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Plants Containing Coumarin-like Ingredients Similar to Warfarin, Producing a Synergistic Effect

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Angelica sinensis (Oliv) Diels. (Danggui): The root of Angelica sinensis (Oliv) Diels. in the family Umbelliferae has pharmacological effects which include increasing coronary flow, reducing myocardial oxygen consumption, anti-arrhythmia, anti-atherosclerosis, inhibiting platelet aggregation, improving microcirculation, and improving immunity in the body. In 1995 Lo et al. (1995) showed using chemical analysis that Angelica sinensis contains coumarin-like active ingredients similar to warfarin such as parsley oil methyl ether and psoralen. These ingredients can inhibit the formation of thromboxane and platelet aggregation (Liu et al., 1995), and have a synergistic effect when combined with warfarin; in animal experiments, it was concluded that angelica had no effect on PT and pharmacokinetic parameters in warfarin single-dose experiments (p > 0.05). However, in warfarin steady-state experiments, angelica prolonged PT in rabbits, but had no effect on warfarin blood concentrations. Another reason may be that warfarin is able to displace angelica from its binding to plasma proteins, thereby increasing the blood concentration of angelica, which in excess produces anticoagulant effects due to the presence of coumarin-like components. Ye Z.W. reported (Ye et al., 2014) that ferulic acid in angelica administered in vivo or in vitro inhibits PAF, inhibits platelet aggregation reaction and enhances the anticoagulant effect of warfarin.

Befund HOS-368766 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Lo A. C. Chan K. Yeung J. H. Woo K. S. (1995). Danggui (Aangelica Sinensis) Affects the Pharmacodynamics but Not the Pharmacokinetics of Warfarin in Rabbits. Eur. Drug Metab. Pharmcaokinet. 20, 55–66. 10.1007/BF03192289
• Liu J. H. Xu S. X. Yao X. S. Kobayashi H. (1995). Two New 6-alkylcoumarins from Angelica Pubescens F. Biserrata. Planta Med. 61, 482–484. 10.1055/s-2006-958145
• Ye Z. W. Shi J. N. Wang X. J. (2014). Medication Monitoring of the Interaction between Warfarin and Traditional Chinese Medicine. Zhejiang J. Integr. Tradit Chin. West. Med. 24, 465–476. 10.3969/j.issn.1005-4561.2014.05.046

Reduce Platelet Aggregation

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Carthamus tinctorius L. (Honghua): The dried flower of Carthamus tinctorius L has the functions of promoting blood circulation and menstruation, relieving pain by removing blood stasis, and modern pharmacological studies have shown that it has anticoagulation and antiplatelet aggregation effects (Liu et al., 2012; Xu and Dong, 2012). Studies by Zhao et al. (2009) have shown that Carthamus tinctorius L. extract had a significant inhibitory effect on ADP-induced platelet aggregation in rabbits. It can significantly inhibit platelet aggregation in vivo and in vitro, and has a certain inhibitory effect on the activation of the endogenous coagulation system. It may produce a synergistic anticoagulant effect with warfarin. Studies by Liu et al. (2000), Zang et al. (2007), and Zhang et al. (2013) showed that safflower yellow, the main active ingredient in Carthamus tinctorius L., can inhibit platelet adhesion, 5-hydroxytryptamine (5-HT) release and increase the concentration of free Ca2+ induced by platelet activating factor, significantly improve blood coagulation function, and has anti-thrombotic effects. Zhang et al. (2016) studies in rats showed that the combined use of Carthamus tinctorius L. and warfarin significantly prolonged PT value and bleeding time, but has no effect on the blood concentration of warfarin.

Befund HOS-368745 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Liu L. Duan J. A. Tang Y. Guo J. Yang N. Ma H. (2012). Taoren-Honghua Herb Pair and its Main Components Promoting Blood Circulation through Influencing on Hemorheology, Plasma Coagulation and Platelet Aggregation. J. Ethnopharmacol. 139, 381–387. 10.1016/j.jep.2011.11.016
• Xu L. Dong Z. (2012). Effects of HSYA Injection on Platelet Aggregation, Ultrastructure and the Content of PAF Induced GMP-140 in PRP in Rabbits. Chin. J. Clin. Pharmacol. Ther. 17, 269–273.
• Zhao J. M. Qin W. Y. Qi Y. Chen H. Song D. F. Liu H. (2009). Anticoagulant Activity of Carithamine and its Effect on Platelet Aggregation. Lab. Anim. Sci. 26, 30–32. 10.3969/j.issn.1006-6179.2009.06.008
• Liu Z. F. Li P. Li G. S. Fu F. H. Liu K. (2000). The Effect of the Extracting from Carthamus tinctorius L. On Platelet Aggregation and Thrombosis. Pharmacol. Clin. Chin. Mater. Med. 6, 20–21. 10.3969/j.issn.1001-859X.2000.06.012
• Zhang H. Y. Zhang B. Li Y. Z. (2007). Interactions of Warfarin and its Safe Use. Adverse Drug React. J. 9, 112–116. 10.3969/j.issn.1008-5734.2007.02.010
• Zhang J. Chen H. Z. Wang H. L. Dong L. B. (2013). Extraction and Purification Technology of Hydroxysafflor Yellow A from Carthamus tinctorius. Acta Chin. Med. Pharmacol. 41, 13–15. 10.19664/j.cnki.1002-2392.2013.06.006
• Zhang Y. L. Zhang S. F. Hua G. D. Gong Y. Zhang Q. (2016). Effect of Safflower on Anticoagulation of Warfarin. Inform. Tradit. Chin. Med. 33, 32–35. 10.19656/j.cnki.1002-2406.2016.01.010

Reduction of Warfarin Metabolism

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Conioselinum anthriscoides ‘Chuanxiong’ (Chuanxiong): This is the dried rhizome of Ligusticum chuanxiong Hort of the Umbelliferae family. It has the effect of activating blood circulation and qi circulation, dispelling wind and relieving pain. Its active ingredient of ligustrazine can dilate coronary arteries, increase coronary blood flow, improve myocardial blood oxygen supply, and reduce myocardial oxygen consumption; it can reduce platelet surface activity, inhibit platelet agglutination, and prevent thrombus formation. Li et al. (2016b) found that Conioselinum anthriscoides ‘Chuanxiong’ extract had inhibitory effects on CYP2C9 and CYPlA2, competitively inhibited metabolic enzymes, increased free warfarin, and increased the anticoagulant effect.

Befund HOS-368758 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Li H. Wang Y. Fan R. Lv H. Sun H. Xie H. (2016b). a1.The Effects of Ferulic Acid on the Pharmacokinetics of Warfarin in Rats after Biliary Drainage. Drug Des. Devel. Ther. 10, 2173–2180. 10.2147/DDDT.S107917

Reduction of Warfarin Metabolism

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Curcuma longa L. (Jianghuang): Jianghuang is the dried rhizome of Curcuma longa L., family Zingiberaceae. It has the effect of blood circulation activity and pain relief. It has modern pharmacological effects such as antihypertensive, antibacterial, antiviral, hepatoprotective, antioxidant, hypolipidemic and antitumor. Curcuma longa L. promotes the synthesis of prostaglandin PGI2, reduces the production of TXA2, and interferes with the production of cAMP or Ca2+ in platelets. Xia Q et al. found that Curcuma longa L. had a strong inhibitory effect on the CYP3A isoform of the CYP450 enzyme system (Xia et al., 2012). Therefore, Curcuma longa L. in combination with warfarin may enhance the anticoagulant effect of warfarin and lead to bleeding; thus, INR values should be monitored during clinical treatment.

