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No interaction between omeprazole and amoxicillin during combination therapy in Helicobacter pylori positive healthy subjects
A194
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 1 0 8 , No. 4
• NO INTERACTION BETWEEN OMEPRAZOLE AND AMOXICILLIN DURING COMBINATION THERAPY IN HELICOBACTER PYLORI POSITIVE HEALTHY SUBJECTS W, pommerien, M. Braun, J.P. Idstr6m*, M. Wrangstadh*, W. Londong, 2nd Medical Dept., Krankenhaus Am Urban, Berlin, Germany, *Dept. of Clinical Pharmacology, Astra H~isale AB, M61ndal, Sweden. The combination of omeprazole (OM) and amoxlclllin (AM) is used to eradicate Hellcobacter pylori (Hp) in peptic ulcer disease. It is speculated that OMinduced hypoacidlty Improves the bloavallabllRy of AM. No data exist about possible effects of AM on the pharmacokinetics of OM. This study investigated the phermacoklnetlc and pharmscodynamic Interaction of AM and OM. Methods: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline 24-hour intragastrlc pH-metry 26 Hp positive healthy male subjects (mean age: 29 yrs.) were randomly treated with AM 750 mg tablets bid + placebo, AM 750 mg bid ÷ OM 40 mg bid and placebo + OM 40 mg bid for 5 days, At the last day of each treatment perlQd Intragestrlc pH-metries were performed and blood samples taken for OM and AM serum profiles. During the 24-hour monitoring all subjects remained at the hospital and recalved standardized meals: To prove Hp positlvity during the entire study '=C-urea breath tests were performed before treatment and after the wash-out periods of at least 4 weeks. Reaults: Intragastric pH and area under the serum concentration time curve (AUC) are expressed as estimated mean with corresponding SD and 95% CI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24-hour pH
AUC for OM
(/Jmol x h/I)
AUC for AM
(pmol x h/I)
.......................................................................................................
AM + placebo AM + OM Placebo + OM
2.2 + 1.0 5.2 ± 0.5 5.5 ± 1.0
19 (15-25) 19 (15-24)
87 (78-96) 90 (81-100)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The 24-hour intragastric pH under placebo alone (1.8 ± 0.7) and under AM + placebo was similar. The same was true for the comparison of the pH under AM + OM and placebo + OM (mean difference 0.34, 95% CI: -0.13 - 0.81: p=0.15). The kinetics of OM and AM given In combination were not significantly altered. Conclusion: At clinically recommended doses of the omeprazole amoxlcnlln oomblnation there is neither a pharmacodynamlc (with respect to pH) nor a pharmaeokinetic interaction between the two drugs in Hellcobacter pylorl peaitive healthy subjects.
• LOCATION OF DUODENAL GASTRIC METAPLASIA (DGM) AND HELICOBACTER PYLORI (HP) PREVALENCE IN PATIENTS WITH NON ULCER DYSPEPSIA (NUD) AND DUODENAL ULCER DISEASE. D. PosDai. C. Vissuzaine, M. Merrouche, J. Ouanezar, Z. Boumaza, Th. Vallot, M. Mignon. CHU Bichat - 75877 Paris Cedex 18 - France. DGM is a common histol0gical finding presumably related to high gastric acid output. The aim of this prospective study was to evaluate the prevalence and distribution of DGM in the duodenum of 67 patients before antimicrobial therapy [27 NUD,9 endoscopical duodenal erosions (DE), 20 healed duodenal ulcer (HDU) and 11 active duodenal ulcer (ADU)]. Methods: Multiple pinch biopsies (4 -6) were taken from the middle portion of the first duodenum [anterior wall (AW) posterior wall (PW), lesser and greater curvature (LC) (GC)]; supplementary 2-3 biopsies from the ulcer scar or niche and 2-3 antral biopsies were taken. PAS and Giemsa colorations were performed to detect DGM and HP.Results: table groupe (N) DNU (27) DE (9) HDU ( 2 0 ) ADU (11) 55** 100 DGM+ (%) 33 33 scars 100 * niche 75 * location of PW 22 PW 33 other sites 11 other sites 54 DGM(%) LC 22 LC 33 GC 33 GC 0 duodenitis 72% 90% in DGM area 44% 0 90 % 72% HP antrum 33% 33% 0 9% HP duoden: 0 0 *p<0.05 ; **In the HDU group 12 pts had long-term antisecretory treatment (41% DGM+, vs 59% DGM- p=0.03) suggesting that DGM is an acidrelated reversible condition. The median proportion of the biopsied surface area involved with gastric metaplasia (M%+SD%) was : 22±5 in NUD, 33+10 in DE, 25±8 in the scars of HDU, 40-2_10 in niches and 8±3 in the extralesional sits of ADU. Conclusions: 1. In NUD and DE, the DGM was located preferentially in the anterior wall of the I st duodenum, not associated with duodenitis in about 60 % of cases and without HP in metaplastic areas. 2. In DU disease (HDU and ADU) the significantly more frequent location in niches or scars, in comparison with extralesional areas of the DGM and its frequent association with duodenal inflamation, suggest that both conditions are sufficient for ulcer lesion development even in absence of HP in DGM : HP absent in DGM (95.5%) of cases although present in the antrum (81%) of cases.
