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Previous studies have consistently found strong positive associations between refined sugar intake and Crohn's disease (CD) and recently between smoking and CD. As refined sugar intake and smoking are themselves associated we have enquired about smoking and added sugar intake (AS) and smoking in CD using a postal questionnaire sent to 104 CD patients and 153 community controls. Smoking and AS were associated with one another. After adjusting for AS, smoking showed a significant association with CD with a relative risk of 1.8. After adjusting for smoking habit, AS was also strongly associated with CD in never and exsmokers and in a dose response pattern, with the relative risks for no AS, less than 50 g/day and greater than 50 g/day being respectively 1.0, 1.8, and 4.6 (chi 2 = 12.1; p less than 0.005). No association between CD and AS was evident in smokers. The AS relationship was supported by a separate association between frequency of confectionery consumption and CD. These findings indicate that while smoking and AS are individually associated with CD combined exposure results in no further increase in risk, suggesting that they may operate through a common mechanism.

Famotidine, a new H2-receptor antagonist was tested for drug interactions using 14C-aminopyrine and antipyrine. Elimination of these model drugs was studied before and during 8 days of famotidine dosing in 8 healthy volunteers. Famotidine 40 mg b.d. did not inhibit aminopyrine 14CO2 half-life or antipyrine clearance although an unexpected mild enzyme inducing effect could not be excluded. It is unlikely that famotidine will inhibit hepatic drug metabolism during routine clinical use as the daily dose is expected to be 40 mg/day but interactions should be looked for if more prolonged or larger doses are used.

Searches for useful medical treatments for upper gastrointestinal bleeding have generally ignored the need for very large case numbers if useful effects are to be detected. Available results are compatible with clinically valuable treatment effects, which can only be detected if present in very large studies.

1 A decrease was found in the binding capacity of elderly people for warfarin. 2 The decrease in binding correlated with a fall in plasma albumin concentrations. 3 No changes in the association constant were observed.

Gastroenterologists believe that non-steroidal anti-inflammatory drugs (NSAIDs) cause dyspepsia, may cause ulcers to develop de novo and cause ulcer bleeding and perforation. Regulatory authorities are aware that NSAID-associated adverse events are reported more often than for any other drug class, and that gastrointestinal events are most common and often serious. A case-control study in the UK indicates that those who use NSAIDs may be between two and four times as liable to gastrointestinal bleeding and probably perforation as non-users, particularly if elderly. It has further been suggested that the chances of dying of ulcer complications are very high in NSAID users. By contrast, studies in the USA conducted prospectively and post-marketing surveillance in the UK have appeared to show little risk. Differences may be partially, if not completely, explained by the variable methodologies employed. Dispute also exists about the rank order and significance of toxic effects among the various agents.

The outcome in bleeding gastric and duodenal ulcer has been compared in two hospitals in Nottingham which take their patients randomly from a common source according to a fixed daily admission rota. Bleeding seemed equally severe in the two groups but 66 (32%) of 206 patients were operated upon at hospital A compared with 44 (46%) of 96 at hospital B (P=0.03), where operations also tended to be done earlier. Postoperative mortality-rates were virtually identical at the two hospitals, but at hospital B the overall death-rate from bleeding ulcer was higher, partly because of its higher operation-rate. The value of an aggressive surgical policy in bleeding peptic ulcer is questionable.

During 1975-80, 908 patients admitted to Nottingham hospitals with gastrointestinal bleeding and found to have gastric or duodenal ulcers were analysed retrospectively for short-term outcome of treatment. Overall one-quarter of all patients underwent operation, but when the years 1975-7 were compared with 1978-80 the operation rate fell from one in three to just over one in five. Death rates were much lower in patients treated medically than in those who underwent operation, and the risks of operation were greater for patients with gastric ulcer. Less conventional operations were attended by greater mortality. Almost all patients who died during medical treatment and three-quarters of those who died after operation were over 65. No differences in age or clear variations in haemoglobin concentrations or transfusion requirements were found between the earlier and later periods. Reduction in operation rates had no appreciable effect on mortality, despite the accepted view that early operation is advisable.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and some 24 million prescriptions are issued for them each year in the United Kingdom. Although animal and human experimental studies can yield confusing and disparate findings, complaints of gastro-intestinal side effects are common, and spontaneous reports of serious gastro-intestinal adverse effects of NSAIDs form by far the most commonly reported variety to the United Kingdom's Committee on the Safety of Medicines. Experimental suggestions that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) cause gastritis and erosions have been overshadowed by evidence that takers of NSAIDs tend to develop serious complications with acute bleeding and perforations of duodenal and gastric ulcers. Findings in clinical case series that a third or more of patients with bleeding or perforated ulcers have been taking non-aspirin NSAIDs contrast with the outcome of surveillance studies where, in sets of 10,000 takers of such drugs, there appeared to be no material differences in ulcer complication rates in takers and non-takers. Data obtained in formal case control studies however, have suggested a relative risk which is increased by between two- and four-fold in non-aspirin NSAID takers for both gastric and duodenal ulcer in elderly people. The findings in case-control and surveillance studies can be reconciled by taking account of the very large numbers of prescriptions for non-aspirin NSAIDs issued each year, now approaching 24 million in the United Kingdom.(ABSTRACT TRUNCATED AT 250 WORDS)