Befund HOS-368754 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Xia Q. Wang X. Xu D. J. Chen X. H. Chen F. H. (2012). Inhibition of Platelet Aggregation by Curdione from Curcuma Wenyujin Essential Oil. Thromb. Res. 130, 409–414. 10.1016/j.thromres.2012.04.005

Reduction of Warfarin Metabolism

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Danhong Injection: Danhong injection (Salvia miltiorrhiza Bunge and Carthamus tinctorius L., 10 ml/stem, Shandong Danhong Pharmaceutical Co., Ltd.) significantly increased PT and INR values in rats (p < 0.01), and the effect of Danhong injection on APTT values was relatively small (p < 0.05). This suggests that Danhong injection has anticoagulant effects. It was shown that the combination of Danhong injection and warfarin could produce pharmacodynamic synergy and enhance the anticoagulant effect of warfarin mainly through the exogenous coagulation pathway, but also had some effect on the endogenous coagulation pathway (Feng et al., 2016). The combination of Danhong injection and warfarin increases the anticoagulant effect of warfarin and also increases the risk of bleeding, and the combination should be avoided or the dose should be reasonably adjusted and monitored.

Befund HOS-368782 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Feng L. Y. Liang X. L. Li T. T. Sun J. H. Liu G. F. (2016). Influence of Danhong Injection on Anticoagulant Effect of Warfarin in Rats In Vivo . Chin. Pharm. 19, 1–4. 10.3969/j.issn.1008-049X.2016.01.001

Reduction of Warfarin Metabolism

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Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Ciwujia): Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. is the rhizome or stem of Acantha panax senticosus (Rupr. et maxim) Harms, a plant of the genus Wujia, family Wujia. It has the effect of benefiting the qi, strengthening the spleen, tonifying the kidney and calming the mind. It has modern pharmacological effects of excitement or inhibition of the central nervous system, antitussive, expectorant and anti-platelet aggregation. Li et al. (2015) showed that Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. injection had no significant effect on APTT, PT and INR in rats, and the Cmax, AUC0-∞, t1/2, APTT and PT increased when combined with warfarin, suggesting that Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. injection itself had no anticoagulant effect, but can affect its pharmacokinetics and anticoagulant effect when combined with warfarin, and weaken warfarin metabolism by inhibiting the effect of CYP2C9 and CYP3A4 (Zeng et al., 2012).

Befund HOS-368756 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Li T. T. Liu Y. Feng L. Y. Liang X. L. Zhao H. F. Liu G. F. (2015). Influence of Ciwujia Injection on Anticoagulant Effect of Warfarin in Rats. Pract. Pharm. Clin. Remed. 18, 1280–1283. 10.14053/j.cnki.ppcr.201511003
• Zeng C. Liu Y. Liu G. F. Li X. (2012). Effects of Ciwujia Injection on Four Cytochrome P450 Isoforms in Rat Liver Microsomes In Vitro . Chin. J. Clin. Pharmacol. Ther. 17, 164–170.

Reduction of Warfarin Metabolism

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Fufang Danshen Dripping Pills: Fufang Danshen Dripping Pills have the effect of activating blood circulation, resolving blood stasis, regulating qi and relieving pain. Fufang Danshen Dripping Pills consist of Salvia miltiorrhiza Bunge, Panax notoginseng, and borneol. Yi et al. (2013) found that Fufang Danshen Dripping Pills (Salvia miltiorrhiza Bunge, Panax notoginseng, and borneol, 27 mg/pill, Tianshili Pharmaceutical Group Co., Ltd.) could alter the pharmacokinetic parameters of warfarin. Total Panax notoginseng saponin can reduce the metabolic rate of warfarin and enhance its anticoagulant effect by inhibiting its hydroxylation in rats. Yi et al. (2013) found that Fufang Danshen Dripping Pills alone for 4 weeks had a significant effect on coagulation. A significant increase in PT values was observed following the combination of Fufang Danshen Dripping Pills and warfarin, thus it was hypothesized that Fufang Danshen Dripping Pills and warfarin have a synergistic effect on anticoagulation. A clinical study (Guo and Zheng, 2009) found that the Cmax, AUC0∼144, AUC0∼∞, t1/2, PT, and APTT of warfarin were increased in healthy volunteers who were co-administered Fufang Danshen Dripping Pills, suggesting that Fufang Danshen Dripping Pills can affect the metabolism of warfarin and enhance its anticoagulant effect. However, animal experiments have also shown (Chu et al., 2011) that there were no significant changes in warfarin pharmacodynamics and pharmacokinetics when Fufang Danshen Dripping Pills were administered with warfarin, suggesting that regular doses of Fufang Danshen Dripping Pills may have no effect on warfarin pharmacodynamics and pharmacokinetics in humans. Due to inconsistent results between animal experiments and clinical applications, further research is needed.

Befund HOS-368780 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Yi D. Luo X. B. Lu X. H. Luo S. P. Zhou Y. L. (2013). The Effects of Compound Danshen Dripping Pills on the Pharmacodynamics and Pharmacokinetics of Warfarin in Humans. Chin. J. Pharmacovigilance 10, 65–67. 10.3969/j.issn.1672-8629.2013.02.001
• Guo L. Zheng D. R. (2009). The Influence of Compound Danshen Dropping Pill in Coronary Heart Disease on PT, APTT and FIB. Chin. Med. Herald 6, 87–88. 10.3969/j.issn.1673-7210.2009.18.050
• Chu Y. Zhang L. Wang X. Y. Guo J. H. Guo Z. X. Ma X. H. (2011). The Effect of Compound Danshen Dripping Pills, a Chinese Herb Medicine, on the Pharmacokinetics and Pharmacodynamics of Warfarin in Rats. J. Ethnopharmacol. 137, 1457–1461. 10.1016/j.jep.2011.08.035

Induction of Cytochrome P450 Enzyme Activity and Reduction of Warfarin Anticoagulation

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Ginkgo biloba L. (Yinxinye): Ginkgo biloba L. can induce hepatic cytochrome P450 enzymes, accelerate the metabolism of warfarin, thereby reducing the anticoagulant effect of warfarin (Zhang et al., 2007), and its mechanism of action is still unclear.

Befund HOS-368774 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Zhang H. Y. Zhang B. Li Y. Z. (2007). Interactions of Warfarin and its Safe Use. Adverse Drug React. J. 9, 112–116. 10.3969/j.issn.1008-5734.2007.02.010

Reduction of Warfarin Metabolism

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Ginkgo biloba extract (GBE): Ginkgo is a genus of Ginkgo biloba L. in the family Ginkgoaceae, also known as white fruit tree, gongsun tree, and duck palm tree, whose medicinal parts are mainly the leaves and fruits. Ginkgo has the functions of invigorating blood circulation, and removing blood stasis. Modern pharmacological studies have shown that ginkgo has hepatoprotective, antitumor, antiradiation, and renal protective effects, as well as antioxidant, pro-intellectual, anti-anxiety, sedative, lipid regulating and reducing ischemia-reperfusion injury effects (Han et al., 2007; Shi, 2008). Tan et al. (2011) found that Ginkgo biloba extract (GBE) could block the production of platelet-derived growth factors through the inhibition of tyrosine kinase, thereby inhibiting thrombin-induced platelet activation and aggregation, with no or minimal effect on coagulation. In vitro studies have shown that GBE affects the enzymatic activity of CYP2C9 in vivo, thereby affecting S-warfarin 7-hydroxylation. However, in vivo studies have shown that GBE has no effect on the metabolism of the CYP2C9 substrates diclofenac and toluenesulfonylurea, and that neither GBE nor ginkgolide B affects the coagulation process, but that ginkgolide attenuates the anticoagulant effect of warfarin by inducing S-warfarin hydroxylase. Some experiments in rats have shown that GBE induces CYPs, but enzyme activity is quickly restored after discontinuation of dosing. GBE had no significant effect on single-dose warfarin pharmacodynamics, no effect on PT and APTT, and no significant change in apparent volume of distribution, but increased peak warfarin concentration, AUC, half-life, and decreased its clearance (Zhou and Zeng, 2011).