FUNDIC MUCOSA OF GER PATIENTS CONTINUOUSLY TREATED WITH RANITIDINE: COMPARISON WITH OMEPRAZOLE-TREATED PATIENTS AND CONTROLS.
D Posnai, G Cadiot, C Vissuzaine, F Potet,.M Mignon. Dpts of Gastroenterology and Pathology. CHU Bichat-Claude Bernard, 75877 Pads cedex 18, France. The fundic mucosa of gastroesophageal reflux (GER) patients (pts) continuously treated for more than 7 years with ranitidine was studied and compared with that of GER patients continuously treated with omeprazole for more than 4 years and with that of normal subjects. PATIENTS: 1/Ranitidine (R) (n=7): OF/7M; median (med) age: 57 yrs, extremes: 26-67; med treatment duration: 144 months, extr: 84-168; med R dose: 300 mg/d, extr: 150-600. Maximal esophagitis grading (SavaryMiller): 2 in 5 pts, 3 in 2 pts, associated Barrett's in 2 pts. 2/Omeprazole (OM) (n=10): 4F/6M; med age 66 (25-76); reed treatment duration 56 mo (48-96; P<0.01 vs R); reed OM dose 20 mg/d (20-80). Max esophagitis grading: 0 in 1 pt, 1 in 1 pt, 2 in 6 pts, 3 in 1 pt, 4 in 1 pt, Barret's in 5 pts. 31 Controls (n=10): 4F/6H; age 39 (22-67, P<0.01 vs OM). METHODS: Degree of fundic atrophic gastritis, density and qualitative Cell growth grading (Solcia's classification) of the fundic argyrophil (Grimelius) cells, serum gastrin levels. RESULTS: l/Table (med-extr), P<0.01 vs (a) OM, (b) controls (U test) Fundic argyrophil cells Serum gastrin (N° ceUs/640}.tm2) (p~/ml) RANITIDINE (n=7) 7.0 (6.0-9.4)a 43 (35-73)ab OMEPRAZOLE (n=10) 11.4 (7.0-41.2)b 124 (40-249)b CONTROLS (n=10) 7.0 (5.8-7.3) 70 (53-88) 2/No fundic argyrophil cell dysplasia and no carcinoid in any group. No fundic argyrophil cell hyperplasia in controls and ranitidine-treated patients. In omeprazole-treated patients: diffuse fundic argyrophil cell hyperplasia (n=2) and micronodular hyperplasia (n=2)~ 3/Correlation between fundic argyrophil cell density and serum gastrin r'=0.60 (Spearman P<0.01). 4/No fUndic atrophic gastritis in any group. CONCLUSION: After a median treatment duration of 12 years with ranitidine, the density and the degree of qualitative growth of fundic argyrophil ceils and serum gastrin levels were not higher than in controls. After a median treatment duration of 5 years with omeprazole, the density and the degree of qualitative growth of fundic argyrophil cells and serum gastrin levels were higher than in controls and ranitidine-treated patients. No fundic atrophic gastritis was noted in any group.
