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Florian J, Matta MK, DePalma R, Gershuny V, Patel V, Hsiao CH, Zusterzeel R, Rouse R, Prentice K, Nalepinski CG, Kim I, Yi S, Zhao L, Yoon M, Selaya S, Keire D, Korvick J, Strauss DG. Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial. JAMA 2021; 326:240-249. [PMID: 34180947 PMCID: PMC8240005 DOI: 10.1001/jama.2021.9199] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
IMPORTANCE In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. OBJECTIVE To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. INTERVENTIONS Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. MAIN OUTCOME AND MEASURE Twenty-four-hour urinary excretion of NDMA. RESULTS Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. CONCLUSIONS AND RELEVANCE In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04397445.
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Affiliation(s)
- Jeffry Florian
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Murali K. Matta
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Ryan DePalma
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Victoria Gershuny
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Vikram Patel
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Cheng-Hui Hsiao
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Robbert Zusterzeel
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Rodney Rouse
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Kristin Prentice
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
- Booz Allen Hamilton, McLean, Virginia
| | | | - Insook Kim
- Division of Inflammation and Immune Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Sojeong Yi
- Division of Inflammation and Immune Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Liang Zhao
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Miyoung Yoon
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Susan Selaya
- Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St Louis, Missouri
| | - David Keire
- Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St Louis, Missouri
| | - Joyce Korvick
- Division of Gastroenterology, Office of Immunology and Inflammation, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - David G. Strauss
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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Gao Z, Karfunkle M, Ye W, Marzan TA, Yang J, Lex T, Sommers C, Rodriguez JD, Han X, Florian J, Strauss DG, Keire DA. In Vitro Analysis of N-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions. JAMA Netw Open 2021; 4:e2118253. [PMID: 34181009 PMCID: PMC8239951 DOI: 10.1001/jamanetworkopen.2021.18253] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Importance A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. Objective To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. Design, Setting, and Participants One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. Main Outcomes and Measures NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. Results At a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L). Conclusions and Relevance In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.
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Affiliation(s)
- Zongming Gao
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Michael Karfunkle
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Wei Ye
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Tim Andres Marzan
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Jingyue Yang
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Timothy Lex
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Cynthia Sommers
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Jason D. Rodriguez
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
| | - Xiaomei Han
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration. Silver Spring, Maryland
| | - Jeffry Florian
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration. Silver Spring, Maryland
| | - David G. Strauss
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration. Silver Spring, Maryland
| | - David A. Keire
- Division of Complex Drug Analysis and Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, St Louis, Missouri
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Abstract
The late 1800s Louis Pasteur and Robert Koch introduced and popularized the germ theory of disease. At that time, gastric cancer was the most common cause of cancer deaths in most countries making the stomach an early site of microbial research with a focus on gastric luminal and mucosal bacteria and the role of Boas-Oppler bacillus (Lactobacillus) in the diagnosis of gastric cancer. In the 1970s, the research focus evolved to studies of the gastric microbiome in the production of nitrosamines and included development of the Correa cascade. Interest in nitrosamine production peaked in the late 1980s and was replaced by studies of the newly described Helicobacter pylori and studies of its role in gastritis, gastric atrophy, and gastric cancer. The last decade has witnessed a rebirth in interest in the gastric microbiota as part of worldwide interest in the human microbiome. Although fungi were prominent in the studies of gastric microbiology in the nineteenth century, their potential role in disease pathogenesis has yet to be addressed using modern techniques. Overall, current studies of the gastric bacterial microbiome do not provide convincing evidence to expand the role of the gastric microbiome in cancer pathogenesis beyond what is directly attributable to the oncogenic potential of H. pylori and its role in persisting acute-on-chronic inflammation.
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Brambilla G, Martelli A. Genotoxic and carcinogenic risk to humans of drug-nitrite interaction products. Mutat Res 2006; 635:17-52. [PMID: 17157055 DOI: 10.1016/j.mrrev.2006.09.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2006] [Revised: 09/18/2006] [Accepted: 09/25/2006] [Indexed: 02/07/2023]
Abstract
The large majority of N-nitroso compounds (NOC) have been found to produce genotoxic effects and to cause tumor development in laboratory animals; four NOC have been classified by the International Agency for Research on Cancer (IARC) as probably and another 15 as possibly carcinogenic to humans. A considerable fraction of drugs are theoretically nitrosatable due to the presence of amine, amide or other groups which by reacting with nitrite in the gastric environment, or even in other sites, can give rise to the formation of NOC, and in some cases other reactive species. This review provides a synthesis of information on the chemistry of NOC formation, the carcinogenic activity of NOC in animals and humans and the inhibitors of nitrosation reactions. It contains information on the drugs which have been tested for the formation of NOC by reaction with nitrite and the genotoxic-carcinogenic effects of their nitrosation products. In an extensive search we have found that 182 drugs, representing a wide variety of chemical structures and therapeutic activities, were examined in various experimental conditions for their ability to react with nitrite, and 173 (95%) of them were found to form NOC or other reactive species. Moreover, 136 drugs were examined in short-term genotoxicity tests and/or in long-term carcinogenesis assays, either in combination with nitrite or using their nitrosation product, in order to establish whether they produce genotoxic and carcinogenic effects; 112 (82.4%) of them have been found to give at least one positive response. The problem of endogenous drug nitrosation is largely unrecognized. Only a small fraction of theoretically nitrosatable drugs have been examined for the possible formation of genotoxic-carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of performing the appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.
