Chinese Salvia Root (Salvia miltiorrhiza / Danshen): A Comprehensive Reference
1. Identity and Botanical Profile
1.1 Nomenclature and Taxonomy
Salvia miltiorrhiza Bunge, commonly known as red sage or Danshen (its Chinese Pinyin name), is a perennial plant in the genus Salvia of the mint family, Lamiaceae. In English, the root is frequently referred to as Chinese Salvia Root, red sage root, or Chinese sage root. Danshen is the dried root of S. miltiorrhiza (Labiatae) and is one of the most versatile Chinese herbal drugs, sometimes described as Chinese sage or red sage root.
According to the Grand Compendium of Materia Medica, "S. miltiorrhiza matches the heart called Chi (Red) Shen," and thus S. miltiorrhiza (Danshen) derives its name from the original red color of its root. The plant is indigenous to the mountainous southern and central parts of China. Outwardly the root is red; internally it is purplish when fresh, and commercially it is sold in short, shriveled pieces of bright, brick-red color.
1.2 Official Drug Definition and Authentication
Danshen, the root and rhizome of Salvia miltiorrhiza Bunge, was one of the earliest and most commonly used herbal drugs in practice. There have been more than 20 Salvia species used under the name of Danshen; however, according to the Chinese Pharmacopoeia (2010), only Salvia miltiorrhiza meets the requirements to be ascribed as the formal Danshen. The official drug of Danshen is the roots and rhizomes of S. miltiorrhiza. The herb has been officially recorded in the Chinese Pharmacopoeia since 1953.
Danshen is the first traditional Chinese medicine that is documented in the United States Pharmacopeia.
1.3 Common Dosage Forms and Preparations
The contents of chemicals in S. miltiorrhiza roots vary among aqueous extracts, organic extracts, oral pills, and injections derived from the single herb of S. miltiorrhiza roots or herbal combinations, such as Fufang (multiple TCM herbs) prescriptions in China. Major marketed forms include:
- Dried whole or fragmented root (decoction/tea): The Chinese Pharmacopoeia defines "Danshen" as the dried whole or fragmented rhizome and root.
- Compound Danshen Dripping Pills (CDDP): Compound Danshen Dripping Pills (CDDP) are a traditional Chinese medicine formulation comprising Salvia miltiorrhiza, Panax notoginseng, and Borneol, widely used in China for cardiovascular benefits.
- Danshen injection (intravenous): Danshen Injection (DSI) is an aqueous extract of Danshen and is widely used to treat chronic kidney disease (CKD).
- Tablets and capsules: Danshen capsule, Danshen pill, FuFangDanshen drop pill, and tanshinone capsules are among the preparations that contain one or more of the plant's active constituents.
- Ethanol extracts: Danshen compounds extracted by ethanol have quality controlled according to China State Food and Drug Administration standards; the main contents of ethanol extracts are tanshinone IIA, cryptotanshinone, tanshinone I, rosmarinic acid, and salvianolic acid B.
2. Traditional and Historical Use
2.1 Earliest Recorded Use
In modern times, pharmacological studies have revealed the bioactive components that confer pharmacological functions to Salvia miltiorrhiza, which has been used in traditional Chinese medicine for over 2,000 years to treat cardiovascular and inflammatory disorders. The herb was first recorded as a "super grade" herb — the ancient term applied to herbs lacking observable toxicity — in the Shennong's Herbal Atlas (Shennong Bencao Jing), written during the reign of the Qin and Han dynasties (221 BC to 220 AD).
Following this first record, Salvia miltiorrhiza was also described in classical traditional Chinese medicine works such as the Compendium of Materia Medica (Bencao Gangmu, Ming dynasty, 1596 AD).
2.2 TCM Characterization and Therapeutic Categories
In TCM, S. miltiorrhiza is recognized as an herb with a bitter flavor and distribution to the heart. It was well described in classical TCM works such as the Compendium of Materia Medica (Ming dynasty, 1596 AD), and in the textbooks of academic TCM it is characterized as a common drug for promoting blood circulation and removing blood stasis.
