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Amoxicillin, clarithromycin, erythromycin, roxithromycin in combination with omeprazole for eradication of H. pylori
April 1995
• AMOXICILLIN, CLARITHROMYCIN, ERYTHROMYCIN, ROXITHROMYCIN IN COMBINATION WITH OMEPRAZOLE FOR ERADICATION OF H. PYLORI H Hallberg, J-P Idstr6m, A. Jonsson, M. Wrangstadh, T Lind Dept. Surg., K/irnsjukhuset, Sk6vde, Sweden, Clin. Pharmacol., Astra H~ssle AB, MOlndal, Sweden. A close relationship exists between Helicobacter Pylori (H.p.) infection and peptic ulcer disease. We have studied the eradication rates of H:p. using potent acid inhibition in combination with amoxiciUin or with different macrolides. Furthermore, we have also studied whether a relationship exists between degreee of acid inhibition as well as plasma level of antibiotics and H.p. eradication. METHOD~ 96 patients with a mean age of 56 years referred to our endoscopy unit and CLO-positive for H.p. were randomized to one of four treatment groups receiving' Omeprazole (Ome.) 40 mgb.i.d, combined with b.i.d. administration of either Amoxicinin (Amox.) 750 rag, Clarithromycin (Clar.) 250 mg, Erythromycin (Ery.) or Roxithromycin (Rox.) 150 mg for two weeks. ~3C Urea-breath test (UBT) was performed before treatment and four weeks after cessation of therapy. Cut-off point for a positive UBT-test was >5 per nail exess '3CO2.Ten patients in each group were also, at steady state during the treatment, investigated with a 24-hour intragastric pH as well as an antibiotic plasma profile measurement. RESULTS: 8 patients were excluded due to either negative UBT-test at inclusion, pathology in lab. screen or non-compliance. 65 % of the patients had a previous ulcer history while 35 % were diagnosed as NUD. The eradication rates were: Amox. 64 % (15/23), Clar. 87 % (20/23), Ery. 52 % (11/21) and Rox. 33 % (7/21). Percent time with intragastric pH>4 was significantly larger during treatment with Clar. and Ery. as compared to Amox. (p=0,03 resp. 0,01). Neither % time with pH >4 nor antibiotic plasma levels correlated to the UBTresults. Side effects were few and most commonly from the GI-tract. Four patients in the Clar-group reported taste disturbances. CONCLUSION: The most effective treatment was b.i.d, treatment with omeprazole 40 mg and clarithromycin 250 nag. Neither intragastric pH nor plasma antibiotic levels were predictors for H.p. eradication. Clarithromycin and erythromycin increased the effect of omeprazole on intragastric pH.
O C A F F E I N E INHIBITS A G O N I S T - D E P E N D E N T C A L C I U M MOBILIZATION IN HUMAN GASTRIC EPITHELIAL CELL LINE. E~ Hamada, K. Ogura, M. Takahashi, T. Shimada, T. Nakajima, T. Kawabe, S. Ota, Y. Kurachi*, M. Omata. The 2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. *) The Division of Pharmacology II, University of Osaka, Osaka, Japan.
It is well known that caffeine causes gastric mucosal injury by increasing acid secretion through the rise of cyclic AMP, but the effect of caffeine on mucus secretion is unclear. To clarify the action of caffeine in gastric epithelial calls, the effects of caffeine on agonist-induced [Ca2+]i mobilization were examined in JR-! cells, a mucin-producing epithelial cell line derived from human gastric signet ring cell carcinoma. The measurement of [Ca2+]i using Indo-I fluorescence and the whole cell voltage clamp technique were applied. Caffeine (10 mM) by itself failed to increase [Ca2*]iand affect the membrane currents significantly. But caffeine (1-10 mM) d o s e dependently inhibited agonist (acetylcholine, histamine and ATP)induced [Ca2+]i risel resulting in inhibition of Ca2+-dependent K÷ current (Ijcca) reversively. The inhibitory effect Of caffeine could be overcome by an incremental dose of the agonist. On the other hand, caffeine failed to suppress [Ca2÷]i rise and activation of IK.ca evoked by A23187, a Ca2+ ionophore, or intracellular application of inositol trisphosphate (IP3). Ryanodine did not mimic the effects of caffeine at all, proposing that the Ca2+ release from the intracellular store sites is not involved in caffeine action in this cell. These results indicate that caffeine selectively inhibited agonistmediated [Ca~+]i rise in JR-1 cells, probably through the blockade of receptor-IP3 signaling pathway, which may result in decrease of mucus secretion: Thus caffeine induces gastric mucosal injury not only by increasing acid secretion but also by decreasing gastric mucus secretion.
