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2.  Low dose famotidine and cimetidine in single postprandial doses: a placebo controlled comparative study of overnight pH. 
Gut  1995;37(3):325-328.
To investigate the relative abilities of low doses of famotidine and cimetidine to raise intragastric pH after a single postprandial evening dose, 16 healthy volunteers were recruited to a four period crossover trial of famotidine 10 mg, cimetidine 100 mg and 200 mg compared with placebo. Intragastric pH was monitored between 1800 and 0730 with a nasogastric pH electrode. Median gastric pH rose from 1.35 (interquartile range 1.1-1.65) with placebo to 1.95 (1.6-5.35, p < 0.001 Friedman rank) after dosing with famotidine 10 mg, to 1.46 (1.3-2.0, 0.05 < p < 0.1) after cimetidine 200 mg, and remained 1.35 (1.1-1.6, p > 0.2) after cimetidine 100 mg. Intragastric pH was above 3 for 34% (p < 0.005) of the time after dosing with famotidine, compared with 13.6% (p > 0.2) after cimetidine 200 mg, 9.5% (p > 0.2) after cimetidine 100 mg, and 4.7% after placebo. The rise of intragastric pH after famotidine 10 mg is significantly greater than that after either 200 mg or 100 mg cimetidine when the drugs are used postprandially.
PMCID: PMC1382810  PMID: 7590425
3.  Rising death rate from non-malignant disease of the oesophagus (NMOD) in England and Wales. 
Gut  1995;36(4):488-491.
Between 1968 and 1991, the number of deaths from non-malignant oesophageal disease (NMOD) (International Classification of Diseases code 530), recorded by the Office of Population Censuses and Surveys (OPCS) in England and Wales, trebled in women, from 118 to 340 (5 to 13 per million) and doubled in men, from 131 to 251 (5.5 to 10 per million). Calculation of age specific death rates, shows the increase to result from a rise in mortality in those over 75 years and age standardised mortality confirms a rise in overall frequency from 2.9 to 7.0 deaths per million men and 5.2 to 13.1 per million women. Between 1974 and 1988 when specific diagnoses were coded, deaths from oesophageal ulcer rose from 1.5 to 2.5 per million. In men, the death rate from oesophageal stricture increased from 2.5 to 3 per million and in women from 3.5 to 6 per million. Mortality from oesophageal perforation did not change (1 per million). Some of these changes reflect the increasing age of the population in general, but further explanations are required. Review of 84 sets of case notes from a total of 281 inpatients whose coded diagnoses had included NMOD and who had died suggested that in 28 (33%) death was actually due to NMOD, and in seven of these endoscopic intervention was responsible. The certified underlying cause of death was compared with that suggested from case note review in 62 cases; death from NMOD was substantially underestimated. This study concludes that a rising death rate attributed to NMOD is underestimated on death certificates and that endoscopic intervention explains only a few of the cases.
PMCID: PMC1382484  PMID: 7737551
4.  Use of automatic computerised pump to maintain constant intragastric pH. 
Gut  1990;31(11):1246-1249.
We used continuous variable rate infusions of famotidine in eight normal volunteers under fasting conditions to raise intragastric pH to 5.0. An intragastric glass electrode continuously monitored acidity and this information was automatically computed to regulate an intravenous infusion system (GastroJet). The computer was programmed to aim for pH 6.0, increasing and lowering infusion rates accordingly. Two regimens were compared with placebo (10 mg bolus followed by infusion or infusion of famotidine alone). Volunteers were admitted to an investigation ward and each study was preceded by a standard normal meal. Hydration was maintained with intravenous fluids. During placebo treatment the median pH was 1.5 and the pH was less than 5.0 for 98% of the time. All volunteers responded to famotidine but dosage requirements varied (range 41 mg to 126 mg). The median pH rose to 6.5 when infusions of famotidine followed boluses and to 6.6 when infusions alone were used - the pH was less than 5.0 for 20% and 16% of the time respectively (p less than 0.05 Wilcoxon compared with placebo). Mean drug use was greater with boluses (98 mg v 87 mg p = 0.03: paired Student's t test) and onset was not apparently faster. Blood famotidine concentrations followed infusion rate changes. Famotidine infused by GastroJet maintains a high fasting intragastric pH and priming boluses are probably unnecessary.
