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BACKGROUND & AIMS We evaluated treatment withdrawal, long-term outcomes, and safety of budesonide oral suspension (BOS) 2.0 mg twice daily in patients with eosinophilic esophagitis who completed a 12-week induction study. METHODS Induction full responders (≤6 eosinophils per high-power field [eos/hpf] and ≥30% reduction in the Dysphagia Symptom Questionnaire score) to BOS 2.0 mg twice daily (ORBIT1/SHP621-301/NCT02605837) were randomized to continue BOS (BOS-BOS) or withdraw to placebo (BOS-PBO) for 36 weeks (ORBIT2/SHP621-302/NCT02736409). Induction partial responders and nonresponders, and patients who received induction placebo, received BOS for 36 weeks. The primary end point was the proportion of BOS-BOS and BOS-PBO patients who relapsed (≥15 eos/hpf and ≥4 days of dysphagia [Dysphagia Symptom Questionnaire] over 2 weeks) by week 36. The key secondary end point was the proportion of induction partial responders and nonresponders who fully responded after 52 weeks of total BOS therapy. Other secondary end points included the proportion of induction full responders with histologic responses (≤1, ≤6

SummaryBackground Previous studies have reached conflicting conclusions regarding the efficacy of mesalazine in the prevention of recurrent diverticulitis. Aim To investigate the efficacy and safety of mesalazine granules in the prevention of recurrence of diverticulitis after acute uncomplicated diverticulitis. Methods Two phase 3, randomised, placebo-controlled, double-blind multicentre trials (SAG-37 and SAG-51) investigated mesalazine granules in patients with prior episodes (1 episode. Safety data revealed no new adverse events. Conclusion Mesalazine was not superior to placebo in preventing recurrence of diverticulitis.

Objectives: Breath tests (BTs) are important for the diagnosis of carbohydrate maldigestion syndromes and small intestinal bacterial overgrowth (SIBO). However, standardization is lacking regarding indications for testing, test methodology and interpretation of results. A consensus meeting of experts was convened to develop guidelines for clinicians and research. Methods: Pre-meeting survey questions encompassing five domains; indications, preparation, performance, interpretation of results, and knowledge gaps, were sent to 17 clinician-scientists, and 10 attended a live meeting. Using an evidence-based approach, 28 statements were finalized and voted on anonymously by a working group of specialists. Results: Consensus was reached on 26 statements encompassing all five domains. Consensus doses for lactulose, glucose, fructose and lactose BT were 10, 75, 25 and 25 g, respectively. Glucose and lactulose BTs remain the least invasive alternatives to diagnose SIBO. BT is useful in the diagnosis of carbohydrate maldigestion, methane-associated constipation, and evaluation of bloating/gas but not in the assessment of oro-cecal transit. A rise in hydrogen of ≥20 p.p.m. by 90 min during glucose or lactulose BT for SIBO was considered positive. Methane levels ≥10 p.p.m. was considered methane-positive. SIBO should be excluded prior to BT for carbohydrate malabsorption to avoid false positives. A rise in hydrogen of ≥20 p.p.m. from baseline during BT was considered positive for maldigestion. Conclusions: BT is a useful, inexpensive, simple and safe diagnostic test in the evaluation of common gastroenterology problems. These consensus statements should help to standardize the indications, preparation, performance and interpretation of BT in clinical practice and research.

The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated.A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

A capsule formulation of mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission.Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC-related adverse event (AE).Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P0.001) and across subgroups based on select demographic and baseline characteristics (P0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%).Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

Summary Background Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. Aim To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. Methods Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. Results Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P

Background Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. Aim The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Methods Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. Results A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0 %, respectively). Adverse events occurred in 41.4 and 36.3 % of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic–pituitary–adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. Conclusions This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic–pituitary–adrenal axis.

Aliment Pharmacol Ther 2010; 32: 990–999 Summary Background Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. Aim To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. Methods Randomized, double-blind, placebo-controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance

Goals To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. Background Mesalamine is a first-line treatment for induction and maintenance of UC remission. Study A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. Results A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. Conclusions Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

Background Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults. Aims Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission. Methods Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months. Results Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25–0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31–0.84; P = 0.009) that was sustained during the OLE. Conclusions MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. ClinicalTrials.gov NCT00744016, NCT00767728, and NCT00326209.

