A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern understanding of actions and interactions of drugs which act at distinct molecular sites. It rests on a comparison of observed combined effects with calculated effects of independent action of A plus B--greater than independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of the antisecretory action of
pirenzepine and H2-receptor antagonists (
cimetidine,
ranitidine). Briefly,
peptone-stimulated
acid output was measured in 15 min periods over 3 h after the injection of drugs in three trials, one with five
duodenal ulcer patients, two of them with 8 healthy volunteers each. The doses of
pirenzepine and H2-blockers were fixed in each trial. The results were either expressed by the total
acid output (single-dose analysis) or by the
acid secretion over 15 min as time course. The results with the
drug combination show greater reduction in
acid secretion in all three trials with respect to independent effects. The time-course studies more clearly showed greater reduction in
acid output than the analysis of total
acid output, not the least with respect to p-values of differences between observed combined effects and calculated independent effects. They were obtained by the chi-square (chi 2) goodness-of-fit test, recently applied for the evaluation of dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)