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Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9-16 months) and 11 months in the placebo arm (95% CI 9-14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo.

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.

A total of 9928 cimetidine users were identified from prescriptions in four centres and followed for 10 years. The 'all-cause' mortality ratio fell from 1.9 in year 1 to 1.0 in years 8 to 10. Most of the early excess in mortality was attributable to cimetidine being given in the late stages of many diseases, often to counter adverse gastric effects of other drugs. Specific causes of mortality during years 5-10 of the study, were generally unremarkable. Significant increases in mortality ratios were apparent, however, for oesophageal cancer (years 5-7, 2.3; years 8-10, 1.9); lung cancer (years 5-7, 1.1; years 8-10, 1.7); diseases of the oesophagus, stomach, and duodenum (years 5-7, 3.3; years 8-10, 2.3); and chronic liver disease (years 5-7, 2.4; years 8-10, 3.3). None of these increases in mortality seems to be attributable to an adverse effect of cimetidine use. Data are also presented for mortality from diseases of the nervous system. Eight deaths (of which one was miscoded) were certified as being from motor neurone disease, representing a mortality ratio of 2.6 for years 2-10 of the study which is of borderline statistical significance. This study confirms that cimetidine is safe. Mortality from some diseases increased over the study period, but selection rather than any adverse effect of the drug is likely to be the explanation.

The long-term effects of cimetidine on the occurrence of gastric and oesophageal cancer were assessed in a prospective cohort study of 9928 patients who had been prescribed cimetidine. They were first identified between 1978 and 1980, and cancer registrations and deaths were identified among them over a period of up to 10 years. One hundred and eleven cancers were identified after the start of cimetidine treatment: 71 were adenocarcinomas of the stomach, 27 were carcinomas of the cardia and/or oesophagus (22 adenocarcinomas, five unknown histology) and the remaining 13 tumours were squamous cell cancers of the oesophagus. Only six patients presented with early gastric cancers. Over a period of eight years the ratio of observed to expected (O/E) gastric cancer deaths has fallen from 10.7 (p < 0.001) to 1.2 (NS). The O/E ratio of oesophageal cancer deaths also fell over the first six years of study, from 5.4 (p < 0.01) to 1.4 (NS) but it has risen slightly in years 7 and 8 to 3.7 (p < 0.05). These findings do not suggest that there is an increased risk of developing oesophageal or gastric cancer from cimetidine treatment, and are generally consistent with cimetidine being used inadvertently to treat the early symptoms of gastric and oesophageal cancer. The slight rise in oesophageal cancer deaths in years 7 and 8 was unexpected and will be the subject of further observation.

Two histamine H2 antagonists, cimetidine and ranitidine, given in doses of 1 g daily and 200 mg daily to 18 and 20 patients respectively proved equivalent in promoting healing of duodenal ulcer. No adverse effects occurred during the trial, though serum urea and creatinine concentrations tended to rise slightly during treatment with cimetidine but not ranitidine. Choice between the two drugs is likely to be influenced by overall patterns of adverse effects rather than considerations of individual potency.

Forty-two patients with endoscopically diagnosed duodenal ulcer were studied in a double-blind trial after their ulcers had been healed with cimetidine. Cimetidine was effective in preventing relapse, only five of the 20 patients allocated to cimetidine 400 mg twice daily relapsing during the six months' treatment, compared with 16 of the 22 on placebo treatment (P less than 0.01). Cimetidine was safe in the dosage and duration used, no symptomatic, haematological, or biochemical abnormalities occurring during the trial. Subsequent follow-up at the end of the trial when treatment had been stopped showed that relapse was frequent, particularly in the cimetidine group, making the cumulative relapse rate eight months after completion of the trial similar in the two groups (75% in the cimetidine group, 86% in the placebo group). It seems likely that maintenance cimetidine treatment has to be continued indefinitely in patients with duodenal ulcer, and, until such treatment is shown to be safe and effective, surgical treatment remains a logical option for many patients.

A total of 9928 patients taking cimetidine and 9351 controls were included in a post-marketing drug surveillance study in Glasgow, Nottingham, Oxford and Portsmouth; 98.8 per cent of the takers and 97.7 per cent of the controls were successfully followed up for at least one year during which hospital visits and deaths were recorded. Methods of identification of subjects and 12-month mortality results have been reported previously. A general analysis of the morbidity experienced by these patients during the study year is presented here. Thirty-nine per cent of takers and 21 per cent of controls were seen at outpatient clinics, and 18 per cent of takers and 8 per cent of controls were admitted to hospital; 15 325 individual diagnoses in takers and 5002 diagnoses in controls were reviewed. An association with cimetidine treatment was found, as expected, for gastrointestinal diseases. Weaker associations were found for haematological disorders, some tumours, infections, disorders of the locomotor system and respiratory diseases. Detailed examination revealed that these were mainly due to confounding from several sources, for example, from the underlying cause of the dyspepsia which resulted in cimetidine use, from the higher level of physician contact in cimetidine takers, and smoking. The scheme successfully detected and quantified some already known adverse effects of cimetidine and did not detect any new effects. It is concluded that this method of collecting information is feasible and useful, but several interpretive pitfalls arise, some of which can be avoided by careful analysis. No evidence of any major unrecognised risk of cimetidine treatment emerged from the study.

Widespread publicity has been given to te possibility that cimetidine treatment might cause gastric cancer. Preliminary data are given from a post-marketing surveillance study in four centres. A total of 9940 patients taking the drug entered study and 9504 were observed for at least a year. Seventy-four cases of gastric cancer were identified in those taking cimetidine, but 23 of these were diagnosed before the use of the drug and 29 others with advanced malignancy had received cimetidine within the previous six months only. Ten of the remaining 22 had gastric cancer diagnosed within a year of starting treatment, and 12 after more than a year; only four of the total group had histologically "early" cancer. The occurrence of gastric cancer a long time after starting cimetidine treatment cannot be explained in every case, but it is noteworthy that in control group (which is not directly comparable) gastric cancer was observed in eight patients. The hypothesis that cimetidine treatment predisposes to gastric cancer cannot be excluded by our findings: in our view, however, they do not support such an association.

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.

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.

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.

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.