Salvianolic acid

Other Names

Dan phenolic acid ADan Shen SuanDan Shen Suan BDanfensuan BDanphenolic acid ADanshansuic acid ADanshen phenolic acidsDanshensuIsosalvianolic acid CLithospermate BLithospermic acid BMagnesium tanshinoate BMonardic acid BRadix Salviae Miltiorrhizae phenolic acidsSal ASal BSal CSal DSalASalBSalvianic acidSalvianic acid ASalvianolateSalvianolic acid ASalvianolic acid BSalvianolic acid CSalvianolic acid DSalvianolic acid ESalvianolic acid FSalvianolic acid GSalvianolic acid HSalvianolic acid ISalvianolic acid JSalvianolic acid KSalvianolic acid LTanshinoate B

Synopsis

Salvianolic Acid: A Comprehensive Reference

1. Identity, Botanical Source, and Chemistry

1.1 Botanical and Chemical Names

Salvianolic acids are a group of polyphenolic acids consisting of several combinations of caffeic acid and danshensu (salvianic acid) through ester and enol bonds. They are water-soluble components produced by many species of the genus Salvia, mainly extracted from Salvia miltiorrhiza. The parent plant, Salvia miltiorrhiza Bunge, also known as red sage or Danshen, is a perennial plant in the genus Salvia of the mint family, Lamiaceae.

More than 10 distinct salvianolic acids, identified by letters from A to J, have been recognized. Notably, salvianolic acid A (Sal-A) and salvianolic acid B (Sal-B) are the most abundant forms. The combination of danshensu and a caffeic acid derivative or caffeic acid dimer produces several kinds of skeletons. Sal-A is formed by a molecule of danshensu and a dimer of caffeic acid.

Danshensu [(R)-3-(3,4-Dihydroxyphenyl)-2-hydroxypropanoic acid] is the basic chemical structure of various salvianolic acids. More than eighteen components can be identified in Radix S. miltiorrhiza. Sal-B is the most abundant while Sal-A is the most potent water-soluble phenolic component in Radix S. miltiorrhiza.

Regarding the relationship between the major congeners, salvianolic acid B and lithospermic acid B are the major components of Salvia miltiorrhiza, which is one of the most popular herbal traditional medicines in Asian countries. They are reported to have identical structures except for the configurational assignments of two stereocenters. Through chemical correlation between a degradation product of salvianolic acid B and synthetic material, the absolute configuration of salvianolic acid B has been corrected to establish that salvianolic acid B and lithospermic acid B are in fact the same compound.

Salvianolic acid B is extracted from the roots and rhizomes of Danshen (Salvia miltiorrhiza Bge., family Labiatae). It is a water-soluble, weakly acidic drug. The major components of Danshen are hydrophilic salvianolic acids and lipophilic tanshinones.

1.2 Natural Sources and Geographic Distribution

Radix et rhizoma Salviae miltiorrhizae (Danshen, from Salvia miltiorrhiza Bunge, Lamiaceae) has been used commonly as a traditional Chinese medicine in many Asian countries such as China, Japan, and Korea. It is one of the most important botanical drugs in modern TCM. There have been more than 20 Salvia species used under the name of Danshen; however, according to the Chinese Pharmacopoeia (PPRC-2010), only Salvia miltiorrhiza meets the requirements to be ascribed as the formal Danshen.

At least 19 other Salvia species have been used traditionally as Danshen in some local areas, and of these, S. bowleyana Dunn. and S. przewalskii Maxim. are the most common substitutes. Both have a chemical composition similar to S. miltiorrhiza, including salvianolic acids and tanshinones.

In 2015, the total demand of Danshen was estimated to be 18.4 thousand tons according to a market report.

1.3 Common Forms and Preparations

With the development of science and technology, the dosage forms containing Danshen have been gradually diversified. Tablet, injection solution, dripping pill, oral liquid, capsule, slow-release formulation, and soft gel are all dosage forms that have been prepared into medicines. Among these diverse preparations, composite Danshen droplet pills, used to treat angina pectoris and coronary heart disease, represent a star drug and, moreover, a demonstration of traditional Chinese medicine entering the international market.