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Affiliation(s)
- Giovanni Brambilla
- Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV, 2, I-16132 Genoa, Italy.
| | - Antonietta Martelli
- Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV, 2, I-16132 Genoa, Italy
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Shiotani A, Iishi H, Uedo N, Higashino K, Kumamoto M, Nakae Y, Tatsuta M. Hypoacidity combined with high gastric juice nitrite induced by Helicobacter pylori infection is associated with gastric cancer. Aliment Pharmacol Ther 2004; 20 Suppl 1:48-53. [PMID: 15298605 DOI: 10.1111/j.1365-2036.2004.01978.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND In patients with Helicobacter pylori infection, the concentration of nitrite in gastric juice is elevated. The degree of elevation correlates with that of inflammation and H. pylori density. AIM The aim of this study was to examine hypoacidity and high nitrite levels related to H. pylori infection in patients with gastric cancer. METHODS We studied 88 patients with more than one history of endoscopic mucosal resection (EMR) for early gastric cancer and 88 age-matched controls. Concentration of nitrite in gastric juice was measured by Griess reaction, and serum pepsinogen levels were measured by RIA. RESULTS Multiple malignant lesions were found in 20 of the 88 patients. Serum gastrin, gastric juice pH and nitrite levels in patients with gastric cancer were significantly higher and pepsinogen I and pepsinogen I/II significantly lower than in control subjects. Pepsinogen I level and I/II ratio were lower and gastric juice pH was higher in the protruded-type group than in the depressed-type group. Pepsinogen I and pepsinogen I/II were lower and gastric juice pH was higher in multiple than in single cases. CONCLUSIONS Hypoacidity combined with high gastric juice nitrite induced by H. pylori infection is associated with the intestinal type of gastric cancer, especially protruded lesions.
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Affiliation(s)
- A Shiotani
- Health Administration Center, Wakayama University, Wakayama, Japan
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Ma ZF, Wang ZY, Zhang JR, Gong P, Chen HL. Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy. World J Gastroenterol 2001; 7:376-80. [PMID: 11819793 PMCID: PMC4688725 DOI: 10.3748/wjg.v7.i3.376] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether study on the carcinogenic potential of reflux juice from patients with remote gastrectomy could clarify the inherent relationship between duodenal reflux and gastric stump cancer.
METHODS: A total of 37 reflux juice samples (13 Billroth I, 24 Billroth II) were employed in the present study. A two-stage transformation assay using BALB/c 3T3 cells was carried out to test the initiating or promoting activity of these samples.
RESULTS: Two of 18 (11.1%) reflux samples exerted initiating activities, whereas 9/19 (47.4%) samples enhanced the MNNG-initiating cell transformation, suggesting the duodenal reflux juice might more frequently possess the tumor-promoter activity (P = 0.029). In addition, there was no difference in initiating activities of the samples irrespective of surgical procedures (P = 0.488), while Billroth II samples exhibited stronger tumor-promoter activity than Billroth I samples (P = 0.027). Furthermore, the promoter activities were well correlated with the histological changes of the stomas (rs = 0.625, P = 0.004), but neither their cytotoxicities nor initiating activities had this correlation (Probabilities were 0.523 and 0.085, respectively).
CONCLUSION: The duodenal reflux juice from patients with remote postgastrectomy did have carcinogenic potential, and suggested that tumor-promoting activity should principally account for the high incidence of gastric cancer in gastrectomy patients. In contrast, it is difficult to explain the high stump-cancer incidence with the "N-nitroso compounds" theory-a popular theory for the intact stomach carcinogenesis, and it seemed to be justified to focus chemoprevention of this cancer on the tumor-promoting potential of reflux juice.
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Affiliation(s)
- Z F Ma
- Department of General Surgery, First Hospital, Dalian Medical University, Dalian 116011, China.
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H2-receptor antagonists may increase the risk of cardio-oesophageal adenocarcinoma: a case-control study. Eur J Cancer Prev 2000. [PMID: 10954258 DOI: 10.1097/00008469-200006000-00007] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Adenocarcinoma of the lower oesophagus and the gastric cardia has shown a dramatic worldwide increase in incidence over the last 25 years, but the cause is unknown. A large number of drugs have been introduced over this period of time, and it has been suggested that drugs that relax the lower oesophageal sphincter (DRLOS) might be causative, and on the other hand that non-steroidal anti-inflammatory drugs (NSAIDS) may be protective. H2-receptor antagonists (H2RAs) may allow achlorhydric reflux to continue without symptoms, and it is postulated that such asymptomatic reflux is uncontrolled by the usual conservative measures and may lead to increased oesophageal damage. H2RAs were first marketed in 1970 and might be the cause of the observed increase of cardio-oesophageal adenocarcinoma (COA). In a case-control study, the records of 56 subjects who died of COA in the period 1 January 1990 to 31 December 1992 were compared with those of 56 age-/sex-matched controls who died of myocardial infarction. They were 28 females and 84 males, mean age 69.8 years. The NHS records containing the lifetime prescription history of each subject were retrieved from the health authority. Each prescription was recorded, omitting drugs taken in the two years before diagnosis. Analysis was performed using conditional logistic regression. Other variables, including the use of antacids, steroids, smoking and alcohol, were also examined. Subjects dying of COA were more likely to have consumed H2RAs (relative risk (RR) 7.50, 95% CI 1.33-42.09, P < 0.02). On the other hand, they were less likely to have consumed NSAIDs (RR 0.16, 95% CI 0.03-0.93, P < 0.04) or DRLOS (RR 0.14, 95% CI 0.02-1.0, P = 0.05). This study supports a protective effect from NSAIDs against COA, but the similar effect of DRLOS is related to the increased use of cardiac drugs in the control group. H2RAs appear to have a harmful effect, which may be related to the worldwide increase in COA. However, the trend may have been apparent before cimetidine was widely available, and it is possible that the cause is multi-factorial.
