Scientific Name(s): Salvia miltiorrhiza Bunge Family: Lamiaceae (mints)
Common Name(s): Danshen , dan shen , tanshen , tan-shen , Radix Salviae miltiorrhiza , Fu Fang Dan Shen
Uses of Danshen
Danshen has been used extensively in Chinese medicine for many years. Limited studies have shown efficacy in coronary artery disease and acute ischemic stroke, but the quality of methodology limits the validity of the findings.
Active components in commercially available preparations vary greatly. Commonly cited dosages include the following: 10 “dripping” pills taken 3 times a day (oral or sublingual), 3 Fu Fang Dan Shen tablets taken orally 3 times a day, or danshen 20 mg/kg capsules. Doses of 100 mg/kg as a bolus injection have been used in children.
Data are lacking.
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Danshen may interfere with laboratory digoxin plasma levels and increase the anticoagulant effect of warfarin. It may reduce midazolam plasma concentrations, decreasing the pharmacologic effects, and inhibits numerous cytochrome P450 (CYP-450) enzymes in vitro.
Danshen Adverse Reactions
Adverse reactions appear to be limited to allergy, dizziness, headache, mild GI symptoms, and reversible thrombocytopenia.
Information is limited.
Danshen is a perennial herb found mainly on sunny hillsides and stream edges in China. It has violet-blue flowers that bloom in the summer, with oval, finely serrated leaves. The fruit is an oval brown nut, and danshen's roots, to which many of the common names apply and which are the primary medicinal part, are a vivid scarlet red. Danshen is related to common sage, the culinary herb. 1 , 2 A study of samples sold in Chinese markets identified 17 related Salvia species sold as danshen, and evaluated their folk usage, traditional functions, and chemistry. 3 Although only S. miltiorrhiza is official in the Pharmacopoeia of the People's Republic of China , Salvia przewalskii Maxim is widely used in southern China. Genetic diversity and population structure of S. miltiorrhiza has been studied. 4
Danshen is considered one of the most important traditional Chinese medicines and has widespread use in Asian countries. Fu Fang Dan Shen (a mixture of S. miltiorrhiza , Panax notoginseng , and Cinnamomum camphora ) is registered as a drug in several countries including Vietnam, Russia, Cuba, Korea, and Saudi Arabia. Danshen is also used in combination with Pueraria lobata (gegen). 5 In 2010, danshen was the first traditional Chinese medicine to pass US phase 2 clinical trials for cardiovascular indications and the Tianjin Tasly Pharmaceutical Company, which plans extensive phase 3 trials. 6 In addition to standard dosage forms, danshen is available as an injection, as well as in rapid-soluble, liposomal, and solid dispersion forms. The “dripping” pill is made by a process of thermally blending the extract with excipients and then dripping the mixture into an insoluble cooling liquid until solidified droplets are achieved. 2
Traditionally, danshen has been used to improve bodily functioning, as well as to treat hemorrhage, dysmenorrhea, miscarriage, swelling, insomnia, and hepatitis. More recent primary uses include treatment of cardiovascular and cerebrovascular conditions. 2 , 7
More than 50 compounds have been identified in danshen, the majority falling into 1 of 2 classes: 1) lipophilic diterpenes, known as tanshinones, and 2) polar phenolic compounds. 7 Antibacterial, antioxidant, and antineoplastic effects are attributed to the lipophilic compounds, of which more than 30 have been described; tanshinone I, tanshinone IIA, and cryptotanshinone are the major constituents. Hydrophilic compounds from danshen consist of phenolic acids, including caffeic acid and its derivatives, such as danshensu, salvianolic acids A and B, rosmarinic acid, and prolithospermic acid. 7 , 8 Antioxidant and anticoagulant effects may derive from these hydrophilic compounds. Other compounds include baicalin, beta-sitosterol, daucosterol, flavanones, vitamin E, and tannins. 2 , 7 , 8
A study of chemical variations of 13 constituents in 74 samples of danshen collected in China has been conducted using high-performance liquid chromatography (HPLC) analysis. 9 Seasonal and cultivar variation in danshen grown in Australia has also been analyzed. 10 , 11 , 12 A metabonomic nuclear magnetic resonance study examined primary metabolites of 3 phenotypically distinct cultivars of danshen. 13 Analytical procedures for determination of important constituents in crude danshen have proliferated recently, with HPLC/diode array/mass spectral techniques most prominent. 14 , 15 Measurements of danshen compounds in body fluids have been achieved, 16 and several pharmacokinetic and distribution studies have been conducted on isolated constituents and their interactions with each other. 17 , 18 , 19 , 20
