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Effect of high dose omeprazole on urease activity in vivo
A226
AGA ABSTRACTS
GASTROENTEROLOGY, VoI. IO8. No. 4
• EFFECT OF HEPATOCYTEGROWTH FACTOR ON EXPRESSIONOF TREFOIL PEPTIDES IN INJURED GASTRIC MUCOSA. Ch. Steltler 1, A. Schmassmann 1 R. Poulsom 2 C. Hirschi 1 B. Flogerzi 1, K. Matsumoto 3, T. Nakamura a, F. Halter L 1: Gastrointestinal Unit, Univ. Hospital, Inselspital, Bern, Switzerland. 2: Histopathology Unit; Imperial Cancer Research Fund, London. 3: Division of Biochemistry, Osaka University School Of Medicine Japan Backoround: In gastric ceil culture systems, hepatocyte growth factor (HGF) has been shown to accelerate cell migration and proliferation. In vivo, HGF competes, however, with other growth factors which promote healing. We assessed effects of HGF administration on the expression of trefoil peptides and cell proliferation in a gastric ulcer model in rats. Methods: Cryoulcers were produced on gastric corpus in 20 Wistar rats. Rats were daily treated s.c. either with placebo or HGF (2x100 p.g/kg) for 3 and 15 days, respectively. BrdU (+) epithelial cells were measured in Ulcer margin (BrdU injection before sacrifice). On day 3, mRNA were localized w th n tissue Sections by in situ hybridization with specific rat spasmolytic polypePtide (rSP), rat intestinal trefoil peptide (rlTF), and mouse one p-domain (pS2) ass antisense ribopr0bes. Prostaglandin synthesis in oxyntie mucOsa Was measured (RIA). Results: HGF increased (P < 0.05) 6-keto-prostaglandin Fl,and E2 synthesis on day 3 by +50% and +67%, respectively. BrdU (+)cells in ulcer margin were unchanged on day 3, but significantly (P < 0 001) increased on day 15 by +80%. On day 3, rSP mRNA and protein were detected in gastric glands Of non-ulcerated oxyntic mucosa and were strongly increased in regenerative epithelia, rlTF mRNA was detected in small amounts in regenerative epithelia, but was not detected in nonulcerated oxyntic mucosa, pS2 mRNA showed accentUation of signals in regenerative epithelia and monolayers of epithelial cells extending over the ulcer crater. However, not all monolayers and not all cells in the monolayers were positive for pS2. HGF administration did not affect expression of trefoil peptides. Conclusion: 1) HGF increases prostaglandin synthesis on day 3 and epithelial cell proliferation in the ulcer margin on day 15. 2) HGF does not affect expression of trefoil peptides at the given dose. 3) Induction Of rSP, rlTF, and pS2 mRNA in regenerative epithelia suggests that they fulfill immediate roles in initiating healing.
• PROSPECTIVE STUDY OF THE EFFECT OF LONG-TERM GASTRIC ACID ANTISECRETORY TREATMENT ON SERUM VITAMIN Bn LEVELS IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME. C.A. Stewart, B. Termanini, F. Gibril, H.C. Weber, R.T. Jensen~ Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD
@EFFECT OF HIGH DOSE OMEPRAZOLE ON UREASE ACTIVITY IN VlVO. B. Stoschus, N. Kalhori, E. Dominguez-Munoz, T. Sauerbruch, P. Malfertheiner. Department of Medicine University of Bonn, FRG.
