Biomedical subjects
Publications and source records attributed to G J Milton-Thompson.
The effect of fenoctimine, a new anti-secretory agent, has been studied on food stimulated acid secretion in six normal volunteers. When tested between 2 and 4 h after dosing, and compared with placebo, fenoctimine 50 mg inhibited acid secretion by a mean of 29%, 150 mg by 43% and 250 mg by 47%.
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Eight healthy subjects were studied half-hourly or hourly for 24 h periods before, during, and after cimetidine treatment. No significant differences in intragastric bacterial counts or bacterial species or in intragastric nitrite or N-nitroso-compound concentrations were found as a result of cimetidine treatment. Bacterial counts and nitrite concentrations tended to increase with pH, but N-nitroso-compound concentrations did not. This study provides no evidence that cimetidine treatment may increase the risk of gastric carcinoma by raising N-nitroso-compound concentrations.
The gastric antisecretory effects of oxmetidine, a new H2-receptor antagonist, have been studied in 33 healthy subjects. The relative potency of oxmetidine compared with that of cimetidine depended on the route of administration and the experimental conditions. Oxmetidine intravenously infused was approximately four times as potent as cimetidine, weight for weight, in inhibiting impromidine stimulated gastric acid secretion but was twice as potent when food was used as a stimulus. After oral administration there were no differences in the weight-for-weight potency of oxmetidine and cimetidine, although oxmetidine was twice as potent on a molar basis. These apparent differences according to the route of drug administration are probably due to first pass metabolism of oxmetidine. There were no differences in the duration of action of oxmetidine and cimetidine. Twenty-four hour monitoring of intragastric pH showed that oxmetidine 400 mg twice daily reduced mean hourly 24 hour intragastric pH by 59%, suggesting that a twice daily dosage regimen should be evaluated in the treatment of duodenal ulceration.
Twenty-four hour intragastric acidity and nocturnal acid secretion were measured in 10 males with duodenal ulcer in four separate 24 hour studies, during which the subjects ate normal meals, had unrestricted physical activity, and consumed their customary quantities of tobacco. The medication consisted of either placebo, cimetidine 200 mg tds and 400 mg at night, or ranitidine 150 mg bd, or 200 mg bd. Ranitidine 150 mg bd decreased mean 24 hour hydrogen ion activity from 41.8 mmol/l to 13.1 mmol/l (-69%, P less than 0.001) and nocturnal acid output from 6.1 mmol/h to 0.6 mmol/h (-90%, P less than 0.01). This degree of inhibition was significantly greater than that due to cimetidine (P less than 0.001 for 24 hours acidity, less than 0.05 for night time acid output). Plasma concentrations of ranitidine were greater than the IC50 for more than eight hours after the 150 mg dose. Ranitidine 200 mg conferred no additional advantage. Ranitidine 150 mg bd should be tested in therapeutic trials.
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.
A double-blind controlled trial of the effect of sodium cromoglycate (SCG) in preventing relapse in ulcerative colitis has been completed in 100 subjects. In patients already taking sulphasalazine, SCG did not prove to be of any additional benefit. However, in patients not on any other maintenance therapy, the relapse rate was 40% for SCG as compared with 75% for placebo. A large study of the effect of SCG in patients intolerant of sulphasalazine is indicated.
Ten duodenal ulcer patients were studied during four 36 h periods, receiving either ranitidine 150 mg twice daily, or ranitidine 200 mg twice daily, or cimetidine 200 mg t.d.s. and 400 mg at night, or placebo. Conditions during the four experimental days were standard. Mean 24 h intragastric hydrogen ion activity on placebo (41.8 +/- 1.5 mmol 1(-1)) was decreased to 21.6 +/- 1.2 mmol 1(-1) on cimetidine, and to 13.1 +/- 1.0 and 12.1 +/- 1.1 mmol 1(-1) by the two dose levels of ranitidine. Nocturnal acid output was decreased by 70% by cimetidine and by 90 and 89% by the two dose levels of ranitidine. In this test system ranitidine was more than four times as potent as cimetidine. Greater decreases in daytime acidity and nocturnal acid secretion were produced by twice-daily ranitidine than by the standard four daily doses of cimetidine
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Intrinsic factor (IF) secretion in healthy male subjects was studied in response to pentagastrin stimulation with and without cimetidine, and to impromidine, a histamine H2 receptor agonist. Peak and total IF output were reduced by cimetidine, but the concentration was unchanged and the response was unaffected by administration of the compound for 1 week. The IF secretory response to impromidine was similar to that to pentagastrin. It is suggested that the acid and IF components of the parietal cell secretory response are mediated via different intracellular pathways, that histamine H2 receptors do not fulfill and obligatory role in the secretion of IF and that synthesis of IF is probably not altered by cimetidine.
Impromidine (SK&F 92676), a potent selective histamine H2-receptor agonist in animals has been studied in healthy male volunteers. Impromidine 10 micrograms kg-1h-1 i.v. produced near maximal acid secretion and cimetidine 2 mg kg-1h-1 inhibited this output by a mean of 65% in 5 subjects. The log dose-response curve to impromidine in 5 subjects was linear over the dose range 2.5--20 micrograms kg-1h-1. Cimetidine 0.5 mg kg-1h-1 caused a highly significant parallel shift of the dose-response curve, consistent with direct competitive antagonism. The gastric secretory responses to impromidine 10 micrograms kg-1h-1 i.v., histamine acid phosphate 40 micrograms kg-1h-1 i.v., and pentagastrin 6 micrograms kg-1h-1 i.v. were similar. Cardiovascular effects of impromidine were less marked than those due to histamine. Gastric secretory and cardiovascular effects of impromidine are dose dependent. No significant difference was seen in peak acid output between impromidine 10 micrograms kg-1 and pentagastrin 6 micrograms kg-1 whether injected intramuscularly or subcutaneously. Headache which accompanied infusion with histamine occurred less frequently with impromidine, and nausea and abdominal discomfort which occurred with pentagastrin did not occur with impromidine. Impromidine will be valuable in the study of gastric secretion and the role of histamine H2 receptors in other systems.
Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.
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