Objective-To evaluate the prophylactic effect of ranitidine 150 mg twice daily in patients requiring one of the following non-steroidal anti-inflammatory drugs: naproxen, piroxicam, diclofenac, and indomethacin. In addition, risk factors were studied in order to help in targeting of such treatment to specific groups of patients.Design-Double blind, placebo controlled, randomised, parallel group with endoscopic assessments at 0, 4, and 8 weeks.Setting-Multicentre outpatient study at secondary referral centres in five European countries.Patients-297 patients with rheumatoid arthritis or osteoarthritis over the age of 18 without lesions in the stomach and duodenum at baseline endoscopy (after one week without taking non-steroidal antiinflammatory drugs). Those taking other antirheumatic agents, concomitant ulcerogenic drugs, or treatment for peptic ulcers within the previous 30 days were excluded. Age, sex, arthritic disease, and type of non-steroidal anti-inflammatory drug used were comparable in the two treatment groups. In all, 263 patients completed the trial.Interventions-Ranitidine 150 mg twice daily or placebo (plus the selected non-steroidal antiinflammatory drug) was prescribed within five days after the baseline endoscopy for two consecutive periods of four weeks. Paracetamol was permitted during the study, but not antacids. Patients were withdrawn if the most severe grade of damage (including ulceration) was found at the four week endoscopy or when indicated, or with lesser damage at the investigator's discretion.End point-Frequency of gastric and duodenal ulceration or lesions, or both.Measurements and main results-The cumulative incidence of peptic ulceration by eight weeks was 10-3% (27/263); 2 out of 135 (1-5%) developed duodenal ulceration in the ranitidine group, compared with 10 out of 126 (8%) taking placebo. The frequency ofgastric ulceration was the same (6%) for the two groups at eight weeks. Though significantly fewer gastric lesions developed in the ranitidine group by four weeks, this difference was not evident by eight weeks. The frequency of non-ulcerative lesions in the duodenum did not differ greatly for the two groups at either time point. Twelve out of 75 (16%) patients taking piroxicam developed peptic ulceration, of whom two thirds had duodenal ulceration. Patients with a history of peptic ulcer were particularly susceptible to recurrent ulceration, against which ranitidine offered some protection.Conclusions-Ranitidine 150 mg twice daily significantly reduced the incidence of duodenal ulceration but not gastric ulceration when prescribed concomitantly with one of four commonly used non-steroidal anti-inflammatory drugs.

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1 Six subjects participated in a detailed pharmacokinetic study of tolbutamide (pilot study). Using parameters based on these data, sixty-three non-diabetic volunteers underwent a simple screening test designed to identify slow metabolisers of tolbutamide. 2 The screening test was an estimate of tolbutamide plasma elimination half-life from plasma concentrations at 8 and 24 h after 500 mg tolbutamide orally, and urinary recovery of the hydroxy-and carboxytolbutamide metabolites over the 4-8 h post-dose period.3 The mean tolbutamide half-life for 61 of the screened subjects was 7.5 ± 1.5 h (range 5.2-12.2 h). Two subjects had half-lives of 21.6 and 16.1 h. Their urinary metabolite recoveries were within the range of those in the screening test but lower than those in the pilot study. 4 The subject with the 21.6 h half-life was restudied with intensive serial sampling for 72 h post-dose. She was confirmed as a 'slow' metaboliser of tolbutamide since her terminal half-life was 25.9 h but plasma Cmax and tmax were within the range of those in the detailed study. This subject's 24 h urinary recoveries of both hydroxytolbutamide and carboxytolbutamide were clearly different from the mean values for the pilot study subjects implicating hydroxylation of tolbutamide as the metabolic defect. 5 The two point plasma half-life is therefore a discriminatory screening test but a 4-8 h urinary recovery is not. 6 A partial family study did not provide conclusive evidence of the inheritance of slow tolbutamide metabolism but the screening test should allow simple identification of slow metabolisers for further study.

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Published pharmacokinetic studies investigating possible interaction between H2-receptor antagonists (n = 22) or prostaglandin analogues (n = 6) and nonsteroidal anti-inflammatory drugs (NSAIDs) have been reviewed. With two exceptions the studies were carried out in young, healthy male volunteers rather than in arthritis patients. In addition some of the studies were poorly designed and inadequately described. Cimetidine appeared to increase the area under the plasma concentration-time curve, and hence to decrease the apparent oral clearance, of several NSAIDs including piroxicam, indomethacin, flurbiprofen, sulindac, oxaprozin and aspirin, while ranitidine co-administration resulted in similar changes for oxyprozin alone. The data currently available for prostaglandin analogues are insufficient to draw firm conclusions. It therefore remains a possibility that clinically relevant pharmacokinetic interactions may occur in elderly arthritic patients, and this issue needs to be addressed.