PMCID: PMC1378693  PMID: 2253907
5.  Effect of Wy-45,727 on 24 h intragastric acidity in twenty normal volunteers. 
1. The effects of single daily doses of 20, 50 and 150 mg of WY-45,727, a novel H2-receptor antagonist, and placebo were compared using long term pH-monitoring in 20 male volunteers. 2. Intragastric acidity was measured using combined Ingold glass electrodes. Subjects underwent four studies each under identical dietary conditions. Medication was taken after the evening meal. 3. Median 24 h pH rose from 1.3 (1.2-1.4 interquartile range) on placebo to 1.9 (1.6-2.8) on 20 mg WY-45,727, to 3.1 (2.3-3.7) on 50 mg WY-45,727 and to 4.5 (3.7-4.7) on 150 mg WY-45,727. All three doses increased 24 h and night-time pH significantly compared with placebo (P less than 0.0001). 4. The PAGE test for order effects confirmed clear dose dependent inhibition of acidity (P less than 0.0001). 5. Highly consistent individual responses were found during the night following 150 mg WY-45,727.
PMCID: PMC1379772  PMID: 2565728
6.  Vitamin A treatment for night blindness in primary biliary cirrhosis. 
Three patients with late stage primary biliary cirrhosis were found to have appreciable night blindness. Serum vitamin A concentrations were low in all three patients despite regular intramuscular supplementation in two. All patients responded dramatically to high dose oral supplementation, with full recovery of adaptation to dark and visual fields. Oral rather than intramuscular vitamin A supplementation seems appropriate in the prevention of ocular complications of vitamin A deficiency in biliary cirrhosis.
PMCID: PMC1442628  PMID: 6423181
7.  Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. 
Ten healthy volunteers were studied before, during, and after treatment with omeprazole 30 mg daily for two weeks. On the 14th night mean nocturnal (2100-0700) intragastric acidity was significantly decreased by 75% (p less than 0.001). At 0700, 22 hours after the last dose of omeprazole, there were significant increases in the bacterial count and the nitrite and N-nitrosamine concentrations in the gastric juice (p less than 0.001). Three days later these changes had resolved. Short term treatment of healthy volunteers with omeprazole is associated with a short lived increase in the gastric bacterial flora, with endogenous production of N-nitroso compounds.
PMCID: PMC1442819  PMID: 6434053
8.  Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine. 
1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.
PMCID: PMC1380019  PMID: 2590612
9.  Effect of food on H2-receptor blockade in normal subjects and duodenal ulcer patients. 
Gut  1990;31(2):148-150.
Two separate studies of 24 hour intragastric acidity were carried out in normal volunteers and duodenal ulcer patients to define the interaction of food and the antisecretory effects of H2-receptor blockers. Both investigations were double blind randomised comparisons using ranitidine 300 mg with either different meal times or ad libitum snacks after an evening meal. Meals taken after drug administration nearly abolished measurable antisectory effects. Median 24 hour pH was 1.3 on placebo, 2.6 when ranitidine was administered after the evening meal and 1.9 when administered before the evening meal. Snacks taken after evening dosing with ranitidine also significantly decreased pharmacodynamic efficacy. During placebo, median night-time pH was 1.3 without snacks and 1.4 with snacks. pH rose to 5.9 during ranitidine treatment when snacks were forbidden but was only 3.1 when snacks were allowed. These findings could be of therapeutic importance and should rationalise dietary advise to patients receiving H2 blockers. The timing of drug administration can be adjusted according to individual life styles.
PMCID: PMC1378369  PMID: 2179066
10.  Devastating diarrhoea caused by azathioprine: management difficulty in inflammatory bowel disease. 
Gut  1988;29(5):686-688.
Azathioprine toxicity complicated the management of four patients with inflammatory bowel disease. All patients received the drug as adjunctive therapy to steroids when responses to the latter were poor. After a variable sensitising period the patients developed severe diarrhoea and abdominal pain and this was believed at first to be a manifestation of their underlying diseases but rechallenge with azathioprine reproduced the problem. During three episodes described emergency admission to hospital and resuscitation with intravenous fluids was required. The cases illustrate the difficulty clinicians have in recognising drug induced effects which mimic the underlying disease. When a patient suspects a reaction to azathioprine we believe any rechallenge should only be undertaken in the controlled hospital environment.
PMCID: PMC1433640  PMID: 3396955
11.  Intravenous omeprazole rapidly raises intragastric pH. 
Gut  1985;26(9):902-906.