Danshen Uses and PharmacologyStroke
Many studies reflect danshen's extensive use as a standard treatment for acute ischemic stroke in China. The injury to the vasculature following ischemia and reperfusion may be ameliorated by danshen treatment. 21 , 22In vitro data
Rat basilar artery rings precontracted with the prostaglandin analog U46619 were relaxed by danshen/gegen extract treatment. This effect was not dependent on voltage-sensitive or inwardly rectifying potassium channels, but could be blocked by glibencamide, an inhibitor of adenosine triphosphate (ATP)–sensitive potassium channels. The authors concluded that danshen's vasorelaxant effect is independent of the arterial endothelium. 23 Tanshinone IIA was found to inhibit vascular smooth muscle cell proliferation and reduce intimal hyperplasia through a mitogen-activated protein kinase and c-fos mechanism. 24Animal data
Animal experiments with extracts of danshen demonstrate increased cerebral microcirculation. A study of balloon-induced vascular injury in rats showed that oxidative damage was limited by treatment with magnesium lithospermate, a danshen constituent. 25 Two reviews summarize the pharmacologic effects of polar and lipophilic danshen constituents in models of cerebral infarction, with emphasis on antioxidant pathways. 21 , 22Clinical data
Three meta-analyses have been conducted on human trials meeting inclusion criteria for analysis. One meta-analysis included 11 trials in which danshen was compared with other medicines, 26 and another included 6 trials in which danshen was compared with placebo. 1 A third meta-analysis of many traditional Chinese medicines for ischemic stroke included the danshen trials. 27 Although improvement in neurological deficit was reported for danshen, 1 , 27 quality of life was not assessed and deaths (of any cause) were not reported. No long-term follow-up was reported, and few trials reported adverse reactions. All 3 meta-analyses question the quality of trials, and ultimately none were able to make definitive statements about the role of danshen in therapy. 1 , 2 , 26 , 27 A pilot study found reduced stroke recurrence over a year long follow-up in patients treated with a danshen combination product; however, there were no differences in mortality or intracranial hemorrhage between groups. 28Coronary artery disease
In vitro data
A standardized extract of danshen protected rat cardiac myocytes from tumor necrosis factor–induced apoptosis. In cultured cardiac fibroblasts, the extract reduced collagen synthesis. 29 The isolated constituent 15,16-dihydrotansinone I inhibited collagen-induced platelet aggregation, blocking intracellular calcium mobilization and liberation of arachidonic acid. 30 Several tanshinones inhibited prostaglandin and nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells, further supporting anti-inflammatory mechanisms for danshen. 31 Tanshinone IIA inhibited migration of human aortic smooth muscle cells through an AKT and matrix metalloprotease-9 pathway. 32Animal data
In rats, danshen was cardioprotective for infarct size and mortality, and in another experiment, was comparable with captopril. 33 A polyherbal mixture, Guanxin No.2 decoction, that included danshen was studied for effects on gene expression in rats with coronary artery ligation-induced infarcts. Five genes were identified that were altered by herbal treatment, and reverse transcriptase polymerase chain reaction confirmed the changes. 34 A similar rat coronary artery ligation experiment found that tanshinone IIA reduced monocyte chemoattractant protein 1 expression, thereby blocking inflammation. Macrophage infiltration and transforming growth factor (TGF)–beta secretion were also blocked. 35 The effect of danshensu on the homocysteine pathway was studied in a rat model, with the compound lowering elevated plasma total homocysteine levels after 3 weeks of treatment, which may result in activation of the transsulfuration pathway. 36Clinical data
A meta-analysis of trials conducted among patients with angina found that compound salvia pellets (a mixed preparation containing danshen) improved angina symptoms and electrocardiogram parameters compared with nitrates. However, the trials were of poor methodological quality. 2 , 33 , 37 A review of trials using danshen to treat angina reported that danshen may be more suitable than isosorbide dinitrate for long-term management of angina. Danshen also appears to be effective in relieving angina caused by coronary artery spasm, possibly because of its calcium antagonistic properties. 2 , 33 A trial of danshen/gegen found modest improvements in cardiovascular parameters over 1 year of treatment. 5
