Pui Kuan Cheong

Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial

BACKGROUND & AIMS The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumins efficacy in inducing remission in patients with active mild-to-moderate UC. METHODS We performed a multicenter randomized, placebo-controlled, double-blind study of 50 mesalamine-treated patients with active mild-to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI ≤2) at week 4. Clinical and endoscopic responses were also recorded. RESULTS In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of ≥3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score ≤1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups. CONCLUSIONS Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436.

Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial

BACKGROUND Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. METHODS For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT00153660. FINDINGS Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3-9·2) in the celecoxib group and 12·3% (8·8-17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23-0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. INTERPRETATION In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. FUNDING The Research Grant Council of Hong Kong.

Decreased Basal and Postprandial Plasma Serotonin Levels in Patients With Functional Dyspepsia

BACKGROUND & AIMS Patients with diarrhea-predominant irritable bowel syndrome (IBS) have been found to have increased postprandial levels of serotonin (5-HT). Functional dyspepsia (FD) and IBS have been proposed to have common methods of pathogenesis, but little is known about the role of 5-HT in FD. METHODS We measured postprandial levels of 5-HT in 54 patients with FD (based on Rome III criteria) and 28 asymptomatic healthy individuals (controls). Patients with gastroesophageal reflux disease and IBS as their predominant symptom were excluded. After an overnight fast, the subjects drank a liquid meal (Ensure; 1.06 kcal/mL at 30 mL/min) and underwent a (13)C-octanoic acid breath test to measure gastric emptying times. Blood samples were collected at 0, 30, 60, 90, and 120 minutes after the liquid meal for the 5-HT assay. RESULTS Thirty-five patients with FD (65%) had postprandial distress syndrome, and 6 (11%) had a combination of postprandial distress syndrome and epigastric pain syndrome. There were no differences in rates of gastric emptying between patients with FD (103.6 ± 19.4 minutes) and controls (83.1 ± 4.0 minutes; P = .30). However, patients with FD had lower caloric intake (823.40 ± 44.1 kcal) than controls (1021 ± 68.2 kcal; P = .026). Patients with FD also had lower basal (P = .03) and postprandial plasma levels of serotonin at 30 minutes (P = .04), 60 minutes (P = .01), 90 minutes (P = .02), and 120 minutes (P = .002) than controls, as well as area under the curve values over the 120-minute time period (P = .005). Repeated-measures analysis of variance correlated 5-HT level with FD (P < .001). CONCLUSIONS In contrast to patients with diarrhea-predominant IBS, those with FD have decreased basal and postprandial plasma levels of 5-HT. These findings indicate that the pathogenic mechanism of FD differs from that of diarrhea-predominant IBS, and that strategies to alter 5-HT levels or activity might be developed to treat patients with FD.

A Randomized, Double-Blind, Placebo-Controlled Trial of Low Dose Imipramine for Treatment of Refractory Functional Dyspepsia (FD)

G A A b st ra ct s to assess dose response. Funnel plot analysis was performed to test for publication bias. Results: Systematic review identified 3,403 citations. Detailed evaluation identified 18 potentially relevant journal articles/abstracts, of which 5 fulfilled our inclusion criteria. Of the 1803 IBS patients randomized, 96% had non-constipated IBS. Meta-analysis of data from 5 studies demonstrated that rifaximin was superior to placebo for global symptom improvement (p=0.0038, see table). Raw data was available from 4 studies for the secondary endpoint of bloating. For this endpoint, the response rate with rifaximin was significantly higher than with placebo (p<0.0001). Based on data from 4 studies, rifaximin significantly reduced abdominal pain scores compared to placebo. Data from 3 studies demonstrated that rifaximin significantly improved stool consistency compared to placebo. A logistic regression model showed no linear trend for a dose response. Funnel plot analysis revealed no evidence of publication bias. The most common AEs (≤10%) with rifaximin were headache, upper respiratory infection, urinary tract infection, nausea, vomiting, & diarrhea which were similar to placebo. Serious AEs with rifaximin were rare (<2%) and similar to placebo. There were no confirmed reports of C. difficile associated diarrhea. Conclusion: In high quality studies, rifaximin was more effective than placebo at improving global symptoms and bloating in patients with IBS. Rifaximin was well tolerated in short term trials. Efficacy and safety data beyond 10 weeks of therapy are not available.

Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters

Objective Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID. Design 1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters. Results Nine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence). Conclusion We found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.