Befund HOS-368776 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Han S. Z. Ping F. Li X. (2007). Effect of the Ginkgo Leaves Extract on Platelet Activation in the Patients with Chronic Cor Pulmonale during Acute Period. Hebei Med. J. 29, 49. 10.3969/j.issn.1002-7386.2007.01.022
• Shi J. M. (2008). Advances in Pharmacological Research on Ginkgo Biloba. Int. Med. Health Guid. News 14, 122.
• Tan P. Hao Y. Ding S. J. Peng K. R. Liu Y. (2011). Mechanism of Platelet Anti-aggregation with Ginkgo Biloba Extract. Chin. J. Neuromed. 10, 260–263. 10.3760/cma.j.issn.1671-8925.2011.03.011
• Zhou Y. L. Zeng R. (2011). Effects of Ginkgo Biloba Extract on Anticoagulation and Blood Drug Level of Warfarin in Healthy Volunteers. Chin. J. Chin. Mater. Med. 36, 2290–2293. 10.4268/cjcmm20111628

Reduction of Warfarin Metabolism

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Glycyrrhiza glabra L. (Gancao): Glycyrrhiza glabra L. is the dried root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L., a genus of licorice in the family Fabaceae. It has the effects of benefiting the qi and tonifying the middle, moistening the lung and relieving cough, clearing heat and detoxifying, relieving pain and harmonizing medicinal properties. It has modern pharmacological effects such as adrenocorticotropic hormone-like effects, anti-platelet aggregation, anti-peptic ulcer, antipyretic, sedative, and immune enhancing. Qiao et al. (Qiao et al., 2014) analyzed the interaction of more than 40 chemical components in Glycyrrhiza glabra L. with cytochrome P450 enzymes and showed that the flavonoids, terpenoids and coumarins in Glycyrrhiza glabra L. had different degrees of inhibitory effects on the activities of CYP1A2, 2C9, 2C19, 2D6 and 3A4/5, which resulted in slower warfarin metabolism, longer half-life and higher INR. Flavonoids can inhibit platelet function through multiple links (Xiang et al., 2008), mainly including blocking platelet activating factor (PAF) binding to platelet receptors, inhibiting the release of platelet endogenous substances, inhibiting the increase in intra-platelet Ca2+ and balancing the intra-platelet thromboxane B2-6-keto-prostaglandin (TXB2-6-keto-PGFla) system, which synergistically anticoagulated with warfarin.

Befund HOS-368751 · warfarin · HOS-085950 · Originalquelle ↗

Plants Containing Coumarin-like Ingredients Similar to Warfarin, Producing a Synergistic Effect

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Glycyrrhiza glabra L. (Gancao): The coumarin derivatives in Glycyrrhiza glabra L. (Chen et al., 2018) may show antiplatelet activity by increasing intra-platelet cAMP. However, animal tests have also shown that Glycyrrhiza glabra L. activates pregnane X receptors (PXR) and increases the clearance of warfarin, thereby reducing its anticoagulant effect, so the mechanism of interaction between Glycyrrhiza glabra L. and warfarin requires further investigation.

Befund HOS-368752 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Qiao X. Ji S. Yu S. W. Lin X. H. Jin H. W. Duan Y. K. (2014). Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/Ms/Ms Cocktail Assay and Metabilic Profiling. AAPS J. 16, 101–113. 10.1208/s12248-013-9544-9
• Xiang Y. Z. Shang H. C. Zhang B. L. (2008). Advances in Studies on Chinese Materia Medica with Antiplatelet Function. Chin. Tradit. Herbal Drugs 39, 290–294. 10.3321/j.issn:0253-2670.2008.02.04910.1002/chin.200810266
• Chen Z. Zhao M. Gao N. (2018). INR Elevation Caused by the Interaction of Strengthening and Regulating Qi and Warfarin in 1 Case. Chin. J. Mod. Appl. Pharm. 35, 434–435. 10.13748/j.cnki.issn1007-7693.2018.03.029

Induction of Cytochrome P450 Enzyme Activity and Reduction of Warfarin Anticoagulation

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Hypericum perforatum (Guanyejinsitao): The dried above-ground part of Hypericum perforatum L., family Garciniaceae has the effects of soothing the liver and relieving depression, clearing heat and dampness, reducing swelling and clearing milk, and can be used to relieve mild and moderate depression, and its main active ingredient is hypericin. Combined with warfarin it significantly induces the apparent clearance of S- and R-type warfarin and attenuates its anticoagulant effect (Jiang et al., 2004). Hypericum perforatum can induce the activity of CYP3A4 through the PXR (Wang et al., 2009), and induces the expression of CYP1A2 (Silva et al., 2016), promotes the metabolism of warfarin and weakens its anticoagulant effect.

Befund HOS-368768 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Jiang X. Williams K. M. Liauw W. S. Ammit A. J. Roufogalis B. D. Duke C. C. (2004). Effect of St John’s Wort and Ginseng on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects. Br. J. Clin. Pharmacol. 57, 592–599. 10.1111/j.1365-2125.2003.02051.x
• Wang X. Lee W. Y. Or P. M. Yeung J. H. (2009). Effects of Major Tanshinones Isolated from Danshen (Salvia Miltiorrhiza) on Rat CYP1A2 Expression and Metabolism of Model CYPIA2 Probe Substrates. Phytomedicine 16, 712–725. 10.1016/j.phymed.2009.03.004
• Silva S. M. Martinho A. Moreno I. Silvestre S. Granadeiro L. B. Alves G. (2016). Effects of Hypericum perforatum Extract and its Main Bioactive Compounds on the Cytotoxicity and Expression of CYP1A2 and CYP2D6 in Hepatic Cells. Life Sci. 144, 30–36. 10.1016/j.lfs.2015.11.004

Reduction of Warfarin Metabolism

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Lycium barbarum L. (Gouqizi): The mature fruit of Lycium barbarum L., family Solanaceae has the effect of nourishing the liver and kidney, benefiting the essence and brightening the eyes, treating liver and kidney yin deficiency and premature aging. It has anti-aging, hypolipidemic, hypoglycemic and hematopoietic effects. In an in vitro study (Leung et al., 2008), noted that Lycium barbarum L. tea inhibited warfarin metabolism by weakly inhibiting CYP2C9 activity in human liver microsomes, suggesting that this interaction may be due to the effect of factors such as absorption, P-glycoprotein or the anticoagulant effect of the herb itself. It was also observed that it was possible that the metabolites of Lycium barbarum L. displaced warfarin from its plasma protein binding site, leading to an increase in INR. Cheng (2012) confirmed using a Caco-2 cell assay that Lycium barbarum polysaccharides (LBP) may increase the absorption of the drug when combined with P-glycoprotein substrate, resulting in a higher blood concentration and enhanced efficacy. The high concentration of LBP increased the absorption of the drug by inhibiting the efflux transport of P-glycoprotein and increased the blood concentration and enhanced the effect of warfarin. Studies (Rivera et al., 2012; Zhuang et al., 2020) reported an unexplained and significant increase in INR value along with symptoms of rhinorrhagia, skin petechiae and rectal bleeding in an American woman after taking Lycium barbarum L. juice. Guzmán et al. (2021) reported a 75-year-old female patient who had a mitral valve replacement 3 years ago and was taking oral warfarin postoperatively with an INR controlled within the target range (2.5–3.5). Recent consumption of Lycium barbarum L. tea (1-2 cups per day) to prevent neocoronavirus infection eventually led to an increase in INR due to warfarin overdose.