Esophageal, Gastric, and Duodenal Disorders A107
• EFFECTS OF N E U R O K I N I N A AND HISTAMINE DUODENAL FUNCTIONS IN THE RAT IN VIVO.
ON
A. Halbren. S. Hellgren and O. Nylander. Dept. of Physiology and Medical Biophysics, Biomedical Center, Uppsala University, Uppsala, Sweden. The aim of this study was to investigate whether the pro-inflammatory mediators neurokinin A (NKA) and histamine influence duodenal mucosal permeability, bicarbonate secretion, fluid flux and motility. Method: Rats were anesthetized and a segment of the duodenum was peffused with saline. Duodenal mucosal alkaline secretion (DMAS, measured by back titration), mucosal permeability ( c l ~ of 51Cr-EDTA from bloodto-lumen), motility (intraluminai pressure) and net fluid flux (changes in effluent weight) were monitored simultaneously. Results: Intravenous infusion of histamine (4 mg/kg,h, n--5) decreased DMAS by 32 % (p<0.01) from a basal level of 6.8i-0.9 pmol/cm,h to 4.6+1.0 graol/cm,h. Upon termination of the infusion DMAS returned to the basal levelwithin 30 rnim Histamine alsodecreasedarterialblood pressureby 21:~.3m m Hg (P<0.001) and tended to decrease effluentweight althoughthis change did not attain statisticalsignificance.No effect on motilitywas obtainedand mucesal permeabilityto 51Cr-EDTA remained unchanged. N K A w a s infused i.v.at two differentdoses: 12 nmol/kg,h (n=6) and 24 nmol/kg,h (n=6). Both doses induced intense duodenal motility (P<0.001) which disappearedonly minutes afterterminationof the infusion. The time occupied by contractionswas similarat both 12 and24 nmol/kg,h NKA. DMAS inerea,wxlsignificantly (P<0.001) in both NKA groups and the mean increase did not differ between doses (2.55-'0.7pmol/ern,h and 2.3:L0.6 ~mol/em,h respectively). The sdmulatory effect of NKA on DMAS declined with time and returned to control level or below after cessation of the infusion. Both doses of NKA significantly increased mucesai permeability (P<0.01). The mean increase in mucosal permeability was larger at 24 nmol/kg,h (0.36+0.08 ml/min.100g) as compared to 12 nmol/kg,h (0.115:0.07 ml/min.100g, P<0.05). Infusion of NKA also i n ~ effluent weight. The mean increases were 2.53:£-0.21 g/g,h (P<0.001) and 1.86.-H).30 (P<0.01) g/g,h 1 12 nmol/kg,h and 24 nmol/kg,h respectively and there was no significant diffca'ence between the groups. Conclusion: The NKA induced motility was accompanied by increased DMAS, mucosal permeability and fluid output. Histamine decreases DMAS. It is possible that NKA and histamine may alter duodenal function during inflammation.