During topical dissolution of gallstones,solvent can escape to the duodenum causing toxic effectsthat have not yet been adequately quantified. Wecompared the local intestinal cytotoxic and systemichepatotoxic effects of two gallstone solvents, methyltert-butyl ether and ethyl propionate, on the rabbit'sduodenum. Methyl tert-butyl ether, ethyl propionate, orsaline (control) was infused intraduodenally for 3 hr in 32 male New Zealand rabbits. Thesolvents were infused either at a high infusion rate of8.5 μl/min or at a low rate of 4.0 μl/min. Bloodsamples were collected for biochemical analysis fromeach animal before and after the 3-hr infusionperiod. A standardized histologic scoring system wasused by a pathologist blinded to the treatments toquantify liver and intestinal tissue injury. None of the animals studied showed any significant changesin serum alkaline phosphatase, amylase, bilirubin, ortheir hepatic histology or histologic scoring formucosal necrosis and ulceration. At the higher dose, methyl tert-butyl ether produced significantlymore submucosal inflammation (P = 0.0017) and showed atrend of causing more submucosal edema than ethylpropionate, but ethyl propionate led to significantly higher elevations of aminotransferases thanmethyl tert-butyl ether as compared to saline. Therewere no detectable blood levels of methanol or ethanolin any of the animals studied. Ethyl propionate may be less damaging to the intestinal mucosa ofthe rabbit than methyl tert-butyl ether, but at thehigher dose (equivalent to 60 ml/3 hr in a 70-kg human)it appears to produce more biochemical liver injury when administered intraduodenally.

During contact dissolution of gallstones, solvents may escape from the gallbladder and damage the intestinal mucosa. In order to compare the extent of this potential injury, we developed a method to objectively quantify the effects of two commonly used cholesterol solvents, methyl tert-butyl ether and mono-octanoin, on mucosal transport function in the rat intestine. Two intestinal segments in each of 184 anesthetized rats were cannulated. Three milliliters of either solvent were instilled in one segment and left for varying periods of time, while saline was instilled in the other as control. The segments were then washed and perfused for 45 min with an isotonic solution containing [3H]polyethylene glycol 4000 (a nonabsorbable reference marker) and either [14C]alpha-aminoisobutyric acid (a marker for active absorption) or [14C]mannitol (a marker for passive permeability). Methyl tert-butyl ether caused more inhibition of alpha-aminoisobutyric acid absorption (64%) than mono-octanoin (48%) and a greater reduction of dry weight per centimeter of the perfused segment (22%) compared with mono-octanoin (10%). Such effects appeared after only 1 min of solvent exposure and did not appreciably increase with longer exposures. Permeation of mannitol increased by 26% after 1 min of exposure to mono-octanoin and by 54% after a similar period of exposure to methyl tert-butyl ether. Longer exposures to both solvents did not seem to cause progressive increases in mannitol permeation. The results indicate that brief exposure of the rat jejunum to either of the two solvents causes a reduction in active transport ([14C]alpha-aminoisobutyric acid absorption), an increase in passive permeability (mannitol permeation), and a loss of mucosal constituents. We conclude that the intestinal mucosa is susceptible to solvent damage and may be used as a selectively sensitive model that can characterize the biological injury of gallstone solvents. The study also suggests that escape of the currently available solvents into the small intestine in patients undergoing contact dissolution of gallbladder stones may cause injury to the small intestine.

BACKGROUND Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS. METHODS In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study. RESULTS Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P

Contact dissolution of cholesterol gallstones with organic solvents is emerging as a rapid, safe, alternative treatment for symptomatic cholesterol gallbladder stones. Placement of a percutaneous transhepatic catheter into the gallbladder is a rapid and safe technique. The availability of safe, effective cholesterol solvents and solvent transfer devices means that cholesterol gallbladder stones can be eliminated rapidly and safely by CDOS, without the risk of general anesthesia or surgical dissection of the gallbladder bed. Patients with single gallstones are better candidates for CDOS than are patients with multiple gallstones because recurrence after dissolution is less common. Contact dissolution may well be judged the treatment of choice by the medical-surgical gallstone management team in some patients.

