A rational usage of combined using of herbal medicines and synthetic medicines: A time interval window research

Abstract

The combined use of herbal and traditional medicine with synthetic drugs is a common clinical issue in China, as well as in other countries around the world. The improper combination of Traditional Chinese Medicine (TCM) with synthetic drugs may increase the risk of severe adverse drug reactions (ADRs). In China, the combination of Shuanghuanglian (SHL) and Ribavirin injections (RB) is one such example that has led to a higher risk of pseudo-allergic ADRs, observed during post-marketing safety monitoring. Such combination-related ADRs may be associated with concurrent drug exposure concentrations in vivo . Thus, it is important to administer both formulations at acceptable intervals to prevent ADRs. In this study, we propose an appropriate time interval of administration to reduce ADR risk in combination drug use. SHL and RB combination was then tested in rats. This combination was tested at different administration intervals. Ear weight was chosen as the quantitative index to indicate tissue edema and intensity of pseudo-allergic reactions. Compared to the control group, rats that were simultaneously administered with SHL and RB intravenously, showed different behaviors and symptoms such as ear edema and increase in weight, swelling of limbs and huddling, which were similar to those seen in pseudo-allergic reactions. By contrast, rats administered solely with either RB or SHL did not exhibit obvious pseudo-allergic reactions. With respect to the combination groups at different administration intervals, there were two different types of responses. One of them was similar to the concurrent administration of drug pairs, which occurred in groups at intervals of 0, 1.5, 2, 3.5 and 4 h. The other type was similar to the sole use of RB or SHL, which occurred in groups with intervals of 6, 8, 12 and 24 h. We also determined serum concentrations of complement C5 (C5) and thrombomodulin (THBD), proteins that mediate the complement system and coagulation cascade-depended pseudo-allergic reactions. Results showed that there was significant increase in these two indices in combination groups, with intervals below or equal to 4 h and non-significant increase in combination groups with intervals above or equal to 6 h. These results indicate that a “safe window” of administration interval exists when using the drug pair: SHL and RB, thus reducing the risk of pseudo-allergic reactions. Moreover, we tested serum metabolomic profiles of each group. The principal component analysis revealed that there was an obvious distinction between the rat groups, of both clusters: One cluster included the normal control group where either SHL or RB group was administered and the combination groups that were administered both SHL and RB at intervals of over or equal to 6 h. The other cluster involved combination groups that were administered both drugs at intervals below or equal to 4 h. Thus, the metabolomic results also elucidated a “safe window” administration interval, when using such drug pairs. We then screened out metabolites that might be used to distinguish these two clusters of rat groups. The results of ROC curves showed that compounds of m / z 154.0592, m / z 433.2357, and m / z 331.0528 could distinguish rats where SHL was used after and before 6 h. These metabolites were identified as L-2-Amino-3-(1-pyrazolyl) propanoic acid, [2-hydroxy-1-(6-hydroxy-1-oxo-1H-isochromen-3-yl) butoxy] sulfonic acid and LysoPA (0:0/18:2 (9Z, 12Z)) according to their MS/MS spectrum, respectively. This study verified the hypothesis of the “safe window” of administration interval in combination drug use, including TCM and synthetic drugs. Administered at appropriate intervals, it can reduce ADR risk and prevent safety-related issues from occurring. This study thus provides a new perspective for improving safety, when using Chinese herbal medicines in combination with synthetic medicine.