Befund HOS-368749 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Leung H. Hung A. Hui A. C. Chan T. Y. (2008). Warfarin Overdose Due to the Possible Effects of Lycium Barbarum L. Food Chem. Toxicol. 46, 1860–1862. 10.1016/j.fct.2008.01.008
• Cheng R. H. (2012). Effects of Lycium Barbarum Polysaccharide on P-Glycoprotein. Changsha: Central South University.
• Rivera C. A. Ferro C. L. Bursua A. J. Gerber B. S. (2012). Probable Interaction between Lycium Barbarum (Goji) and Warfarin. Pharmacotherapy 32, 50–53. 10.1002/j.1875-9114.2012.01018.x
• Zhuang W. Sun G. Lin X. Chen B. Wu L. Jiang D. (2020). Medication with Caution: Analysis of Adverse Reactions Caused by a Combination of Chinese Medicine and Warfarin Sodium Tablets. J. Ethnopharmacol. 254, 112586. 10.1016/j.jep.2020.112586
• Guzmán C. E. Guzmán-Moreno C. G. Assad-Morell J. L. Carrizales-Sepúlveda E. F. (2021). Flecainide Toxicity Associated with the Use of Goji Berries: a Case Report. Eur. Heart J. Case Rep. 5, 1–6. 10.1093/ehjcr/ytab204

Induction of Cytochrome P450 Enzyme Activity and Reduction of Warfarin Anticoagulation

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Panax ginseng C.A.Mey. (Renshen) and Panax quinquefolius L. (Xiyangshen): The dried roots of Panax ginseng C.A.Mey. of the family Pentacostaceae have the effects of invigorating qi, promoting body fluid, soothing the nerves, and nourishing the mind. The modern pharmacological effects include anti-shock, increasing the amplitude of heartbeat and heart rate, anti-fatigue, promoting hematopoiesis, regulating cholesterol metabolism, enhancing the immune function of the body, and lowering blood sugar. Xiyangshen is the root of Panax quinquefolius L., a plant in the Araliaceae family, with the effects of tonifying qi and nourishing yin, clearing heat and generating fluid, improving immunity, inhibiting platelet coagulation, promoting blood circulation, and preventing arterial atherosclerosis. You et al. (2015) showed that these two herbs combined with warfarin decreased the INR in patients. Panax ginseng C.A.Mey. and Panax quinquefolius L. contain a variety of ginsenosides, of which ginsenoside F1 may induce the gene expression of CYP3A4 and enhance its enzymatic activity by activating the progesterone receptor in a concentration-dependent manner. However, it has also been shown (Malati et al., 2012) that ginsenosides Rg3, Rh2, and C-K inhibit the activities of CYP2C9, CYP3A4, and CYP2C19, while Rb1 and C-K moderately inhibit the activity of CYP1A2, and low doses of ginseng do not alter the activities of CYP3A4 and P-glycoprotein (Janetzky and Morreale, 1997; Hao et al., 2008). There are mixed findings in the literature regarding the effects of ginseng on CYP450 enzymes, and the mechanism by which it attenuates the anticoagulant effect of warfarin remains to be further clarified.

Befund HOS-368770 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• You W. T. Zhou T. Ma Z. C. Liang Q. D. Tang X. L. Xiao C. R. (2015). Ginsenoside F1 Induces CYP3A4 Expression through Activation of Human Pregnane X Receptor. Chin. Pharmacol. Bull. 31, 1536–1540. 10.3969/j.issn.1001-1978.2015.11.012
• Malati C. Y. Robertson S. M. Hunt J. D. Chairez C. Alfaro R. M. Kovacs J. A. (2012). Influence of Panax Ginseng on Cytochrome P450 (CYP) 3A and P-Glycoprotein (P-Gp) Activity in Healthy Participants. J. Clin. Pharmacol. 52, 932–939. 10.1177/0091270011407194
• Janetzky K. Morreale A. P. (1997). Probable Interaction between Warfarin and Ginseng. Am. J. Health Syst. Pharm. 54, 692–693. 10.1093/ajhp/54.6.692
• Hao M. Zhao Y. Chen P. Huang H. Liu H. Jiang H. (2008). Structure-activity Relationship and Substrate-dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes. PLoS One 3 (7), e2697. 10.1371/journal.pone.0002697

Reduce Platelet Aggregation

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Panax notoginseng (Burkill) F.H. Chen (Sanqi): The dry radix et rhizome of Panax notoginseng (Burk.) F.H. Chen has the effects of removing blood stasis, stopping bleeding, promoting blood circulation and relieving pain. Modern pharmacological effects include hemostasis (promoting blood clotting), anti-thrombosis, promoting hematopoiesis, inhibiting the heart, expanding blood vessels, and lowering blood pressure. The main components of Panax notoginseng are total saponins (Panax notoginseng saponins, PNS). PNS mainly consists of Panax notoginseng saponin Rg1 and Panax notoginseng saponin Rb1. It is widely used in the clinical treatment of various cerebrovascular diseases. When combined with warfarin, it can increase the peak concentration of warfarin to enhance its anticoagulant effect, and significantly increase the PT value and INR value of warfarin (p < 0.05). The mechanism underlying the reduction of thrombosis may be through increasing the cAMP content in platelets and reducing thromboxane A-2 (TXA-2) (Xu et al., 1997). Therefore, Panax notoginseng combined with warfarin may cause increased INR and multiple subcutaneous hemorrhage and ecchymosis.

Befund HOS-368747 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Xu H. L. Liu W. B. Rao M. R. (1997). [Effect of Sanchinoside Rg1 on Experimental Thrombosis and its Mechanisms]. Yao Xue Xue Bao 32, 502–505. 10.16438/j.0513-4870.1997.07.005

Induction of Cytochrome P450 Enzyme Activity and Reduction of Warfarin Anticoagulation

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Panax ginseng C.A.Mey. (Renshen) and Panax quinquefolius L. (Xiyangshen): The dried roots of Panax ginseng C.A.Mey. of the family Pentacostaceae have the effects of invigorating qi, promoting body fluid, soothing the nerves, and nourishing the mind. The modern pharmacological effects include anti-shock, increasing the amplitude of heartbeat and heart rate, anti-fatigue, promoting hematopoiesis, regulating cholesterol metabolism, enhancing the immune function of the body, and lowering blood sugar. Xiyangshen is the root of Panax quinquefolius L., a plant in the Araliaceae family, with the effects of tonifying qi and nourishing yin, clearing heat and generating fluid, improving immunity, inhibiting platelet coagulation, promoting blood circulation, and preventing arterial atherosclerosis. You et al. (2015) showed that these two herbs combined with warfarin decreased the INR in patients. Panax ginseng C.A.Mey. and Panax quinquefolius L. contain a variety of ginsenosides, of which ginsenoside F1 may induce the gene expression of CYP3A4 and enhance its enzymatic activity by activating the progesterone receptor in a concentration-dependent manner. However, it has also been shown (Malati et al., 2012) that ginsenosides Rg3, Rh2, and C-K inhibit the activities of CYP2C9, CYP3A4, and CYP2C19, while Rb1 and C-K moderately inhibit the activity of CYP1A2, and low doses of ginseng do not alter the activities of CYP3A4 and P-glycoprotein (Janetzky and Morreale, 1997; Hao et al., 2008). There are mixed findings in the literature regarding the effects of ginseng on CYP450 enzymes, and the mechanism by which it attenuates the anticoagulant effect of warfarin remains to be further clarified.

