Understanding synergy

Abstract

Analysis of the interactive effects of combinations of hormones or other manipulations with qualitatively similar individual effects is an important topic in basic and clinical endocrinology as well as other branches of basic and clinical research related to integrative physiology. Functional, as opposed to mechanistic, analyses of interactions rely on the concept of synergy, which can be defined qualitatively as a cooperative action or quantitatively as a supra-additive effect according to some metric for the addition of different dose-effect curves. Unfortunately, doseeffect curve addition is far from straightforward; rather, it requires the development of an axiomatic mathematical theory. I review the mathematical soundness, face validity, and utility of the most frequently used approaches to supra-additive synergy. These criteria highlight serious problems in the two most common synergy approaches, response additivity and Loewe additivity, which is the basis of the isobole and related response surface approaches. I conclude that there is no adequate, generally applicable, supra-additive synergy metric appropriate for endocrinology or any other field of basic and clinical integrative physiology. I recommend that these metrics be abandoned in favor of the simpler definition of synergy as a cooperative, i.e., nonantagonistic, effect. This simple definition avoids mathematical difficulties, is easily applicable, meets regulatory requirements for combination therapy development, and suffices to advance phenomenological basic research to mechanistic studies of interactions and clinical combination therapy research.

Synergistic Suppression of Dengue Virus Replication Using a Combination of Nucleoside Analogs and Nucleoside Synthesis Inhibitors

“…Chalice Analyzer (32) was used to evaluate synergy. The theories of Loewe additivity, Bliss independence, and the highest single agent (HSA) were previously described in detail (33)(34)(35).…”

Application of a Microfluidic Chip with Mechanical Stimuli for Culturing Mouse Embryos in vitro

“…Much evidence of the superiority of combinations of drugs as compared to single agent use has been published already [5,6,14]. Some methodologies are discussed in details elsewhere [12,25]. In the present study, we focus on median-dose effect methodology and its practical advantages and drawbacks during particular calculations by using the most popular software from CompuSyn Inc., which is based on the work of Chou and Martin [7].…”

“…However, their implementation into a robust and working methodology is still not an easy task to solve and requires much more than simplified solutions [5,12]. It is useful to highlight the methodological basis of combination effect studies in order to understand effect-based approaches and dose-effect based approaches, in order to evaluate their practical advantages and limitations.…”

Additive Dose Response Models: Explicit Formulations and the Loewe Additivity Consistency Condition

“…10 by violating the condition in Eq. 11 232 and 12 has been commented upon before by Tallarida 233 and Geary [6,13], but no general proof has been pro-234 posed.…”

“…Further, we introduce 71 an explicit null reference model derived from the Loewe 72 Additivity principle, which describes the same null refer-73 ence model as the General Isobole Equation, when the 74 Loewe Additivity consistency condition is met. As this 75 consistency condition is often violated by experimental 76 data [6,13] we investigate in section IV the consequences 77 of these violations and provide solutions to the arising 78 issues, which we evaluate in section V.…”