According to the Chinese Pharmacopoeia, Salviae Miltiorrhizae Radix & Rhizoma exerts a beneficial action by promoting blood circulation to remove blood stasis and assuage pain, clearing the heart. In the TCM five-element framework, the Danshen root is associated with the heart, and its red color traditionally suggests the blood and the circulatory system. It has been recommended for all blood difficulties including circulation, hemorrhages, menstrual disorders, and many heart disorders.
In the TCM energetic system, it is classified as bitter and slightly cold, and enters the heart, liver, and pericardium meridians. It is especially valued for "cooling the blood, dispelling stasis, and calming the mind," and was traditionally used to treat chest pain, palpitations, insomnia, and menstrual irregularities.
Specific traditional indications within the TCM canon include: invigorating blood and breaking up blood stasis in the lower abdomen — such as dysmenorrhea, amenorrhea, palpable masses, lochioschesis, pain due to blood stasis, chest and epigastric pain, and soreness in the ribs due to liver qi stagnation with blood stasis. Clearing heat and soothing irritability, including restlessness, irritability, and insomnia due to heat entering the ying level.
Danshen had been used in traditional Chinese medicine to treat irregular menstruation, cold hernia, and abdominal pain, because the theory of TCM holds that it activates blood circulation to dissipate blood stasis, calms the mind, and relieves pain.
2.3 Use in Korea and Other East Asian Traditions
S. miltiorrhiza, also known as dansam in Korean and danshen in Chinese, has been used for the treatment of cardiovascular and cerebrovascular diseases, especially in Asia.
3. Key Constituents and Active Compounds
3.1 Overview of Phytochemistry
More than 200 individual compounds have been isolated and characterized from S. miltiorrhiza, which exhibit various pharmacological activities targeting different pathways. The chemical constituents of Danshen can be divided into two categories: water-soluble and fat-soluble.
3.2 Lipophilic Fraction: Tanshinones
So far, several chemical components of Danshen have been identified, including more than 30 lipophilic compounds with a diterpene structure, such as tanshinones I–VI, cryptotanshinone, isothiophenes I–II, and salvianphenol A. The lipophilic tanshinones include tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, and dihydrotanshinone I.
Among tanshinones, Tanshinone IIA (molecular weight 294.3 g/mol) is the most abundant compound from the Salvia species. Tanshinone IIA (Tan IIA) is a pharmacologically lipophilic active constituent isolated from the roots and rhizomes of the Chinese medicinal herb Salvia miltiorrhiza Bunge (Danshen). The roots of Salvia miltiorrhiza are the source of the class of tanshinones — particular quinoid nor-diterpenoids of the abietane type — of which cryptotanshinone, dihydrotanshinone I, tanshinone I, and tanshinone IIA have been extensively studied for their anticancer potential due also to their high abundance in S. miltiorrhiza.
Water-soluble constituents, including salvianolic acids A–G and lithospermic acid B, mainly exhibit cardiovascular protective activities, while the lipid-soluble constituents, including tanshinone IIA, dihydrotanshinone I, and cryptotanshinone, show remarkable properties of anti-cancer and anti-inflammation.
3.3 Water-Soluble Fraction: Phenolic Acids and Salvianolic Acids
More than 50 hydrophilic compounds have been identified, including danshensu, salvianolic acid A (SalA), salvianolic acid B (SalB), and protocatechuic aldehyde, mostly composed of phenolic acids. More than 30 phenolic acids have been isolated from Danshen, including salvianolic acid A, salvianolic acid B, salvianolic acid C, rosmarinic acid, protocatechuic acid, protocatechualdehyde, carnosol or danshensu, lithospermic acid, and other derivatives.
Salvianolic acids are the most abundant water-soluble substances in Danshen. Salvianolic acids (including Sal A and Sal B), the most abundant compounds from S. miltiorrhiza, are known to exhibit diverse biological activities such as antioxidant, anti-inflammatory, antithrombotic, and cardioprotective activities.
