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Helicobacter pylori and non-ulcer dyspepsia: Is there a causal link?
AGAA1301
April 2000
5938 VARIANTS OF THE 3'REGION OF THE CAGA GENE AND ITS ASSOCIATION WITH GASTRODUODENAL DISEASES. Claudia A. Rota, Julio C. Pereira-Lima, Carolina Blaya, Angelo A. Mattos, NETLAB - Molecular Biology Unit, Porto Alegre, Brazil; Dept of Gastroenterology of Santa Casa Hosp, Porto Alegre, Brazil. Background and Aims: The cagA gene of Helicobacter pylori (Hp) has been associated with increased pathogenicity. The 3'region of the cagA gene contains repeated sequences that might predict outcome of Hp infection. The aim of this study is to averiguate if there is an association among cagA subtypes and peptic ulcer. Methods: The 3'region of the cagA gene was amplified by PCR using primers that included the repeated sequences of the 3' region in 88 Hp infected patients (14 with gastritis,14 with duodenitis, 31 with gastric ulcer and 29 with duodenal ulcer). Depending on the size of the PCR products they were classified in subtypes A, B or D and C according to YAMAOKA et al.(J Clin Microbiol; 36: 2258-63, 1998). Results: Of the 28 patients with gastritis and duodenitis, l3 were cagA positive, of these 9 were A-type, 2 were B or D-type and 2 were C-type. Among the patients with gastric ulcer, 16 were cagA positive (7 A-type, 3 B or D-type and 5 C-type) and among the cases with duodenal ulcer 18 were positive (15 A-type, 7 B or D-type and 8 C-type) (p=0.21). Conclusion: There was no association between cagA positivity nor cagA subtypes and peptic ulcer disease when analyzing H. pylori strains with 3 region cagA primers. 5939
H. PYLORI COLONIZATION MAY PROTECT CHILDREN FROM DIARRHEA. RESULTS OF A POPULATION-BASED STUDY IN 2477 CHILDREN. Dietrich Rothenbacher, Martin J. Blaser, Guenter Bode, Hermann Brenner, Dept of Epidemiology, Univ of Ulm, Ulm, Germany; Vanderbilt Univ, Nashville, TN; Dept of Epidemiology, Ulm, Germany. Objectives - Because it has been suggested that human colonization of H. pylori may have benefit against infections by exogenous intestinal pathogens, we conducted a population-based study to compare rates of diarrheal illnesses in H. pylori-positive and H. pylori-negative children. Methods The study included all children who were screened for school fitness in 1996 to 1998 in Ulm, and in 1997 also in two other nearby communities. H. pylori status was determined by l3C-urea breath test, and parents provided clinical information via standardized questionnaire. Results Overall, 2477 5-to 8-year old children were studied; 304 (12.3%) were H. pylori-positive. For H. pylori-positive children, diarrhea within the prior 3 months was less often reported than in H. pylori-negative children (54.3% versus 76.1%; P <0.001, adjusted for nationality). Diarrhea occurrence was inversely related to the delta l3C-value, an indirect measure of H. pylori density in the gastric lumen. Compared to H. pylori-negative children, the Odds ratio (OR) for the occurrence of diarrhea within the prior three months was 0.37 (95% CI 0.28-0.49) for H. pylori-positive children. The inverse relation between H. pylori carriage and history of diarrhea remained significant after adjustment for nationality ( OR 0.56 (95% CI 0.41-0.75)), and after further adjustment for covariates (OR 0.56 (95% CI 0.42-0.76)). Conclusion - These data support the hypothesis that H. pylori gastric colonization may protect against diarrheagenic gastrointestinal infections. 5940 PROSPECTIVE EVALUATION OF PROPOSED GASTRIC ACID SECRETORY CRITERIA FOR DIAGNOSIS OF ZOLLINGER-EL· LISON SYNDROME (ZES). Praveen K. Roy, Kathryn M. Feigenbaum, Pamela D. Koviack, Alaa Abou-Saif, Houmayoun Shojamanesh, Fathia Gibril, Robert T. Jensen, National Inst of Health, Bethesda, MD. Gastric hypersecretion is a cardinal feature of ZES, however the available data on it is limited. Relatively few patients were studied, most series contain collective data from a few cases in different centers and although the specificity has been well studied, there are no prospective studies on the sensitivity of the proposed criteria of hypersecretion for the diagnosis of ZES. To address these points, we prospectively studied initial gastric acid