Twenty four hour intragastric acidity was measured in five duodenal ulcer patients studied at least three times. The effects of different dosage regimens of intravenous omeprazole was compared with placebo. Mean intragastric acidity from 1000 to 0800 was 34.3 +/- 4.3 mmol/l on placebo. After omeprazole 80 mg at 0900 and 40 mg at 1700 mean acidity was 2.1 +/- 0.9 mmol/l and after omeprazole 80 mg at 0900 and 80 mg at 1700 it was 0.7 +/- 0.2 mmol/l. pH remained above 4.0 for about 80% of recordings with these regimens and for only 5% with placebo. Three of the five patients also received omeprazole 80 mg at 0900, 40 mg at 1700 and 40 mg at 0100 when pH remained above 4.0 for 90% of recordings with 99% inhibition of acidity. Omeprazole rapidly raised intragastric pH in all patients and maintained a gastric pH of greater than 4.0 for most of the time. Large doses of IV omeprazole were required compared with studies using the oral compound.
PMCID: PMC1432870  PMID: 4029717
12.  The effect of ranitidine on the plasma clearance and hepatic extraction of indocyanine green in patients with chronic liver disease. 
Since hepatic clearance of ICG is reduced by H2-receptor antagonists in normal subjects, it has been suggested that they reduce liver blood flow. We have studied the effect of intravenous ranitidine on ICG clearance in twelve patients with chronic liver disease. Wedged and free hepatic venous pressure were measured before and after intravenous ranitidine in nine of the patients, and the hepatic extraction of ICG was determined in six patients. ICG clearance fell by 22 +/- 11% (s.e. mean) 60 min after ranitidine. In patients in whom ICG clearance fell after intravenous ranitidine the hepatic extraction of ICG was also reduced. There was no significant change in the gradient between wedged and free hepatic venous pressure after ranitidine. It is therefore unlikely that ranitidine lowers liver blood flow.
PMCID: PMC1427973  PMID: 6137230
13.  Effect of daily oral omeprazole on 24 hour intragastric acidity. 
Twenty four hour intragastric acidity was measured in nine patients with duodenal ulcer before and after one week of treatment with oral omeprazole 30 mg daily, a drug that inhibits gastric secretion by inhibition of parietal cell H+K+ adenosinetriphosphatase (ATPase). Omeprazole virtually eliminated intragastric acidity in all patients: the median 24 hour intragastric pH rose from 1.4 to 5.3 and the mean hourly hydrogen ion activity fell from 38.50 to 1.95 mmol(mEq)/1 (p less than 0.001). This inhibition of 24 hour intragastric acidity is more profound than that previously reported with either cimetidine 1 g daily or ranitidine 300 mg daily.
PMCID: PMC1548155  PMID: 6407676
14.  Effect of transdermally administered hyoscine methobromide on nocturnal acid secretion in patients with duodenal ulcer. 
Use of anticholinergic drugs in treatment of duodenal ulcers is limited by the side effects of widespread parasympathetic blockade evoked by usual therapeutic doses. A study was conducted into the effectiveness of transdermal delivery of hyoscine methobromide using a new system which releases the drug into the circulation at a controlled rate. In six patients whose duodenal ulcer had healed secretion of acid was measured over two nights, the first on placebo and the second on hyoscine methobromide. All patients responded to the active drug and showed a significant inhibition of acid secretion. Four subjects complained of a dry mouth after overnight treatment with hyoscine methobromide; no other side effects were reported. Transdermal delivery of anticholinergic drugs may be useful in maintenance treatment of duodenal ulcers and further clinical tests are indicated.
PMCID: PMC1498662  PMID: 6805690
15.  Comparison of twice-daily ranitidine with standard cimetidine treatment of duodenal ulcer. 
Gut  1981;22(4):319-322.
One hundred and three outpatients with endoscopically diagnosed duodenal ulcer were randomly allocated to treatment with either cimetidine 200 mg tds and 400 mg nocte, or ranitidine 150 mg bd for four weeks. The endoscopists were not aware of the treatment and took no part in the clinical management. On completion of treatment ulcers had healed in 43 of 51 (84%) patients given cimetidine and in 40 of 52 (77%) patients given ranitidine. There were no serious unwanted effects in either treatment group. The results show no significant difference between healing rates after four weeks of standard cimetidine therapy or ranitidine 150 mg bd.