The active ingredients in S. miltiorrhiza can be mainly divided into two categories: fat-soluble tanshinone compounds and water-soluble salvianolic acids. Both ingredients have significant pharmacological activities and are representative active ingredients in traditional Chinese medicine.

Danshen, scientifically known as Salvia miltiorrhiza Bunge, is a traditional Chinese medicinal botanical drug. Salvianolate for injection (SFI), a metabolite derived from Danshen, received approval from the Chinese Food and Drug Administration in 2005 for the treatment of cardiovascular disease (CVD).

2. Traditional and Historical Use

2.1 Origins and Classical Texts

Its roots are highly valued as a "super grade herb" (herbs lacking observable toxicity) in the Shennong's Herbal Classic of Materia Medica (Shennong Bencao Jing) written during the reign of the Qin and Han dynasties (221 BC to 220 AD), and has been clinically used for more than 2000 years. Following this first record, S. miltiorrhiza was well described in classical traditional Chinese medicine (TCM) works such as in the Compendium of Materia Medica (Bencao Gangmu, Ming dynasty, 1596 AD).

Between 200 and 300 BC, "Shen Nong's Classic of the Materia Medica"—Shennong Ben Cao Jin—cited Danshen as a better-class medicine.

2.2 Traditional Indications and Preparations

Based on traditional Chinese medicine theory, Danshen has the properties of removing blood stasis and promoting blood circulation; clearing menstruation and relieving pain and swelling. The common medical indications for Danshen include menstrual disorders, cardiovascular diseases, chronic pain, and thoracic obstruction.

Danshen, a traditional herbal medicine in China, had been used to treat irregular menstruation, cold hernia, and abdominal pain, because the theory of traditional Chinese medicine holds that it activates blood circulation to dissipate blood stasis, calming, and relieving pain.

Renowned for its diverse therapeutic properties, including promoting blood circulation, removing blood stasis, calming the mind, tonifying the blood, and benefiting the "Qi," recent studies have revealed its significant positive effects on bone metabolism.

Salvianolic acids have been used in traditional Chinese medicine for the treatment of cardiovascular diseases for more than a thousand years.

2.3 Geographical Spread of Traditional Use

Danshen is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Danshen is widely used in Asia to treat coronary artery disease, hyperlipidemia, and cerebrovascular disease. The estimated number of patients using Danshen is approximately 5 million worldwide.

3. Key Constituents and Chemical Composition

To date, there are more than 10 different salvianolic acids identified and named: salvianolic acid A, B, C, D, E, F, G, etc. Sal-A and Sal-B are the most abundant compounds among salvianolic acids.

S. miltiorrhiza is enriched with liposoluble tanshinones (dihydrotanshinone I, tanshinone I, tanshinone IIA, and cryptotanshinone) and water-soluble phenolic acids (salvianolic acid A, salvianolic acid B, salvianolic acid C, and rosmarinic acid).

Salvianolic acid B's molecular formula is C₃₆H₃₀O₁₆ and it is the predominant polyphenol by mass in the dried root. Salvianolic acid B (Sal-B), the most active and abundant component of the water-soluble extract of the traditional Chinese medicine Danshen, has been demonstrated to exert atheroprotective effects.

4. Established Mechanisms of Action

4.1 Antioxidant and Free Radical Scavenging

Salvianolic acids, the most effective and abundant compounds extracted from Salvia miltiorrhiza (Danshen), are well known for their good anti-oxidative activity. Both Sal-A and Sal-B have effects against oxidative stress, platelet aggregation, coagulation, thrombosis, endothelial dysfunction, and inflammation targeting multiple vascular cell types. As potent polyphenols, Sal-A and Sal-B have direct ROS scavenging ability against different types of free radicals.

Salvianolic acids reduce intracellular and intravascular oxidative stress, which protect cells from peroxidation and free radical damage.

4.2 Anti-inflammatory Mechanisms

Several studies have shown that Sal-B can inhibit the expressions of TNF-α, IL-1β, IL-6, and other pro-inflammatory factors in a variety of diseases to exert a good anti-inflammatory effect, and its mechanisms mainly involve the TNF-α/NF-κB signaling pathway and TLR pathway.

Salvianolic acid B exerts anti-inflammatory effects by inhibiting the receptor for advanced glycosylation end products (RAGE)/Diaphanous1 (DIAPH1) pathway in microglia, and it alleviates neuronal loss caused by microglia activation.