secretion assessment in 235 patients with ZES. After stopping all antisecretory medications, basal and maximal secretory parameters were measured including volume, [H +], pH and output (mEq/hr). The mean BAO in patients with or without prior gastric surgery was 41.2 ± 1.7 and 27.6±3.5mEq/hr, respectively. The sensitivity of proposed BAO criteria for ZES in patients without gastric surgery was 94% for BAO 20 10, 91% for BA02015, 86% for BA02018, 61% for BA02031 and 49% for BA02038. Similarly for patients with prior gastric surgery, 100% had BA0205 mEq/hr, 73% for BA02014.4 and 37% for BA02019.2. The criterion of BAO pHS I was met by 32% without and 20% with previous gastric surgery. The mean MAO was 61.4±2.1 mEq/hr and only 39% without and 10% of patients with previous gastric surgery met the proposed criterion of MA02070. The criterion of a BAOIMAO ratio 200.6 was met by 63% without and 80% with gastric surgery. The proposed criterion based on acid concentration of BACIMAC 200.6 was met in 93%. The combination criterion of BA02015 + BAOIMAO 200.6 was met by 61% of patients without gastric surgery, and BA02015 + pHSI in 32%. The gastric volume during the BAO was 313± 10 mllhr in patients without and 304±25 mllhr in patients with previous gastric surgery. In patients without
previous gastric surgery, 98% had 2075 ml, 96% 20100ml and 90% 20140 ml. In patients with previous gastric surgery, this occurred in 97%, 93% and 87%. In patients who had BAO<15 (without gastric surgery) pH was S I in II %, BAOIMAO 200.6 in 24%, BACIMAC 200.6 in 65%, and volume was >75 ml in 77%, > 100 ml in 61%, and > 140 ml in II %. These data demonstrate gastric secretory criteria of a BAO 20 15 and BA0205 for patients without or with previous gastric surgery, respectively were met by >91 % of patients with ZES. Similarly, the criterion of BACIMAC 200.6 had a high sensitivity but not the BAOIMAO 200.6, pH or MAO 2070. A BAO volume > 140 ml/hr is a neglected finding with high sensitivity (2090%) that should suggest ZES. A number of proposed BAO or MAO criteria or combinations lack sensitivity and will not be generally useful for diagnosing ZES. 5941
HELICOBACTER PYLORI AND NON-ULCER DYSPEPSIA: IS THERE A CAUSAL LINK? Johannes J. Sadikin., Jose D. Sollano Jr., Margaret L. Quiblat, Univ of Santo Tomas, Manila, Philippines. Background In the high prevalence area of Helicobacter pylori (Hp) infection such as in he Philippines, Hp infection is linked causally to peptic ulcer disease. However, it is uncertain whether Hp infection is common in non-ulcer dyspepsia thus responsible for the dyspeptic symptoms. Methods Between July 1999 and October 1999, a total of 390 patients with dyspepsia were assessed of whom 296 patients underwent upper gastrointestinal endoscopic investigation. Patients were excluded if they had strong family history of gastrointestinal malignancy, peptic ulcer disease or gastroesophageal reflux disease, significant change in bowel habits, melaena or passage of blood per rectum, anemia, jaundice, weight loss and visceromegaly, predominance of lower abdominal symptoms, an alteration in bowel habits and associated with disturbance in defecation, and the patient had abnormal findings on upper endoscopy. Symptoms were assessed utilizing the Glasgow Dyspepsia Severity Score with minimal symptoms defined as a score of 0-1 ( maximal score, 20). Two-sample, independent-groups t test was used to explore the relationship between Hp infection with non-ulcer dyspepsia. Result Of 296 patients, 245 patients were excluded because of gastric or duodenal ulcer (n=238), inability to tolerate endoscopy (n=2), declined to undergo endoscopy (n=4), and serious medical condition (n= I). The prevalence of non-ulcer dyspepsia was 17.2%. Rapid urease test was positive in 9 patients (17.6%), and negative in 42 patients (82.4%). The mean dyspepsia severity scores in those with and without H pylori were 7± 2.89 and 7.6± 0.85, respectively (p=0.554). Conclusion There appears no significant association between Helicobacter pylori infection and non-ulcer dyspepsia. Helicobacter pylori is probably not the dominant etiology of dyspeptic symptoms. 