The salvianolic acids in Danshen include many compounds, namely salvianolic acids A–H, J–N, T/U, and Y; among these, salvianolic acid A and salvianolic acid B are particularly regarded as having the highest antioxidant activity. Chemically, salvianolic acid A is identified as (R)-3-(3,4-dihydroxyphenyl)-2-(((E)-3-(2-((E)-3,4-dihydroxystyryl)-3,4-dihydroxyphenyl)acryloyl)oxy)propanoic acid (molecular formula C₂₆H₂₂O₁₀). Structurally, it is a trimer consisting of danshensu and caffeic acid as its fundamental units.
Tanshinone IIA and salvianolic acid B are usually chosen as major markers to assess the quality of Danshen and its products.
3.4 Other Constituents
A variety of other chemical constituents such as polysaccharides, flavonoids, and volatile oils have been isolated and identified from Danshen.
4. Mechanisms of Action
4.1 Cardiovascular Mechanisms
Pharmacological examinations showed that the plant and its active ingredients — tanshinones and salvianolic acids — have anticoagulant, vasodilatory, blood-flow-increasing, anti-inflammatory, free radical scavenging, and mitochondrial protective activities.
Many in vivo and in vitro studies have shown that salvianolic acid regulates multiple signal transduction pathways in vascular endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Studies have summarized the cardiovascular protective effects of salvianolic acids and the multiple mechanisms of these small compounds in terms of reactive oxygen species (ROS) scavenging ability, leukocyte–endothelial adhesion regulation, inflammation inhibition, and immune modulation.
Taken together, Salvia miltiorrhiza and its ingredients, including lithospermic acid B, tanshinone IIA, and Danshensu, offer therapeutic promise on hypertension through regulating expressions of TRPC/Ca²⁺, Cx/eNOS/ET-1, MMP/TIMPs, ACE, and TNF-α.
Other active water-soluble compounds, such as protocatechuic aldehyde (PAl), 3,4-dihydroxyphenyl lactic acid (DLA), and salvianolic acid B with peroxide-scavenging activities, are able to prevent the expression of adhesion molecules in vascular endothelium and inhibit vascular damage; additionally, components such as tanshinone IIA and tanshinone IIB can inhibit the activity of NADPH oxidase and the aggregation of platelets.
4.2 Antithrombotic Mechanisms
Salvianolic acid A and C antagonize the activity of both P2Y1 and P2Y12 receptors in the low µM range, while salvianolic acid B antagonizes the P2Y12 receptor. These three salvianolic acids are the major active components of the broadly used hemorheologic TCM Danshen, the antithrombotic molecular mechanisms of which were largely unknown until these findings.
4.3 Anti-Inflammatory and Immunomodulatory Mechanisms
Anti-inflammatory properties of major ingredients salvianolic acid B, tanshinone IIA, and protocatechuic acid, including prevention of the expression of adhesive molecules, cytokines, chemokines, and platelet P-selectin, have been observed. Tanshinones can modulate multiple molecular pathways such as PI3K/Akt, MAPK, and JAK/STAT3, exerting pharmacological effects against different malignancies.
4.4 Antioxidant Mechanisms
Danshen may enhance endogenous anti-oxidative enzyme activities such as the expression of endothelial nitric oxide synthase and may scavenge oxygen free radicals. Substantial evidence has shown that Danshen extracts could suppress oxidative stress by increasing the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), as well as by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels.
4.5 Hepatoprotective Mechanisms
Salvianolic acid B regulates insulin resistance mainly through the AMPK/GLUT4 and/or SREBP-1/PPARγ signaling pathway and modulates fatty acids through PPAR-mediated pathways; tanshinone IIA exhibits anti-inflammatory and antioxidant roles by regulating signals such as MAPK, JAK/STAT, and PXR/CYP and modulates fatty acids through PPARγ and SREBP pathways; cryptotanshinone exerts antioxidant effects by CYP2E1 and regulates fatty acids through AMPK and PPAR-mediated pathways.
4.6 Pharmacokinetics
In animal studies, both danshensu and tanshinone IIA — the two major components in Danshen — were absorbed rapidly after oral administration of either extract formulation or individual components. On the other hand, salvianolic acid B, another major component, was found to be poorly absorbed in animal studies. Cryptotanshinone was found to be metabolized to tanshinone IIA after intravenous administration and could not be absorbed after oral administration.
