Danshen

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

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.

Dosing

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.

Contraindications

Data are lacking.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

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.

Adverse Reactions

Adverse reactions appear to be limited to allergy, dizziness, headache, mild GI symptoms, and reversible thrombocytopenia.

Toxicology

Information is limited.

Botany

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

History

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

Chemistry

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

Uses and Pharmacology

Stroke

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 , 22

In 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. 24

Animal 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 , 22

Clinical 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. 28

Coronary 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. 32

Animal 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. 36

Clinical 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. 33

Hyperlipidemia
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. 39

Animal 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. 41

Clinical 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. 2

Hypertension
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. 44

Animal 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. 46

Clinical 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. 33

Cancer
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. 52

Animal 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 , 56

Clinical 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. 33

Other
Alcoholism

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. 65

Antithrombotic effects

Antithrombotic actions of danshen were reported in animal experiments, 66 , 67 , 68 , 69 but human trials are lacking.

Hepatitis

Earlier studies suggest danshen affects patients with chronic hepatitis in relieving nausea, malaise, liver pain, and abdominal distention. 66 , 70

Immunomodulation

Tanshinones inhibited cutaneous anaphylaxis in mice. 71 A preparation of danshen and Coriolus versicolor alleviated lymphopenia caused by radiotherapy in nasopharyngeal cancer patients. 55

Diabetes

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

Dosage

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

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

Digoxin

Danshen may interfere with laboratory values for digoxin plasma levels. Monitoring free digoxin concentrations can circumvent the positive and negative interference caused by danshen. 33 , 80