5942 NMI·377: A NOVEL NITROSOTHIOL-DICLOFENAC NSAID WITH GASTROINTESTINAL·SPARING ANTIINFLAMMATORY AND ANALGESIC ACTIVITIES. Joy K. Saba, Upul Bandarage, Liqing Chen, Alicia Glavin, David R. Janero, David S. Garvey, Joseph D. Schroeder, L. Gordon Letts, S. W. Tam, NitroMed, Inc, Bedford, MA; NitroMed, Inc, Beford, MA. The wide use of NSAIDs is hampered by side effects, mainly gastric mucosal damage and ulceration. Nitric oxide (NO) helps maintain gastric mucosal integrity. To counteract the gastric toxicity of NSAIDs, we have covalently linked a nitrosothiol-based NO-donor tether to diclofenac and synthesized a structurally new NSAID, the stable diclofenac derivative NMI-377 (3-(methyl[(nitrosothio cyclohexyl)methyl]amino)propyl 2-{2[(2,6-dichlorophenyl)amino]phenyl} acetate). The present study reports the preclinical evaluation of NMI-377, including gastrointestinal and pharmacological effects, in fasted male SD rats and CD-I mice. All compounds were dosed intragastrically as suspensions. The NO-releasing property of NMI-377 was demonstrated in vitro by its concentration-dependent relaxation of precontracted rat aortic ring smooth muscle. In vivo, NMI-377 did not change systemic blood pressure in rats when given intragastrically. Pharmacokinetic studies reveal that diclofenac is detected in the plasma of rats receiving NMI-377. The relative bioavailability of diclofenac from NMI-377 was approximately 50% that of an equimolar dose of diclofenac sodium (10 Mmol/kg). The gastrointestinal lesion effect of NMI-377 is weak at doses of 10-100 Mmol/kgand was about 5% of that of diclofenac when both were tested at a dose of 100 Mmol/kg. NMI-377 showed potencies similar to diclofenac in both the carrageenan-induced paw edema antiinflammatoiry test in rats and phenylbenzoquinone-induced writhing analgesic test in mice at all the doses (3-100 Mmol/kg) tested. In these pharmacology studies, the duration of action was similar for both compounds. A derivative of NMI-377 lacking the NO-donor group was significantly less gastrointestinal sparing compared to NMI-377 suggesting the beneficial effects of NO. Thus, NMI-377 is one of a novel class of GI-sparing NSAIDs with equipotent analgesic and antiinflammatory activities and significantly less GI side effects than diclofenac.
April 2000
5938 VARIANTS OF THE 3'REGION OF THE CAGA GENE AND ITS ASSOCIATION WITH GASTRODUODENAL DISEASES. Claudia A. Rota, Julio C. Pereira-Lima, Carolina Blaya, Angelo A. Mattos, NETLAB - Molecular Biology Unit, Porto Alegre, Brazil; Dept of Gastroenterology of Santa Casa Hosp, Porto Alegre, Brazil. Background and Aims: The cagA gene of Helicobacter pylori (Hp) has been associated with increased pathogenicity. The 3'region of the cagA gene contains repeated sequences that might predict outcome of Hp infection. The aim of this study is to averiguate if there is an association among cagA subtypes and peptic ulcer. Methods: The 3'region of the cagA gene was amplified by PCR using primers that included the repeated sequences of the 3' region in 88 Hp infected patients (14 with gastritis,14 with duodenitis, 31 with gastric ulcer and 29 with duodenal ulcer). Depending on the size of the PCR products they were classified in subtypes A, B or D and C according to YAMAOKA et al.(J Clin Microbiol; 36: 2258-63, 1998). Results: Of the 28 patients with gastritis and duodenitis, l3 were cagA positive, of these 9 were A-type, 2 were B or D-type and 2 were C-type. Among the patients with gastric ulcer, 16 were cagA positive (7 A-type, 3 B or D-type and 5 C-type) and among the cases with duodenal ulcer 18 were positive (15 A-type, 7 B or D-type and 8 C-type) (p=0.21). Conclusion: There was no association between cagA positivity nor cagA subtypes and peptic ulcer disease when analyzing H. pylori strains with 3 region cagA primers. 5939