The pharmacokinetic plasma profile of tanshinone IIA after a single intravenous dose exhibited a triexponential pattern consisting of rapid distribution (t₁/₂ alpha: 0.024 h), slow redistribution (t₁/₂ beta: 0.34 h), and a terminal elimination phase (t₁/₂ gamma: 7.5 h). Tanshinone IIA preferentially distributed into the reticuloendothelial system, especially the liver and lung, after either intravenous or oral doses, and bound highly (99.2%) to plasma proteins, with lipoprotein playing an important role (77.5%).
In general, tanshinones have poor bioavailability and can be more effective when injected intravenously. Researchers have been trying to improve the bioavailability of Danshen through ameliorating the dosage form, such as sodium caprate and lipid nanoparticle formulations.
5. Scientific Evidence by Area of Use
5.1 Cardiovascular Disease
5.1.1 Coronary Heart Disease
Since 2000, 39 clinical trials have been identified that used S. miltiorrhiza in TCM prescriptions alone or with other herbs for the treatment of patients with CVD. Danshen, a commonly used herbal medicine in TCM for the treatment of coronary heart disease, has a long history of clinical application due to its blood-activating and stasis-removing properties; it contains two major metabolite classes — hydrophilic phenolic acids and lipophilic tanshinones — both of which possess anti-oxidative stress, anti-inflammatory, and anti-thrombotic effects.
A controlled clinical trial involving patients with coronary heart disease evaluated the effect of Danshen on biochemical risk markers. Sixty-one patients completed the trial in the Danshen group. Danshen treatment significantly reduced the levels of TG, TC, LDL-C, Lp(a), GGT, DBil, UA, and Hcy, while increasing the levels of HDL-C, ApoA, ApoB, ApoE, TBil, and IBil (P < 0.05). However, the short treatment period meant that reduction in cardiac death and heart failure could not be detected, and the safety of the medicine was not identified in this study.
A meta-analysis of Danshen combined with clopidogrel for coronary heart disease enrolled 22 articles and 2,587 patients. The meta-analysis showed that Danshen combined with clopidogrel was more effective than clopidogrel alone in treating coronary heart disease by improving clinical curative effect, reducing the frequency of angina pectoris, improving electrocardiogram results, shortening the duration of angina pectoris, and easing adverse reactions. Danshen inhibited carboxylesterase 1 and most enzymes of cytochrome P450 — especially cytochrome P450 1A2 — which may affect the metabolism of clopidogrel.
Evidence strength: Clinical trials in cardiovascular disease exist and some meta-analyses show positive signals; however, while the results have been encouraging so far, the quality of many of the available studies has been low, and clinical studies have yet to fully determine safety. Most trials were conducted in China, using combination formulations, which limits independent replication.
5.1.2 Heart Failure
Danshen decoction is used to treat several cardiovascular diseases including heart failure (HF), and a meta-analysis evaluated the clinical efficacy of Danshen decoction for this indication. A large number of clinical and experimental studies have shown that Danshen decoction plays an important auxiliary function in the treatment of HF, with therapeutic effects including improving cardiac function, reducing peripheral vascular resistance, and alleviating inflammation. However, there is still a lack of evidence-based medical evaluation to prove the safety and efficacy of Danshen decoction in clinical treatment.
5.2 Cerebrovascular Disease and Stroke
Prevention and treatment of cerebral infarction by Danshen involves multiple pathways, including anti-atherosclerosis, anti-hypertension, anti-platelet aggregation, anti-inflammatory, and anti-oxidative effects. Danshen is the dried root of Salvia miltiorrhiza and is used in Chinese medicine to treat vascular disease.
In one trial that included 106 people, those taking the Danshen dripping pill were less likely to have another stroke, and they also had lower levels of C-reactive protein, a marker of inflammation. A larger analysis of clinical trials, however, found a similar lack of high-quality evidence when Traditional Chinese Medicines, including Danshen, were given to people with stroke. Overall, there is some evidence that this herb could be useful for preventing strokes or enhancing recovery, but because of the lack of high-quality studies, the evidence remains preliminary.