THE 'EFFECT OF CYCLIC AMP-DEPENDENT PROTEIN KINASE INHIBITORS ON GASTRIC ACID SECRETION IN THE PERFUSED RAT STOMACH. A Stranko. MC Bosche, J Nandi, RA Levine. Department of Medicine, State University of New York - Health Science Center, Syracuse, New York. TWo protein kinases-eyclic AMP-dependent protei n kinase (PKA) and protein kinase C (PKC)-have been isolated in gastric parietal cells (PC). We have .previously shown that activators and inhibitors of PKC, respectively, inhibit and augment gastric acid secretion (GAS) in both isolated rabbit PC and in the rat stomach. We also demonstrated suppression of IV secretion in PC exposed to PKA inhibitors. This study examines the effects of various PKA inhibitors on GAS in vivo. METHODS: Fasted, anesthetized male Sprague-Dawley rats underwent gastric cannulation from both esophageal and pylorie ends. The esophageal catheter was perfosed with NS at 0.5 ml/min. The rats received NS ( 1 ml/h) via tail vein, then histamine (0.25 pg/kg/h) or pentagastrin 2 pg/kg/h). Various PKA antagonists, including HA-1004, H-8, H-89, PKI and RpcAMPS, were then administered parenterally. In a separate experiment, a potent PKC inhibitor, H-7, (1 nmol/h) was administered to ratsprctreated with pentagastrin and Pied (5 pg/kg/h). Gastric effluents were collected in 15 rain aliquots over 4h for GAS measurement. ~ S U L T S : 1) HA-1004 (10), H-8 (10, 25 and 50), Rp-cAMPS (100), H-89 (10 and 50) (in nmol-h) and Pied (2.5 pg/kg/la) failed to inl~'bitseeretagogue-stimulated GAS. 2) PKI (5 and 10 ~tg/kg/h) and H-89 (100 nmol-h) significantly inhibited o 64~A o and 44~, 0 respectively. 3) Basal secretagogne-stimulated GAS by 46~, GAS was unaffected by all PKA inhi'bitorsexcept H,89 (100 nmol-H) which produced a 55% decrease. 4) Blood pressure recordings revealed systemic hypotension only with PKI at doses >5 pg/kg/h. 5) H-7 caused a partial reversal of acid inhibition in PKI-treated rats. CONCLUSIONS: 1) PKA antagonists, when administered in vivo, can inhibit histamine-and pentagastrin-stimulated GAS, suggesting the involvement of PKA in both seeretagogue-stimulatorypathways. 2) A PKC inhibitor partially reversed the effects of a PKA inhibitor on GAS, supporting the hypothesis that 'crosstalk' may occur between the two signal transduction pathways and thereby influence GAS at the cellular level.
Prnton-Pump-lnh~itors (PPI) exert a potent inhfoitory effect on the urense activity of Helicobacter pylori (Hp) in vitro. Aim of this study was to investigate the effect of PPI on urease activity for Hp in vivo. Material and Method: 12 patients with Hp positive gastritis firmly established by histology, CLO-test, serology and 13C- urea breath test (t3C- UBT) were given omeprazole 40 (n=6) or 80 mg (n=6) o~d. for 5 days. Urense activity was studied by t h e 13C- UBT 30 minutes after omeprazole administration on day 1, 3 and 5. The 13C- UBT was performed with 200 ml 0,1 N citric acid and 75 mg 13C-urea in 50 ml water. Breath samples were collected before and 30 minutes after ~3Curea administration. Results were expressed as normalized delta (5,). A positive ~C- UBT was defined by a ~ > 0,25. Results: Under high dose omeprazole administration there was a significant (p < 0.002; t-test for paired samples)inh~itien of urease activity. After 5 days high dose omeprazole intake 2 patients had a negative 13C- UBT. With iow dose omeprazole no significant reduction of urease activity was observed (Table).
dayl
day3
day5
Omeprazole (M~SEM) (M~.SEM) .(M~.+SEM) 40 mg 1.36-2-0.09 2.46:£-0.30 2.03-2-0.12 n.s. 80m$ 1.16_+0.44 0.77_+0.30 0.23+0.11 p < 0.002 Conclusions: In vivo urease activity is inhibited by high dose omeprazole. This finding is of clinical importance as urease based diagnostic procedures may report false negative results for Hp.