Apparent efficacy in treatment of myocardial infarction (MI) may be caused by sedative, antioxidant, and antiplatelet effects, as well as by improved coronary microcirculation. Danshen also decreases myocardial reperfusion injury in patients with acute MI following percutaneous intervention. 33Hyperlipidemia
In vitro data
A mixture of danshen and gegen decreased total cholesterol, while increasing intracellular adhesion molecule (ICAM-1) expression and cellular adhesion in human monocyte-derived macrophages. 38 Two constituents of danshen, salvianolic acid A and magnesium tanshinoate B, inhibited low-density lipoprotein (LDL) oxidation. A functional proteomics study of danshen extract in rat smooth muscle cells found effects on oxidative stress pathways. 39Animal data
ICAM-1 was validated as a hyperlipidemic target of danshen in an apolipoprotein E(-/-) mouse model. While lipid levels were not altered, increased expression of ICAM-1 in circulating leukocytes driven by an athergenic diet was abolished by danshen treatment. Atherosclerotic plaque was also attenuated in this experiment. 40 In a rabbit model, serum triglycerides were lower in the danshen-fed group compared with the control group. A rat model of hyperlipidemia treated with danshen extract showed decreases in total cholesterol, LDL, and triglycerides, with elevation of high-density lipoprotein (HDL). 41 Molecular analysis implicated a mechanism operating through farnesoid X receptor/liver X receptor coagonism. 41Clinical data
A study among elderly patients with hyperlipidemia (N = 96) showed decreased total cholesterol and LDL with danshen. 33 In other human experiments, a reduction in cholesterol, triglyceride, and LDL levels was seen with administration of the Fu Fang Dan Shen dripping pill, but the component responsible for the effect was not identified. 2Hypertension
In vitro data
Dihydrotanshinone relaxed isolated rat coronary arteries stimulated with 5-hydroxytryptamine (HT). The effect was blocked by the guanylate cyclase inhibitor ODQ, indicating a mechanism involving inhibition of calcium influx in smooth muscle cells of the vasculature. 42 A novel phenolic compound from danshen, IDHP, also had a vasorelaxant effect on rat mesenteric artery contracted with 5-HT or epinephrine. The authors posited a direct effect on vascular smooth muscle cells through intracellular calcium release and inhibition of calcium influx. Potassium channels may also be involved. 43 In contrast, the phenolic danshen constituent danshensu had a biphasic effect on isolated rat aortic rings, with high doses producing vasodilation. 44Animal data
With intact spontaneously hypertensive rats, the danshen constituent tanshinone IIA lowered systolic blood pressure when given i.p. at 10 mg/kg. The same dose had no effect on blood pressure in normotensive rats. Oral administration had the same effects, and in vitro experiments with isolated arteries implicated ATP-sensitive calcium channels in the mechanism. 45 Rats treated with phenylephrine followed by either danshen extract or magnesium tanshinoate B displayed lower blood pressure values. 46Clinical data
Danshen is used for the management of hypertension in China, Korea, and Japan, and is thought to act via inhibition of angiotensin-converting enzymes. Experiments in rats suggest that the constituents lithospermic acid B and salvianolic acid B are responsible for this activity. Reductions in blood pressure were achieved in pregnant women given intravenous danshen infusions for 10 days. 33Cancer
In vitro data
Danshen and its constituents inhibit the growth of several types of cancer cell lines, including breast, 47 prostate, 48 , 49 and liver. 50 The effects appear to be primarily due to tanshinones. The effect in hepatocellular cancer may be mediated through TGF-beta/SMAD signaling, 51 while the effect in prostate cancer cells has been attributed to the PI3-kinase/AKT pathway. 49 Experiments show that danshen inhibits angiogenesis, possibly due to cryptotanshinone and tanoshinone IIa. 52Animal data
Tanshinone I inhibited prostate cancer xenografts in mice, 48 while a polyherbal crude extract containing danshen was effective against a hepatocellular xenograft in mice. 53 Several studies have evaluated the immunomodulatory effects of danshen combined with yunzhi ( Coriolus versicolor ) in nasopharyngeal and breast cancer. Enhanced cellular immunity was demonstrated, as well as improvement in quality of life indicators. 54 , 55 , 56Clinical data
There are no reported studies of danshen or its constituents in human cancer patients.Renal