Befund HOS-368772 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• You W. T. Zhou T. Ma Z. C. Liang Q. D. Tang X. L. Xiao C. R. (2015). Ginsenoside F1 Induces CYP3A4 Expression through Activation of Human Pregnane X Receptor. Chin. Pharmacol. Bull. 31, 1536–1540. 10.3969/j.issn.1001-1978.2015.11.012
• Malati C. Y. Robertson S. M. Hunt J. D. Chairez C. Alfaro R. M. Kovacs J. A. (2012). Influence of Panax Ginseng on Cytochrome P450 (CYP) 3A and P-Glycoprotein (P-Gp) Activity in Healthy Participants. J. Clin. Pharmacol. 52, 932–939. 10.1177/0091270011407194
• Janetzky K. Morreale A. P. (1997). Probable Interaction between Warfarin and Ginseng. Am. J. Health Syst. Pharm. 54, 692–693. 10.1093/ajhp/54.6.692
• Hao M. Zhao Y. Chen P. Huang H. Liu H. Jiang H. (2008). Structure-activity Relationship and Substrate-dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes. PLoS One 3 (7), e2697. 10.1371/journal.pone.0002697

Inhibiting the Effect of Warfarin Antagonist Vitamin K

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Pyrola calliantha Andres calliantha Andres (Luticao): This is the whole plant of Pyrola rotundifolia L. Subsp. Chinensis H. Andres, P. decorata H. Andres or P. rotundifolia L., also known as deer’s-foot herb. Pyrola calliantha Andres has antibacterial, cardiac contractility enhancing, antiarrhythmic and contraceptive effects, and is mainly used in lung infections, intestinal and urinary tract infections, liver abscesses and other diseases (Wang, 1983). Xie et al. (2001) reported that Pyrola calliantha Andres, whose active ingredients are salicylates, can affect thrombin synthesis by inhibiting the oxidoreductase enzyme of vitamin K impeding its metabolic cycle and reducing the absorption of vitamin K. It may also be due to salicylates displacing warfarin from plasma protein binding and elevating the blood concentration of warfarin resulting in an enhanced anticoagulant effect of warfarin.

Befund HOS-368762 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Wang Y. S. Deng W. L. Xue C. S. (1983). Pharmacology and Application of Traditional Chinese Medicine. 1st edition. Beijing: People's Medical Publishing House, 1094–1097.
• Xie H. J. Li C. H. Li C. Guan L. P. (2001). Interaction of Warfarin with Angelica Sinensis (Oliv) Diels., green tea and Pyrola Calliantha Andres Calliantha Andres. Hebei Med. 7, 946–948. 10.3969/j.issn.1006-6233.2001.10.05810.1241/johokanri.43.946

Reduce Platelet Aggregation

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Salvia miltiorrhiza Bunge (Danshen): The dried radix et rhizome of Salvia miltiorrhiza Bunge has the functions of promoting blood circulation and removing blood stasis, relieving pain by dredging meridians, clearing heart fire, relieving restlessness, and cooling blood to diminish carbuncle. Modern pharmacological effects are anti-coagulation, anti-thrombosis, improvement of microcirculation, improvement of blood rheology, anti-myocardial ischemia, anti-cerebral ischemia, anti-oxidation, etc. In vivo (Fan et al., 2010), salvianolic acid A (SAA) did not affect coagulation parameters in rats after intravenous administration for five successive days. In vitro, pretreatment with SAA on washed rat and human platelets significantly inhibited various agonists, stimulated platelet aggregation and caused an increase in cyclic adenosine monophosphate (cAMP) level in platelets activated by adenosine diphosphate (ADP). SAA possesses antithrombotic activities. The antithrombotic effect might be related to its antiplatelet action and ability to modulate hemorheology without affecting the coagulation system. The mechanisms underlying such activities may involve the induction of cAMP. Li Le reported that Salvia miltiorrhiza can increase the activity of coagulation factor Ⅲ and fibrinolysis by inhibiting platelet aggregation, and can reduce the clearance rate of warfarin to enhance its anticoagulant effect (Li L. et al., 2016). A pharmacological study by Xie H.J. et al. showed that Salvia miltiorrhiza has the effect of anti-platelet aggregation, but does not affect blood coagulation function in rats (Xie et al., 2009). When combined with warfarin, it can increase the steady-state blood concentration and INR of warfarin in rats, and enhance the anticoagulation of warfarin.

Befund HOS-368740 · warfarin · HOS-085950 · Originalquelle ↗

Reduction of Warfarin Metabolism

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Salvia miltiorrhiza Bunge (Danshen): Wang et al. (2010a) studied human cells and showed that tanshinone I, tanshinone IIA and cryptotanshinone strongly inhibited CYP1A2, moderately inhibited CYP2C9, tanshinone I and cryptotanshinone, weakly inhibited CYP3A4, dihydrotanshinone and competitively inhibited CYP1A2 and CYP2C9, but had no effect on CYP3A4. Qiu et al. (2008), Wang (2015) investigated the effects of various components of Salvia miltiorrhiza Bunge on the activity of cytochrome P450s (CYPs) in humans and found that cryptotanshinone, tanshinone I and tanshinone IIA competitively inhibited CYP1A2, cryptotanshinone and tanshinin moderately inhibited CYP2C9, protocatechualdehyde slightly inhibited CYP3A4, while the lipid soluble components of Salvia miltiorrhiza Bunge could induce CYP3A4. Wang et al. (2009), Wang et al. (2010b) showed in both in vivo and ex vivo experiments in rats that tanshinones inhibited the activity of CYP2C11, but had fewer pharmacodynamic effects on the CYP2C11-specific substrate toluene sulfonylurea, which had the same specific metabolic substrate as human CYP2C9, therefore it can be concluded that various components of Salvia miltiorrhiza Bunge may affect the anticoagulant effect of warfarin by inhibiting CYP2C9 and CYP1A2, inhibiting or inducing CYP3A4, and competitively binding to human albumin and other ways. Wu and Yeung (2010) also found that tanshinone reduced CYP1A1, CYP2C6 and CYP2C11 mediated 4-, 6- and 7-hydroxywarfarin hydroxylation reactions in rats, thereby inhibiting warfarin metabolism. Zhou et al. (2012) also concluded that Salvia miltiorrhiza Bunge affected the anticoagulant effect of warfarin in relation to CYP450 enzyme metabolism.

Befund HOS-368741 · warfarin · HOS-085950 · Originalquelle ↗

Reduction of Warfarin Metabolism

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Salvia miltiorrhiza Bunge (Danshen): Lo et al. (1992) studied the effect of Salvia miltiorrhiza Bunge on warfarin metabolism in rats. It was found that Salvia miltiorrhiza Bunge decreased the absorption rate, apparent volume of distribution and clearance half-life of warfarin, and increased the peak concentration and time to peak thereby enhancing the anticoagulant effect of warfarin.

Befund HOS-368742 · warfarin · HOS-085950 · Originalquelle ↗

Competitive Binding to Plasma Proteins Increases Free State Warfarin Concentration

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Salvia miltiorrhiza Bunge (Danshen): Wang Q. et al. (Tan et al., 2002; Liu et al., 2008; Guo and Zheng, 2009; Wang, 2013) concluded that the binding rate of Salvia miltiorrhiza Bunge and tanshinone IIa to human serum proteins was comparable to that of warfarin, and could replace warfarin in warfarin-albumin complexes, which could significantly reduce the plasma protein binding rate of warfarin, increase the free warfarin concentration in blood, and enhance the anticoagulant effect. Wang (2013) also found that tanshinone IIa and oleanolic acid in Salvia miltiorrhiza Bunge also have certain inhibitory effects on coagulation factor Xa. When Salvia miltiorrhiza Bunge is used in combination with warfarin, the anticoagulant effect is enhanced, which may lead to bleeding adverse reactions.