Long-term maintenance therapy with omeprazole (OMEP) is being increasingly used for "chronic esophageal reflux disease and therefore possible side-effects of such treatment are of in,easing concern. One of the possible sideeffects is a decrease in vitamin Bn (VBn) absorption, primarily because of decreased acid outpuL Short-term studies show OMEP (20 mg) decreases VBn absorption, but information with long-term 0MEP treatment is limited. To assess the possible long-term risk, we prospectively studied 90 consacative patients with Znllinger-Ellison syndrome (ZES),who require life-long treatment with OMEP or other antisecretory agents. 75 patients were taking OMEP and 15 ranitidine (RAN). All patients had serum VB12levels, folate, heritatnlogic studies, fasting gastrin 'and acid output levels prior to the next dose of antisacretory drug determined. The mean (_T_SEM)age was 54_.+1 yr (range 16-72), 60% were males, 13% had MEN-I and the mean disease durationwes 12.9 yrs. The mean duration of OMEP treatment was 4.4 yrs (range 0.1-10.7 yrs) with 25% treated 0.1-2 yrs, 44% for 2-5 yrs and 31% > 5 yrs, and WithRAN treatment the mean duration was 7.6 yrs. For the patients on OMEP the mean acid output post drug (1 hr before next drag dose) was 1.6 mEq/h and with RAN treatment it .was 3 6 mEq/h (p <0.01). For the 75 patients on OMEP, 18% were adflorhydric 1 hr prior to the next drug dosage, 21% had 0.1-1 mEq/h of acid, 34% from 1:1-2.5 mEq/h and only 10% >4 mEq/h. The mean ~ ISEM) serum VBn level and folate level were 502+31 pg/ml and 8.9+1.0 ng/ml, respectively in patients treated with OMEP, and in patients treated with RAN 776__+160 pg/rnl and 13.1+15 ng/ml, respectively (p=NS). The semm VBn did not correlate with length of treatment with OMEP, level of acid control prior tO next antisecretury drug dose, pretreatment basal acid output or total duration of acid control. 2 patients treated with OMEP and 1 patient treated long-term with RAN (15 yrs) had low serum VBn leveisbetween 157-169pg/ml (nl >200) but no patient was anemic or had macrocytosis. None of the 3 patients had previous gastric surgery. These daia demonstrate that 3% of patients with ZES treated 'for up to 10.7 yrs with OMEP developed a low serum VBn level. Because 35% of these patients had achlorhydria-hypochlorhydria with long-term OMEP, the frequency of low s e r u m V B t 2 levels may increase further with longer treatment. Because complications of low serum VBn levels can occur without hematologic changes, these data suggest all patients treated long-term with OMEP should have periodic serum VBn levels performed.
AGA ABSTRACTS
GASTROENTEROLOGY, VoI. IO8. No. 4
• EFFECT OF HEPATOCYTEGROWTH FACTOR ON EXPRESSIONOF TREFOIL PEPTIDES IN INJURED GASTRIC MUCOSA. Ch. Steltler 1, A. Schmassmann 1 R. Poulsom 2 C. Hirschi 1 B. Flogerzi 1, K. Matsumoto 3, T. Nakamura a, F. Halter L 1: Gastrointestinal Unit, Univ. Hospital, Inselspital, Bern, Switzerland. 2: Histopathology Unit; Imperial Cancer Research Fund, London. 3: Division of Biochemistry, Osaka University School Of Medicine Japan Backoround: In gastric ceil culture systems, hepatocyte growth factor (HGF) has been shown to accelerate cell migration and proliferation. In vivo, HGF competes, however, with other growth factors which promote healing. We assessed effects of HGF administration on the expression of trefoil peptides and cell proliferation in a gastric ulcer model in rats. Methods: Cryoulcers were produced on gastric corpus in 20 Wistar rats. Rats were daily treated s.c. either with placebo or HGF (2x100 p.g/kg) for 3 and 15 days, respectively. BrdU (+) epithelial cells were measured in Ulcer margin (BrdU injection before sacrifice). On day 3, mRNA were localized w th n tissue Sections by in situ hybridization with specific rat spasmolytic polypePtide (rSP), rat intestinal trefoil peptide (rlTF), and mouse one p-domain (pS2) ass antisense ribopr0bes. Prostaglandin synthesis in oxyntie mucOsa Was measured (RIA). Results: HGF increased (P < 0.05) 6-keto-prostaglandin Fl,and E2 synthesis on day 3 by +50% and +67%, respectively. BrdU (+)cells in ulcer margin were unchanged on day 3, but significantly (P < 0 001) increased on day 15 by +80%. On day 3, rSP mRNA and protein were detected in gastric glands Of non-ulcerated oxyntic mucosa and were strongly increased in regenerative epithelia, rlTF mRNA was detected in small amounts in regenerative epithelia, but was not detected in nonulcerated oxyntic mucosa, pS2 mRNA showed accentUation of signals in regenerative epithelia and monolayers of epithelial cells extending over the ulcer crater. However, not all monolayers and not all cells in the monolayers were positive for pS2. HGF administration did not affect expression of trefoil peptides. Conclusion: 1) HGF increases prostaglandin synthesis on day 3 and epithelial cell proliferation in the ulcer margin on day 15. 2) HGF does not affect expression of trefoil peptides at the given dose. 3) Induction Of rSP, rlTF, and pS2 mRNA in regenerative epithelia suggests that they fulfill immediate roles in initiating healing.
