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Abstract
Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.
Highlights
The study of combination therapy—the treatment of disease with mixtures of drugs—is a growing field in modern pharmacology, but an old science as far as the actual application of medicine is concerned [1]
The objective of this study is to present the extract fractional inhibitory concentration index (EFICI), a new application of existing analytical methods, for use in the quantification of synergy and other interactions in natural substances
Note that when the IC50 of a fraction is equal to the IC50 of the parent, the FIC is equal to the yield
Summary
The study of combination therapy—the treatment of disease with mixtures of drugs—is a growing field in modern pharmacology, but an old science as far as the actual application of medicine is concerned [1]. While single-compound drugs have revolutionized the treatment of many conditions, the development of resistance, among other factors, has prompted a return to combination therapies for several diseases, including cancer [2], malaria [3], HIV [4], and antibioticresistant infections [5]. Combination therapy has a variety of potential benefits, including synergy: greater potency of a drug mixture than would be predicted from the activity of each.
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