Animal and human experiments suggest that danshen exerts an effect on glomerular filtration rate and renal blood flow. 33 , 57 Tanshinone IIA given to rats with experimental renal insufficiency led to improvement in many end points. 58 Pretreatment of rats with danshen before experimental kidney transplantation reduced ischemia reperfusion injury. 59 Similarly in humans, danshen injections given daily for 10 days in renal transplant patients resulted in an increase in urinary volume and endogenous creatinine clearance rates over control. 33 Danshen has been used as add-on therapy to conventional steroid treatment in children with primary nephrotic syndrome. 33Other
Cryptotanshinone and danshen extract were protective against ethanol injury to hepatocytes. 60 Studies suggested tanshinone IIA may act to inhibit voluntary intake of alcohol in rats with induced alcoholism. 33 , 61 A compound extract of Astragalus and danshen reduced fibrosis in myofibroblasts of rats exposed to carbon tetrachloride injury. 62 Danshen was effective in limiting the effects of experimental pancreatitis or obstructive jaundice in rats. 63 , 64 It was also effective in protecting from ischemia reperfusion injury in experimental liver transplantation. 65Antithrombotic effects
Thanshinone enhanced the activity of insulin in Chinese hamster ovary cells and in adipocytes. 72 Pathways through which dihydrotanshinone might affect blood glucose were examined in cellular experiments. 73 Inhibition of advanced glycation end products through alpha-glucosidase blockade by danshen was reported. 74
Other effects of danshen or its constituents include attenuation of beta-amyloid deposition, 75 cholinesterase inhibition for Alzheimer disease, 76 inhibition of osteoclastogenesis, 77 and protection against cisplatin-induced ototoxicity. 78
Active components in commercially available preparations vary greatly. 2 The Pharmacopoeia of the People's Republic of China describes standards for the Fu Fang Dan Shen dripping pill (no less than 0.08 mg/pill of danshensu) and the Fu Fang Dan Shen tablet (no less than tanshinone 0.2 mg and salvianolic acid B 5 mg per tablet). 2 Commonly cited dosages include 10 dripping pills taken 3 times a day orally or sublingually, 3 Fu Fang Dan Shen tablets taken orally 3 times a day, 2 danshen 20 mg/kg capsules, 6 , 8 and danshen 100 to 200 mg/kg injection. 33 , 79 Danshen has been used in children with pulmonary hypertension (2 to 15 years of age) at a total dose of 400 mg/kg (100 mg/kg bolus followed by 100 mg/kg continuous infusion repeated twice) 79 and in pregnant women with hypertension. Deaths, however, were not reported in either study. 33
Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.
Three case reports of overcoagulation exist for coadministration of warfarin and danshen. Pharmacokinetic and dynamic factors are suggested for this effect. In rats, danshen appears to increase the absorption rate and area under the curve (AUC) and to decrease clearance and volume of distribution. 2 , 81 , 82 , 83Other
Danshen and salicylate may compete for protein-binding sites. 2 , 81 Danshen induces CYP-450 in rats but not in mice. 2 Danshen aqueous extract competitively inhibited CYP1A2 metabolism of caffeine in human and rat liver microsomes, and decreased caffeine clearance in rats. Tanshinones were responsible for the inhibition. 84 , 85 Different modes of inhibition (competitive, uncompetitive, and non-competitive) were posited for tanshinones on 4 human CYP isoforms. 86 Danshen decreased CYP3A in rats, increasing the effect of midazolam. 87 In a study of 12 healthy men, pretreatment with danshen extract 4 g 3 times daily increased midazolam oral clearance approximately 35% and reduced the maximum plasma concentration and AUC approximately 31% and 27%, respectively. 88 In healthy volunteers, however, no effect was seen on theophylline metabolism. 89 In rats, no effect on the metabolism of metoprolol by salvianolic acid B was detected. 90
Experiments suggest that danshen may exhibit a protective effect against the nephrotoxic and ototoxic effects of gentamicin. 33
Few trials report adverse reactions related to danshen usage in detail; therefore, any comments regarding safety are difficult to qualify. Allergy, dizziness, headache, mild GI symptoms, and reversible thrombocytopenia have been reported. 1 , 2 , 33 , 37
Research reveals little information regarding toxicology with the use of danshen. Oral danshen (2,500 mg/kg body weight) given to rats for 90 days at a dosage 400 times that of the recommended human dosage was reported to be nontoxic. The median lethal dose of the water-soluble extract of danshen is reported to be 25 g/kg body weight in mice. 2
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