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Background: The diagnosis of colorectal cancer (CRC) can be difficult as symptoms are variable with poor specificity. Thus, there is a quest for simple, non-invasive testing that can help streamline those with significant colonic pathology., Aim: To assess using faecal immunochemical test for haemoglobin (FIT) or faecal calprotectin (FCP) to detect CRC and adenoma in symptomatic patients referred from primary care., Methods: A total of 799 referred for urgent lower gastrointestinal investigations were prospectively recruited. Of these, 430 completed colonic investigations and returned stool samples, and were included in the final statistical analysis. Faecal immunochemical test for haemoglobin was performed on HM-JACKarc analyser (Kyowa Medex, Tokyo, Japan), and FCP by the EliA Calprotectin immunoassay (Thermo Fisher Scientific, Waltham, United States)., Results: The negative predictive value (NPV) using FIT alone or both markers (FIT and FCP) in combination was similar at 99% for CRC, with a sensitivity and specificity of 84% and 93%, respectively. FIT measurements were significantly higher in left-sided colonic lesions compared with the right side; 713 vs. 94; P = 0.0203). For adenoma, the NPV using FIT alone, or both markers (FIT and FCP) in combination, was similar at 94% with a sensitivity and specificity of 69% and 56%, respectively., Conclusions: Undetectable faecal immunochemical test for haemoglobin is sufficiently sensitive to exclude colorectal cancer, with higher values in left-sided lesions. FCP in combination does not appear to provide additional diagnostic information. Further studies to determine the health economic benefits of implementing faecal immunochemical test for haemoglobin in primary care are required., (© 2016 John Wiley & Sons Ltd.)

Background: Ulcerative colitis (UC) is an idiopathic disease of the large intestine with evidence pointing to the role of epigenetic changes., Methods: Searches were performed in three databases (EMBASE, MEDLINE and Web of Science), following PRISMA protocol. DNA methylation was the only epigenetic mechanism affecting genes linked to inflammatory response in UC., Results: A total of 25 differentially methylated inflammatory genes were identified. Hypermethylation of miR-1247 significantly correlates (p = 0.0006) with refractory UC while PAR2 hypermethylation correlates (p = 0.007) with corticosteroid dependence., Conclusion: Evidence points to a step-wise increase in methylation status of the genome between a healthy colon, quiescent UC and when inflamed. Inflammatory genes (which are aberrantly methylated), have also been implicated in cancer development in UC.

Background & Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is the commonest cause of chronic liver disease in the western world. Current diagnostic methods including Fibroscan have limitations, thus there is a need for more robust non-invasive screening methods. The gut microbiome is altered in several gastrointestinal and hepatic disorders resulting in altered, unique gut fermentation patterns, detectable by analysis of volatile organic compounds (VOCs) in urine, breath and faeces. We performed a proof of principle pilot study to determine if progressive fatty liver disease produced an altered urinary VOC pattern; specifically NAFLD and Non-Alcoholic Steatohepatitis (NASH)., Methods: 34 patients were recruited: 8 NASH cirrhotics (NASH-C); 7 non-cirrhotic NASH; 4 NAFLD and 15 controls. Urine was collected and stored frozen. For assay, the samples were defrosted and aliquoted into vials, which were heated to 40±0.1°C and the headspace analyzed by FAIMS (Field Asymmetric Ion Mobility Spectroscopy). A previously used data processing pipeline employing a Random Forrest classification algorithm and using a 10 fold cross validation method was applied., Results: Urinary VOC results demonstrated sensitivity of 0.58 (0.33 - 0.88), but specificity of 0.93 (0.68 - 1.00) and an Area Under Curve (AUC) 0.73 (0.55 - 0.90) to distinguish between liver disease and controls. However, NASH/NASH-C was separated from the NAFLD/controls with a sensitivity of 0.73 (0.45 - 0.92), specificity of 0.79 (0.54 - 0.94) and AUC of 0.79 (0.64 - 0.95), respectively., Conclusions: This pilot study suggests that urinary VOCs detection may offer the potential for early non-invasive characterisation of liver disease using 'smell prints' to distinguish between NASH and NAFLD.

Coeliac disease (CD), a T-cell-mediated gluten sensitive enteropathy, affects ∼ 1% of the UK population and can present with wide ranging clinical features, often being mistaken for Irritable Bowel Syndrome (IBS). Heightened clinical awareness and serological screening identifies those with potential coeliac disease; the diagnosis is confirmed with duodenal biopsies, and symptom improvement with a gluten-free diet. Limitations to diagnosis are false negative serology and reluctance to undergo biopsy. The gut microbiome is altered in several gastrointestinal disorders, causing altered gut fermentation patterns recognisable by volatile organic compounds (VOC) analysis in urine, breath and faeces. We aimed to determine if CD alters the urinary VOC pattern, distinguishing it from IBS. 47 patients were recruited, 27 with established CD, on gluten free diets, and 20 with diarrhoea-predominant IBS (D-IBS). Collected urine was stored frozen in 10 ml aliquots. For assay, the specimens were heated to 40 ± 0.1°C and the headspace analysed by Field Asymmetric Ion Mobility Spectrometry (FAIMS). Machine learning algorithms were used for statistical evaluation. Samples were also analysed using Gas chromatography and mass spectroscopy (GC-MS). Sparse logistic regression showed that FAIMS distinguishes VOCs in CD vs D-IBS with ROC curve AUC of 0.91 (0.83-0.99), sensitivity and specificity of 85% respectively. GCMS showed a unique peak at 4'67 found only in CD, not D-IBS, which correlated with the compound 1,3,5,7 cyclooctatetraene. This study suggests that FAIMS offers a novel, non-invasive approach to identify those with possible CD, and distinguishes from D-IBS. It offers the potential for monitoring compliance with a gluten-free diet at home. The presence of cyclooctatetraene in CD specimens will need further validation.