A case-control study was performed to determine whether aspirin confers a similar risk of bleeding from gastric or duodenal ulcers in the elderly as non-aspirin, non-steroidal anti-inflammatory drugs. The intake of analgesics in 230 patients with bleeding ulcers aged 60 and over and in hospital and community controls matched for age and sex was examined. Those who had taken aspirin were between two and three times more likely to be admitted to hospital with bleeding ulcers. This increased risk was not accounted for by aspirin taken for indigestion or by concurrent use of non-aspirin, non-steroidal anti-inflammatory drugs. A similar effect was not seen for paracetamol. When aspirin and other non-steroidal anti-inflammatory drugs were considered together the overall risk attributed to the drugs suggested that these drugs may be responsible for over a third of admissions for bleeding peptic ulcers in the elderly.

Hourly gastric aspiration has commonly been used to assess the efficacy of antisecretory compounds. We have compared continuous ambulatory 24-hour pH monitoring using a radiotelemetry capsule with standard nasogastric aspiration. Eight studies were performed on four male duodenal ulcer patients in remission receiving either placebo or an antisecretory agent. A significant correlation was found between capsule and aspirate pH measurements (r = 0.88, p less than 0.01). Radiotelemetry capsule measurements clearly showed the onset of action of an antisecretory drug, and the buffering effect of food. Radiotelemetric pH monitoring is shown to be as good as gastric sampling in the measurement of 24-hour intragastric acidity, allows continuous measurement of pH during normal activity and can accurately assess the effect of drugs on gastric acidity.

Adverse effects associated with nonsteroidal antiinflammatory drug treatment are reported more commonly to regulatory authorities than the adverse effects of any other form of treatment. Epidemiologic evidence in general suggests a doubling or quadrupling of the risk of ulcer complications or death in recipients of such treatment. The risk appears to be related to increasing age, but no other associated factor has yet been identified. It is uncertain whether individuals with preexisting ulcer are at special risk or whether treatment predisposed equally to ulcer and ulcer complications, and there is no clear evidence that the nature of the disability leading to nonsteroidal antiinflammatory drug treatment influences the risk of gastrointestinal complications.

Rates of ulcer perforation, hospital admission, and death are usually regarded as the best available measures of the frequency of severe peptic ulcer disease. Overall admission rates have tended to decline, which almost certainly reflects the widespread adoption of effective outpatient therapy. The overall incidence of ulcer perforation and death may also have fallen. However, at least in Europe, and in the United Kingdom in particular, there may be differences between the young and the elderly; rates of perforation and death in the young appear to be declining, whereas they are rising or static in the elderly. Although there are various interpretations for these changing patterns, data for the United Kingdom suggest that during the last 15 to 20 years some unidentified factor or factors began to influence the rates of severe peptic ulcer disease among the elderly. At least part of this change may reflect increasingly frequent prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs). In the United Kingdom, most adverse drug reactions attributable to NSAIDs are gastrointestinal and are usually serious. Bleeding and perforation are common, may occur in the absence of warning symptoms, and are associated with a high mortality rate. In some countries, other factors, including smoking and diet, may be equally important. It is difficult to determine the relative contribution of each factor, though the widespread perception that the gastrointestinal tolerance of NSAIDs is poor, particularly in the elderly, may be well founded. About half the prescriptions for non-aspirin NSAIDs in the United Kingdom are for patients over 60 years of age. About one quarter of all cases of upper gastrointestinal bleeding in the elderly are likely caused by NSAIDs and are associated with a death rate of 10 percent or possibly higher. Although the absolute risk of a serious gastrointestinal complication may be low, perhaps one in several thousand NSAID prescriptions, the total burden of disease is high because of the multimillion NSAID prescriptions issued yearly.

The anal skin tags of a young man with ileal and perianal Crohn's disease underwent malignant transformation. This was not associated with immunosuppressive drug therapy and has not been previously described.