4.3 Cardioprotective Mechanisms

Salvianolic acid B has demonstrated antitumor and anti-inflammatory effects on various organs and tissues. The mechanisms underlying the protective effects of salvianolic acid B are mainly related to its anti-inflammatory, antioxidant, anti- or pro-apoptotic, anti- or pro-autophagy, anti-fibrotic, and metabolism-regulating functions. Salvianolic acid B can regulate various signaling pathways, cells, and molecules to achieve maximum therapeutic effects.

Modern pharmacological studies have demonstrated that Sal-B exerts comprehensive cardioprotective effects through multiple mechanisms, including antioxidant and anti-inflammatory activities, induction of mitochondrial autophagy, enhancement of endothelial function, anti-fibrotic actions, and improvement of hemorheology.

Sal-B regulates AKT/mTOR, Hippo/YAP, PI3K/AKT/HIF-1α, TGF-β1/Smad, mortalin/RECK/STAT3, and NDRG2/PTEN/PI3K/AKT signaling pathways to promote anti-cancer effects and exerts neuroprotective effects by modulating CD40/NF-κB, IGF-1/AKT, ERK/CREB/BDNF, and miRNA-1/MLCK signaling pathways.

Sal-B substantially abrogated ER stress-induced cell death and reduction in capillary tube formation, with declined intracellular reactive oxygen species (ROS) amounts and restored mitochondrial membrane potential, as well as increased expression of HO-1 and SOD2 in bone marrow-derived endothelial progenitor cells.

4.4 Anti-fibrotic Mechanisms

The downregulation of Ang-II signaling such as decreasing AT1R expression and ERK and c-Jun phosphorylation, and the inhibition of TGF-β expression stimulated by Ang-II, is an important action mechanism for Sal-B against HSC activation and liver fibrosis.

Sal-B also regulates a variety of signalling pathways including the MAPK, angiotensin II, and NF-κB signalling pathways during liver fibrosis.

4.5 Anti-thrombotic and Antiplatelet Mechanisms

SAA treatment can resist ADP and collagen-induced human blood platelet aggregation and thrombosis by inhibiting the abnormal increase of the phosphorylation of Akt and also inhibits PI3K, and these effects of SAA were comparable to that of the PI3K inhibitor LY294002 both in vitro and in vivo in a mouse model of arterial thrombosis.

NO is known to play a central role in maintaining cardiovascular homeostasis, and SAA treatment increases rat left ventricle NO content after myocardial ischemia/reperfusion.

5. Scientific Evidence by Area of Use

5.1 Cardiovascular Diseases

5.1.1 Overview and Clinical Use

Salvianolic acids are the most abundant water-soluble compounds extracted from Radix Salvia miltiorrhiza (Danshen). In China, Danshen has been widely used to treat cardiovascular diseases for hundreds of years. Danshen is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy, and cardiac fibrosis.

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.

5.1.2 Myocardial Infarction — Preclinical Evidence

Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving blood vessel density compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). This meta-analysis was confined to animal models, and evidence remains preclinical.

5.1.3 Atherosclerosis — Preclinical Evidence

Salvianolic acid B, the most active and abundant component of the water-soluble extract of Danshen, has been demonstrated to exert atheroprotective effects. Salvianolic acid B is the main effective water-soluble component of Salvia miltiorrhiza. In preclinical studies, the anti-inflammatory effect of Sal-B was explored in high-fat-diet-induced LDLR^-/- mice and oxidized low-density-lipoprotein (ox-LDL)-induced or LPS-induced RAW264.7 cells. The lack of clinical evidence limits the application of salvianolic acids in treating atherosclerosis, and the bulk of data to date remain preclinical.

5.1.4 Myocardial Ischemia–Reperfusion — Preclinical and Mechanistic Evidence

SAA can also exert cardioprotective effects through ERK1/2. Possible mechanisms include modulation of oxidative stress, inflammatory response, mitochondrial dysfunction, ferroptosis, and apoptosis through pathways such as PI3K/Akt, JAK/STAT, and NF-κB.