Warfarin

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 , 83

Other

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

Adverse Reactions

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

Toxicology

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

Bibliography

1. Wu B, Liu M, Zhang S. Dan Shen agents for acute ischaemic stroke. Cochrane Database Syst Rev . 2007;(2):CD004295.
2. Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol . 2005;45(12):1345-1359.
3. Li MH, Chen JM, Peng Y, Wu Q, Xiao PG. Investigation of Danshen and related medicinal plants in China. J Ethnopharmacol . 2008;120(3):419-426.
4. Song Z, Li X, Wang H, Wang J. Genetic diversity and population structure of Salvia miltiorrhiza Bge in China revealed by ISSR and SRAP. Genetica . 2010;138(2):241-249.
5. Tam WY, Chook P, Qiao M, et al. The efficacy and tolerability of adjunctive alternative herbal medicine ( Salvia miltiorrhiza and Pueraria lobata ) on vascular function and structure in coronary patients. J Altern Complement Med . 2009;15(4):415-421.
6. Fang Y. Chinese patent traditional medicine first time passes U.S. FDA crucial clinical trials. English.News.cn. August 7, 2010. http://news.xinhuanet.com/english2010/china/2010-08/07/c_13434173.htm. Accessed July 8, 2011.
7. Wang X, Morris-Natschke SL, Lee KH. New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev . 2007;27(1):133-148.
8. Jiang RW, Lau KM, Hon PM, Mak TC, Woo KS, Fung KP. Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza . Curr Med Chem . 2005;12(2):237-246.
9. Zhong GX, Li P, Zeng LJ, Guan J, Li DQ, Li SP. Chemical characteristics of Salvia miltiorrhiza (Danshen) collected from different locations in China. J Agric Food Chem . 2009;57(15):6879-6887.
10. Li CG, Sheng SJ, Pang EC, et al. Cultivar variations of Australian-grown Danshen ( Salvia miltiorrhiza ): bioactive markers and root yields. Chem Biodivers . 2009;6(2):170-181.
11. Li CG, Sheng SJ, Pang EC, May B, Xue CC. HPLC profiles and biomarker contents of Australian-grown Salvia miltiorrhiza f. alba roots. Chem Biodivers . 2009;6(7):1077-1086.
12. Sheng SJ, Pang EC, Xue CC, Li CG. Seasonal variations in bioactive marker contents in Australian-grown Salvia miltiorrhiza roots. Chem Biodivers . 2009;6(4):551-560.
13. Dai H, Xiao C, Liu H, Hao F, Tang H. Combined NMR and LC-DAD-MS analysis reveals comprehensive metabonomic variations for three phenotypic cultivars of Salvia Miltiorrhiza Bunge. J Proteome Res . 2010;9(3):1565-1578.
14. Chen H, Zhang Q, Wang X, Yang J, Wang Q. Qualitative analysis and simultaneous quantification of phenolic compounds in the aerial parts of Salvia miltiorrhiza by HPLC-DAD and ESI/MS(n). Phytochem Anal . 2011;22(3):247-257.
15. Park EJ, Ji HY, Kim NJ, et al. Simultaneous determination of tanshinone I, dihydrotanshinone I, tanshinone IIA and cryptotanshinone in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study of a standardized fraction of Salvia miltiorrhiza , PF2401-SF. Biomed Chromatogr . 2008;22(5):548-555.
16. Lu T, Yang J, Gao X, et al. Plasma and urinary tanshinol from Salvia miltiorrhiza (Danshen) can be used as pharmacokinetic markers for cardiotonic pills, a cardiovascular herbal medicine. Drug Metab Dispos . 2008;36(8):1578-1586.
17. Bi HC, Zuo Z, Chen X, et al. Preclinical factors affecting the pharmacokinetic behaviour of tanshinone IIA, an investigational new drug isolated from Salvia miltiorrhiza for the treatment of ischaemic heart diseases. Xenobiotica . 2008;38(2):185-222.
18. Chang BB, Zhang L, Cao WW, et al. Pharmacokinetic interactions induced by content variation of major water-soluble components of Danshen preparation in rats. Acta Pharmacol Sin . 2010;31(5):638-646.
19. Pan Y, Bi HC, Zhong GP, et al. Pharmacokinetic characterization of hydroxylpropyl-beta-cyclodextrin-included complex of cryptotanshinone, an investigational cardiovascular drug purified from Danshen ( Salvia miltiorrhiza ). Xenobiotica . 2008;38(4):382-398.
20. Xiaohui Z, Xinfeng Z, Xin Z, Shixiang W, Yinmao W, Jianbin Z. Determination of the main bioactive metabolites of Radix salvia miltiorrhizae in compound Danshen dripping pills and the tissue distribution of Danshensu in rabbit by SPE-HPLC-MSn. J Sep Sci . 2007;30(6):851-857.
21. Han JY, Fan JY, Horie Y, et al. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol Ther . 2008;117(2):280-295.