Surveillance of takers of the antisecretory drug cimetidine has failed to reveal any disturbing trends. This pattern is reassuring but the difficulties of detecting drug-induced disease mimicking ordinary community complaints deserve emphasis. Experience since the surveillance study began has not revealed any disturbing trends. Observed mortality rates have fallen to match population expectation, both for ordinary disease and for cancer. The pattern is generally reassuring and suggests that significant drug-induced disease is not being missed. Nevertheless the ability of this or any other surveillance study to detect drug-induced illness mimicking ordinary disease is likely to be low.

Despite generally held beliefs to the contrary, worthwhile improvements in outcome in patients with haematemesis and melaena may be achievable with H2 antagonist or antifibrinolytic treatment.

Experience obtained during post-marketing surveillance of the safety of cimetidine emphasizes the difficulties in interpretation posed by the high background frequency of disease of all types in drug takers. The multiple sources of confounding factors, and their high prevalence, make it impossible to detect adverse events which mimic ordinary disease, particularly when a consistent relationship between adverse event and drug exposure is not observed. The inclusion of controls emphasizes the difficulties but does not ease interpretation.

Intragastric pH was measured continuously from 1800 to 1200 hours the following day in 22 duodenal ulcer patients and in eight gastric ulcer patients, all of whom had been admitted as emergencies with acute upper gastrointestinal haemorrhage. The effects of intravenous cimetidine or ranitidine were compared with no treatment. In patients with duodenal ulcer, median intragastric pH was 1.8 (range 1.0-4.9) in the group receiving no treatment. In the cimetidine group (400 mg, 6-hourly, n = 8) median pH was 4.7 (range 1.5-7.7) and after ranitidine (50 mg, 6-hourly, n = 10) it was 3.8 (range 1.2-7.8). The pH remained above 4.0 for 67% of the recording time with cimetidine, 47% with ranitidine and for only 3% with placebo. Intragastric pH in gastric ulcer patients without treatment was higher (median 3.4, range 1.0-6.9) than in duodenal ulcer patients with treatment. Both H2 antagonists raised intragastric pH in patients with gastric ulcer and maintained a gastric pH of greater than 4.0 for at least 50% of the time. Presently recommended i.v. doses of cimetidine and ranitidine do not consistently maintain gastric pH above 4.0 for long periods in patients with peptic ulcer bleeding.

All cases of Crohn's disease in the Nottingham area were ascertained and dates and places of domicile and work before and after onset of symptoms were noted. Similar information was taken from matched control subjects and the Pike and Smith (Biometrics 30:263-279, 1974) case control technique for evaluating clustering of patients in time and space was applied. These results do not support the infectious hypothesis.

This international case control study was conducted in 14 centers in 9 countries to investigate factors in childhood which may have a bearing on the etiology or pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). 197 patients with UC and 302 with CD (499 with inflammatory bowel disease (IBD] whose disease started before age 20 years and whose age at time of study was less than 25 years were investigated, with two age- and sex-matched controls for each patient. All subjects were studied with uniform questionnaires. Eczema was found significantly more frequently in patients with CD (p less than 0.005) and in their fathers (p less than 0.025), mothers (p less than 0.002), and siblings (p less than 0.01) as compared with their respective controls. IBD was significantly more frequent in parents, siblings, cousins, grandparents, and uncles of patients than in their respective controls. The fathers of patients with UC had significantly more major gastrointestinal and cardiovascular diseases at the time of the patient's birth than the fathers of controls. In North America mothers of patients with UC and CD took vitamin, mineral, and iron preparations during pregnancy significantly less frequently than mothers of controls. Patients with CD and UC consumed a lower residue diet than controls. Recurrent respiratory infections were more frequent in patients with UC and CD (p less than 0.001); it is uncertain whether this preceded disease. Hospitalization for respiratory diseases was more frequent in patients than controls, and the use of antibiotics more frequent in patients with CD. Smallpox vaccination was less frequent (p less than 0.05) in patients with CD, and chickenpox infection was less common in patients with UC (p less than 0.01). No significant differences were found between patients and controls in relation to various human and non-human contacts during childhood. Number of siblings, being an only child, and birth order did not differ markedly between patients and controls, and we could not confirm the 'sheltered child' hypothesis in IBD. The parents of controls were slightly better educated and their social class tended to be higher than those of parents of patients. There were significant associations between some of the main factors investigated in this study. No significant differences were found between patients and controls in the frequency of breast feeding, cereal consumption, sugar added to milk in infancy, gastroenteritis in childhood, major stressful life events, and many other factors.(ABSTRACT TRUNCATED AT 400 WORDS)

630 patients with haematemesis and melaena were randomly allocated to treatment by a constant intravenous infusion of either somatostatin or an apparently identical placebo in a double-blind controlled trial. Rebleeding was less common in treated patients (70 episodes in 315 individuals compared with 89 episodes in 315 controls) but the difference was not significant. Operation rates were virtually identical (35 treated patients and 34 controls), while there were slightly more deaths in the treated group than in the controls (31 and 25, respectively). These results are in clear disagreement with those of other smaller series. Though it is not possible to be completely sure that treatment is not useful in some individuals, earlier claims of marked benefit seem unlikely to be justified.