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Tuo BG, Yan YH, Ge ZL, Ou GW, Zhao K. Ascorbic acid secretion in the human stomach and the effect of gastrin. World J Gastroenterol 2000; 6:704-708. [PMID: 11819678 PMCID: PMC4688847 DOI: 10.3748/wjg.v6.i5.704] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the changes of gastric mucosal ascorbic acid secretion in patients with nonulcer dyspepsia and the effect of gastrin on it, and to relate any observed changes to H. pylori infection and mucosal histology.
METHODS: Ascorbic acid secretions in patients were examined by collecting continuously gastric juice for one hour after having aspirated and discarded fasting gastric juice. Using the clearance rate (mL/min) of ascorbic acid from blood to gastric juice represented ascorbic acid secretion in the gastric mucosa. Ascorbic acid concentrations in plasma and juice were measured by ferric reduced method.
RESULTS: Gastric ascorbic acid secretions in H. pylori -positive patients (1.46 mL/min, range 0.27-3.78) did not significantly differ from those in H. pylori -negative patients (1.25 mL/min, 0.47-3.14) (P > 0.05). There were no significant differences in ascorbic acid secretions between patients with mild (1.56 mL/min, 0.50-3.30), moderate (1.34 mL/min, 0.27-2.93) and severe (1.36 mL/min, 0.47-3.78) inflammation (P > 0.05). There were no significant differences in ascorbic acid secretions between patients without activity (1.45 mL/min, 0.27-3.14) and with mild (1.32 mL/min, 0.61-2.93), moderate (1.49 mL/min, 0.50-3.78) and severe (1.43 mL/min, 0.51-3.26) activity of chronic gastritis either (P > 0.05). Ascorbic acid secretions in patients with severe atrophy (0.56 mL/min, 0.27-1.20) were markedly lower than those in patients with out atrophy (1.51 mL/min, 0.59-3.30) and with mild (1.43 mL/min, 0.53-3.78) and moderate (1.31 mL/min, 0.47-3.16) atrophy (P < 0.005). There was a significant negative correlation between ascorbic acid secretion and severity of atrophy (correlation coefficient = -0.43, P < 0.005). After administration of pentagastrin, ascorbic acid secretions were markedly elevated (from 1.39 mL/min, 0.36-2.96 to 3.53 mL/min, 0.84-5.91) (P < 0.001).
CONCLUSION: Ascorbic acid secretion in gastric mucosa is not affected by H. pylori infection. Gastric ascorbic acid secretion is markedly related to the severity of atrophy, whereas not related to the severity of inflammation and activity. Gastrin may stimulate gastric ascorbic acid secretion. A decreased ascorbic acid secretion may be an important factor in the link between atrophic gastritis and gastric carcinogenesis.
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Guadagni S, Pistoia MA, Valenti M, Leocata P, Coletti G, Calvisi G, Madonna R, Deraco M, Reed PI. N-Nitroso compounds, bacteria, and carcinoembryonic antigen in the gastric stump. J Surg Res 1998; 80:345-51. [PMID: 9878336 DOI: 10.1006/jsre.1998.5444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Analyses of biochemical and microbiological parameters such as pH, N-nitroso compound (NOC) concentration, carcinoembryonic antigen (CEA) level, and total viable counts (TVCs), and identification of microorganisms were carried out on 65 fasting gastric juice samples obtained at endoscopy from 45 patients previously submitted to partial gastrectomy for benign peptic ulcer disease (23 Billroth I, 22 Billroth II/Reichel-Polya) and 20 normal controls. Biopsy specimens were taken to determine histology, the Helicobacter pylori status, and both tissue CEA immunoreactivity and level. Significantly higher mean pH values, NOC and CEA concentrations, and TVCs were found in partial gastrectomies compared with normal controls. In relation to surgical methods, higher mean pH values, NOC concentrations, TVCs, and anaerobic bacterial counts were observed in the juice of patients with Billroth II compared with Billroth I gastrectomies. Mild CEA immunoreactivity and apical CEA localization were found significantly more often in Billroth II than in Billroth I stumps. Intensive CEA immunoreactivity and cytoplasmatic localization were found significantly more often in Billroth I than in Billroth II stumps. Independent of the type of surgical reconstruction, higher mean NOC levels were recorded in patients with more severe histological changes and H. pylori infection. Higher mean CEA levels in gastric juice and tissue were detected in the gastric stumps with more severe histological changes. All these data suggest that high levels of NOCs in the gastric juice could be a cofactor in gastric stump carcinogenesis and determination of CEA level in gastric juice and tissue could be included as a very useful marker in quantifying this process.