Sal-B inhibits the TGF-β1 signaling pathway by upregulating Smad7 expression, which reduces myocardial fibrosis and inflammatory cell infiltration, effectively alleviating diabetic myocardial damage.

5.1.5 Human Clinical Trials — Cardiovascular

The clinical effect of S. miltiorrhiza, or its active ingredient tanshinone IIA, or Fufang Danshen, has been examined in patients with various conditions of cardiovascular diseases in several clinical studies from about the 1980s. However, due to limited study design and rigor, definitive conclusions remain elusive. A randomized, placebo-controlled, double-blind crossover study evaluated Danshen water-extract on hyperlipidemia and hypertension. This was a randomized, placebo-controlled, double-blind crossover study. Participants were randomized to treatment with Danshen (water-extract of the Salvia miltiorrhiza root) or placebo for 4 consecutive weeks. Of the 20 analysed participants, 11 received placebo first. Inclusion criteria were: age 40–70 years, hyperlipidemia, and hypertension. This small study found no statistically significant benefit on these cardiovascular risk factors, illustrating the limited state of high-quality human clinical evidence for salvianolic acids specifically.

One of the most commonly used TCM drugs, Dantonic (or Fufang Danshen), has been recorded in the Chinese Pharmacopoeia (2015), which documented its application in conditions such as coronary atherosclerosis, angina pectoris, hyperlipidemia, and Alzheimer's disease in China and some other Asian countries. It is a China Food and Drug Administration-approved drug since 2008.

Salvianolic acids for injection (SAFI) serve as a safe and effective treatment option for cardiovascular and cerebrovascular conditions by influencing various signaling pathways and molecular targets associated with these diseases. Evidence suggests that salvianolic acids, mainly from Salvia miltiorrhiza Bunge, have been formulated into injections and are widely used in clinical treatments for cardiovascular and cerebrovascular diseases, including stroke.

5.2 Hepatic Fibrosis and Liver Protection

5.2.1 Clinical Evidence in Hepatic Fibrosis

One published clinical study aimed to evaluate the clinical efficacy of salvianolic acid B (SA-B) on liver fibrosis in chronic hepatitis B. Sixty patients with definite diagnosis of liver fibrosis with hepatitis B were included in the trial. Interferon-γ (IFN-γ) was used as control drug. The patients took orally SA-B tablets or received muscular injection of IFN-γ in a double-blind randomized test. The complete course lasted 6 months. Histological changes of liver biopsy specimen before and after the treatment were the main evidence in evaluation, in combination with the results of contents of serum hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C), procollagen III (P-III-P), liver ultrasound imaging, and symptoms and signs.

The reverse rate of fibrotic stage was 36.67% in the SA-B group and 30.0% in the IFN-γ group. Inflammatory alleviating rate was 40.0% in the SA-B group and 36.67% in the IFN-γ group. The average content of HA and IV-C was significantly lower than that before treatment. This was a relatively small, single-center trial conducted in China. The comparator (IFN-γ) is not a globally standard-of-care treatment for fibrosis, and independent replication in larger, multicenter studies has not yet been reported.

5.2.2 Preclinical Mechanisms

Salvianolic acid B has shown hepatic anti-fibrotic activity. Hepatic stellate cells (HSC) activation is considered the determining event in liver fibrogenesis. Numerous experimental data indicated that salvianolic acids slowed the progression of fibrosis diseases by reducing excessive deposition of extracellular matrix (ECM).

Previous studies have shown that salvianolic acid B is effective in improving liver function, alleviating ischemic damage, antioxidation, antihepatotoxicity, and anticoagulation.

The analysis of liver function and serum fibrotic markers before treatment showed that the effect of SA-B in anti-fibrosis was related to the level of liver injury before treatment. Patients having regression of fibrosis after treatment had much lower ALT and AST activities and total bilirubin content before treatment than those having aggravation of fibrosis after treatment.

5.3 Neurological Diseases

5.3.1 Ischemic Stroke and Cerebral Ischemia/Reperfusion

In animal models of cerebral ischemia/reperfusion injury, Sal-B reduces infarct size and enhances neurological recovery via anti-inflammatory, anti-oxidative stress, and angiogenic pathways. Neurological diseases such as stroke and Alzheimer's disease pose increasing challenges to global public health. Salvianolic Acid B, a major active component of Salvia miltiorrhiza, has garnered attention due to its anti-inflammatory, antioxidant, neuroprotective, and pro-angiogenic properties in neurological disease treatment.

