Shahriar Sedghi

Excessive Production of Reactive Oxygen Metabolites by Inflamed Colon: Analysis by Chemiluminescence Probe

Reactive oxygen metabolites (ROMs) are involved in inflammatory diseases and are postulated to contribute to tissue injury in colitis. To determine whether excessive ROMs are generated by inflamed colonic mucosa and to identify possible sources and type of ROMs, mucosal ROMs were estimated in rats and humans using a chemiluminescence probe. Colitis was induced in rats by intracolonic injection of acetic acid or intraperitoneal injection of mitomycin C. Intact, inflamed colon in rats produced more ultraweak chemiluminescence than normal colon. Inflamed mucosal scrapings from both rat models produced significantly more luminol-enhanced chemiluminescence. Addition of catalase, an H2O2 scavenger, or azide, a myeloperoxidase inhibitor, into the media significantly decreased chemiluminescence from inflamed mucosal scrapings. Indomethacin, an antioxidant cyclo-oxygenase inhibitor, also decreased chemiluminescence, but MK-866, a 5-lipoxygenase inhibitor, had no effect. Colonic biopsy specimens obtained during colonoscopy from patients with ulcerative colitis also produced more catalase-inhibitable chemiluminescence than normal colonic mucosa. These data indicate that excessive ROMs are produced by inflamed colonic mucosa in both humans and rats, which may contribute to tissue injury.

Role of reactive oxygen metabolites in experimental colitis.

Reactive oxygen metabolites are potent inflammatory mediators that may be involved in tissue injury in inflammatory bowel disease. To evaluate their role in inflammatory bowel disease, we investigated the effects of lowering the activities of reactive oxygen metabolites in experimental colitis induced by intracolonic administration of acetic acid in rats. Intracolonic administration of 5% acetic acid caused severe inflammation (mean (SEM) inflammatory score was 24.3 (0.7) of a maximum score of 32). Acetic acid at 2.5% produced moderate inflammation (score = 17 (1.4) v 4.0 (0.5) in control rats). This lower dose was used for subsequent experiments. Specific superoxide anion scavenger methoxypolyethylene glycol:superoxide dismutase, and reactive oxygen metabolites scavenger, sulfasalazine, significantly decreased the severity of inflammation (scores: 8 (4.4) and 9.8 (2.2) respectively). The xanthine oxidase inhibitors, tungsten and pterin aldehyde, failed to improve inflammation but another xanthine oxidase inhibitor, allopurinol, a compound with known superoxide anion scavenging effect, did limit the inflammation (10(2)). Inhibition of hydroxyl radical production by deferoxamine or lowering hydroxyl radical values by a scavenger, dimethyl sulfoxide, did not affect the severity of inflammation. These data suggest: (1) that reactive oxygen metabolites play an important role in experimental colitis, (2) that the xanthine oxidase pathway is not a major source of reactive oxygen metabolites in colitis, and (3) that tissue injury in experimental colitis is not caused by generation of hydroxyl radicals.

Impact of sleep disturbances in inflammatory bowel disease

Background:  Normal sleep is paramount for a healthy lifestyle and high quality of life. Sleep modulates the immune system and thus affects the course of several chronic inflammatory conditions. There are no reported studies that address the role of sleep disturbance in the course of inflammatory bowel disease (IBD). The aim of this study was to characterize sleep disturbance in IBD using validated measures of sleep and quality of life.

Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis.

Reactive oxygen species have been implicated as mediators of inflammation in ulcerative colitis. Chemiluminescence is a reliable means of estimating reactive oxygen species in biological media. Increased reactive oxygen species values in the inflamed colonic mucosa in rats were seen by chemiluminescence. The aims of the study were to find out if chemiluminescence is raised in the colonic mucosa of patients with ulcerative colitis and correlates with disease activity, and to elucidate the sources of the chemiluminescence. It was found that reactive oxygen species, as measured by the chemiluminescence technique, are raised in inflamed colonic mucosa and correlates with symptom score, sigmoidoscopic score, disease activity, and activity of the neutrophil enzyme myeloperoxidase. Chemiluminescence was inhibited by a myeloperoxidase inhibitor (azide) and an H2O2 scavenger (catalase) but not by allopurinol, an inhibitor of the enzyme xanthine oxidase. Chemiluminescence was also inhibited by indomethacin, but this did not seem to be related to inhibition of cyclo-oxygenase. These findings suggest that a likely cellular source of reactive oxygen species in the inflamed colon of patients with ulcerative colitis is the neutrophil and that myeloperoxidase conversion of H2O2 to hypochlorous acid, contributes to the chemiluminescence signal and possibly, to the tissue injury. Neither cyclo-oxygenase nor lipoxygenase seem to play a part as sources for the chemiluminescence.