5.3 Liver Disease and Hepatoprotection
A classic TCM herb used for centuries to treat liver diseases, a study of the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) showed that Danshen could alleviate hepatic inflammation, fatty degeneration, and hepatic fibrogenesis in ALD and NAFLD models.
The total extracts of Danshen and its components — such as tanshinol A, tanshinone I, tanshinone IIA, dihydrotanshinone I, neotanshinone A, cryptotanshinone, salvianolic acid A, and salvianolic acid B — were found to exhibit hepatoprotective effects in various hepatic cell lines and animal models against viral hepatitis, paracetamol-induced hepatitis, hepatic fibrosis, and hepatocarcinoma.
A meta-analysis examined the clinical value of Danshen injection in liver cirrhosis. The meta-analysis showed that, compared with controls, the total effectiveness rate and the level of serum albumin increased, while serum total bilirubin, alanine transaminase, type III procollagen, hyaluronic acid, laminin, and type IV collagen decreased in the treatment group. The Jadad score of the included trials ranged from 1 to 2, and funnel plot analysis suggests that publication bias may have occurred. Danshen injection combined with Huangqi injection may promote the curative efficacy of liver cirrhosis, but the exact outcome requires rigorously designed, multicenter, large randomized controlled trials.
Although Danshen is claimed to be hepatoprotective in NAFLD, the molecular mechanisms of combination therapy have not been fully clarified, and further multicenter large-sample randomized clinical trials are required to confirm therapeutic efficacy and safety.
5.4 Kidney Disease and Renal Fibrosis
Danshen, a prominent TCM, has been used to treat various diseases including kidney diseases. Danshen Injection (DSI) is an aqueous extract widely used to treat chronic kidney disease (CKD). Several studies have documented that DSI exerts anti-inflammatory, anti-oxidation, and anti-fibrosis effects to protect renal function in CKD.
Results from one study suggest that one of the pharmacological activities of Danshen extract that protects the liver and potentially kidney tissue is the inhibition of key cell-signaling kinases, such as DDR2 in liver stellate cells.
Evidence strength: Evidence for kidney protection is primarily from preclinical (animal and cell) studies and small clinical series conducted in China. Large, well-designed RCTs are lacking.
5.5 Anticancer Activity
Tanshinone IIA and Tanshinone I compounds have shown remarkable potential as anti-cancer molecules, especially against breast, cervical, colorectal, gastric, lung, and prostate cancer cell lines, as well as leukemia, melanoma, and hepatocellular carcinoma, among others. Recent data indicate that tanshinones can modulate multiple molecular pathways such as PI3K/Akt, MAPK, and JAK/STAT3, exerting pharmacological effects against different malignancies.
The main water-soluble active ingredient salvianolic acid A influences cell migration, invasion, apoptosis, and proliferation — all of which notably impact the occurrence and development of tumors. Unlike most chemotherapeutic drugs, which typically target a single pathway, small-molecule components derived from Danshen often exhibit antitumor effects by modulating multiple pathways.
Tanshinone IIA is one of the most investigated with both in vitro and in vivo anticancer effects.
Evidence strength: Tan IIA could have a wide range of antitumor effects on several human tumor cell lines, but the research on the mechanism of Tan IIA is relatively scattered in cancer. The overwhelming majority of anticancer data for Danshen constituents comes from in vitro cell-line experiments and animal models. Clinical (human) oncology trials of sufficient quality and size are currently lacking.
5.6 Osteoporosis
Red sage (S. miltiorrhiza) has been used historically and is currently exploited in combination with other herbs to treat skeletal diseases in TCM. With the advance of modern analytical technology, a multitude of bone-targeting, pharmaceutically active compounds has been isolated and characterized from various sources of TCM, including those produced in Salvia miltiorrhiza root.
The inclusion of Salvia miltiorrhiza in more than 30% of all herbal clinical trials successfully targeting osteoporosis has stimulated significant interest in the identification and characterization of individual constituents of this herb.