• PROSPECTIVE STUDY OF THE EFFECT OF LONG-TERM GASTRIC ACID ANTISECRETORY TREATMENT ON SERUM VITAMIN Bn LEVELS IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME. C.A. Stewart, B. Termanini, F. Gibril, H.C. Weber, R.T. Jensen~ Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD
@EFFECT OF HIGH DOSE OMEPRAZOLE ON UREASE ACTIVITY IN VlVO. B. Stoschus, N. Kalhori, E. Dominguez-Munoz, T. Sauerbruch, P. Malfertheiner. Department of Medicine University of Bonn, FRG.
THE 'EFFECT OF CYCLIC AMP-DEPENDENT PROTEIN KINASE INHIBITORS ON GASTRIC ACID SECRETION IN THE PERFUSED RAT STOMACH. A Stranko. MC Bosche, J Nandi, RA Levine. Department of Medicine, State University of New York - Health Science Center, Syracuse, New York. TWo protein kinases-eyclic AMP-dependent protei n kinase (PKA) and protein kinase C (PKC)-have been isolated in gastric parietal cells (PC). We have .previously shown that activators and inhibitors of PKC, respectively, inhibit and augment gastric acid secretion (GAS) in both isolated rabbit PC and in the rat stomach. We also demonstrated suppression of IV secretion in PC exposed to PKA inhibitors. This study examines the effects of various PKA inhibitors on GAS in vivo. METHODS: Fasted, anesthetized male Sprague-Dawley rats underwent gastric cannulation from both esophageal and pylorie ends. The esophageal catheter was perfosed with NS at 0.5 ml/min. The rats received NS ( 1 ml/h) via tail vein, then histamine (0.25 pg/kg/h) or pentagastrin 2 pg/kg/h). Various PKA antagonists, including HA-1004, H-8, H-89, PKI and RpcAMPS, were then administered parenterally. In a separate experiment, a potent PKC inhibitor, H-7, (1 nmol/h) was administered to ratsprctreated with pentagastrin and Pied (5 pg/kg/h). Gastric effluents were collected in 15 rain aliquots over 4h for GAS measurement. ~ S U L T S : 1) HA-1004 (10), H-8 (10, 25 and 50), Rp-cAMPS (100), H-89 (10 and 50) (in nmol-h) and Pied (2.5 pg/kg/la) failed to inl~'bitseeretagogue-stimulated GAS. 2) PKI (5 and 10 ~tg/kg/h) and H-89 (100 nmol-h) significantly inhibited o 64~A o and 44~, 0 respectively. 3) Basal secretagogne-stimulated GAS by 46~, GAS was unaffected by all PKA inhi'bitorsexcept H,89 (100 nmol-H) which produced a 55% decrease. 4) Blood pressure recordings revealed systemic hypotension only with PKI at doses >5 pg/kg/h. 5) H-7 caused a partial reversal of acid inhibition in PKI-treated rats. CONCLUSIONS: 1) PKA antagonists, when administered in vivo, can inhibit histamine-and pentagastrin-stimulated GAS, suggesting the involvement of PKA in both seeretagogue-stimulatorypathways. 2) A PKC inhibitor partially reversed the effects of a PKA inhibitor on GAS, supporting the hypothesis that 'crosstalk' may occur between the two signal transduction pathways and thereby influence GAS at the cellular level.