22. Lin TH, Hsieh CL. Pharmacological effects of Salvia miltiorrhiza (Danshen) on cerebral infarction. Chin Med . 2010;5:22.
23. Lam FF, Deng SY, Ng ES, et al. Mechanisms of the relaxant effect of a danshen and gegen formulation on rat isolated cerebral basilar artery. J Ethnopharmacol . 2010;132(1):186-192.
24. Li X, Du JR, Yu Y, Bai B, Zheng XY. Tanshinone IIA inhibits smooth muscle proliferation and intimal hyperplasia in the rat carotid balloon-injured model through inhibition of MAPK signaling pathway. J Ethnopharmacol . 2010;129(2):273-279.
25. Hur KY, Seo HJ, Kang ES, et al. Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury. Eur J Pharmacol . 2008;586(1-3):226-233.
26. Sze FK, Yeung FF, Wong E, Lau J. Does Danshen improve disability after acute ischaemic stroke? Acta Neurol Scand . 2005;111(2):118-125.
27. Wu B, Liu M, Liu H, et al. Meta-analysis of traditional Chinese patent medicine for ischemic stroke. Stroke . 2007;38(6):1973-1979.
28. Xu G, Zhao W, Zhou Z, Zhang R, Zhu W, Liu X. Danshen extracts decrease blood C reactive protein and prevent ischemic stroke recurrence: a controlled pilot study. Phytother Res . 2009;23(12):1721-1725.
29. Ling S, Luo R, Dai A, Guo Z, Guo R, Komesaroff PA. A pharmaceutical preparation of Salvia miltiorrhiza protects cardiac myocytes from tumor necrosis factor-induced apoptosis and reduces angiotensin II-stimulated collagen synthesis in fibroblasts. Phytomedicine . 2009;16(1):56-64.
30. Park JW, Lee SH, Yang MK, et al. 15,16-dihydrotanshinone I, a major component from Salvia miltiorrhiza Bunge (Dansham), inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization. Arch Pharm Res . 2008;31(1):47-53.
31. Jeon SJ, Son KH, Kim YS, Choi YH, Kim HP. Inhibition of prostaglandin and nitric oxide production in lipopolysaccharide-treated RAW 264.7 cells by tanshinones from the roots of Salvia miltiorrhiza bunge. Arch Pharm Res . 2008;31(6):758-763.
32. Jin UH, Suh SJ, Chang HW, et al. Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. J Cell Biochem . 2008;104(1):15-26.
33. Cheng TO. Cardiovascular effects of Danshen. Int J Cardiol . 2007;121(1):9-22.
34. Zeng X, Yang J, Yang X, Hong D, Wu L, Yu J. Effect of Guanxin No.2 decoction on gene expression in different areas of the myocardial infarcted heart of rats using microarray technology. J Pharm Pharmacol . 2009;61(2):213-219.
35. Ren ZH, Tong YH, Xu W, Ma J, Chen Y. Tanshinone II A attenuates inflammatory responses of rats with myocardial infarction by reducing MCP-1 expression. Phytomedicine . 2010;17(3-4):212-218.
36. Cao Y, Chai JG, Chen YC, et al. Beneficial effects of danshensu, an active component of Salvia miltiorrhiza , on homocysteine metabolism via the trans-sulphuration pathway in rats. Br J Pharmacol . 2009;157(3):482-490.
37. Wang G, Wang L, Xiong ZY, Mao B, Li TQ. Compound salvia pellet, a traditional Chinese medicine, for the treatment of chronic stable angina pectoris compared with nitrates: a meta-analysis. Med Sci Monit . 2006;12(1):SR1-SR7.
38. Sieveking DP, Woo KS, Fung KP, Lundman P, Nakhla S, Celermajer DS. Chinese herbs Danshen and Gegen modulate key early atherogenic events in vitro. Int J Cardiol . 2005;105(1):40-45.
39. Hung YC, Wang PW, Pan TL. Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions. Biochim Biophys Acta . 2010;1804(6):1310-1321.
40. Ling S, Dai A, Guo Z, Komesaroff PA. A preparation of herbal medicine Salvia miltiorrhiza reduces expression of intercellular adhesion molecule-1 and development of atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol . 2008;51(1):38-44.
41. Ji W, Gong BQ. Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats. J Ethnopharmacol . 2008;119(2):291-298.
42. Lam FF, Yeung JH, Chan KM, Or PM. Dihydrotanshinone, a lipophilic component of Salvia miltiorrhiza (danshen), relaxes rat coronary artery by inhibition of calcium channels. J Ethnopharmacol . 2008;119(2):318-321.
43. Wang SP, Zang WJ, Kong SS, et al. Vasorelaxant effect of isopropyl 3-(3, 4-dihydroxyphenyl)-2-hydroxypropanoate, a novel metabolite from Salvia miltiorrhiza , on isolated rat mesenteric artery. Eur J Pharmacol . 2008;579(1-3):283-288.
44. Zhang N, Zou H, Jin L, et al. Biphasic effects of sodium danshensu on vessel function in isolated rat aorta. Acta Pharmacol Sin . 2010;31(4):421-428.