Sal-B protects the blood-brain barrier and inhibits neuronal apoptosis in stroke models. Sal-B has been demonstrated to reduce the activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two important enzymes that impair blood–brain barrier integrity.

The pharmacological properties of salvianolic acids in stroke include reducing neuroinflammation, alleviating oxidative stress injury, inhibiting cellular apoptosis, preserving endothelial function, maintaining blood–brain barrier integrity, and promoting angiogenesis.

Important limitation: Sal-B exhibits promising prospects in the treatment of neurological diseases. However, its clinical application faces challenges such as chemical stability and bioavailability. Further research on the mechanisms of Sal-B and innovative drug delivery strategies is needed to advance its application in neurological disease therapy. The available neurological evidence is predominantly preclinical (animal and cell models); large-scale randomized human trials are lacking.

5.3.2 Alzheimer's Disease

In Alzheimer's disease models, Sal-B suppresses amyloid-beta formation and neuroinflammation. These effects are mediated through the regulation of signaling pathways, including NF-κB, AMPK, PI3K/Akt, and Nrf2, highlighting Sal-B's broad therapeutic potential in neurological diseases. These findings remain confined to in vitro and animal models; no robust human clinical trials for Alzheimer's disease have been completed and published for isolated salvianolic acids.

5.3.3 Depression and Pain

In rats undergoing chronic mild stress, salvianolic acid B can reverse the hyperactivity of the hypothalamic–pituitary–adrenal axis and decrease the levels of inflammatory cytokines while improving the antioxidant status. Moreover, salvianolic acid B downregulates the protein expression of NLRP3 and its associated proteins ASC and cleaved caspase-1 and increases body weight and sucrose consumption rate while decreasing immobility time, exerting anti-depressant effects. These are animal studies, and human evidence is absent.

5.4 Fibrosis in Other Organs

Numerous studies have clarified Sal-B's potential therapeutic effectiveness in a wide range of pathological conditions, including but not limited to myocardial infarction, membranous nephropathy, ischemic brain injury, retinal defects, intervertebral disc degeneration, diabetes mellitus, sepsis, and various other ailments.

Fibrosis is a public health issue of great concern characterized by the excessive deposition of extracellular matrix, leading to the destruction of parenchymal tissue and organ dysfunction. Salvianolic acid B has positively affected various human diseases, including fibrosis. Evidence across non-hepatic fibrotic conditions (e.g., pulmonary, cardiac, renal fibrosis) currently derives predominantly from in vitro and animal studies.

5.5 Cancer

Numerous in vitro and in vivo studies have demonstrated that Sal-B exhibits promising anticancer effects against various types of cancers because of its ability to inhibit cancer cell proliferation, induce cell cycle arrest, and promote apoptosis in cancer cells.

These compounds target breast cancer cells by altering mechanisms such as: induction of apoptosis, autophagy, and cell cycle arrest, anti-metastasis, formation of cancer stem cells, and potentiation of antitumor immunity.

The levels of proteins that inhibit apoptosis have been shown to be decreased by salvianolic acid A (SAA), such as anti-apoptotic Bcl-2, while pro-apoptotic proteins such as Bak and Bax are simultaneously activated.

Some studies have predicted that Sal-A and Sal-B have a good therapeutic effect on breast cancer. MCF-7/PTX cells have strong migration and invasion abilities and are highly resistant to the anticancer drug paclitaxel. Sal-A reversed the resistance of these cells to paclitaxel. Transgelin 2 inhibited the apoptosis of MCF-7/PTX cells by activating PI3K/Akt signaling pathway and mediating the drug resistance of paclitaxel in breast cancer patients. All current anticancer evidence for salvianolic acids is preclinical (cell lines and animal models); no randomized controlled human clinical trials have established efficacy in oncology indications.

5.6 Diabetes and Metabolic Conditions

Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway. Professor Du Guanhua, at the Institute of Materia Medica, Chinese Academy of Medical Sciences, first discovered that salvianolic acid A can alleviate diabetic complications and improve patients' quality of life. A Phase I single-dose escalation clinical trial of salvianolic acid A tablets for diabetic complications was initiated at Peking University First Hospital (ClinicalTrials.gov), representing early-stage human evaluation; results are not yet broadly published.

