MODERN APPROACH TO THE EVALUATION OF COMBINED EFFECTS OF SINGLE-DOSE TRIALS AND CLINICAL TIME-COURSE STUDIES, EXEMPLIFIED BY COMBINATIONS OF PIRENZEPINE AND H-2-RECEPTOR ANTAGONISTS

A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern under standing of actions and interactions of drugs which act at distinct mo lecular sites. It rests on a comparison of observed combined effects w ith calculated effects of independent action of A plus B - greater tha n independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of th e antisecretory action of pirenzepine and H-2-receptor antagonists (ci metidine, ranitidine). Briefly, peptone-stimulated acid output was mea sured 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 hea lthy volunteers each. The doses of pirenzepine and H-2-blockers were f ixed in each trial. The results were either expressed by the total aci d output (single-dose analysis) or by the acid secretion over 15 min a s time course. The results with the drug combinations show greater red uction in acid secretion in all three trials with respect to independe nt effects. The time-course studies more clearly showed greater reduct ion in acid output than the analysis of total acid output, not the lea st with respect to p-values of differences between observed combined e ffects and calculated independent effects. They were obtained by the c hi-square (chi2) goodness-of-fit test, recently applied for the evalua tion of dose-response curves. The results are discussed with respect t o ''expected'' combined effects of drugs with similar but distinct act ion, and it is concluded that the examples described can be regarded a s typical.