45. Chan P, Liu IM, Li YX, Yu WJ, Cheng JT. Antihypertension induced by tanshinone IIA isolated from the roots of Salvia miltiorrhiza . [published online ahead of print June 19, 2009]. Evid Based Complement Alternat Med . doi:10.1093/ecam/nep056.
46. Leung SW, Zhu DY, Man RY. Effects of the aqueous extract of Salvia miltiorrhiza (danshen) and its magnesium tanshinoate B-enriched form on blood pressure. Phytother Res . 2010;24(5):769-774.
47. Yang W, Ju JH, Jeon MJ, Han X, Shin I. Danshen ( Salvia miltiorrhiza ) extract inhibits proliferation of breast cancer cells via modulation of Akt activity and p27 level. Phytother Res . 2010;24(2):198-204.
48. Gong Y, Li Y, Lu Y, et al. Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice. Int J Cancer . 2011;129(5):1042-1052.
49. Won SH, Lee HJ, Jeong SJ, et al. Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull . 2010;33(11):1828-1834.
50. Lee WY, Cheung CC, Liu KW, et al. Cytotoxic effects of tanshinones from Salvia miltiorrhiza on doxorubicin-resistant human liver cancer cells. J Nat Prod . 2010;73(5):854-859.
51. Liu X, Yang Y, Zhang X, et al. Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/Smad in HepG2 cell. J Gastroenterol Hepatol . 2010;25(2):420-426.
52. Fan TP, Yeh JC, Leung KW, Yue PY, Wong RN. Angiogenesis: from plants to blood vessels. Trends Pharmacol Sci . 2006;27(6):297-309.
53. Huang XY, Wang L, Huang ZL, Zheng Q, Li QS, Tang ZY. Herbal extract “Songyou Yin” inhibits tumor growth and prolongs survival in nude mice bearing human hepatocellular carcinoma xenograft with high metastatic potential. J Cancer Res Clin Oncol . 2009;135(9):1245-1255.
54. Wong CK, Bao YX, Wong EL, Leung PC, Fung KP, Lam CW. Immunomodulatory activities of Yunzhi and Danshen in post-treatment breast cancer patients. Am J Chin Med . 2005;33(3):381-395.
55. Bao YX, Wong CK, Leung SF, et al. Clinical studies of immunomodulatory activities of Yunzhi-Danshen in patients with nasopharyngeal carcinoma. J Altern Complement Med . 2006;12(8):771-776.
56. Wong CK, Tse PS, Wong EL, Leung PC, Fung KP, Lam CW. Immunomodulatory effects of yun zhi and danshen capsules in health subjects--a randomized, double-blind, placebo-controlled, crossover study. Int Immunopharmacol . 2004;4(2):201-211.
57. Wojcikowski K, Johnson DW, Gobé G. Medicinal herbal extracts—renal friend or foe? Part two: herbal extracts with potential renal benefits. Nephrology (Carlton) . 2004;9(6):400-405.
58. Ahn YM, Kim SK, Lee SH, et al. Renoprotective effect of Tanshinone IIA, an active component of Salvia miltiorrhiza , on rats with chronic kidney disease. Phytother Res . 2010;24(12):1886-1892.
59. Guan X, Dei-Anane G, Bruns H, et al. Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation. Transpl Int . 2009;22(2):232-241.
60. Yin HQ, Choi YJ, Kim YC, Sohn DH, Ryu SY, Lee BH. Salvia miltiorrhiza Bunge and its active component cryptotanshinone protects primary cultured rat hepatocytes from acute ethanol-induced cytotoxicity and fatty infiltration. Food Chem Toxicol . 2009;47(1):98-103.
61. Xu BJ, Zheng YN, Sung CK. Natural medicines for alcoholism treatment: a review. Drug Alcohol Rev . 2005;24(6):525-536.
62. Yang Y, Yang S, Chen M, Zhang X, Zou Y, Zhang X. Compound Astragalus and Salvia miltiorrhiza Extract exerts anti-fibrosis by mediating TGF-beta/Smad signaling in myofibroblasts. J Ethnopharmacol . 2008;118(2):264-270.
63. Xiping Z, Yang C, Dijiong W, et al. Effects of Salvia miltiorrhiza on intercellular adhesion molecule 1 protein expression in the lungs of rats with severe acute pancreatitis or obstructive jaundice. Pancreas . 2009;38(3):309-317.
64. Xiping Z, Jun F, Chengjun W, et al. Effect of salvia miltiorrhizae on pulmonary apoptosis of rats with severe acute pancreatitis or obstructive jaundice. Inflammation . 2009;32(5):287-295.
65. Liang R, Bruns H, Kincius M, et al. Danshen protects liver grafts from ischemia/reperfusion injury in experimental liver transplantation in rats. Transpl Int . 2009;22(11):1100-1109.
66. Chang HM, et al, ed. Advances in Chinese Medicinal Materials Research . Singapore: World Scientific;1985:559-580.
67. Dong JC, Xu LN. Beneficial effects of acetylsalvianolic acid A on focal cerebral ischemic rats subjected to middle cerebral artery thrombosis [in Chinese]. Yao Xue Xue Bao . 1996;31(1):6-9.