6. Body Systems and Health Areas Associated

Salvianolic acid B has demonstrated effects on various organs and tissues such as the lung, heart, kidney, intestine, bone, liver, and skin, and protective effects in diseases such as depression and spinal cord injury.

Salvianolic acid B has been used in the treatment of liver diseases, kidney diseases, brain and neurological diseases, heart diseases, skin diseases, vascular diseases, bone diseases, lung diseases, tumors, diabetes, and diabetes-related complications.

Salvianolic acids, the compounds found in danshen, have well-established bioactivities. Both in vitro and in vivo, most of the salvianolic acids showed anti-inflammatory, antioxidative, and free radical scavenging activities, and could protect cells from a variety of harmful factors.

7. Dosage Forms and Reported Dosages

7.1 Available Formulations

With the development of science and technology, dosage forms containing Danshen have been gradually diversified. Tablet, injection solution, dripping pill, oral liquid, capsule, slow-release formulation, and soft gel are all dosage forms that have been prepared into medicines.

Since the compound danshen dripping pill (CDDP) was launched in China in 1994, it has been widely used in the prevention and treatment of cardiovascular diseases (the recommended dose is 10 pills/time, 3 times/day, 27 mg/pill), such as coronary heart disease, angina pectoris, and hyperlipidemia.

7.2 Dosages Reported in Clinical Studies

In the Phase 1 clinical trial of salvianolic acid B injection in healthy Chinese volunteers, this phase 1, randomized, double-blind, placebo-controlled, single-center study aimed to evaluate the safety, tolerance, and pharmacokinetics of Sal-B injection. For the single-ascending-dose study, forty-seven healthy volunteers were randomly divided into 25, 75, 150, 200, 250, and 300 mg groups. For the multiple-ascending-dose study, sixteen healthy volunteers were randomly divided into 150 and 300 mg groups.

In the clinical study for liver fibrosis in chronic hepatitis B, SA-B was administered to sixty patients with definite diagnosis of liver fibrosis. The patients took SA-B orally in a double-blind randomized test for a complete course of 6 months. The precise oral tablet dose used in this study was not reported in the available abstract.

In the atherosclerosis animal model referenced above, the LDLR^-/- mice were randomly divided into four groups after 12 weeks of high-fat diet. The mice were administered with 0.9% saline or Sal-B (25 mg/kg) or Atorvastatin (1.3 mg/kg) for 12 weeks. This was an animal study.

7.3 Bioavailability Considerations

Salvianolic acid B was found to be poorly absorbed in animal studies. LC–MS/MS showed that after salvianolic acid B was given in conscious and freely moving rats, the AUCs were 5030 ± 565 and 582 ± 222 min·μg/mL for intravenous (100 mg/kg) and oral (500 mg/kg) doses, respectively, and the oral bioavailability of salvianolic acid B in rats was 2.3%. The bioavailability of salvianolic acids B in dogs was only 1.07 ± 0.43%.

The limited absorption in the gastrointestinal tract has a detrimental effect on the clinical application of S. miltiorrhiza; injections can increase the concentration of effective substances in vivo and increase bioavailability.

As a natural ingredient, salvianolic acid B is safe and less toxic and has strong activity; however, its poor stability limits its use to some extent.

To address these limitations, several strategies can be employed. Modifications to dosage forms such as nanoparticles, injectable hydrogels, and core-shell nanofibers enhance Sal-B's stability and delivery efficiency. Additionally, structural modifications to Sal-B itself represent an effective means to optimize its pharmacokinetic properties and improve bioavailability.

8. Safety, Adverse Effects, and Drug Interactions

8.1 Phase 1 Human Safety Data

A Phase 1 randomized, double-blind, placebo-controlled, single-center study aimed to evaluate the safety, tolerance, and pharmacokinetics of Sal-B injection in healthy Chinese volunteers. For the single-ascending-dose study, forty-seven healthy volunteers were randomly divided into 25, 75, 150, 200, 250, and 300 mg groups. For the multiple-ascending-dose study, sixteen healthy volunteers were randomly divided into 150 and 300 mg groups. Their safety was evaluated by skin test, physical examination, vital sign, laboratory examination, 12-lead electrocardiogram, Holter, and clinical symptoms and signs.

