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A previous report analysed the pattern of mortality during the first year of follow up among 9928 patients taking cimetidine who were recruited to a postmarketing drug surveillance study in Glasgow, Nottingham, Oxford, and Portsmouth. A further analysis has now been conducted extending the period of follow up to four years. The 12 month report noted that cimetidine was being given, knowingly or unknowingly, in the late stages of many diseases and also to counter the adverse gastric effects of other drugs used in the treatment of serious disorders. This finding was underlined by a steady fall in the excess death rate among cimetidine users with increasing length of follow up, such that by the fourth year the pattern of observed deaths was not much different from that expected on the basis of national rates. Some excess of observed over expected deaths from gastric cancer, lung cancer, and urinary disorders was still apparent after four years of follow up, but there was no evidence that cimetidine was responsible. Indeed, no fatal disorder emerged as being associated with cimetidine during the follow up period. Deaths from the complications of disease related to gastric acid occurred in only 38 of the 9928 subjects over the four years. These findings provide further evidence of the safety of cimetidine.

The intake of anti-inflammatory drugs by 268 patients with colonic or small bowel perforation or haemorrhage was compared with that by a group of patients, matched for age and sex, with uncomplicated lower bowel disease. Patients with perforation or haemorrhage were more than twice as likely to be takers of anti-inflammatory drugs, but no association was detected with the intake of other types of drugs, particularly cardiovascular drugs. The association between complicated lower bowel disease and intake of anti-inflammatory drugs may be causal.

A comparison of aspirin and acetaminophen consumption in 346 matched pairs of patients with hematemesis and melena and general population control subjects has shown associations between intake of both drugs and bleeding. The association for acetaminophen was weaker and was not detectable for habitual intake, whereas the association for aspirin was detectable for recent and habitual intake. Taken overall, the results suggest, by reference to acetaminophen, that patients frequently take analgesic drugs because of the symptoms of bleeding, and such intake is not causal of bleeding. Investigators who fail to employ appropriate control subjects to take account of this point exaggerate the possible risks of aspirin consumption.

A total of 9928 patients taking cimetidine and 9351 controls were recruited to a postmarketing drug surveillance study in Glasgow, Nottingham, Oxford, and Portsmouth. Takers were identified by the Prescription Pricing Bureau at Nottingham and by dispensing pharmacists at the other three centres. All but 1.2% of the takers and 1.6% of the controls were successfully followed up for one year during which hospital visits and deaths were recorded. Three hundred and seventy five of the cimetidine takers and 198 of the controls are known to have died. Most of the difference in mortality was accounted for by an excess among the takers of deaths from cancers of the oesophagus, stomach, colon, and lung; from neoplasms of the lymphatic and haematopoietic system; and from ischaemic heart disease, chronic liver disease, and accidents and poisonings. So far as can be assessed, however, none of these drug-disease associations represented adverse effects of cimetidine treatment; on the contrary, they resulted from cimetidine being used, knowingly or unknowingly, for treating the symptoms of various diseases or for alleviating adverse effects of other agents such as corticosteroids, non-steroidal anti-inflammatory drugs, and radiotherapy. No evidence of any fatal adverse effects of cimetidine emerged in this study.

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.

Unpublished data from the Hospital In-patient Enquiry in England, Wales, and Scotland between 1958 and 1972 show that the frequency of admissions to hospital for peptic ulcer, particularly gastric ulcer, has fallen. This seems more likely to have been due to a true fall in the incidence of ulcer than to changes in treatment. Some three times as many people are admitted to hospital with duodenal ulcer in the north as in the south, but the frequency of admissions for gastric ulcer seems to vary little. The reasons for these differences are not understood.

Aspirin and paracetamol consumption have been compared in 346 matched pairs of patients with haematemesis and melaena, and control individuals in the general community. Both aspirin and paracetamol intake were more common in patients than in controls, but the association for aspirin was stronger and was apparent with both recent and habitual intake, whereas for paracetamol the association was not detectable for habitual intake. The results for paracetamol suggests that patients with bleeding take analgesic drugs in part because of symptoms associated with bleeding, and such intake is not necessarily causal of bleeding. Failure to control investigations to take account of this point has exaggerated the possible risks of aspirin consumption.

