Definition Of Synergism Research Articles

Combinations of a full and partial agonist: Experimental evidence of curved isoboles

Concentration addition as a classic null model for toxicology and pharmacology is based on Loewe's mathematical formulation and the linearity of the isoboles. Novel mathematical models, however, propose curved isoboles in certain conditions. This article aims to test the hypothesis of the curvature of isoboles in experimental measurements. With the assumption of linear isoboles, a partial agonist acts as an antagonist above its maximal effect level. The isoboles automatically convert to a positive slope. For curved isoboles, a partial agonist acts as an antagonist at higher effect levels than its maximal effect alone. The discrepancies between effect levels were studied with an estrogen receptor binding assay (BMAEREluc/ERα) using a mixture of 17β-estradiol and fulvestrant as a partial agonist. A mixture of 17β-estradiol and fulvestrant acts as a partial agonist and causes the diminishing of the effect level of 17β-estradiol at a significantly higher level than the maximal effect of their partial-agonistic dose-response curve. Measured, elevated effect levels were well predicted by the mathematical model. Nonlinear isoboles may change our understanding and definition of synergism or antagonism and prompt further attention in receptor theory.

The combination index (CI < 1) as the definition of synergism and of synergy claims

Abstract The unified theory of the median-effect equation (MEE) of the mass-action law (MAL) indicates that dose and effect are interchangeable, and all dose-effect curves can be transformed into straight-lines by the median-effect plot. Therefore, it allows pharmacodynamics (PD) analysis using small size experimentation for in vitro and in vivo studies. Further, extension of MEE has proven that the Combination Index Equation (CIE) which defines Synergism (CI 1), can be automatically simulated by CompuSyn software within one second after data entries. With adequate experimental accuracy of measurements, the minimum number of only 10 data points are required for quantitative synergy determination in two-drug combinations, even in animals or in clinical trials. Three articles introducing the CI method (in 1984), the review (2006), and the perspectives (2011) have been well recognized and cited 5516, 2382, and 1701 times in 1117, 768 and 530 biomedical journals, respectively (as of 2.10.2018) [Google Scholar Citations- Ting-Chao Chou]. However, the academic societies and governmental regulatory agencies are still lack of guideline on synergy definition, despite over 20 arbitrary, non-quantitative synergy definitions are still applied and reported. As drug combination is the most widely used therapies for the most dreadful diseases such as cancer and AIDS, a call for open forum on scientific credibility and accountability in these matters is warranted.

Reconceptualizing synergism and antagonism among multiple stressors.

The potential for complex synergistic or antagonistic interactions between multiple stressors presents one of the largest uncertainties when predicting ecological change but, despite common use of the terms in the scientific literature, a consensus on their operational definition is still lacking. The identification of synergism or antagonism is generally straightforward when stressors operate in the same direction, but if individual stressor effects oppose each other, the definition of synergism is paradoxical because what is synergistic to one stressor's effect direction is antagonistic to the others. In their highly cited meta-analysis, Crain et al. (Ecology Letters, 11, 2008: 1304) assumed in situations with opposing individual effects that synergy only occurs when the cumulative effect is more negative than the additive sum of the opposing individual effects. We argue against this and propose a new systematic classification based on an additive effects model that combines the magnitude and response direction of the cumulative effect and the interaction effect. A new class of “mitigating synergism” is identified, where cumulative effects are reversed and enhanced. We applied our directional classification to the dataset compiled by Crain et al. (Ecology Letters, 11, 2008: 1304) to determine the prevalence of synergistic, antagonistic, and additive interactions. Compared to their original analysis, we report differences in the representation of interaction classes by interaction type and we document examples of mitigating synergism, highlighting the importance of incorporating individual stressor effect directions in the determination of synergisms and antagonisms. This is particularly pertinent given a general bias in ecology toward investigating and reporting adverse multiple stressor effects (double negative). We emphasize the need for reconsideration by the ecological community of the interpretation of synergism and antagonism in situations where individual stressor effects oppose each other or where cumulative effects are reversed and enhanced.

Biologic synergism and parallelism.

In epidemiologic studies of two binary exposure factors, much attention has been given to the concept of synergism of the factors. The leading dictionary of epidemiology offers two definitions of synergism, one of which this author labels statistical and the other biologic. The epidemiologic literature has been largely concerned with statistical synergism, which is typically measured using additive or multiplicative interaction. This paper focuses on biologic synergism, on the related concept of biologic parallelism, and on the question of how much information can be gleaned about population amounts of biologic synergism and parallelism--information which is of vital interest to epidemiologists. A fundamental identity equates the difference between the amounts of biologic synergism and parallelism to the additive interaction. Two biologic models, the multistage model and the no-hit or immunity model, enhance the interpretation of multiplicative interaction as a measure of statistical synergism, but it is pointed out here that, unfortunately, both models incorporate the strong assumption that there is no parallelism. A third model, the single-hit or vulnerability model, makes the even stronger assumption that there is no biologic synergism and consequently that the additive interaction is equal to minus the amount of parallelism. A consequence of this fact is that a link which has been perceived in the literature to exist between the single-hit model and the additive interaction is false.

The "Synergistic" Action of Mixed Irradiation with High-LET and Low-LET Radiation

The combined modalities of various agents such as radiation, chemicals and physical agents are often used, and exposure to mixture of agents sometimes occurs in nature. However, it is not clear whether these combined effects are synergistic, partly because definition of the term {open_quotes}synergism{close_quotes} is confusing, as pointed out by Streffer and Mueller. It is, of course, desirable that the definition should be simple and widely applicable to all agents. Yet the underlying mechanisms of the effects of different agents are probably different, and the mechanisms of combined effects are different and more complicated than those of a single agent. It is therefore important to define synergism taking each underlying mechanism into consideration. From this viewpoint, the definitions of synergism which have been used to date are examined with respect to the effect of a mixture of different types of radiation on cells, and they are shown to be inappropriate and misleading. This is probably attributable to simply treating the resulting phenomena (cell survival in most cases) without adequately taking into consideration the knowledge of underlying biological mechanisms in defining the synergism that may occur with irradiation. This commentary discusses the inappropriateness of current definitions and proposes a new definitionmore » in terms of biological mechanisms as a counterproposal. 16 refs., 6 figs.« less

SYNERGISM OF MAGNESIUM SULPHATE AND MORPHINE

This communication is called forth by the repetition of statements to the effect that no satisfactory evidence has been brought forward to show that the synergism. of magnesium sulphate and morphine occurs in animals or in man.1 To my knowledge, the following definition of synergism has not been challenged:2 By synergism (a Greek derivative meaning working together with) is meant the reciprocal augmentation of the action of one drug by that of another. This reciprocal augmentation of the action of one anesthetic agent by that of another induces the state which has come to be known as synergistic anesthesia when accompanied by unconsciousness, and synergistic analgesia when the subject is conscious. The effect of the synergistic action of drugs goes beyond a simple summation of similar pharmacological actions, either in prolonged or deepened action, or both. For example: morphine and magnesium sulphate have a prolonged effect; whereas with