Integrated dose-response metabolomics with therapeutic effects and adverse reactions may demystify the dosage of traditional Chinese medicine

Abstract

Background: Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose-response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment.

Methods: The proposed methodology of integrated dose-response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose-response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM.

Results: This developed strategy was successfully applied to rhubarb. The dose-response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case.

Conclusion: An integrated dose-response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics.

Keywords: Adverse reaction; Dose–response; Metabolomics; Rhubarb; Therapeutic effect; Traditional Chinese medicine.

Fig. 1

Overall workflow for dose–response metabolomics with therapeutic effects and adverse reactions

Fig. 2

Multiple comparison of metabolic features between groups

Fig. 3

Feature numbers changed with the rhubarb dose (q, p, o, m represents feature numbers of moderate positive reaction, excessive positive reaction, negative reaction, and unexpected adverse reaction)

Fig. 4

Dose–response relationships for rhubarb derived from metabolites. X-axis represents the dose examined in treatment group, and Y-axis represents the response. The dotted lines represent 95% CIs. (A, B, C, D represents curves of dose-efficacy, dose-excessive positive reaction, dose-negative reaction, dose-unexpected adverse reaction)

Fig. 5

Dose–response relationships for rhubarb integrated by efficacy value and adverse reactions value

Fig. 6

Characteristics of efficacy and adverse reactions in complex TCM-disease-individual system