In a case-control study 142 patients with Crohn's disease, 189 patients with ulcerative colitis and matched community controls were questioned about their smoking habits. When assessed by smoking habits before the onset of disease, patients with Crohn's disease were four times as likely to have been smokers than their matched controls. In contrast, patients with ulcerative colitis were ten times less likely to have been smokers compared with their matched controls. There was no confounding by social class or alcohol intake differences. The contrasting nature of these associations suggests that there might be an aetiological role for smoking in inflammatory bowel disease.

Examination of Coeliac Society records from eight areas of England has shown that the number of members rose with birth dates from 1900 to 1972, apart from a decline between 1941 to 1962, and then fell steeply. The steep decline in the number of members with birth dates after 1972 is unexplained, and is unlikely to be accounted for by change in diagnostic practice or registration and may reflect a true fall in disease incidence; but the fall in numbers of members with birth dates from 1941 to 1962 is explainable by a tendency for the disease to remit in adolescence or early adult life.

A study was conducted to find whether the higher diagnostic yield of endoscopy compared with barium radiography improves management or survival in patients with acute upper gastrointestinal bleeding. A total of 1037 patients were entered into a randomised study comparing the outcomes after each investigation. The diagnostic yield in patients who underwent endoscopy was 73% (382 of 526 cases) and in those examined by radiography 55% (280 of 511 cases). A fifth of the patients in the radiology group and a tenth of those in the endoscopy group subsequently underwent the alternative investigation; in most cases, however, no additional diagnostic information was obtained. Operation rates were similar in two groups, though patients in the endoscopy group were generally operated on sooner. Mortality rates were also similar in the two groups, though postoperative mortality was higher in the endoscopy group. Endoscopy may be a more accurate means of diagnosis than radiography, but it offers no short-term benefits in management.

Twenty-eight patients with histologically confirmed cirrhosis were followed for up to 3.8 years after [14C]aminopyrine breath analysis. Survival rates were calculated by life-table method and outcome analyzed by log rank test. A normal breath test score was associated with a higher probability of survival than a low score, although the difference was not statistically significant. A normal serum albumin was a better predictor of outcome. Survival curves constructed according to the results of breath analysis and serum albumin differed in that the former appeared to predict early survival and the latter late survival. For this reason, data were reanalyzed by subjects' results for both tests. A normal breath test score and a normal serum albumin was associated with a significantly higher probability of survival than an abnormal result for either test.

Recent data have confirmed that changes in ulcer frequency, at least as measured by altered mortality and perforation rates, continue in the United Kingdom. The causes are largely unclear. Decreases in younger men may be associated with reduced cigarette consumption and increases in the elderly at least in part with non-steroidal anti-inflammatory drug consumption.

Mortality and hospital admission rates for peptic ulcer in England and Wales have fallen in the past twenty years. Within this pattern there has been a wide range of variation. Perforated ulcers have become less common in young adults, and perforated gastric ulcers in young men now occur with between a quarter and a tenth of their previous frequency. Perforated duodenal ulcer has become more common in middle-aged and elderly women. The reasons for these changes are not understood, but they are likely to reflect the impact of environmental influences on people of different ages.

The outcome in 1017 patients with haematemesis and malaena referred to two major hospitals in Nottingham within a 2-year period has been prospectively evaluated. Ninety one (9%) patients died during the time period under consideration and all but four were found to have been over 60 years of age. There were 13 (14%) deaths following rebleeding, of whom 5 (5%) could have been potentially avoided by alterations in management. Some improvement of mortality might result from intensive-care facilities with better management of transfusions and earlier detection of rebleeding allowing earlier endoscopy or surgery. The majority of patients (81%), however, died from concomitant disease which was exacerbated by gastrointestinal haemorrhage or bleeding developed in patients with an already existing end-stage disease. These results show that a reduction of mortality in patients with gastrointestinal bleeding is hampered by the high number of poor-risk patients. The rise in the proportion of elderly patients with this disorder seems to continue.

We examined all available data on HLA-A and -B antigen distributions in patients with Crohn's disease and ulcerative colitis. The risk of Crohn's disease was significantly increased in individuals with HLA-A2, having a relative risk of 1.25, in 730 pooled Caucasoid patients compared with 10 863 pooled controls, and decreased in individuals with HLA-A11, having a relative risk of 0.62. The risk of ulcerative colitis was also significantly increased in individuals with HLA-B27 and -Bw35, having a relative risk of 1.81 and 1.41 respectively, in 560 pooled Caucasoid patients compared with 6151 pooled controls, whilst in 144 pooled Japanese patients who were compared with 442 pooled controls, the risk of colitis was increased in individuals with HLA-B5 with a relative risk of 2.79. All differences remained significant after correction for the number of antigens examined. The bases for these genetic associations are unclear.