PREVALENCE OF GI-SYMPTOMS AND HELICOBACTER PYLORI IN PATIENTS UNDERGOING CHRONIC HEMODIALYSIS. Johann Hammer, Christian Oesterreicher, U. Koch, J. Kovarik, A. Gangl. Depts. of Gastroenterology & Hepatology and Nephrology, University of Vienna, Austria Gastrointestinal disorders are frequently observed and often severe complications in uremic patients; few data are available on the prevalence of gastrointestinal complaints in patients on chronic hemodialysis. Moreover, patients undergoing chronic hemodialysis have a higher risk to develop malignancies; Helicobacter pylori is associated with an increased risk of gastric malignancies. AIM: to obtain data of the prevalence of GI-symptoms and Helicobacter pylori-infeetion in patients undergoing chronic hemodialysis. METHODS: 109 patients in our hemodialysis ward were handed out a questionnaire that was previously validated by Talley et al. (Gastroenterology, 1992, 895); 102 (94%; mean age 69 years, 47 F, 55 M) responded. IgG against Helicobacter pylori were determined in 122 patients using an ELISA test. RESULTS: Frequent vomiting and heartburn had prevalences of 13.7% (n=14) and 117% (n=13), respectively. Dysmotilitylike dyspepsia was reported in 16.6% of patients (n=17), refluxlike dyspepsia in 11.8% (n=12) and ulcerlike dyspepsia in 18.6% (n=19). The prevalence of frequent abdominal pain was 23.5% (n=27); pain was located in the upper abdomen in 5.9% (n=6) and in both the upper and lower abdomen in 8.8% (n=9). 11.8% of patients (n=12) reported frequent severe or extreme abdominal pain. Chronic eonsti!bation and chronic diarrhea were reported in 8.8% (n=9) and 5.9% (n=6), respectively. 11.8% (n=12) had IBS according to the Manning criteria (3 or more criteria positive), 6.9% (n=7) had 4 or more Manning criteria. Serology for Helicobacter pylori was positive in 35.3% (n=43), i.e. in 23.7% of patients <50 years of age, and 40.5% of patients >50 years. CONCLUSION: Complaints of gastrointestinal symptoms are common in patients undergoing chronic hemodialysis; nevertheless, prevalence of GI-symptoms equals the prevalence reported for the general population. Prevalence of Helicobacter pylori shows similar age distribution like in the general population.
• AMOXICILLIN, CLARITHROMYCIN, ERYTHROMYCIN, ROXITHROMYCIN IN COMBINATION WITH OMEPRAZOLE FOR ERADICATION OF H. PYLORI H Hallberg, J-P Idstr6m, A. Jonsson, M. Wrangstadh, T Lind Dept. Surg., K/irnsjukhuset, Sk6vde, Sweden, Clin. Pharmacol., Astra H~ssle AB, MOlndal, Sweden. A close relationship exists between Helicobacter Pylori (H.p.) infection and peptic ulcer disease. We have studied the eradication rates of H:p. using potent acid inhibition in combination with amoxiciUin or with different macrolides. Furthermore, we have also studied whether a relationship exists between degreee of acid inhibition as well as plasma level of antibiotics and H.p. eradication. METHOD~ 96 patients with a mean age of 56 years referred to our endoscopy unit and CLO-positive for H.p. were randomized to one of four treatment groups receiving' Omeprazole (Ome.) 40 mgb.i.d, combined with b.i.d. administration of either Amoxicinin (Amox.) 750 rag, Clarithromycin (Clar.) 250 mg, Erythromycin (Ery.) or Roxithromycin (Rox.) 150 mg for two weeks. ~3C Urea-breath test (UBT) was performed before treatment and four weeks after cessation of therapy. Cut-off point for a positive UBT-test was >5 per nail exess '3CO2.Ten patients in each group were also, at steady state during the treatment, investigated with a 24-hour intragastric pH as well as an antibiotic plasma profile measurement. RESULTS: 8 patients were excluded due to either negative UBT-test at inclusion, pathology in lab. screen or non-compliance. 65 % of the patients had a previous ulcer history while 35 % were diagnosed as NUD. The eradication rates were: Amox. 64 % (15/23), Clar. 87 % (20/23), Ery. 52 % (11/21) and Rox. 33 % (7/21). Percent time with intragastric pH>4 was significantly larger during treatment with Clar. and Ery. as compared to Amox. (p=0,03 resp. 0,01). Neither % time with pH >4 nor antibiotic plasma levels correlated to the UBTresults. Side effects were few and most commonly from the GI-tract. Four patients in the Clar-group reported taste disturbances. CONCLUSION: The most effective treatment was b.i.d, treatment with omeprazole 40 mg and clarithromycin 250 nag. Neither intragastric pH nor plasma antibiotic levels were predictors for H.p. eradication. Clarithromycin and erythromycin increased the effect of omeprazole on intragastric pH.
