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Additive and superadditive vasodilating combinations of diltiazem and glyceryl trinitrate in isolated rabbit aorta
Author(s) -
Freeman Keith A.,
Bove Alfred A.,
Tallarida Ronald J.
Publication year - 1992
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430250209
Subject(s) - superadditivity , diltiazem , vasodilation , pharmacology , aorta , confidence interval , chemistry , mathematics , medicine , cardiology , mathematical economics , calcium
The combined use of two drugs with overtly similar action is a common therapeutic strategy. Combinations in doses that produce synergism are frequently sought. In this study, we examined the vasodilating action of diltiazem (DIL) and glyceryl trinitrate (GTN), tested in several fixed‐ratio combinations on an isolated preparation of the rabbit aorta. This pair of drugs, widely used clinically, exhibited significant superadditivity (synergism) in certain fixed‐ratio combinations tested, i.e., 30:1 and 100:1 of DIL:GTN (based on weight), and only simple additivity in other dose ratios, 1:15, 1:1, and 15:1. A demonstration of synergism requires that the total dose of the mixture needed to produce a level of effect be significantly less than the theoretically additive dose calculated; hence, statistical confidence limits of the additive value are needed. Testing of this nature has been limited for statistical reasons to drug combinations that produce parallel regressions of effect on log (dose). In this paper we illustrate the application of new statistical methodology that permits testing of drug combinations that produce nonparallel assays and report our experimental findings, which show that only certain fixed‐ratio combinations of DIL and GTN are superadditive (synergistic) in this test. Although vasodilation alone does not imply antianginal action, these findings may serve as a guide for further clinical testing.