68. Yu WG, Xu LN. Effect of acetylsalvianolic acid A on platelet function [in Chinese]. Yao Xue Xue Bao . 1994;29(6):412-416.
69. Zou ZW, Xu LN, Tian JY. Antithrombotic and antiplatelet effects of rosmarinic acid, a water-soluble component isolated from radix Salviae miltiorrhizae (danshen) [in Chinese]. Yao Xue Xue Bao . 1993;28(4):241-245.
70. Bai Y. Therapeutic effect of danshen injection on chronic active hepatitis [in Chinese]. Zhong Xi Yi Jie He Za Zhi . 1984;4(2):86-87.
71. Trinh HT, Chae SJ, Joh EH, Son KH, Jeon SJ, Kim DH. Tanshinones isolated from the rhizome of Salvia miltiorrhiza inhibit passive cutaneous anaphylaxis reaction in mice. J Ethnopharmacol . 2010;132(1):344-348.
72. Jung SH, Seol HJ, Jeon SJ, Son KH, Lee JR. Insulin-sensitizing activities of tanshinones, diterpene compounds of the root of Salvia miltiorrhiza Bunge. Phytomedicine . 2009;16(4):327-335.
73. Liu Q, Zhang Y, Lin Z, et al. Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways. J Steroid Biochem Mol Biol . 2010;120(4-5):155-163.
74. Ma HY, Gao HY, Sun L, Huang J, Xu XM, Wu LJ. Constituents with α-glucosidase and advanced glycation end-product formation inhibitory activities from Salvia miltiorrhiza Bge. J Nat Med . 2010;65(1):37-42.
75. Mei Z, Zhang F, Tao L, et al. Cryptotanshinone, a compound from Salvia miltiorrhiza modulates amyloid precursor protein metabolism and attenuates beta-amyloid deposition through upregulating alpha-secretase in vivo and in vitro. Neurosci Lett . 2009;452(2):90-95.
76. Wong KK, Ho MT, Lin HQ, et al. Cryptotanshinone, an acetylcholinesterase inhibitor from Salvia miltiorrhiza , ameliorates scopolamine-induced amnesia in Morris water maze task. Planta Med . 2010;76(3):228-234.
77. Kim HK, Woo ER, Lee HW, et al. The correlation of Salvia miltiorrhiza extract-induced regulation of osteoclastogenesis with the amount of components tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone. Immunopharmacol Immunotoxicol . 2008;30(2):347-364.
78. Xu O, Liu Y, Li X, et al. Protective effects of Salvia miltiorrhiza against cisplatin-induced ototoxicity in guinea pigs. Am J Otolaryngol . 2011;32(3):228-234.
79. Xia Z, Gu J, Ansley DM, Xia F, Yu J. Antioxidant therapy with Salvia miltiorrhiza decreases plasma endothelin-1 and thromboxane B2 after cardiopulmonary bypass in patients with congenital heart disease. J Thorac Cardiovasc Surg . 2003;126(5):1404-1410.
80. Wahed A, Dasgupta A. Positive and negative in vitro interference of Chinese medicine dan shen in serum digoxin measurement. Elimination of interference by monitoring free digoxin concentration. Am J Clin Pathol . 2001;116(3):403-408.
81. Hu Z, Yang X, Ho PC, et al. Herb-drug interactions: a literature review. Drugs . 2005;65(9):1239-1282.
82. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med . 2005;165(10):1095-1106.
83. Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol . 2005;98(1):1-14.
84. Wang X, Lee WY, Or PM, Yeung JH. Effects of major tanshinones isolated from Danshen ( Salvia miltiorrhiza ) on rat CYP1A2 expression and metabolism of model CYP1A2 probe substrates. Phytomedicine . 2009;16(8):712-725.
85. Wang X, Yeung JH. Effects of the aqueous extract from Salvia miltiorrhiza Bunge on caffeine pharmacokinetics and liver microsomal CYP1A2 activity in humans and rats. J Pharm Pharmacol . 2010;62(8):1077-1083.
86. Wang X, Cheung CM, Lee WY, Or PM, Yeung JH. Major tanshinones of Danshen ( Salvia miltiorrhiza ) exhibit different modes of inhibition on human CYP1A2, CYP2C9, CYP2E1 and CYP3A4 activities in vitro. Phytomedicine . 2010;17(11):868-875.
87. Wang X, Lee WY, Zhou X, Or PM, Yeung JH. A pharmacodynamic-pharmacokinetic (PD-PK) study on the effects of Danshen ( Salvia miltiorrhiza ) on midazolam, a model CYP3A probe substrate, in the rat. Phytomedicine . 2010;17(11):876-883.
88. Qiu F, Wang G, Zhang R, Sun J, Jiang J, Ma Y. Effect of danshen extract on the activity of CYP3A4 in healthy volunteers. Br J Clin Pharmacol . 2010;69(6):656–662.
89. Qiu F, Wang G, Zhao Y, Sun H, Mao G, A J, Sun J. Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers. Br J Clin Pharmacol . 2008;65(2):270-274.
90. Wan RZ, Zhou MJ, Liu CX. The effects of salvianolic acid B from radix salvia miltiorrhizae on the oral pharmacokinetics of metoprolol and metoprolol acid in rats. Phytother Res . 2010;24(6):846-851.

Copyright © 2009 Wolters Kluwer Health

Hide
(web4)