The fragmentary knowledge of gastric ulcer aetiology is contrasted with the developing repertoire of short term drug treatments. Reasons are also advanced for believing that gastric ulcer may be a disease of diminishing importance and that this is due to environmental changes rather than to the introduction of effective treatments.

Comparison by equilibrium dialysis of plasma protein binding sites for carbenoxolone in people under 40 years of age and in people over 65 years of age showed that the number of binding sites was reduced in the elderly and that this fall was associated with a reduction in plasma albumin levels. Although carbenoxolone has some aldosterone-like effects, these properties could not be shown to be due to displacement of aldosterone from its protein binding sites by competitive protein binding of carbenoxolone. Single doses of carbenoxolone were found to be removed considerably more slowly from the plasma of elderly individuals than from the young. The results of these three series of experiments suggest that the side-effects of carbenoxolone in the elderly may in part be caused by reduced protein binding, leaving more free drug in the active unbound form, and in part by reduced hepatic clearance mechanisms.

It is plausible that, for pharmacologic and physiologic reasons, antisecretory treatment reduces the chances of rebleeding from gastric and duodenal ulcers and thereby reduces operation and death rates. Currently available evidence is not strong enough to confirm this, in part because trials have been too small to detect any differences present, and perhaps in part because drug doses have been too low to achieve the desired antisecretory potential.

Paired studies of hepatic microsomal function were conducted in eight subjects during treatment with two histamine H2 antagonists, cimetidine and ranitidine. Cimetidine but not ranitidine inhibited the metabolism of antipyrine (phenazone) and demethylation of aminopyrine (aminophenazone) as measured by breath 14CO2 production after intravenous injection of 14C-aminopyrine. These results suggest that the metabolic inhibitory actions on the liver may be separated from H2 antagonist effects, and that ranitidine has an advantage over cimetidine by not inhibiting microsomal drug oxidative function.

Chronic cyanide intoxication of dietary origin and riboflavine deficiency are believed to be major aetiological factors in Nigerian tropical ataxic neuropathy. The results are presented of a double-blind controlled therapeutic trial of combinations of large doses of hydroxocobalamin and cystine as cyanide binding agents together with riboflavine or placebos in Nigerian patients suffering from the tropical ataxic neuropathy. No clinical benefit was demonstrable with any of the treatments.

Five cases of coincident salmonellosis and ulcerative colitis are described. In three the diagnostic combination was recognized late. If corticosteroid therapy is given for the colitis once the combination is recognized, then simultaneous systemic antibiotic cover is advisable. One of the five patients died during corticosteroid therapy alone with salmonella septicaemia due to a usually non-invasive organism.

Patients with subacute combined degeneration who smoked had significantly lowered plasma thiocyanate levels than control smokers, but plasma thiocyanate levels in non-smoking patients with neurological disease due to vitamin B(12) deficiency were not significantly different from control values. The results provide no support for the hypothesis that chronic cyanide intoxication is responsible for the occurrence of neurological disease in a minority of patients with vitamin B(12) deficiency, although they do not conclusively exclude this possibility. The association between smoking and subacute combined degeneration of the cord has been confirmed in this study but it remains unexplained.

In 68 patients with chronic gastric ulcer treated in an outpatient clinical trial with either carbenoxolone or gefarnate ulcer healing was consistently greater during carbenoxolone treatment, even though the dose of gefarnate was ultimately increased to four times that recommended. One-third of the patients receiving carbenoxolone gained weight rapidly and unexpectedly, and were given diuretic treatment, compared with two of the 35 patients receiving gefarnate, neither of whom developed clinical oedema.

Comparison of the ABO blood groups of patients with all forms of gastric cancer and of those with gastric cancer preceded by pernicious anaemia has shown no differences between them. This finding supports the concept that blood group has a single effect associated with an underlying factor predisposing to either disease.

Lymphocyte responses to stimulation with phytohaemagglutinin (PHA) have been compared in 20 patients with large intestinal cancer, 10 patients whose large intestinal cancers have been removed, and in 30 age- and sex-matched control individuals. Responses were markedly reduced in the tumour-bearing patients and were unaffected by substituting normal for autologous plasma during incubation. Responses, however, were normal after tumour resection suggesting that the defect in lymphocyte responsiveness is a reversible one and related to the presence of tumour tissue.