SUPERIOR ANTISECRETORY PROFILE OF THE NOVEL REVERSIBLE GASTRIC .PROTON PUMP INHIBITOR BY841, COMPARED TO RANITIDINE. S.Postius, U.Br~iuer, W.Kromer, Byk Gulden, D-78467 Konstanz The novel H+/K+-ATPase inhibitor BY841 binds to the gastric proton pump and thus inhibits the final step in acid production, however in a reversible manner. The aim of the present investigation was therefore to compare BY841 with the H2-receptor-antagonist ranitidine with respect to their effects on the intragastric 24 h pH profile in either pentagastrin- or carbachol-stimulated gastric fistula Beagle dogs. Methods: pH-metry was performed by inserting a glass electrode in the dog's gastric fistula. Gastric secretion was stimulated b y a continuous s.c. infusion of pentagastrin or carbachol in freely moving, either fed or fasted dogs from noon to 8 a.m., next day. pH-data were evaluated by use of both hard- and software from Synectics, Sweden. Results: 9 to 54 pmol/kg of orally administered BY841 dose dependently elevated intragastric pH in both fed and fasted pentagastrin-stimulated dogs. In contrast to ranitidina, pH-elevations by BY841 were highly reproducible. 27 pmol/kg of BY841 elevated intragastric pH to neutrality, whereas 85 pmol/kg of ranitidine were needed to obtain neutral gastric pH. Also, duration of pH-elevation increased almost linearly to the dose of BY841, but not ranitidine. As expected, 27 pmol/kg of oral BY841, in contrast to the same d o s e of ranitidine, elevated intragastric pH in carbacholstimulated dogs as efficaciously and for the same duration as in pentagastrin-st!mulated dogs. Conclusions: BY841 proved to be a highly efficacious gastric antisecretory drug with fast onset of action and predictable time course o f its pH-elevating effect: The latter is highly reliable. Due to blockade of the final step in acid production, its action is independent of the particular stimulus of acid secretion used. The comparison of the results from this dog study with the first clinical phase I study (Fu'der et al., this meeting) indicate human relevance of the results obtained in the pentagastrin- and carbachol-stimulated fistula dog.
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 1 0 8 , No. 4
• NO INTERACTION BETWEEN OMEPRAZOLE AND AMOXICILLIN DURING COMBINATION THERAPY IN HELICOBACTER PYLORI POSITIVE HEALTHY SUBJECTS W, pommerien, M. Braun, J.P. Idstr6m*, M. Wrangstadh*, W. Londong, 2nd Medical Dept., Krankenhaus Am Urban, Berlin, Germany, *Dept. of Clinical Pharmacology, Astra H~isale AB, M61ndal, Sweden. The combination of omeprazole (OM) and amoxlclllin (AM) is used to eradicate Hellcobacter pylori (Hp) in peptic ulcer disease. It is speculated that OMinduced hypoacidlty Improves the bloavallabllRy of AM. No data exist about possible effects of AM on the pharmacokinetics of OM. This study investigated the phermacoklnetlc and pharmscodynamic Interaction of AM and OM. Methods: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline 24-hour intragastrlc pH-metry 26 Hp positive healthy male subjects (mean age: 29 yrs.) were randomly treated with AM 750 mg tablets bid + placebo, AM 750 mg bid ÷ OM 40 mg bid and placebo + OM 40 mg bid for 5 days, At the last day of each treatment perlQd Intragestrlc pH-metries were performed and blood samples taken for OM and AM serum profiles. During the 24-hour monitoring all subjects remained at the hospital and recalved standardized meals: To prove Hp positlvity during the entire study '=C-urea breath tests were performed before treatment and after the wash-out periods of at least 4 weeks. Reaults: Intragastric pH and area under the serum concentration time curve (AUC) are expressed as estimated mean with corresponding SD and 95% CI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24-hour pH
AUC for OM
(/Jmol x h/I)
AUC for AM
(pmol x h/I)
.......................................................................................................