The safety of anti-secretory treatment can only be confirmed by extensive use, although animal studies, human pharmacological investigations, and examination of outcome in controlled trials form essential preliminaries. The interpretation is, however, hindered by the confounding influence of disease present before treatment started, owing to coincident disease. Careful analysis of data is required to demonstrate this phenomenon, which is a major factor impeding the demonstration of drug-induced illness, which mimics ordinary disease. So far a substantial body of data which covers an extensive time after initial drug use has only been collected for cimetidine. This gives reassurance about drug safety during ordinary use, but confirms the difficulty caused by confounding. Studies of other drugs must take the same problems into account during interpretation.

The effects of a new monochrome mast cell stabilizer (FPL 52694) on gastric secretion have been studied in healthy volunteers. When administered orally for 3 days, FPL 52694 consistently reduced nocturnal and pentagastrin-stimulated secretion of acid by about 50%. Meal-stimulated gastric secretion was not affected by the drug. Inhibition of the gastric secretory response to pentagastrin was not significant when single doses of the drug were administered either into the stomach or the duodenum, but administration of multiple doses resulted in significant inhibition. The drug does not inhibit gastric secretion by injuring the gastric mucosa, since the gastric mucosal barrier to back diffusion of hydrogen ions is not affected. We conclude that this mast cell stabilizer provides an interesting tool for studying aspects of the physiological control of gastric secretion and may have a therapeutic role in peptic ulceration.

Assessments of likely associations between ulcer and other diseases are hindered by the frequent lack of controls, by controls which are inadequate, and by inadequate descriptions of techniques used. The inherent biases in some of the techniques have also probably been insufficiently appreciated. Ulcer is common in the community and much of the evidence adduced to suggest ulcer/other-disease associations may well be describing oridinary ulcer frequency which has been underestimated. With such problems in mind, few of the proposed associations bear examination. Ulcer is probably unusually frequent in patients undergoing treatment for chronic renal failure. It is possibly more frequent in association with hyperparathyroidism and in cirrhotics, in cardiovascular disease (except hypertension), and in chronic respiratory disease. Evidence for other associations is not compelling.

All patients with subdural haematoma presenting to medical wards in Nottingham over a 5-year period have been reviewed. Of twenty-one such patients eight were first diagnosed at post-mortem, whilst all of the remaining thirteen patients in whom the diagnosis was made in life survived following neurosurgical evacuation of the haematoma. Diagnostic failure was caused mainly by failure to consider the possibility of subdural haematoma or misinterpretation of negative investigations. An attempt has been made to characterize the clinical patterns that may suggest the presence of a subdural haematoma, and recommendations are made on the investigation of such patients.

Patients with ulcerative colitis in remission were randomly allocated to treatment with sulphasalazine (2 g/day) or oral sodium cromoglycate (160 mg/day or 2 g/day), and the relapse rates in these treatment groups were compared during continued treatment for one year. The percentage cumulative relapse rate after 12 months' treatment was 30% in the 33 patients treated with sulphasalazine compared with 71% in the 25 treated with high dose sodium cromoglycate, a highly significant difference (P less than 0.01). Patients allocated low dose sodium cromoglycate were only treated for a maximum of six months, and the relapse rate in these 12 patients was similar to that in patients on the high dose. These results suggest that oral sodium cromoglycate is considerably less effective than sulphasalazine in maintaining remission, and by analogy with results in other trials may be no more effective than placebo tablets.

In a case-control study 82 patients with Crohn's disease and matched controls drawn from general practice lists were questioned about their smoking habits. Patients with Crohn's disease were significantly more likely to be smokers than the controls, and the association was stronger for smoking habit before the onset of the disease than for current smoking habit, the relative risks for smokers compared with non-smokers being 4.8 and 3.5 respectively. Taken in conjunction with earlier data showing an association between non-smoking and ulcerative colitis, these results suggest that smoking habit may be an important determinant of the type of inflammatory bowel disease that develops in predisposed subjects.

The mean concentrations of serum lysozyme were markedly higher in patients with Crohn's disease and ulcerative colitis than in normal controls, and mean levels tended to be slightly higher in those with Crohn's disease than in those with colitis. The significance of these differences is unclear but the overlap between values in normal individuals and those with inflammatory bowel disease prevents the measurement having any discriminant value.