Befund HOS-368743 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Fan H. Y. Fu F. H. Yang M. Y. Xu H. Zhang A. H. Liu K. (2010). Antiplatelet and Antithrombotic Activities of Salvianolic Acid. A. Thromb. Res. 126, e17–e22. 10.1016/j.thromres.2010.04.006
• Li L. Cheng X. Wang J. J. (2016a). The Research Progress of TCM Injections with Warfarin Drug Interactions. Chin. J. Geriatr. Care 14, 59–61. 10.3969/j.issn.1672-4860.2016.03.029
• Xie H. J. Fu H. Y. Zhu C. F. Huang Z. Charles D. S. (2009). Effects of Danshen Injection (Salvia Miltiorrhiza) on Pharmacodynamics and Pharmacokinetics of Warfarin in Rats. Herald Med. 28, 36–39. 10.3870/yydb.2009.01.011
• Wang X. Cheung C. M. Lee W. Y. Or P. M. Yeung J. H. (2010a). Major Tanshinones of Danshen (Salvia Miltiorrhiza) Exhibit Different Modes of Inhibition on Human CYP1A2, CYP2C9, CYP2E1 and CYP3A4 Activities In Vitro . Phytomedicine 17, 868–875. 10.1016/j.phymed.2010.05.003
• Qiu F. Zhang R. Sun J. Jiye A. Hao H. Peng Y. (2008). Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450enzyme in Human Liver Microsomes. Drug Metab. Dispos. 36, 1308–1314. 10.1124/dmd.108.021030
• Wang Y. J. (2015). Different Effects of Four Ingredients of Danshen on the CYP3A4 and CYP2C9 Expressions. Shanghai: Shanghai Jiaotong University.
• Wang X. D. Li J. L. Su Q. B. Guan S. Chen J. Du J. (2009). Impact of the Haplotypes of the Human Pregnane X Receptor Gene on the Basal and St John’s Wort-Induced Activity of Cytochrome P450 3A4 Enzyme. Br. J. Clin. Pharmacol. 67, 255–261. 10.1111/j.1365-2125.2008.03344.x
• Wang X. Lee W. Y. Or P. M. Yeung J. H. (2010b). Pharmacokinetic Interaction Studies of Tanshinones with Tolbutamide, a Model CYP2C11 Probe Substrate, Using Liver Microsomes, Primary Hepatocytes and In Vivo in the Rat. Phytomedicine 17, 203–211. 10.1016/j.phymed.2009.07.013
• Wu W. W. Yeung J. H. (2010). Inhibition of Warfarin Hydroxylation by Major Tanshinones of Danshen in the Rat In Vitro and In Vivo . Phytomedicine 17, 219–226. 10.1016/j.phymed.2009.05.005
• Zhou X. Chan K. Yeung J. H. (2012). Herb-drug Interactions with Danshen (Salvia Miltiorrhiza): a Review on the Role of Cytochrome P450 Enzymes. Drug Metabol. Drug Interact. 27, 9–18. 10.1515/dmdi-2011-0038
• Lo A. C. Chan K. Yeung J. H. K. Woo K. S. (1992). The Effects of Danshen (Salvia Miltiorrhiza) on Pharmacokinetics and Pharmacodynamics of Warfarin in Rats. Eur. J. Drug Metab. Pharmacokinet. 17, 257–262. 10.1007/BF03190157
• Tan Y. Z. Wu A. C. Tan B. Y. Wu Y. H. Tang L. F. Li J. H. (2002). Study on the Interactions of Berberine Displace Other Drug from Their Plasma Proteins Binding Sites. Chin. Pharmacol. Bull. 18, 576–578.
• Liu J. Wang X. Cai Z. Lee F. S. (2008). Effect of Tanshinone IIA on the Noncovalent Interaction between Warfarin and Human Serum Albumin Studied by Electrospray Ionization Mass Spectrometry. J. Am. Soc. Mass. Spectrom. 19, 1568–1575. 10.1016/j.jasms.2008.06.005
• Guo L. Zheng D. R. (2009). The Influence of Compound Danshen Dropping Pill in Coronary Heart Disease on PT, APTT and FIB. Chin. Med. Herald 6, 87–88. 10.3969/j.issn.1673-7210.2009.18.050
• Wang Q. (2013). Studies on FXa Inhibitors of Herba Lycopi and Salvia Mitiorrhizae. Nanjing: Nanjing University of Chinese Medicine.

Reduce Platelet Aggregation

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Shunaoxin Dripping Pills: Shunaoxin Dripping Pills are composed of Ligusticum chuanxiong and Angelica sinensis (42 mg/pill, Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Sixth Chinese Medicine Factory). They have the effects of regulating qi, promoting blood circulation, removing blood stasis and relieving pain. Studies by Feng Bo (Feng et al., 2015) have shown that Shunaoxin Dripping Pills have a strong anti-platelet aggregation effect in vitro, and with an increase in dose, the inhibition of platelet aggregation in vivo increased slightly. Shunaoxin Dripping Pills can significantly reduce platelet aggregation induced by ADP and thrombin, and is positively correlated with the dose. High doses combined with warfarin can significantly prolong APTT, PT, and thrombin time (TT), suggesting that Shunaoxin Dripping pills have the effect of anti-platelet aggregation, and high-dose combination with warfarin can increase the anticoagulant effect of warfarin.

Befund HOS-368778 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Feng B. Wang J. L. Zhuang P. W. Liu D. Tong Y. L. Zhang Y. J. (2015). Interaction of Shunaoxin Dripping Pill and Warfarin Sodium on Anticoagulant Applications. Chin. Tradit. Herbal Drugs 46, 2445–2448. 10.7501/j.issn.0253-2670.2015.16.01810.1161/strokeaha.114.008578

Reduction of Warfarin Metabolism

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Silybum marianum (L.) Gaertn. (Shuifeiji): This is the dried and mature fruit of the Silybum, family Asteraceae. It is harvested in autumn when the fruit is ripe, impurities are removed and it is dried in the Sun. It is bitter and cool to taste, with the effect of clearing heat and detoxifying, draining the liver and stimulating the bile. The modern pharmacological effects of Silybum marianum (L.) Gaertn. include protecting against liver injury, and anti-liver virus. Brantley et al. (2014) found that its combination with warfarin could increase the area under drug time curve (AUC) of S-type warfarin, which enhanced its anticoagulant effect. Silybum marianum (L.) Gaertn. can moderately inhibit the activities of CYP1A2, CYP2C8, and CYP2C9 enzymes and weakly inhibit the activities of CYP2A6, CYP2C19, CYP2D6 and other enzymes (Brantley et al., 2010). Silybum marianum (L.) Gaertn. can enhance the anticoagulant effect of warfarin by weakening its metabolism when combined with warfarin.