Colorectal cancer (CRC) is a leading cause of cancer related death in Europe and the USA. There is no universally accepted effective non-invasive screening test for CRC. Guaiac based faecal occult blood (gFOB) testing has largely been superseded by Faecal Immunochemical testing (FIT), but sensitivity still remains poor. The uptake of population based FOBt testing in the UK is also low at around 50%. The detection of volatile organic compounds (VOCs) signature(s) for many cancer subtypes is receiving increasing interest using a variety of gas phase analytical instruments. One such example is FAIMS (Field Asymmetric Ion Mobility Spectrometer). FAIMS is able to identify Inflammatory Bowel disease (IBD) patients by analysing shifts in VOCs patterns in both urine and faeces. This study extends this concept to determine whether CRC patients can be identified through non-invasive analysis of urine, using FAIMS. 133 patients were recruited; 83 CRC patients and 50 healthy controls. Urine was collected at the time of CRC diagnosis and headspace analysis undertaken using a FAIMS instrument (Owlstone, Lonestar, UK). Data was processed using Fisher Discriminant Analysis (FDA) after feature extraction from the raw data. FAIMS analyses demonstrated that the VOC profiles of CRC patients were tightly clustered and could be distinguished from healthy controls. Sensitivity and specificity for CRC detection with FAIMS were 88% and 60% respectively. This study suggests that VOC signatures emanating from urine can be detected in patients with CRC using ion mobility spectroscopy technology (FAIMS) with potential as a novel screening tool.

Background: The detection of airborne gas phase biomarkers that emanate from biological samples like urine, breath and faeces may herald a new age of non-invasive diagnostics. These biomarkers may reflect status in health and disease and can be detected by humans and other animals, to some extent, but far more consistently with instruments. The continued advancement in micro and nanotechnology has produced a range of compact and sophisticated gas analysis sensors and sensor systems, focussed primarily towards environmental and security applications. These instruments are now increasingly adapted for use in clinical testing and with the discovery of new gas volatile compound biomarkers, lead naturally to a new era of non-invasive diagnostics., Aim: To review current sensor instruments like the electronic nose (e-nose) and ion mobility spectroscopy (IMS), existing technology like gas chromatography-mass spectroscopy (GC-MS) and their application in the detection of gas phase volatile compound biomarkers in medicine - focussing on gastroenterology., Methods: A systematic search on Medline and Pubmed databases was performed to identify articles relevant to gas and volatile organic compounds., Results: E-nose and IMS instruments achieve sensitivities and specificities ranging from 75 to 92% in differentiating between inflammatory bowel disease, bile acid diarrhoea and colon cancer from controls. For pulmonary disease, the sensitivities and specificities exceed 90% in differentiating between pulmonary malignancy, pneumonia and obstructive airways disease. These sensitivity levels also hold true for diabetes (92%) and bladder cancer (90%) when GC-MS is combined with an e-nose., Conclusions: The accurate reproducible sensing of volatile organic compounds (VOCs) using portable near-patient devices is a goal within reach for today's clinicians., (© 2014 John Wiley & Sons Ltd.)

Bile acid diarrhoea (BAD) is a common disease that requires expensive imaging to diagnose. We have tested the efficacy of a new method to identify BAD, based on the detection of differences in volatile organic compounds (VOC) in urine headspace of BAD vs. ulcerative colitis and healthy controls. A total of 110 patients were recruited; 23 with BAD, 42 with ulcerative colitis (UC) and 45 controls. Patients with BAD also received standard imaging (Se75HCAT) for confirmation. Urine samples were collected and the headspace analysed using an AlphaMOS Fox 4000 electronic nose in combination with an Owlstone Lonestar Field Asymmetric Ion Mobility Spectrometer (FAIMS). A subset was also tested by gas chromatography, mass spectrometry (GCMS). Linear Discriminant Analysis (LDA) was used to explore both the electronic nose and FAIMS data. LDA showed statistical differences between the groups, with reclassification success rates (using an n-1 approach) at typically 83%. GCMS experiments confirmed these results and showed that patients with BAD had two chemical compounds, 2-propanol and acetamide, that were either not present or were in much reduced quantities in the ulcerative colitis and control samples. We believe that this work may lead to a new tool to diagnose BAD, which is cheaper, quicker and easier that current methods.

It is well known that the electronic nose can be used to identify differences between human health and disease for a range of disorders. We present a pilot study to investigate if the electronic nose and a newer technology, FAIMS (Field Asymmetric Ion Mobility Spectrometry), can be used to identify and help inform the treatment pathway for patients receiving pelvic radiotherapy, which frequently causes gastrointestinal side-effects, severe in some. From a larger group, 23 radiotherapy patients were selected where half had the highest levels of toxicity and the others the lowest. Stool samples were obtained before and four weeks after radiotherapy and the volatiles and gases emitted analysed by both methods; these chemicals are products of fermentation caused by gut microflora. Principal component analysis of the electronic nose data and wavelet transform followed by Fisher discriminant analysis of FAIMS data indicated that it was possible to separate patients after treatment by their toxicity levels. More interestingly, differences were also identified in their pre-treatment samples. We believe these patterns arise from differences in gut microflora where some combinations of bacteria result to give this olfactory signature. In the future our approach may result in a technique that will help identify patients at "high risk" even before radiation treatment is started.

Background: Ghrelin, a potent orexigenic peptide produced by the stomach, may be affected by circulating inflammatory mediators., Aim: To assess the effect of an anti-TNFα antibody on ghrelin in patients with Crohn's disease (CD)., Methods: Fifteen patients with Crohn's receiving infliximab were studied before and 1 week after infusion. Following an overnight fast, blood was sampled before a meal and then every 20 min for 2 h. Total ghrelin and CRP were measured using ELISA. Acylated ghrelin and TNFα, IFNγ, IL-1β and IL-6 were measured with bioplex. Harvey Bradshaw Activity Index was assessed., Results: Median (95% CI) 2-h integrated plasma total ghrelin increased from 162 (99-311) before infliximab to 200 (128-387) pg/mL h, (P = 0.02) after. Following infliximab, 20 min postmeal, median acylated ghrelin decreased from 50.3 (24-64) to 38.6 (26-82) pg/mL, (P = 0.04) thus reverting to a traditional meal related ghrelin curve. Median (range) disease activity decreased from 5 (2-28) before to 3 (0-22), (P = 0.0001) and Median (95% CI) TNFα decreased from 2.8 (1.89-4.48) to 1.31 (0.73-2.06) pg/mL (P = 0.002)., Conclusions: Infliximab increases circulating total ghrelin by 25% in CD and restores the postprandial response of acylated ghrelin to food intake. Acylated and de-sacyl ghrelin remain unchanged, suggesting that an alternate isoform could be affected by infliximab., (© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd.)