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Affiliation(s)
- S Guadagni
- Department of Surgery, University of L'Aquila, L'Aquila, 67100, Italy
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Guadagni S, Walters CL, Smith PL, Verzaro R, Valenti M, Reed PI. N-nitroso compounds in the gastric juice of normal controls, patients with partial gastrectomies, and gastric cancer patients. J Surg Oncol 1996; 63:226-33. [PMID: 8982366 DOI: 10.1002/(sici)1096-9098(199612)63:4<226::aid-jso3>3.0.co;2-e] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND It has been suggested that the variation of biochemical and microbiological parameters in the gastric juice may play a role in the development of gastric cancer. In the present study we concurrently assessed the presence of N-Nitroso compounds (NOC) and their precursors, bacteria and carcinoembryonic antigen (CEA) in the gastric juice of normal controls, patients with gastric resection, and advanced gastric cancer. METHODS Detailed analyses of biochemical and microbiological parameters such as pH, nitrite (NO2) concentration, N-nitroso compounds (NOC) concentration, carcino-embryonic antigen (CEA) level, total viable counts (TVC), nitrate-reductase positive bacterial counts (NRPBC), and identification of micro-organisms were carried out. RESULTS Significantly higher mean pH values, NO2, NOC and CEA concentrations, TVC, and NRPBC were found in partial gastrectomies compared with normal controls, and all these intragastric parameters were significantly higher in patients with gastric cancer than in those with partial gastrectomies. As far as surgical methods are concerned, higher mean pH values, NO2 and NOC concentrations, TVC, NRPBC, and anaerobic bacterial counts were observed in the juice of patients with Billroth II compared with Billroth I gastrectomies. Apart from the type of surgical reconstruction, higher mean NOC levels were recorded in patients with more severe histological changes and H. pylori infection. CONCLUSIONS All these data suggest that the presence of high levels of NOC in the gastric juice of gastroresected patients can be considered a risk factor of gastric stump cancer.
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Affiliation(s)
- S Guadagni
- Department of Surgery, University of L'Aquila, Italy
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Brummer RJ, Stockbrügger RW. Effect of nizatidine 300 mg at night and omeprazole 20 mg in the morning on 24-hour intragastric pH and bacterial overgrowth in patients with acute duodenal ulcer. Dig Dis Sci 1996; 41:2048-54. [PMID: 8888720 DOI: 10.1007/bf02093609] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The study investigated the effect of either nocturnal acid suppression by the H2 antagonist nizatidine 300 mg at night or prolonged acid suppression by the proton- pump inhibitor omeprazole 20 mg in the morning, during four weeks, on intragastric pH profile, occurrence of bacterial growth in gastric fluid and biopsies, and healing rate in 23 patients with an acute duodenal ulcer. The endoscopic healing rate did not differ significantly between the two treatment modalities. The 24-hr acid secretion was significantly more reduced by omeprazole than nizatidine (P < 0.002). After treatment by nizatidine and omeprazole, respectively, median 24-hr intragastric pH increased from 1.5 to 1.8 (P < 0.01) and from 1.5 to 6.1 (P < 0.01), respectively. Nighttime acid inhibition did not differ significantly. The difference in gastric bacterial colonization after either omeprazole or nizatidine did not reach significance. However, median 24-hr pH and the fraction of the day with pH < 3 and pH < 4 were significantly correlated to bacterial colonization of the gastric fluid (P < 0.05).
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Affiliation(s)
- R J Brummer
- Department of Gastroenterology, University Hospital Maastricht, The Netherlands
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12
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Thorens J, Froehlich F, Schwizer W, Saraga E, Bille J, Gyr K, Duroux P, Nicolet M, Pignatelli B, Blum AL, Gonvers JJ, Fried M. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut 1996; 39:54-9. [PMID: 8881809 PMCID: PMC1383231 DOI: 10.1136/gut.39.1.54] [Citation(s) in RCA: 250] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Gastric and duodenal bacterial overgrowth frequently occurs in conditions where diminished acid secretion is present. Omeprazole inhibits acid secretion more effectively than cimetidine and might therefore more frequently cause bacterial overgrowth. AIM This controlled prospective study compared the incidence of gastric and duodenal bacterial overgrowth in patients treated with omeprazole or cimetidine. METHODS 47 outpatients with peptic disease were randomly assigned to a four week treatment regimen with omeprazole 20 mg or cimetidine 800 mg daily. Gastric and duodenal juice were obtained during upper gastrointestinal endoscopy and plated for anaerobic and aerobic organisms. RESULTS Bacterial overgrowth (> or = 10(5) cfu/ml) was present in 53% of the patients receiving omeprazole and in 17% receiving cimetidine (p < 0.05). The mean (SEM) number of gastric and duodenal bacterial counts was 6.0 (0.2) and 5.0 (0.2) respectively in the omeprazole group and 4.0 (0.2) and 4.0 (0.1) in the cimetidine group (p < 0.001 and < 0.01; respectively). Faecal type bacteria were found in 30% of the patients with bacterial overgrowth. Basal gastric pH was higher in patients treated with omeprazole compared with cimetidine (4.2 (0.5) versus 2.0 (0.2); p < 0.001) and in patients with bacterial overgrowth compared with those without bacterial overgrowth (5.1 (0.6) versus 2.0 (0.1); p < 0.0001). The nitrate, nitrite, and nitrosamine values in gastric juice did not increase after treatment with either cimetidine or omeprazole. Serum concentrations of vitamin B12, beta carotene, and albumin were similar before and after treatment with both drugs. CONCLUSIONS These results show that the incidence of gastric and duodenal bacterial overgrowth is considerably higher in patients treated with omeprazole compared with cimetidine. This can be explained by more pronounced inhibition of gastric acid secretion. No patient developed signs of malabsorption or an increase of N-nitroso compounds. The clinical significance of these findings needs to be assessed in studies with long-term treatment with omeprazole, in particular in patients belonging to high risk groups such as HIV infected and intensive care units patients.
