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.

Table 1 A general comparison of conventional anti-CVD drugs and DS − CX

	Western drugs (W)	Danshen (DS)	Chuanxiong (CX)	DS − CX	JI
Compounds	217	188	220	384	0.005[a]
Targets	165	439	339	567	0.339

Abbreviations: CVD, cardiovascular disease; DS–CX, danshen–chuanxiong; FDA, Food and Drug Administration; JI, Jaccard's index.

^a Adenosine is the only common compound of anti-CVD drugs and DS − CX. It was approved in 1989 by FDA for cardiac therapy.

Table 2 Target-based interaction between anti-CVD drugs and DS − CX

	Anti-CVD drug targets	Common targets	JI
Whole network [Fig. 1A]	165	56	0.339
Subnetwork [Fig. 1B]	9	2	0.222
Subnetwork [Fig. 1C]	17	6	0.353
Subnetwork [Fig. 1D]	11	4	0.364

Abbreviations: CVD, cardiovascular disease; JI, Jaccard's index.

Conflicts of Interest

The authors have no conflicts of interest to declare.

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.

• References

• 1 McEwen BJ. The influence of herbal medicine on platelet function and coagulation: a narrative review. Semin Thromb Hemost 2015; 41 (03) 300-314
• 2 Maione F, Mascolo N. Danshen and the cardiovascular system: New advances for an old remedy. Semin Thromb Hemost 2016; 42 (03) 321-322
• 3 Lüscher TF. Improving outcome in acute coronary syndromes: ischaemic conditioning, antithrombosis and bleeding, and inflammasome antagonism. Eur Heart J 2017; 38 (11) 763-766
• 4 Liperoti R, Vetrano DL, Bernabei R, Onder G. Herbal medications in cardiovascular medicine. J Am Coll Cardiol 2017; 69 (09) 1188-1199
• 5 Tachjian A, Maria V, Jahangir A. Use of herbal products and potential interactions in patients with cardiovascular diseases. J Am Coll Cardiol 2010; 55 (06) 515-525
• 6 Chen C, Yang FQ, Zhang Q, Wang FQ, Hu YJ, Xia ZN. Natural products for antithrombosis. Evid Based Complement Alternat Med 2015; 2015: 876426
• 7 Li L, Zhou X, Li N, Sun M, Lv J, Xu Z. Herbal drugs against cardiovascular disease: traditional medicine and modern development. Drug Discov Today 2015; 20 (09) 1074-1086
• 8 Samuels N. Herbal remedies and anticoagulant therapy. Thromb Haemost 2005; 93 (01) 3-7
• 9 McEwen BJ. Comment on “Danshen and the cardiovascular system: new advances for an old remedy.”. Semin Thromb Hemost 2016; 42 (03) 323-324
• 10 Chen XWB, Sneed KB, Pan SY. , et al. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab 2012; 13 (05) 640-651
• 11 Chen Z, Zhang C, Gao F. , et al. A systematic review on the rhizome of Ligusticum chuanxiong Hort. (Chuanxiong). Food Chem Toxicol 2018; 119: 309-325
• 12 Chen X, Guo J, Bao J, Lu J, Wang Y. The anticancer properties of Salvia miltiorrhiza Bunge (Danshen): a systematic review. Med Res Rev 2014; 34 (04) 768-794
• 13 Li G, Cheng YH, Guo YB. , et al. Report on scientific and technological competitiveness of big brand traditional Chinese medicine (2017 edition). Zhongguo Xiandai Zhongyao 2018; 20 (01) 6-13
• 14 Zuo H, Zhang Q, Su S, Chen Q, Yang F, Hu Y. A network pharmacology-based approach to analyse potential targets of traditional herbal formulas: an example of Yu Ping Feng decoction. Sci Rep 2018; 8 (01) 11418
• 15 Knox C, Law V, Jewison T. , et al. DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res 2011; 39 (Database issue, suppl. 1): D1035-D1041
• 16 Ursu O, Holmes J, Knockel J. , et al. DrugCentral: online drug compendium. Nucleic Acids Res 2017; 45 (D1): D932-D939
• 17 Fang J, Little PJ, Xu S. Atheroprotective effects and molecular targets of tanshinones derived from herbal medicine Danshen. Med Res Rev 2018; 38 (01) 201-228
• 18 Guo Y, Nie Q, MacLean AL, Li Y, Lei J, Li S. Multiscale modeling of inflammation-induced tumorigenesis reveals competing oncogenic and onco-protective roles for inflammation. Cancer Res 2017; 77 (22) 6429-6441
• 19 Li S. Mapping ancient remedies: applying a network approach to traditional Chinese medicine. Science 2015; 350 (6262): S72-S74
• 20 Chen CYC. TCM Database@Taiwan: the world's largest traditional Chinese medicine database for drug screening in silico. PLoS One 2011; 6 (01) e15939
• 21 Wang JF, Zhou H, Han LY, Chen X, Chen YZ, Cao ZW. Traditional Chinese medicine information database. Clin Pharmacol Ther 2005; 78 (01) 92-93
• 22 Ye H, Ye L, Kang H. , et al. HIT: linking herbal active ingredients to targets. Nucleic Acids Res 2011; 39 (Database issue, suppl. 1): D1055-D1059
• 23 Ru J, Li P, Wang J. , et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6 (13) 13
• 24 Kim S, Thiessen PA, Bolton EE. , et al. PubChem substance and compound databases. Nucleic Acids Res 2016; 44 (D1): D1202-D1213
• 25 Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotechnol 2007; 25 (02) 197-206
• 26 Santos R, Ursu O, Gaulton A. , et al. A comprehensive map of molecular drug targets. Nat Rev Drug Discov 2017; 16 (01) 19-34
• 27 Szklarczyk D, Franceschini A, Kuhn M. , et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 2011; 39 (Database issue, suppl. 1): D561-D568