AIELLO D

ALTOMARE DF

AMATO A

ARCANÀ F

BASSO, Luigi

BOVE A.

CAFARO D

DE NARDI P

DE STEFANO I

GAGLIARDI G

GRECO VJ

LA TORRE, Filippo

PASCARIELLO A

PULVIRENTI D'URSO A

RINALDI M

VASAPOLLO L

English

ARCANÀ F

Archivio della ricerca- Università di Roma La Sapienza

W1040Optimal Treatment Duration of Glyceryl Trinitrate (GTN) for Chronic AnalFissure (CAF): Results of a Prospective Randomized Multicenter TrialGiuseppe Gagliardi, Donato F. Altomare, Annalisa Pascariello, Francesco Arcanà, DaniloCafaro, Filippo La Torre, Marcella Rinaldi, Paola De Nardi, Luigi Basso, Ines De Stefano,Vincenzo J. Greco, Leoluca Vasapollo, Antonio Amato, Antonino Pulvirenti D'Urso,Domenico Aiello, Antonio BoveBackground: Optimal treatment duration of GTN for CAF is unknown. Methods: Prospectiverandomized trial comparing 40 vs. 80 days with twice daily topical 0.4% GTN treatment(Rectogesic®, Prostrakan Group) for CAF. Chronicity was defined as presence of fibrosisor skin tag or visible sphincter fibers or hypertrophied anal papilla and symptoms presentfor more than 2 months or with pain of less duration but similar episodes in the past. Achronicity score (the sum of anatomical chronic features) and a validated gravity score wereused. Fissure healing, the primary aim of the study and maximum pain at defecation measuredwith VAS were assessed at baseline (which included manometry) and at 2, 4, 6, 8 weeksand at 80 days, when data was gathered. Results: Of 188 patients with chronic fissure 96were randomized to the 40 days treatment and 92 to the 80 days treatment. Patients werewell matched for sex, age, presence of chronic features, fissure scores. There were 35 (19%)patients (21 in the 40 days group and 14 in the 80 days group) who did not completetreatment 14 (40%) because of side effects 5 (11%) because of worsening symptoms, 3 (9%)for both and 13 (37%) did not attend scheduled visits. Of 151 patients who completed theassigned treatment 79 (52%) had their fissures healed and 92 (61%) were pain free. Therewas no difference in healing and absence of symptoms between the two groups. At theanalysis of variance there was a significant improvement in the paired VAS scores betweenbaseline, 2 weeks, 4 weeks and 6 weeks (p<0.001) while there was no additional improvementbetween 6 weeks and 80 days. Average VAS scores were lower among patients assigned to80 days (p<0.01). Final pain score was not different between groups (P=0.33). Persistenceof pain was associated with presence of fibrosis (p<0.05), advanced age (p<0.05), highmaximum resting pressure (p<0.005), high fissure gravity score (p=0.005) and longer dura-tion of symptoms (p<0.01). Failure to heal was correlated with higher chronicity score(p<0.05) and visible sphincter fibers (p<0.05). Conclusion: Pain at defecation from CAFcontinues to improve up to 6 weeks of topical GTN treatment and is on average lower inpatients treated longer then 40 days. Fissures with more chronic features are less likely toheal even after 80 days of treatment.W1041SP-304 to Treat GI Disorders - Effects of a Single, Oral-Dose of SP-304 OnSafety, Tolerability, Pharmacokinetics and Pharmacodynamics in HealthyVolunteersKunwar Shailubhai, William A. Gerson, Craig Talluto, Gary S. JacobPurpose: SP-304 is a new member of a novel class of non-systemic drugs for treatment ofchronic constipation (CC), irritable bowel syndrome with constipation (IBS-C) and otherGI diseases. SP-304 is a synthetic analog of uroguanylin, a natriuretic hormone that regulatesion and fluid transport in the GI tract. Orally administered SP-304 binds to and activatesguanylate cyclase C (GC-C) expressed on the epithelial cells lining the GI mucosa, resultingin activation of the cystic fibrosis transmembrane conductance regulator (CFTR), and leadingto an augmented flow of chloride and water into the lumen of the gut to facilitate bowelmovement. In animal models, oral administration of SP-304 promotes intestinal secretionand ameliorates gastrointestinal inflammation. The purpose of this first clinical study withSP-304 was to characterize the safety, tolerability, pharmacokinetic (PK) and pharmacodyn-amic (PD) effects of the drug in healthy volunteers. Methods: A double-blind, placebo-controlled, randomized single, oral, ascending dose (0.1 mg to 48.6 mg) study was performedin 71 healthy male and female volunteers. Subjects were evaluated for safety, tolerability,PK and PD effects of SP-304. Adverse events (AE) were evaluated using Common TerminologyCriteria for Adverse