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Affiliation(s)
- J Thorens
- Department of Gastroenterology, University Hospital, Lausanne, Switzerland
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13
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McCloy RF, Arnold R, Bardhan KD, Cattan D, Klinkenberg-Knol E, Maton PN, Riddell RH, Sipponen P, Walan A. Pathophysiological effects of long-term acid suppression in man. Dig Dis Sci 1995; 40:96S-120S. [PMID: 7859587 DOI: 10.1007/bf02214874] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori-related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS)
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14
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Yeomans ND, Brimblecombe RW, Elder J, Heatley RV, Misiewicz JJ, Northfield TC, Pottage A. Effects of acid suppression on microbial flora of upper gut. Dig Dis Sci 1995; 40:81S-95S. [PMID: 7859586 DOI: 10.1007/bf02214873] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Decreased acid secretion, due to therapy or disease, predisposes to increased bacterial counts in gastric juice. As bacterial numbers increase, the number of nitrate-reducing strains and the concentration of luminal nitrite usually also increase. However, there is controversy (mainly because of assay problems) about whether decreased acid increases generation of N-nitroso compounds: these may be produced by acid or by bacterial catalysis, and the relative contributions of each are still uncertain. Other potentially important factors include ascorbate secretion (can prevent nitrite conversion to nitroso compounds) and the particular spectrum of nitroso compounds produced. Nitrosation of several histamine H2-receptor antagonists has been demonstrated experimentally, but under conditions that are very unlikely to be encountered clinically. Some acid suppressant therapies have been claimed to aid eradication of Helicobacter pylori, but more work is needed to evaluate this. If ulcer treatment regimens do not also address eradication of H. pylori (when present), gastritis will progress, and the recently documented association between H. pylori and gastric carcinoma needs to be considered. Enteric flora probably also increase if acid secretion is markedly reduced: this does not appear to have nutritional consequences but probably reduces the resistance to occasional infections, of which cholera is the best documented.
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Affiliation(s)
- N D Yeomans
- University of Melbourne Department of Medicine, Western Hospital, Australia
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15
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16
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Tersmette AC, Giardiello FM, Tytgat GN, Offerhaus GJ. Carcinogenesis after remote peptic ulcer surgery: the long-term prognosis of partial gastrectomy. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1995; 212:96-9. [PMID: 8578237 DOI: 10.3109/00365529509090306] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Remote partial gastrectomy for benign disease is a premalignant condition. The overall risk of gastric stump cancer is approximately a twofold increase, but patients more than 20-25 years postoperatively may have a four- to fivefold increased risk, compared to the age- and sex-matched general population. The duration of postoperative interval is the most important risk factor. For the first 10 years after initial surgery, gastric cancer risk may be reduced due to the removal of the most cancer-prone distal part of the stomach, but thereafter there is a rapid increase of the relative risk. The etiology and precise mechanism of carcinogenesis is unknown, but the time relationship with surgery suggests that the anatomical alterations induced by the operation must be important. Hypochlorhydria, reflux, diminished gastrin production, bacterial proliferation, and nitrosation are the putative contributing factors. In addition, smoking appears to contribute to a generalized cancer mortality and decreased life expectancy after peptic ulcer surgery. Digestive tract cancers other than the gastric ones which show an increased risk after peptic ulcer surgery are pancreatic and biliary tract cancers. Premalignant and precursor lesions occur more frequently in the gastric remnant after peptic ulcer surgery and endoscopic bioptic screening can detect early stump cancers at a curable stage. Large-scale screening programs of post-gastrectomy patients are nevertheless not recommended, and surveillance appears not justified.