To improve the efficacy, safety, and convenience of contact dissolution of gallbladder stones, a microprocessor-assisted solvent transfer system was developed. The system's two pumps simultaneously infuse and aspirate solvent into and from the gallbladder at a high flow rate through a multilumen catheter. The microprocessor controls the pumps using a closed-feedback loop control algorithm to regulate intragallbladder pressure to prevent solvent escape into the duodenum. Turbulent solvent flow at the catheter end in the gallbladder is designed to induce rapid stone dissolution and to suspend insoluble residue, thus promoting its aspiration. The system's response and gallbladder emptying capacity was 160-fold faster than the natural gallbladder emptying rate. The rate at which gallstones were dissolved by methyl tert-butyl ether using the system was compared with that achieved with a syringe pump. For 6 of 11 pairs of stones that totally dissolved, the mean dissolution time with the system was 10 ± 6 minutes compared with 112 ± 81 minutes for the syringe pump. In the 5 of 11 stone pairs which dissolved incompletely, insoluble residue was completely eliminated by the system in 21 ± 9 minutes but not by the syringe pump even at 360 minutes. When the system was used in gallstone patients, solvent recovery was 99% ± 1%, and the concentration of a nonabsorbable marker did not change, confirming the lack of appreciable absorption of methyl tert-butyl ether. These studies suggest that the microprocessor-assisted solvent transfer system is a device capable of safe, complete, and fully automatic contact dissolution of cholesterol gallbladder stones using methyl tert-butyl ether or similar solvents.

3 focus groups of 45 SUDD patients and an expert panel of five gastroenterologists and surgeons. We developed the DV-QOL items based on our literature search and input from focus groups and experts, and obtained feedback from patients about those items in cognitive debriefing interviews. We administered the items to a cohort of SUDD patients with persistent symptoms following a confirmed diverticulitis event. We created scales based on factor analysis and evaluated the scales for reliability and validity. Results: Concept elicitation revealed a range of illness experiences attributed to SUDD. Coding of 20,490 transcribed words yielded 52 codes arranged in a network with 4 first-order condition-related concepts: (1) physical symptoms (e.g., pain, bloating); (2) behaviors (e.g., dietary, physical, and social restrictions); (3) cognitions and concerns (e.g., lack of control, feeling something wrong); and (4) impact and consequences (e.g., frustration, anxiety). Initially, we developed 46 items that reflected these four concepts. Using data from a cross-sectional validation sample of 197 patients, we reduced the DV-QOL to a 24-item instrument. The final instrument demonstrated strong internal consistency (Cronbach's Alpha = 0.95) and a reliable fourfactor solution (Tucker and Lewis Reliability Coefficient = 0.90). In our validation sample, the DV-QOL significantly discriminated between patients with recent (i.e., within last month) versus distant diverticulitis events (effect size of DV-QOL score difference = 0.66), and correlated strongly with both the Short-Form 36 subscales (mean correlation = -0.49) and hospital anxiety and depression (HAD) scores (mean correlation = 0.50). Conclusions: Patients with diverticular disease attribute a wide range of negative psychological, social, and physical symptoms to their condition, even outside of acute attacks. The DV-QOL captures these symptoms in a valid and reliable manner.

Ethyl propionate and isopropyl acetate were identified as gallstone solvents with more favorable physicochemical properties than the currently used solvent methyl tert-butyl ether (MTBE). In this study, their efficacy and toxicity were compared.To compare efficacy, matched stones from 33 patients were subjected to dissolution with each solvent. To evaluate cytotoxicity, jejunal segments of the anesthetized rat were exposed to each solvent or saline; the segments were then perfused with markers for active absorption and passive permeability.For 23 gallstone sets that dissolved completely with all three solvents, the average dissolution time was shorter with ethyl propionate (38 +/- 8 minutes) than with MTBE (60 +/- 13 minutes) (P = 0.03) or isopropyl acetate (55 +/- 12 minutes) (P0.001). Four stones did not dissolve with ethyl propionate, seven with MTBE, and eight with isopropyl acetate. After 2 minutes of exposure to the solvents, the dry weight of the segments decreased by 36% after MTBE but was unchanged after the other two solvents (P0.001). MTBE caused more inhibition of active absorption than the other solvents (P0.001) and a greater increase in passive permeation (P0.03).Ethyl propionate and isopropyl acetate are less toxic to the intestinal mucosa than MTBE, and ethyl propionate is more effective for gallstone dissolution.

Development and clinical validation of a solid-state high-resolution pressure measurement system for simplified and consistent esophageal manometry

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

The effect of vanadate (orthovanadate, VO 4 − ) on water and ion transport was studied in rat jejunum. Water transport was tested by single-pass perfusion in vivo and ion fluxes by the Ussing-chamber technique in vitro. The results suggest that vanadate has two actions on ion and water transport: (1) At low concentrations (10 −4 M) it causes Cl − , Na + and water secretion by stimulation of adenylate cyclase; (2) At higher concentrations (10 −3 and 10 −2 M) it decreases net absorption of Na + and Cl − by inhibition of (Na + + K + )-ATPase.

Background & AimsBudesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis.MethodsTwo identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo.ResultsRemission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency.ConclusionsBudesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.