PMCID: PMC1419156  PMID: 6113192
18.  Lack of effect of H2-receptor antagonists on the pharmacokinetics of alcohol consumed after food at lunchtime. 
The possibility of a pharmacokinetic interaction between H2-receptor antagonists and alcohol consumed at lunchtime, was investigated in 24 healthy non-alcoholic male subjects, each receiving ranitidine 150 mg four times daily, cimetidine 400 mg four times daily, famotidine 20 mg four times daily and placebo in an open, four-way cross-over study. The subjects consumed 50 g alcohol after a standard lunch on the eighth day of dosing with study medication. Blood samples taken during the 6 h after alcohol consumption were analysed for alcohol concentrations by gas liquid chromatography using head space analysis. None of the H2-receptor antagonists had any statistically significant effects on any of the pharmacokinetic parameters for alcohol. Mean Cmax (95% CI) results for ranitidine were 547 (516, 580), cimetidine 531 (501, 563), famotidine 563 (530, 598) and placebo 529 (499, 561) mg l-1.
PMCID: PMC1364738  PMID: 8018458
19.  Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. 
BMJ : British Medical Journal  1992;304(6820):143-147.
OBJECTIVE--To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN--Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING--The medical wards of University and City Hospitals, Nottingham. SUBJECTS--1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES--Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS--Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS--Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.
PMCID: PMC1881159  PMID: 1737157
20.  Pattern of 24 hour intragastric acidity in active duodenal ulcer disease and in healthy controls. 
Gut  1988;29(11):1583-1587.
Twenty four hour intragastric acidity was measured by continuous recording using intragastric combined glass electrodes in 46 duodenal ulcer patients within 48 hours of endoscopic confirmation of active ulceration. Acidity during predefined time periods was compared with that measured in 40 healthy controls without gastrointestinal disease: it was significantly higher in duodenal ulcer patients at all times, but 25% of ulcer patients had median 24 hour acidity within the interquartile range of the normal group. During the evening (18,00 to 22,00 h) ulcer patients had considerable acidity with a median of 39.8 (63.1-31.6) mmol/l (interquartile range) compared with 5.6 (22.3-0.4) mmol/l of controls. It is suggested that antisecretory treatment be directed to decrease this period of unbuffered acidity, as well as during the night, which is presently considered of prime importance.
PMCID: PMC1433850  PMID: 3209116
22.  Oral phenytoin pharmacokinetics during omeprazole therapy. 
1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.
PMCID: PMC1386318  PMID: 3689634
23.  Continuous intravenous infusions of famotidine maintain high intragastric pH in duodenal ulcer. 
Gut  1988;29(4):453-457.
Three double blind crossover studies were carried out to assess the ability of primed infusions of famotidine to raise intragastric pH over 24 hours in 12 duodenal ulcer patients. pH was measured continuously using intragastric electrodes and solid state recording devices. The studies compared the effects of placebo, famotidine 10 mg bolus injection iv followed by continuous infusions of 3.2 mg/h and 4 mg/h in random order. Gastric acidity decreased significantly with both dose regimens (p less than 0.0005) but the effects of either dosage were similar. During fasting median pH rose from 1.35 to 7.1 and 7.05 respectively. During the day, when standard meals were taken, median pH rose from 1.30 to 4.3 and 3.65 respectively. Despite continuous infusions the H2-antagonist was less effective during this time. The latter finding raises questions about gastric secretory control during the day when food is eaten.
PMCID: PMC1433542  PMID: 3286384
25.  Double blind comparison of the effects of cimetidine, ranitidine, famotidine, and placebo on intragastric acidity in 30 normal volunteers. 
Gut  1988;29(1):81-84.
Continuous measurement of 24 hour intragastric acidity was carried out in 30 normal volunteers during treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, and famotidine 40 mg in a double blind study. Medication was taken after the evening meal (post cenam nocte, PCN). Median 24 hour acidity decreased with all H2-receptor antagonists from 25.1 mmol/l on placebo to 10 mmol/l (-60.1%) during cimetidine, to 3.2 mmol/l (-87.25%) during ranitidine and to 2.5 mmol/l (-90.0%) during famotidine treatment (p less than 0.0005). All drugs significantly inhibited night time acidity but only famotidine decreased acidity during the late morning compared with placebo. Significantly greater acid reduction was seen with famotidine and ranitidine compared with cimetidine but no difference was found between famotidine and ranitidine.
PMCID: PMC1433250  PMID: 2893761

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