Background: Ghrelin is an orexigenic gut peptide produced predominantly by the stomach. Gastric mucosal ghrelin production could be compromised by an infiltrating adenocarcinoma., Aims: To assess the expression of ghrelin mRNA and peptide in oesophagogastric adenocarcinomas and adjacent non-neoplastic mucosa., Methods: 10 gastric and 22 oesophageal adenocarcinoma archival samples were randomly selected from a database. The presence of ghrelin-positive cells was assessed in cancer and corresponding non-neoplastic mucosa by immunohistochemistry. Quantitative reverse transcriptase polymerase chain reaction (PCR) for ghrelin mRNA was also performed on 24 gastric and 8 oesophageal adenocarcinoma specimens and adjacent non-neoplastic mucosa., Results: Immunohistochemistry and reverse transcriptase PCR confirm a negligible expression of ghrelin in adenocarcinoma specimens. By contrast, non-neoplastic gastric mucosa was rich in ghrelin-positive cells and ghrelin mRNA. The number (median and range) of ghrelin-positive cells per 2 mm section of non-neoplastic mucosa was 73 (45-215) in the corpus; this was significantly higher than in cardia mucosa (9 (0-64), p<0.001) and antral mucosa (5 (0-14), p<0.001)., Conclusions: Gastric and oesophageal adenocarcinomas have no ghrelin-producing cells. The highest level of ghrelin expression was noted in the non-neoplastic mucosa of the gastric corpus. Disruption of the gastric ghrelin-producing mechanism may occur during oesophagogastric malignancy.

Background: Insulin resistance and oxidative stress induced by products of small intestinal bacterial activity are putative factors in the pathogenesis of non-alcoholic steatohepatitis. Acylated ghrelin is the biologically active form of an orexigenic gastric hormone that modifies insulin sensitivity and body composition., Aim: To investigate the effect of ciprofloxacin on small intestinal bacterial activity, ethanol, ghrelin and insulin in non-alcoholic steatohepatitis patients., Methods: Twelve non-alcoholic steatohepatitis patients and 11 controls were studied before and after ciprofloxacin 500 mg b.d. for 5 days. After an overnight fast, 75 g glucose was ingested and blood was sampled every 20 min for 120 min. Acylated and total ghrelin, ethanol and insulin were measured. Small intestinal bacterial activity was detected by glucose hydrogen breath test., Results: Mean (range) integrated plasma acylated ghrelin which was 102 (21-241) and 202 (88-366) pg/mL . 2 h in non-alcoholic steatohepatitis and controls respectively (P = 0.015). This difference persisted after correction for body mass index and was unaffected by ciprofloxacin treatment. One of six non-alcoholic steatohepatitis patients positive for small intestinal bacterial activity remained positive after ciprofloxacin. In contrast, the one healthy control positive for small intestinal bacterial activity remained positive after ciprofloxacin (P = 0.025). Ethanol was detected in two subjects in each group, becoming immeasurable after ciprofloxacin. In non-alcoholic steatohepatitis patients median (range) fasting insulin increased from 113 (10-223) to 152 (32-396) pmol/L (P < 0.02), after ciprofloxacin. This was accompanied by similar changes in insulin resistance., Conclusions: Small intestinal bacterial activity is common in non-alcoholic steatohepatitis. Low acylated ghrelin in non-alcoholic steatohepatitis cannot be attributed to small intestinal bacterial activity. Changes in fasting insulin and ethanol following ciprofloxacin suggest that these parameters may be influenced by small intestinal bacterial activity.

Background: The chromosome instability observed in peripheral blood lymphocytes in ulcerative colitis could be a biomarker of cancer susceptibility., Aim: To determine whether accelerated telomere shortening could explain chromosome instability and assess the effect of drugs and smoking on telomere dynamics in these cells., Methods: Peripheral blood lymphocytes were isolated from ulcerative colitis, Crohn's disease and non-inflammatory bowel disease control patients. Telomere lengths were measured by quantitative real-time polymerase chain reaction. After activation and cell separation, telomerase activity and human telomerase reverse transcriptase messenger ribonucleic acid were measured by telomerase repeat amplification protocol enzyme-linked immunosorbent serological assay and quantitative real-time polymerase chain reaction, respectively., Results: Age-related telomere loss in peripheral blood lymphocytes was similar in ulcerative colitis, Crohn's disease and control patients. Telomerase activity decreased with age in all groups and correlated positively with telomere length (r = 0.489, P = 0.006). Among Crohn's disease patients, azathioprine was associated with decreased telomerase activity (0.66 vs. 1.54, P = 0.026, P < 0.05) and smoking was associated with decreased human telomerase reverse transcriptase mRNA expression (10.5 vs. 33.3, P = 0.036, P < 0.05)., Conclusions: Telomere shortening is not accelerated and therefore cannot be the cause of the chromosome instability observed in ulcerative colitis peripheral blood lymphocytes. Azathioprine and cigarette smoking modify telomerase expression in these cells.

Background: In the Western world, the incidence of oesophageal adenocarcinoma has increased over the last 30 years coinciding with a decrease in the prevalence of Helicobacter pylori. Trends of increasing oesophageal adenocarcinoma can be linked causally to increasing gastro-oesophageal reflux disease (GORD) which can be linked to an increasingly obese population. However, there is no plausible biological mechanism of association between H. pylori, obesity, and GORD. Ghrelin, a peptide produced in the stomach, which regulates appetite, food intake, and body composition, was studied in H. pylori positive asymptomatic subjects., Methods: Plasma ghrelin, leptin, and gastrin were measured for six hours after an overnight fast, before and after cure of H. pylori in 10 subjects. Twenty four hour intragastric acidity was also assessed., Results: After cure, median (95% confidence intervals) integrated plasma ghrelin increased from 1160.5 (765.5-1451) pg/ml x h to 1910.4 (1675.6-2395.6) pg/ml x h (p=0.002, Wilcoxon's rank sum test), a 75% increase. This was associated with a 14% increase in 24 hour intragastric acidity (p=0.006) and non-significant changes in leptin and gastrin. There was a significant positive correlation between plasma ghrelin and intragastric acidity (r(s) 0.44, p=0.05, Spearman's rank correlation)., Conclusions: After H. pylori cure, plasma ghrelin increased profoundly in asymptomatic subjects. This could lead to increased appetite and weight gain, and contribute to the increasing obesity seen in Western populations where H. pylori prevalence is low. This plausible biological mechanism links H pylori, through increasing obesity and GORD, to the increase in oesophageal adenocarcinoma observed in the West.