Prnton-Pump-lnh~itors (PPI) exert a potent inhfoitory effect on the urense activity of Helicobacter pylori (Hp) in vitro. Aim of this study was to investigate the effect of PPI on urease activity for Hp in vivo. Material and Method: 12 patients with Hp positive gastritis firmly established by histology, CLO-test, serology and 13C- urea breath test (t3C- UBT) were given omeprazole 40 (n=6) or 80 mg (n=6) o~d. for 5 days. Urense activity was studied by t h e 13C- UBT 30 minutes after omeprazole administration on day 1, 3 and 5. The 13C- UBT was performed with 200 ml 0,1 N citric acid and 75 mg 13C-urea in 50 ml water. Breath samples were collected before and 30 minutes after ~3Curea administration. Results were expressed as normalized delta (5,). A positive ~C- UBT was defined by a ~ > 0,25. Results: Under high dose omeprazole administration there was a significant (p < 0.002; t-test for paired samples)inh~itien of urease activity. After 5 days high dose omeprazole intake 2 patients had a negative 13C- UBT. With iow dose omeprazole no significant reduction of urease activity was observed (Table).
dayl
day3
day5
Omeprazole (M~SEM) (M~.SEM) .(M~.+SEM) 40 mg 1.36-2-0.09 2.46:£-0.30 2.03-2-0.12 n.s. 80m$ 1.16_+0.44 0.77_+0.30 0.23+0.11 p < 0.002 Conclusions: In vivo urease activity is inhibited by high dose omeprazole. This finding is of clinical importance as urease based diagnostic procedures may report false negative results for Hp.
Long-term maintenance therapy with omeprazole (OMEP) is being increasingly used for "chronic esophageal reflux disease and therefore possible side-effects of such treatment are of in,easing concern. One of the possible sideeffects is a decrease in vitamin Bn (VBn) absorption, primarily because of decreased acid outpuL Short-term studies show OMEP (20 mg) decreases VBn absorption, but information with long-term 0MEP treatment is limited. To assess the possible long-term risk, we prospectively studied 90 consacative patients with Znllinger-Ellison syndrome (ZES),who require life-long treatment with OMEP or other antisecretory agents. 75 patients were taking OMEP and 15 ranitidine (RAN). All patients had serum VB12levels, folate, heritatnlogic studies, fasting gastrin 'and acid output levels prior to the next dose of antisacretory drug determined. The mean (_T_SEM)age was 54_.+1 yr (range 16-72), 60% were males, 13% had MEN-I and the mean disease durationwes 12.9 yrs. The mean duration of OMEP treatment was 4.4 yrs (range 0.1-10.7 yrs) with 25% treated 0.1-2 yrs, 44% for 2-5 yrs and 31% > 5 yrs, and WithRAN treatment the mean duration was 7.6 yrs. For the patients on OMEP the mean acid output post drug (1 hr before next drag dose) was 1.6 mEq/h and with RAN treatment it .was 3 6 mEq/h (p <0.01). For the 75 patients on OMEP, 18% were adflorhydric 1 hr prior to the next drug dosage, 21% had 0.1-1 mEq/h of acid, 34% from 1:1-2.5 mEq/h and only 10% >4 mEq/h. The mean ~ ISEM) serum VBn level and folate level were 502+31 pg/ml and 8.9+1.0 ng/ml, respectively in patients treated with OMEP, and in patients treated with RAN 776__+160 pg/rnl and 13.1+15 ng/ml, respectively (p=NS). The semm VBn did not correlate with length of treatment with OMEP, level of acid control prior tO next antisecretury drug dose, pretreatment basal acid output or total duration of acid control. 2 patients treated with OMEP and 1 patient treated long-term with RAN (15 yrs) had low serum VBn leveisbetween 157-169pg/ml (nl >200) but no patient was anemic or had macrocytosis. None of the 3 patients had previous gastric surgery. These daia demonstrate that 3% of patients with ZES treated 'for up to 10.7 yrs with OMEP developed a low serum VBn level. Because 35% of these patients had achlorhydria-hypochlorhydria with long-term OMEP, the frequency of low s e r u m V B t 2 levels may increase further with longer treatment. Because complications of low serum VBn levels can occur without hematologic changes, these data suggest all patients treated long-term with OMEP should have periodic serum VBn levels performed.