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Affiliation(s)
- A C Tersmette
- Dept. of Pathology, Academic Medical Center, Amsterdam, The Netherlands
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17
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18
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Verdu E, Viani F, Armstrong D, Fraser R, Siegrist HH, Pignatelli B, Idström JP, Cederberg C, Blum AL, Fried M. Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds. Gut 1994; 35:455-60. [PMID: 8174980 PMCID: PMC1374790 DOI: 10.1136/gut.35.4.455] [Citation(s) in RCA: 107] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Previous studies have suggested that profound inhibition of gastric acid secretion may increase exposure to potentially carcinogenic N-nitroso compounds. The aim of this study was to find out if the proton pump inhibitor omeprazole (20 mg daily) is associated with increased concentrations of potentially carcinogenic N-nitroso compounds in gastric juice. The volume of gastric contents, number of bacteria, and concentrations of nitrates, nitrites, and N-nitroso compounds was determined in gastric aspirates obtained after an overnight fast in 14 healthy volunteers (7M:7F) after one week of treatment with placebo, and one and two weeks' treatment with omeprazole. Median bacterial concentrations were 1.0 x 10(4) (range 5.0 x 10(3)-5.0 x 10(6)) colony forming units (CFU)/ml after one weeks' treatment with placebo and increased significantly to 4.0 x 10(5) (0-3.3 x 10(7)) CFU/ml after two weeks' treatment with omeprazole (p < 0.05). A similar increase was seen in the concentration of nitrate reducing bacteria. There was no difference in the volume of gastric aspirates after treatment with omeprazole when compared with placebo (65 (29-155) ml v 42 (19-194) ml). The concentration of N-nitroso compounds was 0.13 (0-1.0) mumol/l after two weeks of omeprazole, which was not significantly different from that seen with placebo (0.15 (0-0.61) mumol/l). There was also no increase in the concentrations of nitrates or nitrites. It is concluded that omeprazole (20 mg once daily) for two weeks in healthy volunteers is associated with gastric bacterial proliferation but does not increase concentrations of N-nitroso compounds.
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Affiliation(s)
- E Verdu
- Division of Gastroenterology, Centre Hospitalier, University Vaudois (CHUV/PMU), Lausanne, Switzerland
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19
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Abstract
For the treatment of duodenal and gastric ulcer and reflux oesophagitis, especially erosive oesophagitis, omeprazole has an advantage over histamine H2-receptor antagonists because it heals significantly more patients significantly faster. Adverse effects have been observed during short term treatment with the same frequency as during treatment with H2-antagonists. Also, maintenance treatment with omeprazole of reflux oesophagitis is significantly superior to H2-antagonist therapy. During long term treatment for up to 8 years no further drug-related adverse effects have been observed. Moderate hypergastrinaemia occurs in some patients, especially if an omeprazole dosage of 40 mg/day is needed. A slight increase of the agyrophil (endocrine) cell volume density and an extension of micronodular hyperplasia in the oxyntic mucosa after several years of omeprazole treatment seem to be related to the severity of the corpus gastritis and not to drug-induced hypergastrinaemia, because similar changes have been observed in equal frequency in patients not receiving anti-secretory drugs. Theoretical arguments against long term treatment with potent acid-suppressing drugs, such as the possible consequences of gastric bacterial overgrowth or hypergastrinaemia, are not supported by clinical observations and epidemiological data and are, therefore, speculative.
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Affiliation(s)
- W Creutzfeldt
- Department of Medicine, Georg-August-University, Göttingen, Germany
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20
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Heatley RV, Sobala GM. Acid suppression and the gastric flora. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1993; 7:167-81. [PMID: 8477111 DOI: 10.1016/0950-3528(93)90036-r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- R V Heatley
- Department of Clinical Medicine, St. James's University Hospital, University of Leeds, UK
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21
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Deakin M, Williams JG. Histamine H2-receptor antagonists in peptic ulcer disease. Efficacy in healing peptic ulcers. Drugs 1992; 44:709-19. [PMID: 1280563 DOI: 10.2165/00003495-199244050-00003] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion and upon the duration of therapy, while gastric ulcer healing is dependent mainly on the duration of therapy. Currently marketed doses of the histamine H2-receptor antagonists heal between 77 and 92% of duodenal ulcers at 4 weeks, and adjuvant treatment to eradicate Helicobacter pylori increases this rate. Once-daily administration is as effective as more frequent dosing regimens and may even result in higher healing rates. Gastric ulcers heal more slowly, but 75 to 88% of ulcers heal after 8 weeks of treatment. While newer more potent acid suppressors such as omeprazole heal ulcers slightly more quickly, the H2-receptor antagonists have an unparalleled safety record of over 15 years. It is unlikely that the prostaglandin analogues can improve on the efficacy of the H2-receptor antagonists with as low an incidence of side effects.
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Affiliation(s)
- M Deakin
- Keele University Postgraduate Medical School, North Staffordshire Medical Centre, Stoke on Trent, Wales
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22
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Abstract
The implications of profound and sustained suppression of acid secretion are of increasing concern. Short-term inhibition of acid secretion by H2-receptor blockade or proton pump inhibition alters the gastric luminal flora and increases the risk of nosocomial pneumonia in critically ill patients who are receiving prophylaxis for stress gastritis. Long-term suppression alters gut flora, carcinogen levels in the gastric lumen, and the hormonal milieu, leading to proliferative changes in the fundic mucosa. Previous reports have noted a significant incidence of gastric malignancies in the achlorhydric environment of atrophic gastritis and pernicious anemia. Concern has also been expressed regarding the possibility of gastric neoplasia that arises after vagotomy and distal gastrectomy. The exact risk of gastric epithelial and endocrine hyperplasia or neoplasia in patients receiving potent antisecretory agents is not yet known, but such risks cannot be dismissed until long-term follow-up studies are available. The relationship between sustained suppression of acid secretion and the proliferation of epithelial and endocrine elements may provide insight into processes that regulate replication and growth of cells in the gastric mucosa.