Cronkhite-Canada Syndrome: Sustained Remission After Corticosteroid Treatment

testinal metaplasia in any of our patients, in contrast to the literature that suggests intestinal metaplasia and atrophy of gastric mucosa when exposed to bile acid (1, 2). Although we could not determine the duration and degree of DGR, this may be a factor in the development of intestinal metaplasia or atrophy. The effect of UDCA on DGR gastritis and dyspeptic symptoms due to DGR is beneficial, and improvement in symptoms after UDCA therapy has been shown to be highly significant compared with placebo (5, 6). Also UDCA is safe and effective for children with DGR (7). We used triple therapy for H. pylori infection and UDCA for DGR, but the eradication of H. pylori infection and symptom relief were achieved in only two of our patients. This low eradication rate may support the synergistic action of DGR and H. pylori infection on gastric mucosa of children. Further controlled studies are needed to clarify the relationship between DGR and H. pylori infection in children.

GI bleeding from duodenal diverticula

iting (one), nausea and headache (one), and chills and diarrhea (one). Stool frequency among responders decreased from 8.3 to 1.3 per day. Two responders received 6-mercaptopurine (50 mg/day) and one received azathioprine (75 mg/day). For responders, average time to discontinuing steroids was 3.5 months. Responders have been asymptomatic on azathioprine/6-mercaptopurine alone for 3–51 months (average 29.3). One patient has twice attempted to discontinue 6-mercaptopurine and on both occasions has had recurrence of diarrhea. Although the number of patients in the study is small, azathioprine/6-mercaptopurine seems to be effective for LC/CC patients who are steroid dependent. In fact, all of our patients who were able to tolerate azathioprine/6-mercaptopurine benefited. The exact mechanism by which these drugs improve symptoms in LC/CC is unclear, but as with Crohn’s disease and ulcerative colitis, it may involve blocking lymphocyte proliferation and activation. The rate of intolerance among our cohort was higher than would have been expected from a series reporting their use for Crohn’s disease or ulcerative colitis. Although azathioprine/6-mercaptopurine sometimes cause serious side effects such as nausea or bone marrow suppression, they are clearly preferable to steroids when a long term maintenance agent is required. Despite the LC/CC’s differences from Crohn’s disease and ulcerative colitis endoscopically and pathologically, this series of patients responding to immunosuppressive therapy with azathioprine/6-mercaptopurine demonstrates yet another similarity in the response to medical therapy among these diseases.

T1202 Once-Daily Mesalamine Granules Effectively Maintain Remission from Ulcerative Colitis: Data from 2 Phase 3 Trials

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.

Increasing efficacy and reducing side effects in treatment of chronic anal fissures: A study of topical diazepam therapy

Abstract This is a single institution nonexperimental study intended to analyze the therapeutic efficacy of topical diazepam in treating symptoms of chronic anal fissures. Anal fissures are a common cause of anal pain. Conventional treatments include nonsteroidal anti-inflammatory drugs, topical creams, such as nitroglycerin and nifedipine, and surgery. However, these treatments are usually suboptimally efficacious or have deterring side effects. Patients at an outpatient community center with a diagnosis of a chronic anal fissure were prescribed either topical 2% (n = 19) or 4% (n = 18) diazepam cream between January 2013 and February 2015. We retrospectively analyzed their responses to treatment. All 19 patients using 2% diazepam cream experienced a positive response in pain, whereas 47.4% experienced a complete response, with a numerical rating scale (NRS) score of 0 (0–10). Eighty-eight percent of patients using 4% dose had a positive response in pain, whereas 23.5% experienced a complete response. Ninety-four percent of patients using 2% dose had a positive response in anal bleeding, whereas 68.8% experienced a complete response with an anal bleeding score (ABS) of 2 (2–9). Ninety-four percent of patients using 4% dose had a positive response in anal bleeding, whereas 64.7% experienced a complete response. Only 1 patient reported a side effect from diazepam cream—perianal pruritus. Both 2% and 4% topical diazepam provided significant pain and bleeding relief from chronic anal fissures that were refractory to conventional therapies. There were insignificant differences when assessing independent comparisons for pain and bleeding between the doses.

T1200 Long-Term Safety of Once-Daily 1.5-G Mesalamine Granules in Patients in Remission from Ulcerative Colitis

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.