H. PYLORI COLONIZATION MAY PROTECT CHILDREN FROM DIARRHEA. RESULTS OF A POPULATION-BASED STUDY IN 2477 CHILDREN. Dietrich Rothenbacher, Martin J. Blaser, Guenter Bode, Hermann Brenner, Dept of Epidemiology, Univ of Ulm, Ulm, Germany; Vanderbilt Univ, Nashville, TN; Dept of Epidemiology, Ulm, Germany. Objectives - Because it has been suggested that human colonization of H. pylori may have benefit against infections by exogenous intestinal pathogens, we conducted a population-based study to compare rates of diarrheal illnesses in H. pylori-positive and H. pylori-negative children. Methods The study included all children who were screened for school fitness in 1996 to 1998 in Ulm, and in 1997 also in two other nearby communities. H. pylori status was determined by l3C-urea breath test, and parents provided clinical information via standardized questionnaire. Results Overall, 2477 5-to 8-year old children were studied; 304 (12.3%) were H. pylori-positive. For H. pylori-positive children, diarrhea within the prior 3 months was less often reported than in H. pylori-negative children (54.3% versus 76.1%; P <0.001, adjusted for nationality). Diarrhea occurrence was inversely related to the delta l3C-value, an indirect measure of H. pylori density in the gastric lumen. Compared to H. pylori-negative children, the Odds ratio (OR) for the occurrence of diarrhea within the prior three months was 0.37 (95% CI 0.28-0.49) for H. pylori-positive children. The inverse relation between H. pylori carriage and history of diarrhea remained significant after adjustment for nationality ( OR 0.56 (95% CI 0.41-0.75)), and after further adjustment for covariates (OR 0.56 (95% CI 0.42-0.76)). Conclusion - These data support the hypothesis that H. pylori gastric colonization may protect against diarrheagenic gastrointestinal infections. 5940 PROSPECTIVE EVALUATION OF PROPOSED GASTRIC ACID SECRETORY CRITERIA FOR DIAGNOSIS OF ZOLLINGER-EL· LISON SYNDROME (ZES). Praveen K. Roy, Kathryn M. Feigenbaum, Pamela D. Koviack, Alaa Abou-Saif, Houmayoun Shojamanesh, Fathia Gibril, Robert T. Jensen, National Inst of Health, Bethesda, MD. Gastric hypersecretion is a cardinal feature of ZES, however the available data on it is limited. Relatively few patients were studied, most series contain collective data from a few cases in different centers and although the specificity has been well studied, there are no prospective studies on the sensitivity of the proposed criteria of hypersecretion for the diagnosis of ZES. To address these points, we prospectively studied initial gastric acid secretion assessment in 235 patients with ZES. After stopping all antisecretory medications, basal and maximal secretory parameters were measured including volume, [H +], pH and output (mEq/hr). The mean BAO in patients with or without prior gastric surgery was 41.2 ± 1.7 and 27.6±3.5mEq/hr, respectively. The sensitivity of proposed BAO criteria for ZES in patients without gastric surgery was 94% for BAO 20 10, 91% for BA02015, 86% for BA02018, 61% for BA02031 and 49% for BA02038. Similarly for patients with prior gastric surgery, 100% had BA0205 mEq/hr, 73% for BA02014.4 and 37% for BA02019.2. The criterion of BAO pHS I was met by 32% without and 20% with previous gastric surgery. The mean MAO was 61.4±2.1 mEq/hr and only 39% without and 10% of patients with previous gastric surgery met the proposed criterion of MA02070. The criterion of a BAOIMAO ratio 200.6 was met by 63% without and 80% with gastric surgery. The proposed criterion based on acid concentration of BACIMAC 200.6 was met in 93%. The combination criterion of BA02015 + BAOIMAO 200.6 was met by 61% of patients without gastric surgery, and BA02015 + pHSI in 32%. The gastric volume during the BAO was 313± 10 mllhr in patients without and 304±25 mllhr in patients with previous gastric surgery. In patients without
previous gastric surgery, 98% had 2075 ml, 96% 20100ml and 90% 20140 ml. In patients with previous gastric surgery, this occurred in 97%, 93% and 87%. In patients who had BAO<15 (without gastric surgery) pH was S I in II %, BAOIMAO 200.6 in 24%, BACIMAC 200.6 in 65%, and volume was >75 ml in 77%, > 100 ml in 61%, and > 140 ml in II %. These data demonstrate gastric secretory criteria of a BAO 20 15 and BA0205 for patients without or with previous gastric surgery, respectively were met by >91 % of patients with ZES. Similarly, the criterion of BACIMAC 200.6 had a high sensitivity but not the BAOIMAO 200.6, pH or MAO 2070. A BAO volume > 140 ml/hr is a neglected finding with high sensitivity (2090%) that should suggest ZES. A number of proposed BAO or MAO criteria or combinations lack sensitivity and will not be generally useful for diagnosing ZES. 5941