Events (CTCAE), version 3. Pharmacodynamic effects were evaluatedby the time to first stool and by the 7-point Bristol Stool Form Scale (BSFS) to monitorstool consistency. Results: SP-304 was well-tolerated at all dose levels with no unexpectedside effects reported. No SAEs were observed at all dose levels throughout this study. Nomeasurable systemic absorption of orally administered SP-304 occurred at all dose levelsstudied ranging from 0.1 mg to 48.6 mg (validated SP-304 serum assay sensitive down to10 ng/ml). Although this trial was not powered for statistical significance, SP-304 appearedto decrease the time to first bowel movement and elicited an increase in the post-dose BSFSversus placebo. Conclusions: In this single-dose Phase I study in volunteers, SP-304 waswell-tolerated across all doses (0.1 mg to 48.6 mg) and exhibited pharmacodynamic activityin healthy volunteers with no detectable systemic absorption. We intend to pursue furtherclinical development of SP-304 to treat patients with CC and IBS-C.W1042Mechanistic Population Pharmacokinetics (PK) Model of PF-00547659, a FullyHuman IgG2 Anti-MAdCAM Antibody, in Ulcerative Colitis Patients: Resultsof a First in Human (Fih) StudySteven W. Martin, Matts O. Magnusson, Ivan T. Matthews, Gary Burgess, WojciechNiezychowskiINTRODUCTION: MAdCAM (mucosal adressin cell adhesion molecule) is expressed onhigh endothelial venules of intestinal lymphoid tissue and expression is increased at sitesof GI inflammation. MAdCAM binds a4b7 integrin on lymphocytes facilitating their migrationto the inflamed intestinal tract. PF-00547659 is a fully human IgG2 anti-MAdCAM antibodywhich by blocking MAdCAM/a4b7 dependent lymphocyte recruitment to the gut is anticip-ated to reduce gut inflammation and mucosal damage. METHODS: This double-blind pla-cebo-controlled FIH study was designed to test efficacy, safety and PK endpoints. Thirtypatients were included in 6 single-dose cohorts (0.03 to 10 mg/kg IV, 3.0 mg/kg SC orplacebo) and an additional fifty in 5 multiple-dose cohorts (0.1 to 3.0 mg/kg IV and 0.3 to1 mg/kg SC or placebo). The PK characteristics of PF-00547659 were determined throughA-641 AGA Abstractsnonlinear mixed-effect modelling (NONMEM, version VI). RESULTS: The PK of PF-00547659 was best described by a 2-compartment disposition model incorporating first-order absorption following SC dosing. Following SC doses 0.3 to 3.0 mg/kg, Cmax wasobserved on day 7 in the majority of subjects. Elimination was best described by 2 parallelpathways: A linear, non-specific pathway typical of monoclonal antibodies (half-life ~28days) and a specific pathway represented by PF-00547659 binding to MAdCAM withsubsequent internalization and elimination of the complex (termed target mediated disposi-tion, TMD). TMD was fully saturated at doses ≥1mg/kg. Incorporation of MAdCAM intothe model allowed estimation of the turnover rate and degree of suppression of MAdCAM.The volume of distribution (~5 L) indicated that the antibody remained predominatelywithin the vasculature which is ideal since MAdCAM is located on high endothelial venules.The model predicted that MAdCAM levels were completely suppressed for 10 to 12 weeksin the majority of subjects following single doses of 3 to 10 mg/kg. No anti-drug antibodieswere detected. CONCLUSION: The pharmacokinetics of PF-00547659 was typical of amonoclonal antibody with sustained concentrations at high doses. TMD was observed atlow doses due to MAdCAM binding and clearance. PF-00547659 remained primarily withinthe vasculature near its target site. Following a single dose of 3 or 10 mg/kg, serum levelswere maintained for up to 3 months with model-predicted complete suppression of freeMAdCAM for the same duration in the majority of subjects and in the absence of any anti-drug antibodies being detected.W1043GI Consultations in PregnancySumona Saha, Joseph Manlolo, Christopher E. McGowan, Steven E. Reinert, Silvia DegliEspostiBackground: Training in gastroenterology requires understanding gastrointestinal (GI) dis-orders in pregnancy. While broad understanding is ideal, determining which conditions aremost commonly referred for consultation may be helpful in focusing trainee education andpreparing for future practice. However, this has not been done. The purpose of this studywas to review the GI consultations at a high-volume obstetrics hospital to determine thereasons for consultation in pregnancy and the final diagnoses. Methods: A chart review ofall consecutive outpatient consultations for pregnant women at Women & Infants' Hospitalbetween October 1, 2004 and October 17, 2007 was performed. 