O C A F F E I N E INHIBITS A G O N I S T - D E P E N D E N T C A L C I U M MOBILIZATION IN HUMAN GASTRIC EPITHELIAL CELL LINE. E~ Hamada, K. Ogura, M. Takahashi, T. Shimada, T. Nakajima, T. Kawabe, S. Ota, Y. Kurachi*, M. Omata. The 2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. *) The Division of Pharmacology II, University of Osaka, Osaka, Japan.
It is well known that caffeine causes gastric mucosal injury by increasing acid secretion through the rise of cyclic AMP, but the effect of caffeine on mucus secretion is unclear. To clarify the action of caffeine in gastric epithelial calls, the effects of caffeine on agonist-induced [Ca2+]i mobilization were examined in JR-! cells, a mucin-producing epithelial cell line derived from human gastric signet ring cell carcinoma. The measurement of [Ca2+]i using Indo-I fluorescence and the whole cell voltage clamp technique were applied. Caffeine (10 mM) by itself failed to increase [Ca2*]iand affect the membrane currents significantly. But caffeine (1-10 mM) d o s e dependently inhibited agonist (acetylcholine, histamine and ATP)induced [Ca2+]i risel resulting in inhibition of Ca2+-dependent K÷ current (Ijcca) reversively. The inhibitory effect Of caffeine could be overcome by an incremental dose of the agonist. On the other hand, caffeine failed to suppress [Ca2÷]i rise and activation of IK.ca evoked by A23187, a Ca2+ ionophore, or intracellular application of inositol trisphosphate (IP3). Ryanodine did not mimic the effects of caffeine at all, proposing that the Ca2+ release from the intracellular store sites is not involved in caffeine action in this cell. These results indicate that caffeine selectively inhibited agonistmediated [Ca~+]i rise in JR-1 cells, probably through the blockade of receptor-IP3 signaling pathway, which may result in decrease of mucus secretion: Thus caffeine induces gastric mucosal injury not only by increasing acid secretion but also by decreasing gastric mucus secretion.
Esophageal, Gastric, and Duodenal Disorders A107
• EFFECTS OF N E U R O K I N I N A AND HISTAMINE DUODENAL FUNCTIONS IN THE RAT IN VIVO.