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Affiliation(s)
- D I Soybel
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06510
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23
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Armstrong D, Nicolet M, Monnier P, Chapuis G, Savary M, Blum AL. Maintenance therapy: Is there still a place for antireflux surgery? World J Surg 1992; 16:300-7. [PMID: 1348594 DOI: 10.1007/bf02071537] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Effective and safe maintenance medical therapy for uncomplicated reflux esophagitis is now feasible with omeprazole and it is likely that other H+K+ATPase blockers, and possibly very high dose H2 receptor antagonist regimens, will also be acceptable. In addition, many patients with ulceration, strictures, and Barrett's esophagus will respond to conservative medical therapy and a proportion of patients with erosive esophagitis may remain in remission with cisapride or with low dose H2 receptor antagonists, if disease is less severe. Thus, there is now a medical "gold standard" against which surgical therapy for uncomplicated esophagitis must be judged and it is essential that all future studies be conducted with clearly defined criteria for the assessment of the symptoms and endoscopic signs of esophagitis and its complications. As ever, the patient's wishes are paramount, but he or she must be allowed to select his or her therapy on the basis of a balanced and fully informed assessment of the long-term and short-term risks of all therapeutic modalities. The burdensome prospect of lifelong tablet ingestion and its potential dangers must be weighed against the alternative, in up to 30% of cases, that surgery may produce dysphagia, gas bloat, or dumping with no guarantee of a long-term cure.
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Affiliation(s)
- D Armstrong
- Department of Otorhinolaryngology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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24
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Creutzfeldt W, Lamberts R. Is hypergastrinaemia dangerous to man? SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1991; 180:179-91. [PMID: 1675024 DOI: 10.3109/00365529109093198] [Citation(s) in RCA: 59] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Achlorhydria has been discussed as a possibly dangerous consequence of therapeutic inhibition of gastric acid secretion since the introduction of H2-receptor antagonists. The risk of long-term hypergastrinaemia has only been considered for about 5 years. The reason for this was the demonstration that gastric carcinoids (ECLomas) observed after life-long treatment of rats with the proton pump inhibitor omeprazole could also be produced in rats by other methods leading to long-lasting profound hypergastrinaemia. Such methods were the 80% resection of the oxyntic mucosa or feeding of ranitidine (2000 mg/day) for 2 years. The endocrine tumours corresponded to the gastric carcinoids found in patients with long-lasting hypergastrinaemia due to pernicious anaemia or with a gastrinoma as part of the MEN I syndrome. Neither in animals nor in man could other endocrine tumours or adenocarcinomas of the gastrointestinal tract be related to hypergastrinaemia. Epidemiologic data do not support gastrin dependence of adenocarcinoma of the stomach or the colon. Experimental findings of gastrin effects on tumour growth in vivo and in vitro have been contradictory and may be explained by the presence of gastrin receptors on tumour cells and the role of gastrin as an autocrine growth factor in some of these tumours. Since acid blockade by proton pump inhibitors or H2-receptor blockers dose-dependently increase serum gastrin levels, patients with ranitidine-resistant peptic ulceration receiving long-term treatment with high-dose omeprazole have been followed up with serial gastric biopsy specimens for up to 5 years. Complete healing, moderate hypergastrinaemia, and a slight hyperplasia but no dysplasia of the ECL cells in the oxyntic mucosa have been observed, which seemed to be correlated to chronic gastritis progressing over the years. Despite these negative findings excessive hypergastrinaemia by overdosage of potent drugs for inhibition of gastric secretion should be avoided and monitoring of plasma gastrin levels is recommended in case of long-term treatment.
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Affiliation(s)
- W Creutzfeldt
- Department of Medicine, Georg-August-University Göttingen, Germany
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25
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Knight TM, Leach S, Forman D, Vindigni C, Packer P, Venitt S, Minacci C, Lorenzini L, Tosi P, Frosini G. N-nitrosoproline excretion in the presence and absence of gastric disease. Eur J Cancer 1991; 27:456-61. [PMID: 1827720 DOI: 10.1016/0277-5379(91)90386-r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
N-nitrosoproline (NPRO) excretion, an indicator of endogenous nitrosation, was measured in a group of hospital inpatients who were identified by endoscopy and gastric biopsy as either having gastric lesions or having healthy stomachs. NPRO was assayed in background 24-hour urine samples and samples collected after loading doses of nitrate and L-proline. The presence of gastric lesions was associated with altered gastric pH and concomitant changes in gastric juice nitrate and nitrite concentration. Gastric juice pH increased with increasing severity of gastric disease (P = 0.031) and patients with normal stomachs had a lower gastric pH than those with chronic atrophic gastritis (CAG) (3.0 vs. 6.5, P = 0.017). The changes in gastric juice nitrate concentration were in the reverse direction (P = 0.002 for trend) with normal patients having higher mean levels than CAG patients (12.7 vs. 5.5 micrograms/ml, P less than 0.0001). Nitrite concentration increased with severity of gastric disease but the results were not significant (normal, 82.9 vs. CAG, 223.4 ng/ml, P = 0.069). No association was found between the presence of gastric lesions and increased urinary NPRO excretion. Mutagenic activity was not detected in any of the gastric juice samples.