HELICOBACTER PYLORI AND NON-ULCER DYSPEPSIA: IS THERE A CAUSAL LINK? Johannes J. Sadikin., Jose D. Sollano Jr., Margaret L. Quiblat, Univ of Santo Tomas, Manila, Philippines. Background In the high prevalence area of Helicobacter pylori (Hp) infection such as in he Philippines, Hp infection is linked causally to peptic ulcer disease. However, it is uncertain whether Hp infection is common in non-ulcer dyspepsia thus responsible for the dyspeptic symptoms. Methods Between July 1999 and October 1999, a total of 390 patients with dyspepsia were assessed of whom 296 patients underwent upper gastrointestinal endoscopic investigation. Patients were excluded if they had strong family history of gastrointestinal malignancy, peptic ulcer disease or gastroesophageal reflux disease, significant change in bowel habits, melaena or passage of blood per rectum, anemia, jaundice, weight loss and visceromegaly, predominance of lower abdominal symptoms, an alteration in bowel habits and associated with disturbance in defecation, and the patient had abnormal findings on upper endoscopy. Symptoms were assessed utilizing the Glasgow Dyspepsia Severity Score with minimal symptoms defined as a score of 0-1 ( maximal score, 20). Two-sample, independent-groups t test was used to explore the relationship between Hp infection with non-ulcer dyspepsia. Result Of 296 patients, 245 patients were excluded because of gastric or duodenal ulcer (n=238), inability to tolerate endoscopy (n=2), declined to undergo endoscopy (n=4), and serious medical condition (n= I). The prevalence of non-ulcer dyspepsia was 17.2%. Rapid urease test was positive in 9 patients (17.6%), and negative in 42 patients (82.4%). The mean dyspepsia severity scores in those with and without H pylori were 7± 2.89 and 7.6± 0.85, respectively (p=0.554). Conclusion There appears no significant association between Helicobacter pylori infection and non-ulcer dyspepsia. Helicobacter pylori is probably not the dominant etiology of dyspeptic symptoms. 5942 NMI·377: A NOVEL NITROSOTHIOL-DICLOFENAC NSAID WITH GASTROINTESTINAL·SPARING ANTIINFLAMMATORY AND ANALGESIC ACTIVITIES. Joy K. Saba, Upul Bandarage, Liqing Chen, Alicia Glavin, David R. Janero, David S. Garvey, Joseph D. Schroeder, L. Gordon Letts, S. W. Tam, NitroMed, Inc, Bedford, MA; NitroMed, Inc, Beford, MA. The wide use of NSAIDs is hampered by side effects, mainly gastric mucosal damage and ulceration. Nitric oxide (NO) helps maintain gastric mucosal integrity. To counteract the gastric toxicity of NSAIDs, we have covalently linked a nitrosothiol-based NO-donor tether to diclofenac and synthesized a structurally new NSAID, the stable diclofenac derivative NMI-377 (3-(methyl[(nitrosothio cyclohexyl)methyl]amino)propyl 2-{2[(2,6-dichlorophenyl)amino]phenyl} acetate). The present study reports the preclinical evaluation of NMI-377, including gastrointestinal and pharmacological effects, in fasted male SD rats and CD-I mice. All compounds were dosed intragastrically as suspensions. The NO-releasing property of NMI-377 was demonstrated in vitro by its concentration-dependent relaxation of precontracted rat aortic ring smooth muscle. In vivo, NMI-377 did not change systemic blood pressure in rats when given intragastrically. Pharmacokinetic studies reveal that diclofenac is detected in the plasma of rats receiving NMI-377. The relative bioavailability of diclofenac from NMI-377 was approximately 50% that of an equimolar dose of diclofenac sodium (10 Mmol/kg). The gastrointestinal lesion effect of NMI-377 is weak at doses of 10-100 Mmol/kgand was about 5% of that of diclofenac when both were tested at a dose of 100 Mmol/kg. NMI-377 showed potencies similar to diclofenac in both the carrageenan-induced paw edema antiinflammatoiry test in rats and phenylbenzoquinone-induced writhing analgesic test in mice at all the doses (3-100 Mmol/kg) tested. In these pharmacology studies, the duration of action was similar for both compounds. A derivative of NMI-377 lacking the NO-donor group was significantly less gastrointestinal sparing compared to NMI-377 suggesting the beneficial effects of NO. Thus, NMI-377 is one of a novel class of GI-sparing NSAIDs with equipotent analgesic and antiinflammatory activities and significantly less GI side effects than diclofenac.