Befund HOS-368760 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Brantley S. J. Gufford B. T. Dua R. Fediuk D. J. Graf T. N. Scarlett Y. V. (2014). Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb-Drug Interaction. CPT Pharmacometrics Syst. Pharmacol. 3, e107. 10.1038/psp.2013.69
• Brantley S. J. Oberlies N. H. Kroll D. J. Paine M. F. (2010). Two Flavonolignans from Milk Thistle (Silybum marianum) Inhibit CYP2C9 Mediated Warfarin Metabolism at Clinically Achievable Concentrations. J. Pharmacol. Exp. Ther. 332, 1081–1087. 10.1124/jpet.109.161927

Inhibiting the Effect of Warfarin Antagonist Vitamin K

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Tribulus terrestris L. (Jili): The mature fruit of Tribulus terrestris L., a plant of the family Tribulus terrestris has the effects of calming the liver and relieving depression, activating the blood and dispelling wind, brightening the eyes, and relieving itching. Modern pharmacological effects include anti-myocardial ischemia, delaying aging, and anti-acetylcholine. Tang (2007) reported that Tribulus terrestris L. and its preparations can inhibit the production of vitamin K by intestinal flora, interfere with platelet aggregation, and affect the absorption, distribution, and metabolism of warfarin, so that the anticoagulant effect of warfarin is enhanced, pending further research.

Befund HOS-368764 · warfarin · HOS-085950 · Originalquelle ↗

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update ↗

Copyright © 2021 Zhuang, Liu, Zhao, Sun, He, Wang, Jia, Lin, Chu and Xi. Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update. DOI: 10.3389/fphar.2021.751107 · CC BY 4.0

Quellen-Hash: b46c221ac01dd09600094fcfc243f39e7e1846720f413ea49157075cd642ed78

• Tang G. M. (2007). Effect of Ginkgo Biloba L. And Tribulus Terrestris L. Preparations on the Anticoagulant Effect of Warfarin. Zhejiang Med. J. 29, 868–869. 10.3969/j.issn.1006-2785.2007.08.041

LiverTox chapter excerpt (PubMed; not full chapter)

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Ephedra is a genus of plants one species of which is known as Ma Huang (Ephedra sinica), which has been used in traditional Chinese medicine for centuries as a stimulant and antiasthmatic agent, and was recently introduced into use in the United States and Europe as a weight loss agent and aid in body building. Ma Huang and Ephedra species containing ephedrine alkaloids have been linked to multiple potentially severe side effects, including clinically apparent liver injury and has been banned from sale in the United States and elsewhere.

Befund HOS-368812 · Originalquelle ↗

Ephedra ↗

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. NIDDK/NLM. Public-domain chapter excerpt supplied by NLM PubMed. · Public domain

Quellen-Hash: 49705cd3771151d47e2e91b6a272f2ce02bc2406c5170432f04eb076ac2f37ca

• NLM PubMed book chapter excerpt

LiverTox chapter excerpt (PubMed; not full chapter)

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Lingzhi (Ganoderma lingzhi), also known as Reishi (usually Ganoderma lucidum), is a large, reddish-brown mushroom with a distinctive fan-like appearance that is used in traditional Chinese medicine for improving health, restoring vitality, and preventing illness. Lingzhi is well tolerated and has not been associated with serum aminotransferase elevations during therapy but has been implicated in rare single instances of acute liver injury, although in most reports other diagnoses were not adequately excluded.

Befund HOS-368800 · Originalquelle ↗

Lingzhi, Reishi ↗

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. NIDDK/NLM. Public-domain chapter excerpt supplied by NLM PubMed. · Public domain

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• NLM PubMed book chapter excerpt

3.3.1. Schisandra sphenanthera

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3.3.1. Schisandra sphenanthera A Schisandra sphenanthera ethanol extract (SchE) is a herbal medicine also referred to as a Wuzhi capsule, or a Wuhzi tablet, which has been used in the traditional Chinese medicine for thousands of years in cases of hepatitis, hepatic and renal insufficiency, menstrual dysfunction, neurosis and others [74,75,76,77]. It is often prescribed in Chinese transplant patients for tacrolimus-induced hepatitis treatment as a liver-protective agent [77,78]. Studies have shown that the co-administration of Wuhzi tablets and tacrolimus may significantly increase tacrolimus blood concentration. Schisantherin A (STA) and schisandrin A (SIA), the main active agents of SchE, inhibit CYP3A4/5 by both reversible inhibition and the permanent loss of enzyme activity through its destruction [76,79]. Other SchE components, schisandrin B and gomisin A, were found to inhibit P-glycoprotein, whereas gomisin C competitively inhibited and irreversibly deactivated CYP3A [78]. Tacrolimus is metabolized by CYP3A isoenzymes and undergoes P-glycoprotein-mediated transport; therefore, an interaction should be expected [4,76,80]. Tacrolimus blood concentrations increased 1.57–4.66-fold following SchE administration [76]. Moreover, parameters, such as the AUC, AUMC and Cmax of tacrolimus, were reported to increase significantly, although in terms of CL/F and V/F a significant decrease was observed [78,81]. The SchE effect on Cmax and AUC in rats was dose-dependent and the maximum mean plasma concentration of tacrolimus was achieved at 450 mg/kg [77]. Interestingly, a higher SchE dose did not result in an increase in tacrolimus concentration. Furthermore, a single SchE dose administration resulted in a higher mean plasma concentration and AUC compared to a multiple SchE dosing [77]. Despite the remarkable increase in the blood AUC of tacrolimus, no significant changes were found in rat tissue concentrations [82]. Moreover, studies on CYP3A5 polymorphism showed that SchE effect was more pronounced in the CYP3A5 expressers compared to the non-expressers [79,81,83]. An increase in tacrolimus concentration was lower, although still significant when combined with a long-term prednisone treatment [84]. Xin et al. reported lower mean creatinine levels and higher mean BUN levels in healthy volunteers after SchE and tacrolimus co-administration [78]. In terms of liver function, ALT and AST levels significantly decreased following 6-month SchE treatment in renal transplant patients receiving tacrolimus [85]. SchE administration in renal transplant recipients not only did not deteriorate graft function but was found to have a protective effect on its survival [81]. Side effects, such as hyperkalaemia or fever, were reported after SchE and tacrolimus co-administration and were accounted for as a result of an increased tacrolimus blood concentration [78,86]. Several population pharmacokinetic models have been developed to support the individualization of tacrolimus dosing for different groups: renal transplant recipients [81,83,85,87,88], liver transplant recipients [89,90], cardiac transplant recipients [91,92], patients with refractory nephrotic syndrome [93,94], membranous nephropathy [95,96], lupus nephritis [97,98] or myasthenia gravis [99]. SchE may significantly increase tacrolimus bioavailability and reduce its therapeutic costs by 40–60%, nevertheless, authors highly recommend blood tacrolimus concentration monitoring while co-administering with SchE [78,79,82,85].