AM + placebo AM + OM Placebo + OM
2.2 + 1.0 5.2 ± 0.5 5.5 ± 1.0
19 (15-25) 19 (15-24)
87 (78-96) 90 (81-100)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The 24-hour intragastric pH under placebo alone (1.8 ± 0.7) and under AM + placebo was similar. The same was true for the comparison of the pH under AM + OM and placebo + OM (mean difference 0.34, 95% CI: -0.13 - 0.81: p=0.15). The kinetics of OM and AM given In combination were not significantly altered. Conclusion: At clinically recommended doses of the omeprazole amoxlcnlln oomblnation there is neither a pharmacodynamlc (with respect to pH) nor a pharmaeokinetic interaction between the two drugs in Hellcobacter pylorl peaitive healthy subjects.
• LOCATION OF DUODENAL GASTRIC METAPLASIA (DGM) AND HELICOBACTER PYLORI (HP) PREVALENCE IN PATIENTS WITH NON ULCER DYSPEPSIA (NUD) AND DUODENAL ULCER DISEASE. D. PosDai. C. Vissuzaine, M. Merrouche, J. Ouanezar, Z. Boumaza, Th. Vallot, M. Mignon. CHU Bichat - 75877 Paris Cedex 18 - France. DGM is a common histol0gical finding presumably related to high gastric acid output. The aim of this prospective study was to evaluate the prevalence and distribution of DGM in the duodenum of 67 patients before antimicrobial therapy [27 NUD,9 endoscopical duodenal erosions (DE), 20 healed duodenal ulcer (HDU) and 11 active duodenal ulcer (ADU)]. Methods: Multiple pinch biopsies (4 -6) were taken from the middle portion of the first duodenum [anterior wall (AW) posterior wall (PW), lesser and greater curvature (LC) (GC)]; supplementary 2-3 biopsies from the ulcer scar or niche and 2-3 antral biopsies were taken. PAS and Giemsa colorations were performed to detect DGM and HP.Results: table groupe (N) DNU (27) DE (9) HDU ( 2 0 ) ADU (11) 55** 100 DGM+ (%) 33 33 scars 100 * niche 75 * location of PW 22 PW 33 other sites 11 other sites 54 DGM(%) LC 22 LC 33 GC 33 GC 0 duodenitis 72% 90% in DGM area 44% 0 90 % 72% HP antrum 33% 33% 0 9% HP duoden: 0 0 *p<0.05 ; **In the HDU group 12 pts had long-term antisecretory treatment (41% DGM+, vs 59% DGM- p=0.03) suggesting that DGM is an acidrelated reversible condition. The median proportion of the biopsied surface area involved with gastric metaplasia (M%+SD%) was : 22±5 in NUD, 33+10 in DE, 25±8 in the scars of HDU, 40-2_10 in niches and 8±3 in the extralesional sits of ADU. Conclusions: 1. In NUD and DE, the DGM was located preferentially in the anterior wall of the I st duodenum, not associated with duodenitis in about 60 % of cases and without HP in metaplastic areas. 2. In DU disease (HDU and ADU) the significantly more frequent location in niches or scars, in comparison with extralesional areas of the DGM and its frequent association with duodenal inflamation, suggest that both conditions are sufficient for ulcer lesion development even in absence of HP in DGM : HP absent in DGM (95.5%) of cases although present in the antrum (81%) of cases.
FUNDIC MUCOSA OF GER PATIENTS CONTINUOUSLY TREATED WITH RANITIDINE: COMPARISON WITH OMEPRAZOLE-TREATED PATIENTS AND CONTROLS.