370 charts were reviewed.Referring source, patient characteristics, reason for consultation, diagnosis (based on ICD-9 code), change in management after consultation and need for follow-up were recorded.Established patients who became pregnant during the study period were excluded. Results:75.6% of women requiring GI consultation in pregnancy were referred by Ob/Gyn. Primigra-vidas comprised 36.7% of patients. The mean weeks gestation at the time of consultationwas 21.3 + 8.8. 35.4% of consultations were for new GI symptoms arising in pregnancy,24.4% for worsening of a pre-existing GI disorder, 15.1% for GI symptoms recurring in asubsequent pregnancy and 3.0% for medication safety recommendations. The most commonreasons for consultation were viral hepatitis (20.2%), nausea and vomiting (18.9%) andabdominal pain (13.5%). 30.5% of patients were diagnosed with a liver disorder in pregnancy(viral hepatitis 11.6%, chronic non-viral hepatitis 5.5%, abnormal LFTs 5.4%, liver disorderunique to pregnancy-e.g. cholestasis of pregnancy, HELLP syndrome-3.8%, other 4.2%).The most frequent non-hepatologic diagnoses were hyperemesis gravidarum (20.8%), GERD(16.2%) and constipation (13.0%). As a result of consultation, 84.5% of patients underwentdiagnostic testing. Consultation led to a change in diagnosis in 25.1% of cases and to achange in management in 78.6%. 77.3% of patients required GI follow-up during pregnancyand 37.8% required follow-up post-partum. Conclusions: Viral hepatitis, nausea and vomitingand abdominal pain are the most common reasons for GI consultation in pregnancy. One-third of patients were diagnosed with a liver disorder. The most common non-hepatologicdiagnoses were hyperemesis gravidarum, GERD and constipation. GI consultation changedpatient management in the majority of cases. Gastroenterologists should be familiar withthe evaluation and management of these conditions in pregnancy as they are most likely tobe the reasons for consultation.W1044Introducing GI Wiki: An Online Point-of-Care Resource for GastroenterologyFellows, Faculty and CliniciansAshish Atreja, Neil Mehta, James B. McGeeThe Gastroenterology Core Curriculum represents the collective wisdom of multiple gastroen-terology (GI) societies regarding the scope of gastroenterology training. While the curriculumoutlines the knowledge and skills expected to be acquired during fellowship training, itdoes not provide the actual content per se. The main aim of GI Wiki is to provide acomprehensive, continuously updated point-of-care reference for GI trainees and facultybased on the Gastroenterology Core Curriculum. The GI Wiki (http://giwiki.org) is built ona web-based wiki platform that allows users to create, edit, and link web pages easily. Thisallows fellows to assimilate and share their learning as they are being exposed to variousclinical cases and seminars during their fellowship. Content authors (GI trainees and faculty)are required to log-in and verify their credentials before given privileges to add or modifycontent. The wiki editorial board tracks revisions and has ability to correct or roll back toa previous version. The GI Wiki consists of chapters outlined according to the core curric-ulum, and links to resources: online pharmacopoeia, recommended reading list, guidelines;and GI-specific online calculators (see Figure). By restricting authoring and editing accessto GI trainees and practitioners, our hope is to develop a high-quality, peer-authored, reliableresource as a ready reference for fellowship training programs. As the user-community ofGI Wiki expands, and with it new content gets created or edited, we plan to formallyevaluate the relevance and accuracy of content in GI Wiki. The beta version of the GI Wiki(available online at http://giwiki.org) went live on July 2008 and currently has 15 completechapters and links to online resources. Audience will get a chance to interact with GI Wikiand add/edit content from a networked workstation at the meeting.AGAAbstracts

Optimal Treatment Duration of Glyceryl Trinitrate (GTN) for Chronic Anal Fissure (CAF): Results of a Prospective Randomized Multicenter Trial.

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Optimal Treatment Duration of Glyceryl Trinitrate (GTN) for Chronic Anal Fissure (CAF): Results of a Prospective Randomized Multicenter Trial.

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