Bleeding esophageal ulcers caused by NSAIDs

AI310 AGA ABSTRACTS

5977 CHANGES IN THE METABOLISM OF THE EXTRACELLULAR MATRIX (ECM) INFLUENCE THE DEVELOPMENT OF CRYPT HYPERPLASIA AND VILLOUS ATROPHY IN MICE. Eckh ard R. Stub er, Dana Richter, Charlotte Kopitz, Ulrich R. Foel sch, I Medi cine Uni-K1inik , Kiel, Germany; I Meidzin ische Uni-K1inik, Kiel, Germ any.

Int roduction : Inte stinal crypt hyperplasia and villou s atrophy develop in a T-cell depend ent way during the course of a semi-allogenic Graft- versusHost reaction (GvHR) in mice. Th e exact immune mechanisms that result in these intestinal manifestations are unknown, so far. Previous studies suggest an important role of certa in matrix metalloproteases (MMP s) and of spec ific ECM components for this intestinal transformation. Thu s, the present study inves tigates changes in the co mposition of the ECM , alte rations in the expression of certain MMP s and the effect of a pharmacological inhib ition of MMP s during the development of villous atrophy and crypt hyperpl asia. Methods : The intestinal expres sion of fibronectin , collagen type IV, laminin and tena scin as well as of MMP -2, MMP-3 and MMP- 9 was determined using specific semi-quantitative RT-PCR. Furthermore, to investigate the relev ance of a putative MMP activation for the intestinal manifestations of the GvHR in mice, the MMP- inhibitor Batirnastat was applied. Results: As measured by RT·PCR the mRNA content of ten ascin is reduced in GvHR-mice by approximately 50% as compared to co ntro l animals. However, the expression of collagen type IV, fibronectin and laminin seems to be grossly unch anged. In addition, the expression of MMP -2, MMP-3 and MMP-9 is markedly upregulated. Furthermore, the application of the MMP-inhibitor Batim astat prevents the development of crypt hyperplasia and villous atrophy in GvHR-mice. Conclusions: Chan ges in the metabolism of the ECM occur during the establishment of crypt hyperplasia and villous atrophy in GvHR-mice. An inhibition of ECM degrading enzymes (MMP s) prevents this intestinal transformation . 5978 BLEEDING ESOPHAGEAL ULCERS CAUSED BY NSAIDS. Choic hi Sugawa, Daisuke Higuchi , Cha rles E. Lucas, Kunio Ukawa, Wayne State Univ, Detroit , MI ; Showa Univ, Yokohama, Japan . Nonsteroidal anti-inflammatory dru gs (NSAIDs) can damage each level of the gastrointestinal tract from the esoph agus through the large intestine. NSAID-induced esophageal ulceration ca uses pain, difficulty swallowing and anemia. Overt gastrointestinal bleeding from NSAID-related esophageal inj ury has rarel y been reported. Thi s report describes seven patients (pts) with NSAID-indu ced bleeding esophageal ulcers. There were three males and four females , with NSAID-induced esophageal ulcers documented by endo scopy from August 1991 to March 1999. The mean