Low-dose imipramine for refractory functional dyspepsia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Guidelines recommend the use of neuromodulators in patients with functional dyspepsia not responding to proton pump inhibitors (PPIs) and prokinetics; however, there is a lack of data from randomised controlled trials supporting their use. We aimed to assess the safety and efficacy of imipramine, a tricyclic antidepressant (TCA), in treatment-refractory functional dyspepsia. METHODS In this single-centre, double-blind, randomised controlled trial, we enrolled consecutive patients with Rome II functional dyspepsia aged 18-80 years. Eligible patients were Helicobacter pylori-negative, had a normal upper gastrointestinal endoscopy and abdominal ultrasound, and remained symptomatic after open-label treatment with 8 weeks of esomeprazole and 4 weeks of domperidone. Patients completed questionnaires assessing dyspepsia symptoms, mood, and insomnia, and were then randomly assigned (1:1) via a computer-generated list of random numbers to receive imipramine (at a dose of 25 mg once nightly for the first 2 weeks, and then 50 mg thereafter) or placebo for 12 weeks. The primary endpoint was overall satisfactory relief of global dyspepsia symptoms at 12 weeks, via patient-reported assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00164775, and is completed. FINDINGS Between Sept 11, 2005, and Aug 20, 2010, 107 patients with treatment-refractory functional dyspepsia were randomly assigned to receive imipramine (n=55) or placebo (n=52). Relief of global dyspepsia symptoms at 12 weeks occurred in 35 (63·6%, 95% CI 50·4-75·1) of 55 patients on imipramine compared with 19 (36·5%, 95% CI 24·8-50·1) of 52 on placebo (p=0·0051). Ten (18%) patients on imipramine discontinued the study due to adverse events (three dry mouth, two constipation, two drowsiness, and one each insomnia, palpitations, and blurred vision), compared with four (8%) on placebo (one dry mouth and constipation, and one each palpitations, worsening of gastro-oesophageal reflux, and limb paraesthesia). There were no serious adverse events. INTERPRETATION Low-dose imipramine should be considered as a possible therapy for patients with functional dyspepsia refractory to both PPIs and prokinetics, although patients should be cautioned about the adverse event profile. FUNDING None.

Sa1132 Proton-Pump Inhibitor (PPI) Versus Histamine-2 Receptor Antagonist (H2RA) for the Prevention of Recurrent Upper Gastrointestinal Bleeding (UGI) in High-Risk Users of Low-Dose Aspirin (ASA): An Interim Analysis

BACKGROUND Previously we showed that PPI prevented recurrent UGI bleeding in ASA users with a history of UGI bleeding. Whether histamine-2 receptor antagonists (H2RAs) are an effective gastroprotective agent in these high-risk ASA users is unclear. We compared a PPI with an H2RA for prevention of recurrent ulcer bleeding with ASA. METHODS This was a 12-month, double-blind, randomized trial of rabeprazole versus famotidine in ASA users with a history of endoscopically confirmed nonvariceal UGI bleeding. After their ulcers had healed, we randomly assigned ASA users (80 mg once daily) with negative tests for Helicobacter pylori to receive either 20 mg of rabeprazole once daily or 40 mg of famotidine once daily for up to 12 months. Endoscopy was repeated if they developed symptoms of recurrent GI bleeding, had a drop in hemoglobin (Hb) >2 g/dL, withdrew early due to

Decreased Basal and Postprandial Plasma 5-Hydroxytryptamine (5-HT) in Patients With Functional Dyspepsia (FD): A Pilot Study

BACKGROUND: Increased postprandial 5-HT levels have been observed in patients with diarrhea-predominant irritable bowel syndrome (IBS). However, it is unclear whether patients with FD have 5-HT dysfunction. AIM: To compare the plasma 5-HT profile in FD patients and healthy controls. METHODS: Consecutive patients with FD (Rome III criteria) were recruited. Patients with GERD and IBS as predominant symptoms were excluded. After an overnight fast, they underwent caloric drinking test (Ensure O,1.06 kcal/ml at 30ml/min) and 13C-octanoic acid breath test for gastric emptying time measurement. Serial blood samples were collected at 0, 30, 60, 90, 120 min postprandially for plasma 5-HT assay. Healthy controls without history of peptic ulcer and dyspepsia were recruited for the same protocol. RESULTS: 29 FD patients (M:F, 8:21; mean age: 45±2) and 20 controls were studied. 18 (62%) patients had postprandial distress syndrome (PDS) and 11 (40%) had both PDS and epigastric pain syndrome. 7 (24%) patients had concomitant IBS. There was no significant difference in total calorie intake (FD: 762±59 kcal; Control: 940±89 kcal, p= 0.11) and gastric emptying rate (T1/2, FD: 76±4min.; Control: 80±5min., p=0.52). However, FD patients had significantly lower basal (FD: 139±17 ng/109platelets, Control: 238.0±11.7 ng/109platelets, p<0.001) and postprandial plasma serotonin contents at 30min (FD: 127±18 ng/109platelets, Control: 206±10 ng/109platelets, p<0.001), 60 min (FD: 119±18 ng/ 109platelets, Control: 193 ±19 ng/109platelets, p=0.006), 90 min (FD: 110±17 ng/109platelets, Control: 171 ± 23 ng/109platelets, p=0.038) and AUC over the period of 120 min (FD: 14410±1968 ng/109platelets.min, control: 23160±1537 ng/109platelets.min, p=0.0062). Repeated measures of ANOVA revealed high correlation between FD and serotonin profile across 120 min (p=0.0021 for FD, time <0.0001) CONCLUSION: In contrast to IBS, FD patients have decreased basal and postprandial plasma 5-HT concentrations. These findings suggest (1) IBS and FD have different pathophysiological mechanism in particular the 5HT dysfunction and (2) Modulation of 5-HT system may have therapeutic value in treatment of FD.