Mathematical formulation of additivity for antimicrobial agents

Boucher, Andrew; Tam, Vincent H.

doi:10.1016/j.diagmicrobio.2006.01.024

Cited by 32 publications

(20 citation statements)

References 9 publications

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“…If the combination effect is higher than the expected value from the preceding equation, the interaction is considered synergistic, whereas if this effect is lower, the interaction is antagonistic. Otherwise, the effect is additive and there is no interaction (Greco et al, 1995;Meletiadis et al, 2003;Boucher and Tam, 2006;Goldoni and Johansson, 2007;Boik et al, 2008;Lee, 2010). In this study, the BI equation was characterized by X 5 RPL554 and Y 5 salbutamol, Y 5 atropine, or Y 5 glycopyrrolate.…”

Section: Analysis Of Resultsmentioning

confidence: 99%

“…The BI, the Berenbaum, and the dose equivalence concept are generally used to study combined effects of substances in vivo and in vitro (Berenbaum, 1977(Berenbaum, , 1989Tallarida, 2001Tallarida, , 2006Grabovsky and Tallarida, 2004;Boucher and Tam, 2006;Goldoni and Johansson, 2007;Boik et al, 2008;Tallarida and Raffa, 2010). The main assumption of the BI theory is that two or more agents act independently from one another in terms of the site of action of the drugs in the mixture (Greco et al, 1995;Goldoni and Johansson, 2007).…”

Section: Rpl554 and Human Bronchial Tonementioning

confidence: 99%

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Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

Calzetta

Page²,

Spina³

et al. 2013

J Pharmacol Exp Ther

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The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway smooth muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6, 1-a]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a b 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness (E max ) 91.33 6 3.37%, P , 0.001], relaxed bronchi precontracted with ACh (E max 94.62 6 2.63%, pD 2 4.84 6 0.12, P , 0.001), and abolished the contraction induced by histamine. Analysis of interactions indicated a weak synergism between RPL554 and salbutamol (interaction index: 0.25 6 0.06; BI Deffect: 0.29 6 0.11; dose equivalence: no synergism) but significant synergism between RPL554 and atropine (interaction index: 0.09 6 0.07; BI Deffect: 0.54 6 0.09; dose equivalence: synergism for low concentrations) or glycopyrrolate (ACh: BI Deffect 0.46 6 0.03, Berenbaum Deffect 0.42 6 0.02; histamine: BI Deffect 0.46 6 0.03, Berenbaum Deffect 0.42 6 0.03). This study demonstrates that RPL554 relaxes human bronchi and that it can interact with a muscarinic receptor antagonist to produce a synergistic inhibition of ASM tone. These results suggest that RPL554 may provide a novel treatment of airway diseases, either alone or in combination with antimuscarinic drugs.

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Section: Analysis Of Resultsmentioning

confidence: 99%

Section: Rpl554 and Human Bronchial Tonementioning

confidence: 99%

Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

Calzetta

Page²,

Spina³

et al. 2013

J Pharmacol Exp Ther

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show abstract

“…Previous attempts to quantify arbitrary agent interactions are unsatisfactory as they are associated with multiple implicit assumptions of the interacting system; they have been reviewed in detail previously (5,25). Briefly, the fractional inhibitory concentration index (the most widely used method for the in vitro interaction of antimicrobial agents) is based on Loewe additivity, in which linear concentration-effect relationships are implicitly mandated for all agents in a combination.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii

Lim

Ledesma²,

Chang³

et al. 2008

Antimicrob Agents Chemother

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“…Bliss additivity is often used in the analysis of synergy in antimicrobiology, toxicology, radiation medicine, and other fields (20,39,60,64,123,124,152,174,177). According to Yeh et al (176), an advantage of Bliss additivity is that it is exactly analogous to the definition of epistasis used in molecular biology.…”

Section: Bliss Additivitymentioning

confidence: 99%

“…This is the case, for example, in a recent response additvity approach developed for the detection of synergy in antimicrobial effects (20,92,159) as well as in the Bliss additivity approach (please see Bliss Aditivity).…”

Section: Mathematical Notationmentioning

confidence: 99%

Understanding synergy

Geary¹

2013

American Journal of Physiology-Endocrinology and Metabolism

138

181

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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.

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Mathematical formulation of additivity for antimicrobial agents

Cited by 32 publications

References 9 publications

Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii

Understanding synergy

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