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sorgans and the role of time in development OIE. More studies are needed to define riskfactors, mechanism of OIE, and the potential role of other ARBs.Characteristics of Olmesartan-Induced Enteropathy (OIE)

Table 1. Characteristics of Olmesartan-Induced Enteropathy (OIE) demonstrates the keydemographic, symptoms, complications, and resolution of 35 patients with OIE. AngiotensinII receptor blockers (ARBs)

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Investigation of the Link Between Intestinal Adverse Events and OlmesartanUsing the Food and Drug Administration Adverse Event Reporting SystemSalih Samo, Derrick J. Stobaugh, Eli D. Ehrenpreis

Background: Rubio-Tapia et al recently reported twenty two patients with sprue-like enterop-athy and chronic diarrhea related to the use of olmesartan, an angiotensin receptor blocker(ARB). We sought to assess the risk of intestinal complications of olmesartan and otherARBs using the Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: 1,668,004 cases of adverse events reported between 2006 and 2010 were down-loaded from the FAERS. Data was first queried for all patients using an ARB for hypertension.Then all drugs were limited to those defined as "Primary Suspect". Intestinal adverse eventsand control reactions were then obtained for the five ARBs with the highest US pharmaceuticalsales (olmesartan (Benicar & Benicar HCT), valsartan (Diovan & Diovan HCT), telmisartan(Micardis & Micardis HCT), irbesartan (Avapro), and losartan (Cozaar)). Control reactionswere defined as hernia, deafness and tinnitus, which were predefined to have no associationwith any of the listed drugs. SPSS 20 (IBM Co. Armonk, NY, USA) was used to calculatesignificance for intestinal adverse events using a Chi-Square test with Yate's ContinuityCorrection Factor. All ARBs were compared to olmesartan and sensitivity analyses wereperformed for diarrhea and small intestinal inflammation. Sales of these five ARBs were usedto determine the frequency of reported occurrences. Results: Intestinal adverse reactions,cases of diarrhea and cases of small intestinal inflammation were reported for all five ARBs.The majority of intestinal adverse reactions were reported with valsartan (50.8%), (Table1). In the sensitivity analysis, olmesartan had higher odds of reported diarrhea comparedto valsartan (p<0.0001) and temisartan (p<0.05). In addition, there were higher odds ofreported small intestinal inflammation with olmesartan compared to the four other ARBs.Despite this, the rate of small intestinal inflammation with olmasartan was only 0.0005 per1,000 packages or 1 reported case per 2,000,000 packages sold. Conclusion: A small numberof cases of intestinal adverse reactions, including diarrhea and small intestinal inflammationwere reported to FAERS for the five most commonly prescribed ARBs. The odds of smallintestinal inflammation are higher with olmesartan compared to the other commonly pre-scribed drugs in this class. Although these findings appear to represent adverse events fromolmesartan and other ARBs that merit attention, these unfavorable gastrointestinal side effectsare extremely rare.Table 1: Intestinal Adverse Events

*All ARBs were compared to olmesartan

S-604AGA Abstracts

Figure 1: Cases of Small Intestinal Inflammation per 1,000 Packages Sold

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Ipilimumab-Induced Colitis in Patients With Metastatic MelanomaKara M. De Felice, Svetomir Markovic, Lisa A. Kottschade, Heidi D. Finnes, Edward V.Loftus, Laura H. Raffals