ON
A. Halbren. S. Hellgren and O. Nylander. Dept. of Physiology and Medical Biophysics, Biomedical Center, Uppsala University, Uppsala, Sweden. The aim of this study was to investigate whether the pro-inflammatory mediators neurokinin A (NKA) and histamine influence duodenal mucosal permeability, bicarbonate secretion, fluid flux and motility. Method: Rats were anesthetized and a segment of the duodenum was peffused with saline. Duodenal mucosal alkaline secretion (DMAS, measured by back titration), mucosal permeability ( c l ~ of 51Cr-EDTA from bloodto-lumen), motility (intraluminai pressure) and net fluid flux (changes in effluent weight) were monitored simultaneously. Results: Intravenous infusion of histamine (4 mg/kg,h, n--5) decreased DMAS by 32 % (p<0.01) from a basal level of 6.8i-0.9 pmol/cm,h to 4.6+1.0 graol/cm,h. Upon termination of the infusion DMAS returned to the basal levelwithin 30 rnim Histamine alsodecreasedarterialblood pressureby 21:~.3m m Hg (P<0.001) and tended to decrease effluentweight althoughthis change did not attain statisticalsignificance.No effect on motilitywas obtainedand mucesal permeabilityto 51Cr-EDTA remained unchanged. N K A w a s infused i.v.at two differentdoses: 12 nmol/kg,h (n=6) and 24 nmol/kg,h (n=6). Both doses induced intense duodenal motility (P<0.001) which disappearedonly minutes afterterminationof the infusion. The time occupied by contractionswas similarat both 12 and24 nmol/kg,h NKA. DMAS inerea,wxlsignificantly (P<0.001) in both NKA groups and the mean increase did not differ between doses (2.55-'0.7pmol/ern,h and 2.3:L0.6 ~mol/em,h respectively). The sdmulatory effect of NKA on DMAS declined with time and returned to control level or below after cessation of the infusion. Both doses of NKA significantly increased mucesai permeability (P<0.01). The mean increase in mucosal permeability was larger at 24 nmol/kg,h (0.36+0.08 ml/min.100g) as compared to 12 nmol/kg,h (0.115:0.07 ml/min.100g, P<0.05). Infusion of NKA also i n ~ effluent weight. The mean increases were 2.53:£-0.21 g/g,h (P<0.001) and 1.86.-H).30 (P<0.01) g/g,h 1 12 nmol/kg,h and 24 nmol/kg,h respectively and there was no significant diffca'ence between the groups. Conclusion: The NKA induced motility was accompanied by increased DMAS, mucosal permeability and fluid output. Histamine decreases DMAS. It is possible that NKA and histamine may alter duodenal function during inflammation.
PREVALENCE OF GI-SYMPTOMS AND HELICOBACTER PYLORI IN PATIENTS UNDERGOING CHRONIC HEMODIALYSIS. Johann Hammer, Christian Oesterreicher, U. Koch, J. Kovarik, A. Gangl. Depts. of Gastroenterology & Hepatology and Nephrology, University of Vienna, Austria Gastrointestinal disorders are frequently observed and often severe complications in uremic patients; few data are available on the prevalence of gastrointestinal complaints in patients on chronic hemodialysis. Moreover, patients undergoing chronic hemodialysis have a higher risk to develop malignancies; Helicobacter pylori is associated with an increased risk of gastric malignancies. AIM: to obtain data of the prevalence of GI-symptoms and Helicobacter pylori-infeetion in patients undergoing chronic hemodialysis. METHODS: 109 patients in our hemodialysis ward were handed out a questionnaire that was previously validated by Talley et al. (Gastroenterology, 1992, 895); 102 (94%; mean age 69 years, 47 F, 55 M) responded. IgG against Helicobacter pylori were determined in 122 patients using an ELISA test. RESULTS: Frequent vomiting and heartburn had prevalences of 13.7% (n=14) and 117% (n=13), respectively. Dysmotilitylike dyspepsia was reported in 16.6% of patients (n=17), refluxlike dyspepsia in 11.8% (n=12) and ulcerlike dyspepsia in 18.6% (n=19). The prevalence of frequent abdominal pain was 23.5% (n=27); pain was located in the upper abdomen in 5.9% (n=6) and in both the upper and lower abdomen in 8.8% (n=9). 11.8% of patients (n=12) reported frequent severe or extreme abdominal pain. Chronic eonsti!bation and chronic diarrhea were reported in 8.8% (n=9) and 5.9% (n=6), respectively. 11.8% (n=12) had IBS according to the Manning criteria (3 or more criteria positive), 6.9% (n=7) had 4 or more Manning criteria. Serology for Helicobacter pylori was positive in 35.3% (n=43), i.e. in 23.7% of patients <50 years of age, and 40.5% of patients >50 years. CONCLUSION: Complaints of gastrointestinal symptoms are common in patients undergoing chronic hemodialysis; nevertheless, prevalence of GI-symptoms equals the prevalence reported for the general population. Prevalence of Helicobacter pylori shows similar age distribution like in the general population.