Skip to main content
Log in

A general formulation of the concept of independent action for the combined effects of agents

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Analysis schemes for the classification of synergism and antagonism for mixed agents operate on the discrepancies between observed and calculated results. As such they cannot be confirmed by experiments and therefore have to be tested in terms of mathematical and logical self-consistency. The concept of independent action is close to the literal meaning of the term “non-interaction”. Since this concept does not depend on the mechanisms of actions nor on the type of effect scale used, it is suitable as one of the basic criterion for the definition of synergism and antagonism. A general mathematical framework of independent action is presented in this paper based on the concept of “relative effect” as used in the literature. The, different equations for independent action currently used in various areas are shown to be manifestations, of a general formula under different sets of boundary conditions, which are the natural limiting values of the effects of the corresponding system observed at low and at high doses of the agents. The framework can, be generalized to the combined action ofn-agents as well as to the interaction of an agent with itself. In addition, the differential form of the formula for independent action is derived. This framework of systematic definitions and derived equations enable a more in-depth study of the implications of the concept of independent action and its relation to other concepts of non-interaction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Literature

  • Ashford, J. R. 1958. Quantal responses to mixtures of poisons under conditions of simple similar action—the analysis of uncontrolled data.Biometrika 45, 74–88.

    Article  MATH  Google Scholar 

  • Ashford, J. R. and C. S. Smith. 1964. General models for quantal response to the joint action of a mixture of drugs.Biometrika 51, 413–428.

    Article  MATH  MathSciNet  Google Scholar 

  • Berenbaum, M. C. 1985. The expected effect of a combination of agents: the general solution.J. theor. Biol. 114, 413–431.

    Google Scholar 

  • Berenbaum, M. C. 1989. What is synergy?Pharmacol. Rev. 1989, 93–141.

    Google Scholar 

  • Bliss, C. I. 1939. The toxicity of poisons applied jointly.Ann. Appl. Biol. 26, 585–615.

    Article  Google Scholar 

  • Chadwick, K. H. and H. P. Leenhouts. 1981.The Molecular Theory of Radiation Biology. New York: Springer-Verlag.

    Google Scholar 

  • Connell, E. V., R. L. Cerruti and P. W. Trown. 1985. Synergistic activity of combinations of recombinant human alpha interfereon and acyclovir, administered concomitantly and in sequence, against a lethal herpes simplex virus type 1 infection in mice.Antimicrob. Ag. Chemother.28, 1–4.

    Google Scholar 

  • Dewey, W. C. 1979.In vitro systems: standardization of endpoints.Int. J. Radiat. Oncol. Biol. Phys. 5, 1165–1174.

    Google Scholar 

  • Drury, R. E. 1980. Physiological interaction, its mathematical expression.Weed. Sci. 28, 573–579.

    Google Scholar 

  • Fowler, J. F., K. Kragt R. Ellis, P. J. Lindop and R. J. Berry. 1965. The effect of divided doses of 15 MeV electrons on the skin response of mice.Int. J. Radiat. Biol. 9, 241–252.

    Google Scholar 

  • Hewlett, P. S. 1969. Measurement of the potencies of drug mixtures.Biometrics 25, 477–487.

    Article  Google Scholar 

  • Hewlett, P. S. and R. L. Plackett. 1959. A unified theory for quantal responses to mixtures of drugs: non-interactive action.Biometrics 15, 691–610.

    Article  Google Scholar 

  • Hill, C. K., F. J. Buonoguro, C. P. Myers, A. Han and M. M. Elkind, 1982. Fission-spectrum neutrons at reduced dose rate enhance neoplastic transformation.Nature 298, 67–68.

    Article  Google Scholar 

  • Kellerer, A. M. and H. H. Rossi, 1972. The theory of dual radiation action.Curr. T. Radiat. Res. Q. 8, 85–158.

    Google Scholar 

  • Maisin, J. R., L. De Saint-Georges, M. Janowski, M. Lambiet-Collier and G. Mattelin. 1987. Effect of X-rays alone or combined with diethylnitrosamine on cancer induction in mouse liver.Int. J. Radiat. Biol. 51, 1049–1057.

    Google Scholar 

  • Plackett, R. L. and P. S. Hewlett. 1948. Statistical aspects of the independent joint action of poisons, particularly insecticides I. The toxicity of a mixture of poisons.Ann. Appl. Biol. 35, 347–358.

    Article  Google Scholar 

  • Plackett, R. L. and P. S. Hewlett. 1952. Quantal responses to mixtures of poisons.J. Royal Stat. S. B14, 141–163.

    MATH  Google Scholar 

  • Pöch, G. 1991. Evaluation of combined effects with respect to independent action.ACES 3, 65–74.

    Google Scholar 

  • Pöch, G. 1993.Combined Effects of Drugs and Toxic Agents—Modern Evaluation in Theory and Practice. Vienna: Springer-Verlag.

    Google Scholar 

  • Prichard, M. N. and C. Shipman, Jr. 1990. A three-dimensional model to analyze drug-drug interactions.Antiviral Res. 14, 181–206.

    Article  Google Scholar 

  • Rahal, J. J. Jr. 1978. Antibiotic combinations: The clinical relevance of synergy and antagonism.Medicine 57, 179–195.

    Google Scholar 

  • Rideout, R. C. and T-C. Chou. 1991. Synergism, antagosism, and potentiation in chemotherapy: an overview. InSynergism and Antagonism in Chemotherapy, T-C Chou and D. C. Rideout (Eds), pp. 3–60. San Diego: Academic Press.

    Google Scholar 

  • Rothman, K. J. 1974. Synergy and antagonism in cause-effect relationships.Amer. J. Epidemiol. 99, 385–388.

    Google Scholar 

  • Steel, G. G. 1979. Terminology in the description of drug-radiation interactions.Int. J. Radiat. Oncol. Biol. Phys. 5, 1145–1150.

    Google Scholar 

  • Suhnel, J. 1990. Evaluation of synergism or antagonism for the combined action of antiviral agents.Antiviral Res.13, 23–40.

    Article  Google Scholar 

  • Tyrrell, R. M. 1978. Radiation synergism and antagonism.Photochem. Photobiol. Rev. 3, 35–113.

    Google Scholar 

  • Unkelbach, H.-D. and G. Pöch. 1988. Comparison of independence and additivity in drug combinations.Arzneim.-Forsch./Drub. Res. 38, 1–6.

    Google Scholar 

  • United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). 1982.Ionizing Radiation: Sources and Biological Effects. See Annex L, p. 736. New York: United Nations Publications.

    Google Scholar 

  • Veckenstedt, A., J. Guttner and I. Beladi. 1987. Synergistic action of quercetin and murine alpha/beta interferon in the treatment of Mengo virus infection in mice.Antiviral Res 7, 169–178.

    Article  Google Scholar 

  • Webb, J. L. 1963. Effect of more than one inhibitor. InEnzyme and Metabolic Inhibitors, Vol. 1, pp. 66–79, 488–512, New York: Academic Press.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lam, G.K.Y. A general formulation of the concept of independent action for the combined effects of agents. Bltn Mathcal Biology 56, 959–980 (1994). https://doi.org/10.1007/BF02458276

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02458276

Keywords

Navigation