Background: Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks CTLA-4 and promotes antitumor immunity. It is used to treat stage III/IV melanoma and isassociated with many immune-related adverse events. Ipilimumab-induced colitis is the mostcommon serious adverse event and can occur in up to one third of patients. Methods: Inthis retrospective observational study, we identified patients with stage III/IV melanomatreated with ipilimumab between 03/2011 and 09/2013. Diarrhea was assessed using theCommon Terminology Criteria for Adverse Events (CTCAE): grade 1 (< 4 stools), grade 2(4-6 stools, abdominal pain, blood/mucous stools), grade 3 (>7 stools, severe abdominalpain, ileus, fever, peritoneal signs), and grade 4 (life threatening consequences of diarrhea).Diarrheal treatment regimen, dose, response, and adverse events were recorded. Results: Atotal of 103 patients with metastatic melanoma treated with ipilimumab were identified. Ofthese, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developedmoderate to severe diarrhea (grade ≥ 2) requiring systemic steroid therapy. On average, theonset of diarrhea occurred after 1-2 doses of ipilimumab. Six of 23 patients responded to< 1mg/kg daily prednisone alone. Fifteen (15/26) patients required high-dose prednisone(1-2mg/kg), of whom 6/15 received intravenous steroids. Of those on high-dose prednisone,5/15 patients had steroid-refractory diarrhea and required additional rescue therapy withbudesonide (9-12mg). Once budesonide was added and diarrhea was controlled, a rapidprednisone taper was instituted. Only one patient required rescue therapy with infliximab(5mg/kg for three doses). There was a single case of severe diarrhea (grade 3) treatedsuccessfully with high-dose budesonide (12mg) monotherapy. Median duration of steroidtreatment was 67 days (range, 2-164 days), and all patients had complete response totherapy. Complications included 15 hospitalizations and 4 ER visits for diarrhea. There wereno perforations or colectomies. Steroid-induced side effects included 3 cases of adrenalinsufficiency requiring long-term glucocorticoids, and 1 case of myopathy. Conclusion:Ipilimumab-induced colitis is a common immune-related adverse event that requires earlyrecognition and prompt treatment to avoid life-threatening complications. Treatment withhigh doses of prednisone has been the recommended approach for moderate to severediarrhea (grade ≥ 2). However, up to 33% of patients have prednisone-refractory diarrhea,and require rescue therapy with high-dose budesonide or infliximab. First-line treatmentwith high-dose budesonide, with or without topical steroid therapy, or early addition ofhigh-dose budesonide to systemic steroid therapy should be further investigated.

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Antibiotic Treatment Impairs Memory-Linked Discriminating FunctionNate L. Ritz, Benjamin J. Burnett, Larry L. Barton, Katelyn M. Reinhart, Henry C. Lin

A potentially adverse effect of antibiotic treatment is a changed gut microbiome. Previously,a diet-induced change in the gut microbiome in rodents was reported to alter learning andmemory (Li W et al. Physiol Behav 2009; 96: 557-67). It is not known, however, whetheran antibiotic treatment known to disrupt the gut microbiome would have a similar effect.An 8-arm radial maze is commonly used to test memory. This maze consists of a centralchamber from which 8 runways (arms) radiate out at equal angles. At the start of a trial,the end of each arm is baited and a mouse trained to collect bait is placed in the centralchamber. To collect all 8 baits efficiently, the animal must enter an arm, remove a bait andthen repeat by returning each time to the central chamber to choose the next arm by usingits memory to discriminate between a correct (not yet entered, bait present) and an incorrect(already entered, bait removed) arm. Thus, spending more time in the central chambercould be interpreted as greater difficulty using its memory to make an arm choice. Aim. Totest the hypothesis that antibiotic treatment may impair learning maze performance. Methods:17mice were used in the study for controls (n= 8) or antibiotic treatment (n=9). The antibiotictreatment (Gastroenterology 135, 1984-1992) consisted of colistin 850 U/ml, gentamicin0.035 mg/ml, kanamycin 0.4 mg/ml, metronidazole 0.215 mg/ml and vancomycin 0.045mg/ml) added to the drinking water was given ad libitum for 3 days. Mice were then leftuntreated for next 3 days before administering clindamycin (10 mg/kg) i.p. on day 7. Micewere tested in the radial maze on day 15 and the time spent in the central platform (centertime for successful collection of all 8 baits) compared using t-test. Data are mean +/- SE.Results: Mice treated with antibiotics spent significantly longer center time (39.1 +/- 9.0