Befund HOS-368838 · tacrolimus · HOS-085202 · Originalquelle ↗

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food ↗

© 2022 by the authors. Miłosz Miedziaszczyk; Aleksander Bajon; Ewelina Jakielska; Marta Primke; Jędrzej Sikora; Dagmara Skowrońska; Ilona Idasiak-Piechocka. Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food. DOI: 10.3390/pharmaceutics14102154 · CC BY 4.0

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• 75.Lu Y., Chen D.F. Analysis of Schisandra chinensis and Schisandra sphenanthera. J. Chromatogr. A. 2009;1216:1980–1990. doi: 10.1016/j.chroma.2008.09.070.
• 76.Zhang H., Bu F., Li L., Jiao Z., Ma G., Cai W., Zhuang X., Lin H.S., Shin J.G., Xiang X. Prediction of Drug-Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling. Basic Clin. Pharmacol. Toxicol. 2018;122:331–340. doi: 10.1111/bcpt.12914.
• 77.Wei H., Tao X., Di P., Yang Y., Li J., Qian X., Feng J., Chen W. Effects of traditional Chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats. Drug Metab. Dispos. 2013;41:1398–1403. doi: 10.1124/dmd.112.050302.
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• 79.He Q., Bu F., Zhang H., Wang Q., Tang Z., Yuan J., Lin H.S., Xiang X. Investigation of the Impact of CYP3A5 Polymorphism on Drug-Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling. Pharmaceuticals. 2021;14:198. doi: 10.3390/ph14030198.
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• 81.Yan L., Yang Z.Q., Shi Y.Y., Ren J., Yang C.L., Wan Z.L., Bai Y.J., Luo L.M., Wang L.L., Li Y. Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients. Ann. Transplant. 2019;24:594–604. doi: 10.12659/AOT.918980.
• 82.Qin X.L., Bi H.C., Wang C.X., Li J.L., Wang X.D., Liu L.S., Chen X., Huang M. Study of the effect of Wuzhi tablet (Schisandra sphenanthera extract) on tacrolimus tissue distribution in rat by liquid chromatography tandem mass spectrometry method. Biomed Chromatogr. 2010;24:399–405. doi: 10.1002/bmc.1305.
• 83.Li J., Chen S., Qin X., Fu Q., Bi H., Zhang Y., Wang X., Liu L., Wang C., Huang M. Wuzhi tablet (Schisandra sphenanthera Extract) is a Promising Tacrolimus-Sparing Agent for Renal Transplant Recipients Who are CYP3A5 Expressers: A Two-Phase Prospective Study. Drug Metab. Dispos. 2017;45:1114–1119. doi: 10.1124/dmd.117.076737.
• 84.Qin X.L., Yu T., Li L.J., Wang Y., Gu H.M., Wang Y.T., Huang M., Bi H.C. Effect of long-term co-administration of Wuzhi tablet (Schisandra sphenanthera extract) and prednisone on the pharmacokinetics of tacrolimus. Phytomedicine. 2013;20:375–379. doi: 10.1016/j.phymed.2012.11.008.
• 85.Xin H.W., Li Q., Wu X.C., He Y., Yu A.R., Xiong L., Xiong Y. Effects of Schisandra sphenanthera extract on the blood concentration of tacrolimus in renal transplant recipients. Eur. J. Clin. Pharmacol. 2011;67:1309–1311. doi: 10.1007/s00228-011-1075-7.
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• 88.Wang D.D., Chen X., Li Z.P. Wuzhi capsule and haemoglobin influence tacrolimus elimination in paediatric kidney transplantation patients in a population pharmacokinetics analysis: A retrospective study. J. Clin. Pharm. Ther. 2019;44:611–617. doi: 10.1111/jcpt.12828.
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• 92.Han Y., Zhou H., Cai J., Huang J., Zhang J., Shi S.J., Liu Y.N., Zhang Y. Prediction of tacrolimus dosage in the early period after heart transplantation: A population pharmacokinetic approach. Pharmacogenomics. 2019;20:21–35. doi: 10.2217/pgs-2018-0116.
• 93.Chen X., Wang D.D., Xu H., Li Z.P. Optimization of initial dosing scheme of tacrolimus in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule. Xenobiotica. 2020;50:606–613. doi: 10.1080/00498254.2019.1669844.
• 94.Lu T., Zhu X., Xu S., Zhao M., Huang X., Wang Z., Zhao L. Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome. Pharm. Res. 2019;36:45. doi: 10.1007/s11095-019-2579-6.
• 95.Sun Z., Ren M., Wu Q., Du X. Co-administration of Wuzhi capsules and tacrolimus in patients with idiopathic membranous nephropathy: Clinical efficacy and pharmacoeconomics. Int. Urol. Nephrol. 2014;46:1977–1982. doi: 10.1007/s11255-014-0801-3.
• 96.Zhang Z., Lu X., Dong L., Ma J., Fan X. Clinical observation on the effect of Wuzhi soft capsule on FK506 concentration in membranous nephropathy patients. Medicine. 2019;98:e18150. doi: 10.1097/MD.0000000000018150.
• 97.Chen X., Wang D., Xu H., Li Z. Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration with Wuzhi capsule. J. Clin. Pharm. Ther. 2020;45:309–317. doi: 10.1111/jcpt.13072.
• 98.Chen X., Wang D.D., Xu H., Li Z.P. Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real-world data. Exp. Ther. Med. 2020;20:1423–1430. doi: 10.3892/etm.2020.8821.
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What Do We Know About Safety?

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Short-term oral use (by mouth, up to 6 months) of Asian ginseng in recommended amounts appears to be safe for most people. However, questions have been raised about its long-term safety, and some experts recommend against its use for infants, children, and women who are pregnant or breastfeeding. There isn't enough reliable information to know if Asian ginseng used topically on the skin is safe. It might cause side effects such as irritation and burning. Insomnia (trouble sleeping) is the herb’s most common side effect. Uncommon side effects that have been reported include severe rash, liver damage, and severe allergic reactions. Asian ginseng may worsen autoimmune disorders and interfere with blood clotting. Some evidence suggests that Asian ginseng might lower blood sugar levels. If you have diabetes, consult your health care provider before using Asian ginseng. Asian ginseng might interact with certain medications. If you take any type of medicine, talk with your health care provider before using Asian ginseng or other herbal products; some herbs and medicines interact in harmful ways. Some studies of Asian ginseng suggest it may be unsafe when taken orally during pregnancy. One of the chemicals in it has been found to cause birth defects in animals. If you’re considering using Asian ginseng while pregnant, consult your health care provider. Little is known about whether it’s safe to use Asian ginseng while breastfeeding.

Befund HOS-368784 · Originalquelle ↗

Asian Ginseng ↗

National Center for Complementary and Integrative Health; native text only, no photographs. · Public domain

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• Asian Ginseng: source-qualified safety advice

What Do We Know About Safety?

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Astragalus may be safe when used orally. (Taking up to 60 grams per day for as long as 4 months does not seem to cause adverse effects.) However, a thorough safety evaluation has not been done. There isn’t enough reliable information to know if applying astragalus to the skin is safe or has potential side effects. Because astragalus might worsen symptoms of autoimmune diseases, people with autoimmune diseases should avoid using astragalus. Also, astragalus may interact with medications that suppress the immune system. If you take any type of medicine, talk with your health care provider before using astragalus or other herbal products; some herbs and medicines interact in harmful ways. Little is known about whether it’s safe to use astragalus during pregnancy or while breastfeeding. Some research in animals suggests that during pregnancy, astragalus can be toxic to the fetus.

Befund HOS-368802 · Originalquelle ↗

Astragalus ↗

National Center for Complementary and Integrative Health; native text only, no photographs. · Public domain

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• Astragalus: source-qualified safety advice

What Do We Know About Safety?

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In general, oral or topical thunder god vine seems to be well tolerated. Thunder god vine may have side effects, such as digestive problems, diarrhea, headache, dizziness, lowered white blood cell count, menstrual cycle changes, and skin redness. Adding thunder god vine to a conventional therapy might increase the risk of experiencing side effects, but some research disagrees. Serious side effects may include kidney damage and liver problems, among others. Rare deaths have been reported; these may be related to specific preparations of thunder god vine or high doses of the herb. Triptolide, a component found in thunder god vine, may be toxic in people. The use of thunder god vine during pregnancy is considered unsafe, as it may increase the risk of birth defects. Little is known about whether it’s safe to use thunder god vine while breastfeeding.

Befund HOS-368786 · Originalquelle ↗

Thunder God Vine ↗

National Center for Complementary and Integrative Health; native text only, no photographs. · Public domain

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• Thunder God Vine: source-qualified safety advice