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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Drug Synergism: Its Detection and Applications

Ronald J. Tallarida
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 865-872;
Ronald J. Tallarida
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Abstract

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.

Footnotes

  • This work was supported in part by Grant DA 09793-04 from the National Institute on Drug Abuse.

  • Abbreviations:
    A
    dose (or concentration) of drug A
    α
    interaction index
    B
    dose (or concentration) of drug B
    R
    relative potency
    (a
    b), doses in a combination
    pA
    proportion of total that is drug A
    pB
    proportion of total that is drug B
    fA
    fraction of potency of drug A
    fB
    fraction of potency of drug B
    i.th.
    intrathecal
    i.c.v.
    intracerebroventricular
    Zt
    total dose
    • Received February 23, 2001.
    • Accepted April 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Drug Synergism: Its Detection and Applications

Ronald J. Tallarida
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 865-872;

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Drug Synergism: Its Detection and Applications

Ronald J. Tallarida
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 865-872;
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    • Abstract
    • Independent Similar Action
    • Additivity
    • Isbologram
    • The Additive Composite Curve
    • Response Surface Analysis
    • Synergism and Mechanism
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