D Posnai, G Cadiot, C Vissuzaine, F Potet,.M Mignon. Dpts of Gastroenterology and Pathology. CHU Bichat-Claude Bernard, 75877 Pads cedex 18, France. The fundic mucosa of gastroesophageal reflux (GER) patients (pts) continuously treated for more than 7 years with ranitidine was studied and compared with that of GER patients continuously treated with omeprazole for more than 4 years and with that of normal subjects. PATIENTS: 1/Ranitidine (R) (n=7): OF/7M; median (med) age: 57 yrs, extremes: 26-67; med treatment duration: 144 months, extr: 84-168; med R dose: 300 mg/d, extr: 150-600. Maximal esophagitis grading (SavaryMiller): 2 in 5 pts, 3 in 2 pts, associated Barrett's in 2 pts. 2/Omeprazole (OM) (n=10): 4F/6M; med age 66 (25-76); reed treatment duration 56 mo (48-96; P<0.01 vs R); reed OM dose 20 mg/d (20-80). Max esophagitis grading: 0 in 1 pt, 1 in 1 pt, 2 in 6 pts, 3 in 1 pt, 4 in 1 pt, Barret's in 5 pts. 31 Controls (n=10): 4F/6H; age 39 (22-67, P<0.01 vs OM). METHODS: Degree of fundic atrophic gastritis, density and qualitative Cell growth grading (Solcia's classification) of the fundic argyrophil (Grimelius) cells, serum gastrin levels. RESULTS: l/Table (med-extr), P<0.01 vs (a) OM, (b) controls (U test) Fundic argyrophil cells Serum gastrin (N° ceUs/640}.tm2) (p~/ml) RANITIDINE (n=7) 7.0 (6.0-9.4)a 43 (35-73)ab OMEPRAZOLE (n=10) 11.4 (7.0-41.2)b 124 (40-249)b CONTROLS (n=10) 7.0 (5.8-7.3) 70 (53-88) 2/No fundic argyrophil cell dysplasia and no carcinoid in any group. No fundic argyrophil cell hyperplasia in controls and ranitidine-treated patients. In omeprazole-treated patients: diffuse fundic argyrophil cell hyperplasia (n=2) and micronodular hyperplasia (n=2)~ 3/Correlation between fundic argyrophil cell density and serum gastrin r'=0.60 (Spearman P<0.01). 4/No fUndic atrophic gastritis in any group. CONCLUSION: After a median treatment duration of 12 years with ranitidine, the density and the degree of qualitative growth of fundic argyrophil ceils and serum gastrin levels were not higher than in controls. After a median treatment duration of 5 years with omeprazole, the density and the degree of qualitative growth of fundic argyrophil cells and serum gastrin levels were higher than in controls and ranitidine-treated patients. No fundic atrophic gastritis was noted in any group.
SUPERIOR ANTISECRETORY PROFILE OF THE NOVEL REVERSIBLE GASTRIC .PROTON PUMP INHIBITOR BY841, COMPARED TO RANITIDINE. S.Postius, U.Br~iuer, W.Kromer, Byk Gulden, D-78467 Konstanz The novel H+/K+-ATPase inhibitor BY841 binds to the gastric proton pump and thus inhibits the final step in acid production, however in a reversible manner. The aim of the present investigation was therefore to compare BY841 with the H2-receptor-antagonist ranitidine with respect to their effects on the intragastric 24 h pH profile in either pentagastrin- or carbachol-stimulated gastric fistula Beagle dogs. Methods: pH-metry was performed by inserting a glass electrode in the dog's gastric fistula. Gastric secretion was stimulated b y a continuous s.c. infusion of pentagastrin or carbachol in freely moving, either fed or fasted dogs from noon to 8 a.m., next day. pH-data were evaluated by use of both hard- and software from Synectics, Sweden. Results: 9 to 54 pmol/kg of orally administered BY841 dose dependently elevated intragastric pH in both fed and fasted pentagastrin-stimulated dogs. In contrast to ranitidina, pH-elevations by BY841 were highly reproducible. 27 pmol/kg of BY841 elevated intragastric pH to neutrality, whereas 85 pmol/kg of ranitidine were needed to obtain neutral gastric pH. Also, duration of pH-elevation increased almost linearly to the dose of BY841, but not ranitidine. As expected, 27 pmol/kg of oral BY841, in contrast to the same d o s e of ranitidine, elevated intragastric pH in carbacholstimulated dogs as efficaciously and for the same duration as in pentagastrin-st!mulated dogs. Conclusions: BY841 proved to be a highly efficacious gastric antisecretory drug with fast onset of action and predictable time course o f its pH-elevating effect: The latter is highly reliable. Due to blockade of the final step in acid production, its action is independent of the particular stimulus of acid secretion used. The comparison of the results from this dog study with the first clinical phase I study (Fu'der et al., this meeting) indicate human relevance of the results obtained in the pentagastrin- and carbachol-stimulated fistula dog.