age was 48.5 yea rs (range, 20 to 64 years ). The cause of injury was aspirin in three pts, Ibupr ofen in two pts and a combination of aspirin and Ibuprofen in two pts. Six of seven pts required blood transfusion. Endoscopic hemo stasi s was successful in two pts. Three pts had hiatal hernia . One pt with a hiatal herni a devel oped stricture due to reflu x two year s after a bleeding episode. One pt with an aorto-esophageal fistula died . Six pts responded to medical treatment and their ulcers healed in thre e to four weeks. The most common sympt om s were hematemesis (six pts) , melena, anemia, retrosternal pain and dy sphagia. NSAID-induced bleed ing ulcers in our seven pts had a distin ct endoscopic feature: a large shallo w, discrete ulcer in the midesoph agus. In addition to the large ulcer, a few small shallow ulcers were found in two pts. These findings suggest that the injury resulted from mucosal contact with NSAIDs . Esophageal transit of medications may be delay ed in pts who have anatomic impediments to the passage of pills or in pts with abnorma l peristalsis. Prec ise history and immediate endoscopic examination are most important in establishin g a diagno sis of esophageal ulcer. If drug-induced injury is recogn ized earl y and treated appropriately, it is fully reversible. Offending medi cat ions should be discontinued co mpletel y. Pts should be counseled to take pills in an upright posture with liberal amounts of fluids well before retiring for the night5979 EFFECT OF LANSOPRAZOLE AND RABEPRAZOLE ON INTRA· GASTRIC ACIDITY IN RELATION TO CYP2CI9 GENOTYPE STATUS. Mak oto Suke gawa, Kaku Hokari, Hiroshi Takeda. To shiro Sugiyama, Mototsugu Kato, Masahiro Asaka, Hokkaido Univ Sch of Medic ine, Sapporo, Japan. Background and aim : Proton pump inhibitors are metabolized by polymorphic cytochrome P450 2CI9 enz yme (CYP2C I9) in the liver. The contribution of CYP2CI9 on the metabolism of rabeprazole is much less compared with that of the other proton pump inhibitor s, such as omeprazole and lansoprazole . Several clinical stud ies have been ind icated that CYP2CI9 gen otype status is associated with therap euti c effect of omeprazole, including the effect on intragastric pH and cure rates for H pylori infection. The aim of this study was to investigate whether the effect of lansoprazole and that of rabeprazole on intragastric pH arc modified by CYP2C 19 genotype status. Methods: Seventeen healthy male volunteers with 3 different genotypes of CYP2CI9 were studied. Two mutated alleles responsible for poor metab olizer phenotype, CYP2C19*2 and CYP2C19*3 , were detected by a PCR-RFLP method. All were serologically negative for H pylori. Each volunteer was administered lansoprazole 30 mg or rabeprazole 20 mg once daily for 4 days in a randomized crossover manner. There was a wash out