Aqueous extracts of Salvia miltiorrhiza could enhance in vivo bone mechanical strength and prevent trabecular bone resorption in OVX (ovariectomized) Sprague-Dawley rats and prevented OVX-induced bone loss. Individual tanshinone compound also prevented a decrease in trabecular bone volume and trabecular structure.
Evidence strength: Preclinical evidence is supportive. Notably, S. miltiorrhiza features prominently in herbal clinical osteoporosis trials, but dedicated human trials evaluating it as a stand-alone agent for osteoporosis are not yet well established.
5.7 Neurological and Cerebrovascular Protection
Salvia miltiorrhiza (Chinese red sage) or danshen is used by TCM practitioners to treat neurological, cardiovascular, and cerebrovascular disorders. It is commonly prescribed by TCM practitioners to stroke patients and is included in a TCM drug formulation ding xian wan to control epileptic seizures.
One recent epilepsy model study demonstrated that the acetone crude extract of danshen can significantly decrease convulsions induced in the larval zebrafish-PTZ assay, and a number of its hydrophobic tanshinones are responsible for this activity.
Evidence strength: Neuroprotective and antiepileptic evidence is primarily preclinical (animal and in vitro models). Clinical data in human neurological conditions remain limited and are insufficient to draw efficacy conclusions.
5.8 Metabolic Conditions (Diabetes and NAFLD)
Salvia miltiorrhiza, one of the frequently used herbs in TCM, has now attracted rising interest for possible application in the management of diabetes. Tanshinone IIA is currently used in China and other neighboring countries to treat patients with cardiovascular disease, diabetes, apoplexy, arthritis, and sepsis.
Evidence strength: Much of the diabetes and metabolic evidence for Danshen is derived from animal and in vitro models. Larger, well-designed human clinical trials specifically targeting glycemic outcomes are required.
6. Body Systems and Health Areas of Association
- Cardiovascular system: Modern studies have discovered that Danshen has multiple pharmacological effects, including anti-myocardial ischemia, improvement of atherosclerosis, anti-inflammatory, antihypertensive, lipid-lowering, hypoglycemic, antithrombotic, and anti-tumor effects.
- Cerebrovascular system: According to Chinese medicine theory, Danshen promotes blood flow and resolves blood stasis in cerebrovascular disease.
- Hepatic/gastrointestinal system: The hepatoprotective effects of Danshen have been demonstrated in several clinical trials in NAFLD and hepatocarcinoma patients, and modern pharmacological studies also confirm hepatoprotective effects of Danshen and its active ingredients for liver diseases in vitro and in vivo.
- Renal system: Danshen Injection exerts anti-inflammatory, anti-oxidation, and anti-fibrosis effects to protect renal function in chronic kidney disease.
- Skeletal system: The inclusion of Salvia miltiorrhiza in more than 30% of all herbal clinical trials successfully targeting osteoporosis reflects its relevance to bone health.
- Immune system: The pharmacological effects of tanshinones and salvianolic acids in improving the immunomodulatory effect and the treatment of autoimmune diseases and common immune-mediated inflammatory diseases have been reviewed.
7. Dosage Forms and Reported Dosages
Dosages reported in peer-reviewed clinical sources vary depending on preparation and indication:
- Danshen tablets (oral, in CYP3A4 interaction study): Each Danshen tablet contained 0.26 ± 0.05 mg cryptotanshinone, 0.5 ± 0.1 mg tanshinone I, 0.37 ± 0.04 mg tanshinone IIA, 0.67 ± 0.01 mg protocatechuic aldehyde, 1.7 ± 0.3 mg danshensu, and 13.5 ± 1.1 mg salvianolic acid B; the study used 14 days of administration for pharmacokinetic assessment.
- Danshen pills (coronary heart disease trial): Danshen pills were provided as 27 mg/pill by Tianjin Tasly Group Co., Ltd., in one reported CHD trial.
- Compound Danshen Dripping Pills (CDDP): CDDP, a formulation comprising Salvia miltiorrhiza, Panax notoginseng, and Borneol, is widely used in China for cardiovascular benefits. Specific per-dose amounts vary by product and are typically standardized by the manufacturer to Chinese regulatory standards.