Background: The eradication of Helicobacter pylori decreases the antisecretory activity of omeprazole and lansoprazole. Rabeprazole is a potent proton pump inhibitor that may not be affected as greatly by H. pylori status., Aim: To compare the effect of H. pylori eradication on intragastric acidity and plasma gastrin during dosing with lansoprazole, omeprazole, rabeprazole and placebo., Methods: Twenty-four healthy H. pylori-infected volunteers were studied on day 7 of dosing with placebo, lansoprazole 30 mg, omeprazole 20 mg and rabeprazole 20 mg, before and at least 5 weeks after H. pylori eradication. On each occasion, the 24-h intragastric acidity was measured by gastric aspiration. Plasma gastrin concentrations were measured hourly from 08.00 to 13.00 h., Results: Sixteen subjects completed the study. For all three drugs and placebo, H. pylori eradication increased intragastric acidity, particularly nocturnal acidity, and decreased plasma gastrin. There were no differences between the three drugs with respect to 24-h acidity, percentage of time pH > 4 or 5-h plasma gastrin, either before or after H. pylori eradication. Before eradication, the percentage nocturnal time at pH > 3 was significantly greater during rabeprazole than during lanso-prazole dosing., Conclusions: The increase in intragastric acidity seen after H. pylori eradication during dosing with proton pump inhibitors is a drug-class effect, particularly affecting nocturnal acid control. This is related to increased spontaneous intragastric acidity after H. pylori eradication.

Background: The duration of Helicobacter pylori eradication regimens has decreased to 1 week with cure rates of over 90%. This can be attributed to the use of triple drug regimens including potent inhibitors of gastric acid secretion and clarithromycin. There is no theoretical reason why shorter regimens should not be possible., Aim: To compare two 3-day, low-dose, twice daily regimens with 1 week of omeprazole 20 mg b.d., clarithromycin 250 mg b.d., and metronidazole 400 mg b.d. (OCM) METHODS: Outpatients referred for gastroscopy were screened by biopsy urease test. H. pylori-positive patients were randomized to receive either lansoprazole 30 mg b.d., tri-potassium dicitrato bismuthate one tablet b.d., clarithromycin 250 mg b.d., and amoxycillin 1 g b.d. for 3 days (LTdbCA), or ranitidine bismuth citrate 400 mg b.d., clarithromycin 250 mg b.d. and amoxycillin 1 g b.d. for 3 days (RbcCA) or omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. for 1 week (OCM). They were not pre-treated with a gastric acid inhibitor. After 8 weeks, H. pylori status was assessed by 13C urea breath test., Results: 974 out of 1114 patients referred for gastroscopy were screened by biopsy urease test. 140 patients were not screened either because they were anticoagulated or for technical reasons. 334 patients were H. pylori-positive: 154 were excluded mostly because of allergy to penicillin and personal reasons but 180 were randomized to treatment All regimens were well tolerated. For LTdbCA (n=60), RbcCA (n=59), and OCM (n=61) the H. pylori cure rates (95% CI) were 23% (12-34), 14% (5-23) and 87% (79-95), respectively, using intention-to-treat analysis and 25% (14-36), 15% (6-24) and 88% (80-96), respectively, if analysed per protocol. OCM was significantly superior to LTdbCA and RbcCA (P < 0.001) but there was no significant difference between regimens LTdbCA and RbcCA., Conclusions: OCM is an extremely effective H. pylori eradication regimen. The 3-day regimens tested both have poor cure rates. Pre-treatment with a proton pump inhibitor, higher doses or more frequent dosing may be necessary to increase the cure rate of short duration regimens. However, this could make them less acceptable than the H. pylori eradication regimens currently available.

Background: Amongst the low-dose H2-receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH., Aim: To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose., Methods: Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders., Results: Over the 12 h post-dose period the mean area under the pH/time curve (AUC) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0-12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post-dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to = 8 h., Conclusions: Inhibition of gastric acidity over the 12 h post-dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H2-receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film-coated tablets.

Background: Despite the widespread use of over-the-counter H2-receptor antagonists little is known about their duration of action on human gastric acid secretion. There are studies reporting inhibitory effects for up to 9 h post-dose but few data beyond this period., Methods: Profiles of 20-h intragastric acidity were measured simultaneously in 24 healthy subjects who were dosed (at 12.30 h) with either ranitidine 75 mg, cimetidine 200 mg or placebo in a three-way crossover study, according to a standard protocol. Five-millilitre aliquots of gastric juice were aspirated half-hourly during the day (0-10 h post-dose) and hourly overnight (10-20 h post-dose). pH was measured to three decimal places with a glass electrode. Weighted intragastric acidity (AUC/time) was calculated for both day- and night-times using 2.5-h intervals during the day and 5-h intervals at night. Statistical analysis was by ANOVA., Results: The results are expressed as mean weighted intragastric acidity (mmol/L). (i) Daytime (0-10 h post-dose): when dosed with placebo the weighted intragastric acidity was 31.03, decreasing to 10.37 (P < 0.001 vs. placebo) and 16.23 (P < 0.001 vs. placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited weighted intragastric acidity to a greater degree than cimetidine (P < 0.001) during this period. (ii) Night-time (10-20 h post-dose): when dosed with placebo the weighted intragastric acidity was 21.36 decreasing to 16.65 (P < 0.001 vs. placebo) when dosed with ranitidine and remaining unchanged at 20.03 (P = 0.886 vs. placebo) when dosed with cimetidine. Ranitidine inhibited weighted intragastric acidity to a greater degree than cimetidine (P = 0.010) during this period. A sub-analysis of the two 5-h intervals showed that compared to placebo, ranitidine inhibited weighted intragastric acidity significantly in the 10-15 h period. However, its effect in the 15-20 h period did not differ from placebo., Conclusions: In healthy subjects, the inhibitory effect of ranitidine 75 mg on intragastric acidity can be detected 10-15 h after an oral dose. By contrast, the inhibitory effect of cimetidine 200 mg seems to be restricted to the first 10 h.