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Affiliation(s)
- T M Knight
- Imperial Cancer Research Fund, Radcliffe Infirmary, Oxford, UK
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26
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27
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Farinati F, Lima V, Naccarato R, Garro AJ. Mutagenic activity in gastric juice and urine of subjects with chronic atrophic gastritis, gastric epithelial dysplasia and gastric cancer. Cancer Lett 1989; 48:169-75. [PMID: 2605566 DOI: 10.1016/0304-3835(89)90114-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Gastric juice and urine samples from consecutive patients who underwent endoscopy for upper GI tract complaints were examined for the presence of mutagens. Patients endoscopically and histologically diagnosed as having either chronic atrophic gastritis (CAG) or gastric cancer (GC) had higher than normal levels of mutagens in their gastric juice and urine. The gastric juice pH of these patients was also elevated and, in the case of the CAG patients, contained detectable levels of nitrites. No correlation was however found between gastric mutagen levels and urinary mutagen excretion in the individuals examined.
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Affiliation(s)
- F Farinati
- Cattedra Malattie Apparato Digerente, Istituto di Medicina Interna, Policlinico Universitario, Padua, Italy
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28
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Thomas JM, Misiewicz JJ, Cook AR, Hill MJ, Smith PL, Walters CL, Forster JK, Martin LE, Woodings DF. Effects of one year's treatment with ranitidine and of truncal vagotomy on gastric contents. Gut 1987; 28:726-38. [PMID: 3623220 PMCID: PMC1433039 DOI: 10.1136/gut.28.6.726] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Fifteen patients with peptic ulcer underwent 24 hour studies of gastric contents: before and on completing six weeks' treatment with oral ranitidine 150 mg bd, twice on maintenance treatment for nine to 12 months and one month after stopping the drug. For comparison, 11 patients underwent identical 24 hour studies three to 38 months after truncal vagotomy for duodenal ulcer. During treatment with ranitidine median 24 hour intragastric pH, nitrate concentration, and counts of total and nitrate reducing bacteria increased significantly regardless of dietary nitrate content; there was no significant increase in the median day time concentration of N-nitroso compounds. Despite these changes, an acid tide at some point in each 24 hour study period prevented persistent bacterial colonisation of the stomach. There were no significant differences between the biochemical and microbiological changes recorded during one year of treatment with ranitidine, and the observations on patients after truncal vagotomy. One month after stopping one year's treatment with ranitidine all variables examined returned to pretreatment levels. Treatment with ranitidine or vagotomy was associated with significant positive correlations among pH, nitrate concentration and bacterial counts. Correlations between pH and N-nitroso compound concentration and between concentrations of nitrite and N-nitroso compounds were not significant.
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29
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Hall CN, Kirkham JS, Northfield TC. Urinary N-nitrosoproline excretion: a further evaluation of the nitrosamine hypothesis of gastric carcinogenesis in precancerous conditions. Gut 1987; 28:216-20. [PMID: 3557192 PMCID: PMC1432965 DOI: 10.1136/gut.28.2.216] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Measurement of N-nitroso compounds in gastric juice by different methods has given conflicting results. In order to resolve this controversy, we have assessed endogenous nitrosation by the independent N-nitrosoproline excretion test in subjects who had previously undergone gastric juice analysis by one of these methods. Ten Polya gastrectomy, 10 pernicious anaemia and nine matched control subjects were fed 380 mg of nitrate in beetroot juice and 500 mg proline. N-nitrosoproline (N-Pro) synthesised intragastrically from these precursors, and quantitatively excreted by the kidneys, was measured in 24 hour urine samples (collection checked by creatinine clearance). N-Pro excretion (mean +/- SEM) was reduced (p less than 0.01) in pernicious anaemia (1.1 +/- 0.8 ng/day) compared with matched control (18.0 +/- 7.2 ng/day), and also tended to be lower (NS) in polya gastrectomy (3.2 +/- 2.3 ng/day). Twenty four hour intragastric pH was monitored on a separate occasion in 23 of the 29 subjects; 13 were hypoacidic (pH greater than 4 greater than 50% of 24 hours) and 10 were acidic. N-Pro yields were reduced (p less than 0.01) in the hypoacidic group (0.9 +/- 0.6 ng/day) compared with the acidic group (17.9 +/- 6.6 ng/day), and N-Pro was negatively associated with mean intragastric pH (tau = -0.53, p = 0.001). We conclude that endogenous synthesis of this specific N-nitroso compound is favoured by low rather than high pH. These results are concordant with those previously reported in gastric juice from the same subjects and suggest that nitrosation is chemically rather than bacterially mediated, contrary to the nitrosamine hypothesis of gastric carcinogenesis.
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