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Vol. 298, Issue 3, 865-872, September 2001
Department of Pharmacology, Temple University School of Medicine,
Philadelphia, Pennsylvania
Two drugs that produce overtly similar effects will sometimes produce
exaggerated or diminished effects when used concurrently. A
quantitative assessment is necessary to distinguish these cases from
simply additive action. This distinction is based on the classic
pharmacologic definition of additivity that, briefly stated, means that
each constituent contributes to the effect in accord with its own
potency. Accordingly, the relative potency of the agents, not
necessarily constant at all effect levels, allows a calculation using
dose pairs to determine the equivalent of either agent and the effect
by using the equivalent in the dose-response relation of the reference
compound. The calculation is aided by a popular graph (isobologram)
that provides a visual assessment of the interaction but also requires
independent statistical analysis. The latter can be accomplished from
calculations that use the total dose in a fixed-ratio combination along
with the calculated additive total dose for the same effect. Different
methods may be used, and each is applicable to experiments in which a
single drug is given at two different sites. When departures from
additivity are found, whether in "two-drug" or "two-site"
experiments, the information is useful in designing new experiments for
illuminating mechanisms. Several examples, mainly from analgesic drug
studies, illustrate this application. Even when a single drug (or site) is used, its introduction places it in potential contact with a myriad
of chemicals already in the system, a fact that underscores the
importance of this topic in other areas of biological investigation.
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