Aim: To compare the inhibitory effects of over-the-counter doses of famotidine or ranitidine on nocturnal intragastric acidity in a placebo-controlled study., Methods: Twelve-hour intragastric acidity was measured simultaneously in 24 healthy subjects who ate a standard meal at 18.30 h and were dosed (at 19.30 h) with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period crossover design. Five-millilitre aliquots of gastric juice were aspirated half-hourly 0-3 h post-dose, and then hourly until the end of the study. pH was measured with a glass electrode. Integrated pH (area under the curve (AUC) of the pH-time curve) was calculated for the intervals 0-12 h and 9-12 h post-dose. Statistical analysis was by ANOVA., Results: In the 0-12 h post-dose period, when the 24 subjects were dosed with placebo, mean AUC was 2.12, increasing by 75% to 3.70 with famotidine (P < 0.001) and by 81% to 3.83 with ranitidine (P < 0.001). In the 9-12 h post-dose period, when the subjects were dosed with placebo, mean AUC was 2.13, increasing by 91% to 4.07 with famotidine (P < 0.001) and by 79% to 3.82 with ranitidine (P < 0.001). There was no significant difference between the pH-raising effects of famotidine and ranitidine in both periods., Conclusions: Famotidine and ranitidine in over-the-counter doses have a similar, sustained, effect on post-prandial nocturnal intragastric acidity in healthy subjects lasting up to 12 h after oral dosing.

Background: There are no published comparative studies on the effect of low-dose H2-antagonists on pentagastrin-stimulated gastric acid secretion., Methods: Twenty-four healthy subjects were dosed with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period cross-over design. The subjects were studied in groups of 12, simultaneously, under identical controlled environmental conditions. Gastric juice was aspirated in 15-min aliquots during sub-maximal (0.6 microgram.h/kg) intravenous pentagastrin stimulation in the third and fourth hours (early period) and the eighth and ninth hours (late period) after oral dosing. The hydrogen ion (H+) content of gastric juice was measured ex vivo, by titrating to pH7 known volumes of gastric aspirate against 0.1 M sodium hydroxide, using a versatile microprocessor-controlled auto-titration unit. Gastric acid output during the period of interest was calculated by adding the hydrogen ion content of 15-min aliquots collected during that period. The geometric mean of the cumulative pentagastrin-stimulated gastric acid output during the early and late periods was determined for the subjects dosed with either famotidine, ranitidine or placebo. Comparisons were performed by ANOVA., Results: During the early period (2-4 h post-dose), When the subjects were given placebo, mean gastric acid output was 46.6 mmol, decreasing by 76% to 11.3 mmol (P < 0.001) when treated with famotidine and by 76% to 11.1 mmol (P < 0.001) when treated with ranitidine. During the late period (7-9 h post-dose), when the subjects were dosed with placebo, mean gastric acid output was 41.2 mmol, decreasing by 38% to 25.7 mmol (P < 0.001) when treated with famotidine and by 27% to 30.0 mmol (P = 0.007) when treated with ranitidine. The difference between the inhibitory effects of famotidine and ranitidine on gastric acid output were non-significant during either period., Conclusions: Low-dose famotidine and ranitidine, intended for over-the-counter use, inhibit stimulated gastric acid secretion profoundly in the third and fourth hours after an oral dose. Modest effects are still detectable up to 9 h after dosing.

Thirty two patients (74 (43-93) years; median, (range)) with dysphagia because of inoperable, unresectable or recurrent oesophagogastric carcinoma were treated by ethanol induced tumour necrosis (ETN). Endoscopic injection of absolute alcohol was performed using a variceal injector needle, with 0.5-1 ml aliquots injected retrogradely from distal to proximal tumour margin. Dilatation to 12 mm was used only if the endoscope would not traverse the stricture. In patients with total occlusion, injection into the proximal tumour was followed by a repeat endoscopy 3-7 days later. Dysphagia was graded from 0 = no dysphagia to 4 = total dysphagia. The significance of changes in the dysphagia grade after ETN were assessed using the Wilcoxon rank sum test. Results (median (range)) were as follows: stricture length = 5.0 cm (1-15). Dysphagia grade before treatment was 3 (2-4) improving after first treatment to 1 (0-3), p < 0.003. Best dysphagia grade achieved was 1 (0-3) and interval between treatments was 28.5 days (4-170). The volume of ethanol injected = 10 ml (1.5-29) and survival after first treatment was 93 days (6-660). The number of treatment sessions required to achieve best grade = 1 (1-3). There were no treatment complications. ETN significantly improves dysphagia. Results of palliation are similar to those of laser therapy, but can be achieved quickly and safely on a day case basis in most patients and at a small proportion of the cost.

Objective: To search for evidence of subclinical neurotoxicity in patients treated with tripotassium dicitrato bismuthate., Design: Prospective, controlled, triplicate study using urinary bismuth concentration, magnetic resonance imaging (MRI), nerve conduction studies, visual evoked response and a battery of 10 neuropsychological screening tests., Setting: Out-patient clinics, Walsgrave Hospital, Coventry, UK., Subjects: Fourteen dyspeptic patients; 8 (treatment group) treated with tripotassium dicitrato bismuthate one tablet q.d.s and 6 (control group) treated with ranitidine 150 mg b.d. for 8 weeks., Main Outcome Measures: Changes in urinary bismuth, MRI, nerve conduction studies, visual evoked response, and neuropsychological tests performed before, immediately after and 8 weeks after the cessation of treatment., Results: In the treatment group the median (range) urinary bismuth concentration was 1 (1-12) ng/ml before treatment, increased to 560 (140-1300) immediately after treatment (P < 0.01, Wilcoxon Rank Sum test) and was still significantly elevated (23 (7-53) ng/ml) 8 weeks after the cessation of treatment. In the patient who recorded the highest urinary bismuth, a high intensity signal appeared in the globus pallidus immediately after treatment and was still present (though diminished in intensity) 8 weeks after the cessation of treatment. This isolated MRI finding was not associated with evidence of subclinical neurotoxicity. No changes in the MRI, nerve conduction studies, visual evoked response and neuropsychological tests were observed among the other patients studied., Conclusions: Bismuth accumulation occurs in patients receiving a conventional course of treatment with tripotassium dicitrato bismuthate but this is not associated with significant changes in the nervous system.