- Rat pharmacokinetic study dose (reference): The pharmacokinetics of tanshinones in rats were studied after intragastric administration of Salvia miltiorrhiza ethanol extract (SMEE) at 0.65 g/kg, both alone and combined with Salvia miltiorrhiza water extract (SMWE) at 1.55 g/kg.
An assessment of the recommended posology of the whole drug in humans from experiments of extracted components is not possible, as the pharmacology of the isolated constituents is of limited relevance to the dosing of the whole-herb preparation.
8. Safety Considerations and Drug Interactions
8.1 General Toxicity Profile
S. miltiorrhiza has very low acute toxicity, with an LD₅₀ by injection of 40–80 g/kg in animal studies. At higher dosage levels, S. miltiorrhiza may, on rare occasions, produce adverse effects. The herb is not suitable for patients who have deficiency but not stasis, deficiency accompanied by cold, or a tendency to bleed.
8.2 Interaction with Warfarin
The interaction between Danshen and warfarin can cause bleeding and prolong prothrombin time or the International Normalized Ratio (INR). Co-administration of Danshen and warfarin should be avoided or closely monitored.
Published case reports have pointed to over-anticoagulation associated with concomitant danshen and warfarin use. In one documented case, a 62-year-old man developed hemothorax two weeks after daily consumption of a danshen decoction (INR > 8.4). Withdrawal of danshen with reintroduction of warfarin at the original dosage returned his INR to the therapeutic range.
A controlled clinical trial (n = 40) concluded that concomitant administration of two weeks of danshen with warfarin significantly prolonged prothrombin time (PT) and INR, as compared to those in the control group.
In clinical practice, warfarin is often combined with Compound Danshen Dripping Pill (CDDP) for the treatment of cardiovascular diseases; however, warfarin has a narrow therapeutic index and wide interindividual variability, and previous study has indicated that CDDP might interact with warfarin in individuals with the epoxide hydrolase gene (EPHX1; SNP: rs2292566) A/A subtype.
8.3 Interaction with CYP450 Enzymes
Tanshinones play significant roles in the inhibition and induction of several CYP450 isozymes; precautions should be taken when using Danshen preparations rich in tanshinones together with drugs that are CYP substrates.
A pharmacokinetic interaction study in 12 healthy male Chinese subjects found that the increased clearance of midazolam in vivo after Danshen administration should be mainly attributed to induction of tanshinones on CYP3A4 in the gut wall. P-glycoprotein can also be induced by tanshinone IIA and cryptotanshinone.
Danshen may induce intestinal CYP3A4. Caution should be taken when Danshen products are used in combination with therapeutic drugs metabolized by CYP3A4.
8.4 Interaction with Rivaroxaban and Other Anticoagulants
Danshen tablet potently inhibited the metabolism of rivaroxaban in rat and human liver microsomes. Dihydrotanshinone I, an active component of Danshen tablet, potently inhibited the activities of rat CYP3A and CYP2J, with IC₅₀ values at 13.85 and 6.39 μM, respectively. Danshen tablet was found to be a mixed inhibitor in rivaroxaban metabolism in rat and human liver microsomes. There is, therefore, a potential interaction between Danshen tablet and rivaroxaban; when these are used simultaneously in the clinic, it is necessary to monitor rivaroxaban levels and adjust dosage accordingly.
8.5 Interaction with Clopidogrel
Danshen combined with clopidogrel may compensate for individual differences of clopidogrel resistance among individuals in the treatment of coronary heart disease; meanwhile, the inhibitory effect of Danshen on cytochrome P450 and carboxylesterase 1 could be partly responsible for the synergistic and attenuating effects.
8.6 Quality and Regulatory Considerations
Clinical studies have yet to fully determine the safety of some preparations such as Danshen dripping pills, and these pills are not regulated outside of China; they fall in a grey area of regulation. Tanshinone IIA and salvianolic acid B are isolated not only from Danshen, but also from other plants, such as S. umbratica, S. plebeia, and other Salvia species; therefore, for quality control of Danshen, detecting only these two markers appeared partial and insufficient.
References
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