradication therapy of Helicobacter pylori(Hp) is considered to be important to control of gastric cancer. However, we often meet up with a patient who develops gastric cancer after eradication therapy of Hp received. Expression of cyclooxygenage-2 (COX-2) in chronic atrophic gastritis (CAG) and intestinal metaplasia is reported recently. CAG including intestinal metaplasia occurs in Hp-infected Mongolian gerbils (MGs). We previously showed that a selective COX-2 inhibitor, etodolac, suppressed stomach carcinogenesis in Hp-infected MGs (B B R C 2005, 334; 606-612).Therefore, in the present study, we investigated the effect of etodolac in succession to the eradication therapy of Hp on Hp-associated stomach carcinogenesis in MGs. Methods: A total of 156 MGs were divided into five groups (groups A-E; n = 23, 40, 37, 40 and 16 respectively). Groups A-D were given MNU in the drinking water at a concentration of 30 ppm for alternate weeks for a total of 5 weeks exposure. MNU was not administered to group E. One week after, animals were inoculated with Hp (3.0×108 CFU/ml, ATCC 43504) or vehicle alone (group E).For the eradicated groups (groups C and D), a triple therapy was performed. The drugs lansoprazole, amoxicillin, clarithromycin were suspended in 0.5% wt/wt carboxymethyl cellulose sodium salt solution and administered intra-gastrically twice a day for successive days at doses of 10, 3 and 30 mg/kg body weight, respectively. In groups B and D, the animals were given the stock Etodolac diet from week 45 until week 65, whereas the animals in groups A, C and E received the control diet. The daily administered dosage of etodolac in groups B and D were30 mg/kg/day. On the 65th experimental week, all animals were sacrificed. Tissues sections were stained with H&E. Results: In all the Hp-infected animals (groups A and B),
W1085 Functional Dyspepsia: Are Relapse Rates Influenced By Active Treatment ? Ulrike von Arnim, Bettina R. Vinson, Peter Malfertheiner Background: Functional dyspepsia (FD) is a chronic relapsing and remitting disorder and studies should provide information about the evolution of the disorder over time and following active treatment. However only few trials evaluated patients' symptoms over a time of six months or more after active treatment. We have tried to examine whether active treatment has an influence on the relapse rates observed during follow up. Methods: Trials were identified through PubMed, Embase, Cochrane Col. databases up to October 07.
AGA Abstracts
A-630