The surgical resection rates among parous women with distal ileal and colonic Crohn's disease have been compared with resection rates among distal ileal (n = 197) and colonic (n = 332) Crohn's disease patients. Thirty of 44 parous women with distal ileal Crohn's disease and 28 of 44 with colonic Crohn's disease had achieved their first pregnancy on average 8 years and 6.2 years respectively before the diagnosis of Crohn's disease was established. Resections for each patient were negatively correlated with parity in both groups. (Distal ileal disease (p = 0.034, rs = 0.3207), colonic disease (p = 0.051, rs = -0.2960)). Patients with distal ileal Crohn's disease and a history of pregnancy at diagnosis (n = 30, mean follow up = 15 years) had fewer resections/patient when compared with the published resection group: mean (SD); 1.17 (0.65) v 1.57 (1.05), p = 0.006. Patients with colonic Crohn's disease and a history of pregnancy at diagnosis (n = 28, mean follow up = 16.5 years) had fewer resections/patient when compared with the published resection group: mean (SD); 0.68 (0.77) v 1.05 (0.77), p = 0.019. In summary, patients with distal ileal and colonic Crohn's disease, who had been pregnant in the past subsequently need fewer surgical resections. Pregnancy could influence the natural history of Crohn's disease either by decreasing immune responsiveness or by retarding fibrous stricture formation, which is the commonest indication for surgical intervention.

Nine members of a family with a high incidence of duodenal ulcer disease were studied by interview, examination of hospital records, endoscopy, and antral biopsy. Helicobacter pylori was confirmed by CLO test, histology and culture. DNA extraction from pure isolates of H pylori was possible in six family members and strain typing was performed by restriction fragment length polymorphism. DNA restriction digestion was followed by vacublotting and then DNA hybridisation, using a cDNA probe complimentary to H pylori rRNA cistrons. Eight of the nine family members were H pylori positive by CLO test and histology. Five had duodenal ulcer disease. Three family members (one from each generation) harboured clonal variants of a single parent strain of H pylori but only two had duodenal disease. The other three members harboured different strains. Intrafamilial clustering of clonal variants of H pylori occurs in some duodenal ulcer disease families. Family members however, may develop duodenal disease irrespective of the colonising strain.

Electron microscopic examination of upper gastrointestinal biopsies with x-ray microanalysis was used to detect electron-dense particles of bismuth in the mucosa of the upper gastrointestinal tract, 30-60 minutes after oral dosing with either tripotassium dicitrato bismuthate [De-Noltab; Brocades (Great Britain) Ltd., Weybridge, UK; five patients] or bismuth salicylate (Pepto-Bismol; Richardson Vicks Ltd., Egham, UK; five patients), or without dosing (two patients). Transmucosal penetration of bismuth particles was observed in the gastric antral mucosa of all patients who had been dosed with tripotassium dicitrato bismuthate, but there was no penetration after oral dosing with bismuth salicylate. Persorption of bismuth particles through the gastric mucosa to the vascular endothelium provides an explanation for the rapid rise of plasma bismuth concentration observed only after oral dosing with tripotassium dicitrato bismuthate.

In a series of 24 hour studies, intragastric acidity and plasma gastrin concentration were measured simultaneously in 46 healthy subjects before, during, and 24 to 48 hours after abrupt withdrawal of a histamine H2 receptor antagonist regimen. For 34 days subjects were given either cimetidine 800 mg at night (n = 8), ranitidine 150 mg twice daily (n = 10), ranitidine 300 mg at night (n = 12), nizatidine 300 mg at night (n = 8), or famotidine 40 mg at night (n = 8). All subjects responded to H2 blockade by a decrease in 24 hour intragastric acidity. Withdrawal of H2 blockade resulted in a significant rise in median nocturnal integrated intragastric acidity in 42 of 46 subjects (+36%; 95% CI +19, +55%) compared with prestudy values, but this rise was not associated with a significant change in the median integrated plasma gastrin concentration (+1%; 95% CI -12, +13%). A statistically significant rise in nocturnal acidity was observed after all regimens, except after dosing with famotidine. After stopping, median daytime integrated acidity and plasma gastrin concentrations in the whole group were raised, but not significantly: values were +15% (95% CI +4, +34%) and +5% (95% CI -2, +12%), respectively. A statistically significant increase in daytime acidity was observed only after dosing with ranitidine. In conclusion, intragastric hyperacidity occurs in most subjects after abrupt withdrawal of a histamine H2 receptor blocker, but this phenomenon is not associated with hypergastrinaemia.

GR122311X (ranitidine bismuth citrate Glaxo Group Research Ltd) is a bismuth compound with histamine H2-receptor antagonist activity. The gastric acid antisecretory activity of three oral dosage regimens of GR122311X was compared with placebo and 150 mg ranitidine b.d. The median 24-h integrated intragastric acidity was 38, 26 and 18% of the median placebo value during dosing with GR122311X 196, 391 and 782 mg b.d., respectively. The 24-h acid suppression with GR122311X 391 mg b.d. was not significantly different to that produced by 150 mg ranitidine b.d. (24% of placebo acidity). The median 24-h urinary bismuth excretion increased with rising dosage of GR122311X from 19.2 micrograms with 196 mg b.d., to 36.4 micrograms with 391 mg b.d., to 68.7 micrograms with 782 mg b.d. In conclusion, GR122311X is an effective antisecretory agent with modest systemic bismuth absorption.

