Investigation of Possible Herb-Drug Interactions for the Treatment of Cardiovascular Diseases

Comment on “Investigation of Possible Herb-Drug Interactions for the Treatment of Cardiovascular Diseases”

This correspondence is intended as a brief report of an investigation that furthers the data in previous reports published in this journal by McEwen[1] and Maione.[2]

Cardiovascular diseases (CVDs) are the leading cause of mortality and mainly account for thrombotic events.[3] Herbal medicines are widely used for the treatment of CVDs due to traditional and cultural beliefs and have so for many years. However, in several countries, herbal medicines have relatively loose regulatory requirements and can be considered self-prescribed medications.[1] [4] [5] In numerous experimental studies, herbal medicines have been found to have an effect on biological mechanisms related to the cardiovascular system.[6] [7] Hence, increasingly greater attention has been paid to potential risk of interactions between conventional drugs and widespread active herbs.[4] [8]

The article by McEwen[1] reviewed herbal efficacy and noted their potential to modify progression of CVD via the modification of platelet function. Furthermore, Maione[2] investigated two single compounds of danshen (Salvia miltiorrhiza) and reported their underlying mechanism on platelet function and hemostasis. McEwen[1] [9] also suggested that the herb − drug interactions are not fully understood and outlined underlying mechanisms of action and, in particular, potential risks that herbal medicine create by affecting concomitant anticoagulant therapy. In terms of the complexity and wide prevalence of herbal medicines, it is of great importance to explore the biological mechanism of herb − drug interactions for reasons of safety. This correspondence explains the possible biological mechanism of herb − drug interaction at the drug targets of action.[10] To our knowledge, this issue has not been fully described in the existing literature.

In clinical practice, both Salviae miltiorrhizae radix et rhizoma (Danshen in Mandarin, DS) and Chuanxiong Rhizome (Chuanxiong in Mandarin, CX) are herbs frequently used for invigorating blood circulation and eliminating stasis.[11] [12] A pairing (a basic unit of complex herbal formulae) of the two herbs was one of the most frequently compatible herbal pairs in best-selling herbal formulae released by the China Association of Chinese Medicine in 2017.[13] Therefore, our investigation employs the herbal pair (DS − CX) to analyze the mechanism of action and possible interaction with Western drugs. Moreover, to understand the intrinsic herb − drug interaction on the molecular level, this investigation uses the network of pharmacological approach[14] to integrate the abundant data which have accumulated from previous research on herbal medicines and current approved anti-CVD drugs. For detailed methods, please refer to the Appendix (also refer to [Fig. 1] and [Tables 1], [2]).

In this investigation, the “target − (pathway) − target” network clearly shows that DS − CX interacts with the targets of anti-CVD Western drugs. DS − CX may interact with 56 (33.9%) of targets of anti-CVD Western drugs. Totally, DS − CX's 384 compounds may affect 567 biological molecules. Meanwhile, it is of significance to specify the kind of interactions in the specific pathways, especially the main thrombotic pathways. Our investigation found that two (prostaglandin-endoperoxide synthase 1 [PTGS1], integrin subunit alpha 2b [ITGA2B]; 22.2%) out of nine Western medicine targets on platelet activation are involved in target sets of DS − CX. Similarly, for the pathway of vascular smooth muscle contraction, there are 6 of 17 drug targets (adenosine A2a receptor [ADORA2A], ADORA2B, adrenoceptor alpha 1A [ADRA1A], ADRA1B, ADRA1D, potassium calcium-activated channel subfamily M alpha 1 [KCNMA1]; 35.3%) are relevant to DS − CX. In addition, for the pathway of complement and coagulation cascades, the corresponding number is 4 (F2, F10, Serpin [serine protease inhibitors] family E member 1 [SERPINE1], plasminogen activator, urokinase [PLAU]; 36.4%) out of 11. Refer to the Appendix for more detailed results of network analysis. Higher overlapping intensity between pharmaceutical and herbal targets may mean higher risk in clinical practice of Western drugs.

For example, the verified corresponding targets of aspirin include prostaglandin G/H synthase 1 (COX-1 [Cyclooxygenase-1]; gene name: PTGS1) and prostaglandin G/H synthase 2 (COX-2; gene name: PTGS2).[15] [16] COX-1 mainly contributes to the arachidonic acid metabolism pathway and the platelet activation pathway. COX-2 is mainly involved in the arachidonic acid metabolism pathway directly relevant to thrombosis and the vascular endothelial growth factor (VEGF) signaling pathway relevant to thrombosis indirectly. COX-1 and COX-2 might be targeted by senkyunolide B, senkyunolide C, and senkyunolide E from CX, and phenanthraquinones from DS, including tanshinone I, 1-dehydrotanshinone IIA, neocryptotanshinone, przewaquinone A, isotanshinone I, nortanshinone, etc. Previous studies have partially supported the potential effects of DS and CX on COX-1 and COX-2.[11] [12] [17]

With the wide prevalence of active herbal medicines, it is necessary to add an understanding of the biological mechanism of herb − drug interaction. In general, this kind of herb − drug interaction implies that patients simultaneously taking anti-CVD Western drugs and DS − CX may be exposed to additional risks caused by accumulated effects on common herb − drug targets. More importantly, this kind of risk is not usually visible and difficult for clinical physicians to observe due to wide herbal utilization as undisclosed self-medication. In this context, herb − drug relationships are worthy of further exploration in the future, especially from experimental and clinical perspectives.

Authors' Contributions

Y.J.H. and F.Q.Y. conceived and designed the study; H.L.Z. analyzed data, performed the network analysis, and drafted the manuscript; Y.J.H. and F.Q.Y. revised the manuscript. All authors have read and approved the final manuscript.

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