GASTROENTEROLOGY Vol. 118, No.4

interval of at least 2 weeks between the 2 trials . Twenty-four-hour intragastric pH measurements were performed on day 4 of each dosin g period . Results : When lansoprazole was admini stered, the median intragastri c pH of poor metab olizer genot ype (mUl/ mut) group was sign ificantl y higher than that of the other genotype groups. Howe ver, with rabeprazole, there were no significant differences in median intragastric pH among 3 genotype group s. Conclusion : CYP2CI9 gen otype status has a major influence on the effect of lansoprazole but not on that of rabeprazole. Genotype

Median intragastric pH lansoprazole 30 mg rabeprazole 20mg

wtIwt wt'mul

6 6

mutlmut

5

4.4±1.2 5.3±05 5.B±1.0

3.2±1.2 4.3±O.7 6.2±1.1 ..'t

Allvalues are means±SD, " p<0.01 vs. wtIwt. TP<0.05 VS. wtlmut

5980 COX·2 EXPRESSION, CELLULAR APOPTOSIS AND PROLIFER· ATION IN INTESTINAL METAPLASIA AT ONE YEAR AFTER ERADICATION OF H, PYLORI, Joseph Jy Sung, Minnie Yy Go , Alfred SI Cheng, Wai K. Leung , Francis Kl Chan, Sr Lin, Chinese Univ of Hong Kong, Hong Kong, Hong Kong ; Beijing Med Univ, Beijing. P. R. China. BACKGROUND H pylori infecti on is known to increase apoptosis and proliferation of gastric epithelial cell s and up-regulate COX-2 expre ssion. The relationship of COX -2 expres sion and cellular proliferation/apoptosis in H pylori infection is unclear . Controversies also exist in whether changes in apoptosis/proliferation would lead to regression of prem align ant gastri c lesions. AIM To study the effects of H pylori eradication on COX-2 expression and cellular apoptosis and proliferation in patien ts with intestinal metaplasia (1M). PATIENTS AND METHODS Endoscopic biopsies were taken from the body of the stomach in patients with H. pylori infection and 1M before and at one yea r after eradication of the bacterium . Th e degree of 1M, apopt osis, proliferation indices and COX-2 express ion were determined by H&E stain (Updated Sydne y Classification), term inal uridine deox ynucleotidyl nick end-l abeling (TU NEL), immuno-histochemistry using anti-Ki67 monoclonal antibody and anti-COX-2 antibody . COX-2 expre ssion wa s scored by a semi-quantitative scale of 0-4: O= absence of staining, 1= <5 %, 2 =5-25%, 3= 25-50% and 4= >50% ce ll staining positi ve. All assessment s were done by 2 independent investigators blinded to the treatment received. RESULTS 27 paired biops y samples were exam ined . A significant drop in apoptotic, proliferati ve indices as we ll as COX-2 expre ssion was documented after eradication of H. pylori . Regression of COX -2 expression was associated with reducti on in apoptotic index but not with proliferative inde x. No significant change wa s found in the grading of 1M at one year after treatment. CONCLUSION De spite reduction of apoptosis and proliferation of epithelial cell s and downregulation of COX-2 after eradication of H. pylori, there was no significant change in the 1M at one year.

Before Rx AfterRx p

COX·2

Apoptosls (%)

Ki·67(%)

1M grading

2.59±062 1.88±0.93 0.048

7392±7.22 17.11±15.63 <0.001

71.04±14.02 17.04±14.24 <0.001

1.71±0.77 182±0.88 0.70

5981 A NOVEL PROTON-PUMP INHIBITOR, RABEPRAZOLE, AT· TENUATES THE EXTENSION OF H.PYWRI-ASSOCIA TED GAS· TRIC MUCOSAL OXIDATIVE LESION IN THE MONGOLIAN GERBIL THROUGH ANTI·OXIDANT PATHWAYS. Hidekazu Suzuki, Chikako Watanabe , Shoichi Nagahashi, Masaharu Miyazawa , Masaru Sato, Motoak i Bessho , Chizuko Kawaguch i, Hir oshi Nagata, Soichiro Miura, Hirom asa Ishii, Keio Univ Sch of Medicine, Tokyo, Japan; Eisai Research Lab . Tokyo, Japan ; National Defense Med Coli . Tok orozawa, Japan . Background and Aim . We have previously rep orted that Il.p ylori (Hp) colonization evoked the gastric mucosal inflammation with an extensive increase in lipid peroxides in Mong olian gerbils (Free Radi c. Bioi. Med. 26:679, 1999 ). Rabeprazole (RZ) , a novel proton pump inhibitor, has been reported to have a mild toxicity to Hp and to be the inducer of anti-oxidant, glutathione, in gastri c muco sa. The present study was de signed to exa mine the effect of RZ on gastric muco sal lesion form ation in Hp-colonized gerbils. Methods . Fourt y-on e male Mongolian gerbils (MGS/Sea, 50g) were orally inoculated with Hp (ATCC43 504, 5 X 108CFU /ml) (Hp gro up) and 40 gerbils were inoculated with the culture media (control ). Twentyone gerbils in the Hp group and 20 gerbils in the controls were injec ted with RZ (1.0 mglkg body weight, s.c.) for a week at 5 weeks after the bacterial inoculation. The remainin g gerbils were injected with saline. Fourty two gerbils were evaluated 12 weeks after the inoculation and the remaining 39 gerbils were evaluated 24 weeks after the inoculation. Tissue neutr ophil infiltration was assessed by the activity of myeloperoxidase (MPO) . Mucosal oxidative stress was eva luated by the contents of thiobarbituri c acid-reactive sub stances (TBARS) and total glutathione. Result s.