Twelve healthy male subjects were dosed with six regimens: ranitidine and De-Noltab (tripotassium dicitrato bismuthate; Gist-Brocades Ltd., Weybridge, England), placebo and De-Noltab, ranitidine and Pepto-Bismol liquid [bismuth salicylate; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], placebo and Pepto-Bismol, ranitidine and Roter tablets (bismuth subnitrate; Roter Pharma Ltd., Ashford, England), and placebo and Roter. Ranitidine, 300 mg, or placebo was administered at 10 PM (night before) and at 7 AM; at 9 AM, the oral dose of bismuth was either 2 De-Noltabs, 3 30-mL doses of Pepto-Bismol liquid, or 2 Roter tablets. When predosed with placebo, the median integrated 8-hour plasma bismuth concentration was significantly greater after dosing with De-Noltabs than after dosing with either Pepto-Bismol or Roter (61, 8, and 8 ng.h/mL, respectively), with a similar trend for 8-hour median urinary bismuth excretion (213, 40, and 6 micrograms, respectively). When predosed with ranitidine, only after De-Noltab administration were there significant increases in the 8-hour plasma bismuth concentration (147 ng.h/mL), and 8-hour urinary bismuth excretion (686 micrograms). Eliminating intragastric acidity may enhance bismuth absorption after oral dosing with De-Noltabs by maintaining intragastric tripotassium dicitrato bismuthate as a colloidal suspension.

Repeated dosing with an H2-receptor antagonist results in a modest decrease in antisecretory potency termed "tolerance." The object of this prospective study was to determine whether tolerance is a progressive phenomenon or whether it levels off during prolonged dosing with a standard maintenance dose of an H2-antagonist. The effect of continuous dosing with ranitidine, 150 mg nightly, was compared with intermittent dosing (27 days of placebo each month) with active ranitidine, 150 mg nightly, only on the night of each experiment. Simultaneous 24-hour intragastric acidity and plasma gastrin concentration were measured monthly for 5 months in 17 healthy subjects (7 continuous and 10 intermittent dosing). In the intermittent-dosing group, the antisecretory response to ranitidine, 150 mg nightly, was preserved throughout the 141-day trial period; the median nocturnal integrated acidity decreased from 557 mmol.h/L (day 0) to 38 mmol.h/L on day 1 of dosing, and it ranged between 32 and 55 (median, 45) mmol.h/L during days 29-141. In the continuous-dosing group, there was a significant return of nocturnal intragastric acidity on days 29 and 85 compared with day 1 of dosing. The median nocturnal integrated acidity decreased in the continuous-dosing group from 554 mmol.h/L (day 0) to 87 mmol.h/L on the first day of dosing, and it ranged between 145 and 287 (median, 170) mmol.h/L during days 29-141. Either intermittent or continuous dosing with ranitidine was associated with an elevation of plasma gastrin concentration, which remained constant throughout the 5-month study. Tolerance does develop in healthy subjects during the first month of dosing with ranitidine, 150 mg nightly, but it is not a progressive phenomenon, and it is probably not of clinical relevance.

In a prospective study, eight young healthy subjects (five with an active H. pylori infection in the antral mucosa) were treated with a course of tripotassium dicitrato bismuthate, amoxycillin and metronidazole. The triple therapy eradicated infection when assessed 20-24 weeks later by antral biopsy (urease, histology, and 13C urea breath test [4 out of 5 subjects]). Twenty-four hour intragastric acidity and plasma gastrin concentration were measured before treatment, and 4-6 weeks and 20-24 weeks post-treatment. Treatment did not affect acidity in either the H. pylori-positive or H. pylori-negative groups, nor did it affect the plasma gastrin profile in the H. pylori-negative group. Eradication of H. pylori infection in five subjects caused a drop of the median integrated 24-hour plasma gastrin concentration from 558 pmol.h/L before treatment to 307 and 289 pmol.h/L at 4-6 and 20-24 weeks post-treatment, respectively. It is concluded that H. pylori infection is associated with 24-hour hypergastrinaemia, and that in apparently healthy subjects normal gastric physiology can be restored by eradication of the infection.

The magnitude and duration of changes in nocturnal intragastric acidity caused by 25 days of dosing with the antisecretory drugs ranitidine and omeprazole were investigated in a double-blind study of 22 healthy subjects. Nocturnal intragastric acidity was studied before (twice), during (on day 25), and after (every 3 days for 21 days) dosing with either 300 mg ranitidine at night or 40 mg omeprazole every morning. Three and six days after withdrawal of dosing with ranitidine, median integrated nocturnal intragastric acidity was increased significantly (17% and 14%, P = 0.01 and P = 0.05, respectively) compared with before dosing. Three days after withdrawal of dosing with omeprazole, median integrated nocturnal intragastric acidity was decreased significantly (-23%, P = 0.003). Compared with before dosing, no significant differences were seen in the ranitidine group between days 9 and 21 or the omeprazole group between days 6 and 21 after cessation of dosing. Fasting plasma gastrin concentration was measured on the morning of each study; compared with before treatment, the only significant elevations occurred on the last day of dosing with omeprazole (before, 4 pmol/L; during, 7 pmol/L). It is concluded that rebound intragastric hyperacidity after dosing with 300 mg ranitidine at night or sustained hypoacidity after dosing with 40 mg omeprazole every morning reflect transient disturbances of gastric function that are unlikely to be of clinical importance.

An ELISA test determined serologically that eight of 95 apparently healthy men (aged 19-26 years) had an asymptomatic infection with Helicobacter pylori at the time of simultaneous measurement of 24 hour intragastric acidity and 24 hour plasma gastrin concentration. There was no significant difference in the median integrated 24 hour intragastric acidity between the H. pylori positive and H. pylori negative subjects (688 and 842 mmol/h/l; p = 0.271, respectively), whereas the median integrated 24 hour plasma gastrin concentration was significantly higher in the H pylori positive than in the H pylori negative subjects (389 and 198 pmol/h/l; p less than 0.001). Longterm hypergastrinaemia, associated with persistent H pylori infection, could be a cause of the increased parietal cell mass that is considered characteristic of duodenal ulcer patients.

Plasma bismuth and plasma salicylate concentrations were measured before and after three 30-ml oral doses of bismuth salicylate (Pepto-Bismol liquid) in 10 fasting healthy subjects. From 0 to 120 min following the first dose of bismuth salicylate, the plasma bismuth concentration was less than 1 ng/ml. The peak median plasma bismuth concentration was at +240 min (1.7 ng/ml; range 0.8-5.3 ng/ml). Salicylate appeared in the plasma of all subjects at +30 min, and it reached a peak at +120 min (median 61 mg/L; range 46-104 mg/L). The study demonstrates that, despite rapid and substantial absorption of salicylate, there is negligible absorption of bismuth into the bloodstream from standard oral doses of bismuth salicylate.

Twenty-four-hour intragastric acidity and 24-h plasma gastrin concentration were measured on four occasions in six groups of eight healthy male subjects. Each group was studied before dosing, and on days 1, 15 and 29 of dosing with a standard regimen of an H2-receptor antagonist (cimetidine 800 mg nocte, nizatidine 300 mg nocte, famotidine 40 mg nocte, ranitidine 150 mg nocte, ranitidine 150 mg b.d., or ranitidine 300 mg nocte). On the first day of dosing, each regimen using an H2-antagonist caused a significant decrease of intragastric acidity and a significant rise of plasma gastrin concentration. Continued dosing with each H2-antagonist resulted in a significant attenuation of the effect on intragastric acidity, which was most noticeable overnight, but no significant change of plasma gastrin concentration. When grouped together, median integrated nocturnal acidity for the 48 subjects was 485, 35, 67 and 117 mmol.h/L for days 0, 1, 15 and 29, respectively, associated with a median nocturnal integrated plasma gastrin concentration of 46, 72, 79 and 73 pmol.h/L. The study demonstrates that a degree of tolerance develops during continued dosing with all available H2-receptor antagonists, and that this phenomenon occurs during sustained elevation of plasma gastrin concentration.

In a double-blind study of Latin square design, twelve healthy male subjects were dosed with combinations of ranitidine 300 mg or placebo (at 08.50 hours) and intravenous pentagastrin (0.6 microgram.kg/h) or 0.9% saline (07.00-18.00 hours). Breakfast and lunch were served at 08.15 and 13.15 hours, respectively; hourly intragastric acidity and plasma gastrin concentration were measured from 08.00-18.00 hours. During oral dosing with placebo, intravenous pentagastrin raised median 10-h integrated intragastric acidity (315 to 615 pmol.h/L; P less than 0.001) and lowered gastrin (86 to 55 mmol.h/L; P less than 0.001). During oral dosing with ranitidine 300 mg, compared with intravenous saline, the pentagastrin infusion returned acidity towards normal (67 to 293 pmol.h/L; P less than 0.001) and lowered gastrin (209 to 135 pmol.h/L; P less than 0.001). This study demonstrates that a continuous pentagastrin infusion can overcome H2-blockade and return intragastric acidity towards normal. Hypergastrinaemia observed during continued dosing with an H2-blocker may be the mechanism for the development of tolerance.

Simultaneous 24-h intragastric and plasma gastrin concentrations were measured in 36 healthy subjects, when receiving placebo (day 0) and on days 1 and 8 of dosing with either placebo (n = 8), or high-dose H2-blockade with either ranitidine 300 mg q.d.s. (n = 8), ranitidine 1200 mg o.m. (n = 8), or sufotidine 600 mg b.d. (n = 12). Triplicate placebo studies demonstrated good reproducibility for this technique, with no significant differences of acidity or plasma gastrin concentration between the studies. There was a decrease in the anti-secretory activity of all three high-dose H2-antagonist regimens on day 8, when compared with that observed on day 1. This occurred in the presence of sustained or increasing hypergastrinaemia. It is concluded that a degree of tolerance develops during continued H2-blockade, and that this could be due to increasing gastrin drive to the parietal cells.

In a double-blind, placebo-controlled study of SK&F 94482 (BMY-25368) (400-mg, post-evening meal, for 7 days in 11 healthy subjects), there was a significant 75% decrease in median integrated 24-h intragastric acidity during dosing with the drug (218 mmol h/L) compared with placebo (883 mmol h/L; P = 0.003). The single daily dose of 400 mg SK&F 94482 decreased median hourly intragastric acidity until the time of the next dose 24 h later. There was also a sustained and significant 80% rise in median 24-h integrated plasma-gastrin concentration during dosing with SK&F 94482 (364 pmol h/L) when compared with placebo (202 pmol h/L; P = 0.003). The study demonstrates a significant inverse correlation between 24-h integrated intragastric acidity and 24-h plasma gastrin concentration (rs = -0.484; P less than 0.001). The study shows that a single oral daily dose of an H2-antagonist can provide control of intragastric acidity throughout the day and night, decreased acidity being associated with statistically significantly, but modestly elevated plasma-gastrin levels.

Two studies measured plasma concentrations of bismuth during dosing with tripotassium dicitrato bismuthate (De-Noltab). The first study compared 24 h plasma bismuth concentration and urinary bismuth excretion in six patients who had already received 29-131 days (median 47 days) of treatment with De-Noltab 2 b.d., and six healthy subjects who only received De-Noltab 2 b.d. on the day of study. There was a prompt rise in plasma bismuth concentration after each dose of De-Noltabs. The median 24 h integrated plasma bismuth concentration was similar in both groups, but the median 24 h urinary bismuth excretion was 5.4-fold higher in the patients. The second study compared the plasma bismuth concentrations after the first and third doses of De-Noltab 2 b.d. in 16 healthy subjects. The median peak bismuth concentration occurred 30 min (range 15-105 min) post-dosing. The peak plasma bismuth concentration was greater than 50 ng/ml in 14 of the 16 subjects, and greater than 100 ng/ml in nine of the subjects. There was no significant difference in the median integrated 10-h plasma bismuth concentration after the first or third dose of De-Noltabs. The results of these studies confirm that bismuth is absorbed and sequestrated during dosing with De-Noltabs. Bismuth is absorbed rapidly after oral dosing with De-Noltabs, to produce peak plasma bismuth concentrations hitherto considered to be in the range associated with bismuth neurotoxicity.

Bismuth concentration was measured in plasma, dried leucocytes and urine in nine patients before, during and after treatment with tripotassium dicitrato bismuthate (De-Noltab 2 b.d.) for 6 weeks. During treatment there was an 8.5-fold rise in median plasma bismuth concentration (P less than 0.01), a non-significant doubling of leucocyte bismuth content, and a 349-fold rise in 24-h urinary bismuth excretion (P less than 0.01). The significantly increased urinary bismuth excretion continued for at least 3 months after cessation of treatment with tripotassium dicitrato bismuthate, indicating accumulation of bismuth during treatment with this drug.