With the development and widespread use of TCM injections, adverse drug reactions (ADRs) have gradually become a public concern. The extraction process from the TCMs and the purity of the injections have been considered as the most important factors for severe ADRs.

8.2 CYP450 Enzyme Interactions

Results hint at possible interactions with warfarin, diazepam, and the CYP isoenzymes, according to the EMA's assessment report on Salvia miltiorrhiza.

These findings indicate that salvianolate (which contains a substantial amount of Sal-B) may be involved in potential drug interactions when co-administered with CYP3A4 substrates. The listed drug Salvianolate, which contains a substantial amount of Sal-B, has been used for the treatment of coronary heart disease. Its inhibitory effect on seven cytochrome P450 isoforms—CYP1A2, CYP2A6, CYP2E1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4—was evaluated in human liver microsomes (HLMs) and recombinant enzymes.

The two components of Danshen, SA-B and Tan IIA, have different influences on the metabolism of losartan: SA-B can obviously speed up the metabolism of losartan by inducing CYP3A4/CYP2C9 activities and expression, whereas Tan IIA can slow down the metabolism of losartan by inhibiting CYP3A4/CYP2C9.

8.3 Interactions with Anticoagulants and Antiplatelet Agents

The C_max of DSS (danshensu) increased from 0.05 mg/mL to 0.11 mg/mL, while the area under the curve (AUC) value increased from 5.20 mg/mL·min to 18.47 mg/mL·min when combined with warfarin. This pharmacokinetic interaction is of potential clinical relevance, particularly in patients taking anticoagulants.

Danshen tablet potently inhibited the metabolism of rivaroxaban in rat and human liver microsomes. Danshen tablet is a mixed inhibitor in rivaroxaban metabolism in rat and human liver microsomes, with the K_i value at 0.72 and 0.25 mg/ml, respectively. There is a potential interaction between Danshen tablet and rivaroxaban. Danshen tablet inhibits the metabolism of rivaroxaban, which may be because its lipid-soluble components such as dihydrotanshinone I strongly inhibit the activities of CYP enzymes. Therefore, when Danshen tablet and rivaroxaban are used simultaneously in the clinic, it is necessary to strengthen drug monitoring of rivaroxaban and adjust the dosage.

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 of Danshen combined with clopidogrel.

8.4 CYP4A and CYP4F Considerations

Salvianolic acid C had noncompetitive inhibition on CYP4F2 and CYP4F3B. In human kidney, human liver, or rat heart microsomes, 20-HETE formation was significantly inhibited by dihydrotanshinone I and salvianolic acid A. Given that low plasma concentrations of Danshen components after oral administration mean that Danshen preparations may not play pharmacological roles by inhibiting AA ω-hydroxylases; however, as Danshen components may reach high concentration in human intestine, drugs that have an important pre-systemic metabolism by these CYP4A/4F enzymes should avoid being co-administered with Danshen preparations.

8.5 Chemical Stability Concerns

Sal-B exhibits promising prospects in the treatment of neurological diseases. However, its clinical application faces challenges such as chemical stability and bioavailability. Further research on the mechanisms of Sal-B and innovative drug delivery strategies is needed to advance its application in neurological disease therapy.

9. Evidence Strength Summary

The following summarizes the overall strength and nature of existing evidence for salvianolic acids by domain:

Cardiovascular (preclinical): Substantial in vitro and animal model data supporting anti-atherosclerotic, cardioprotective, and anti-ischemic actions. Animal meta-analyses show significant effects on VEGF, blood vessel density, and infarct size. The mechanism is well characterized at preclinical level.
Cardiovascular (clinical): Limited. A small randomized crossover study found no significant effect of the whole root extract on lipid and blood pressure parameters in 20 participants. Salvianolic acid injection formulations are clinically approved in China but are evaluated mainly within the context of complex TCM preparations; high-quality, placebo-controlled trials isolating salvianolic acids are sparse.
Hepatic fibrosis (clinical): One published small randomized trial (n=60) comparing oral SA-B to IFN-γ injection over 6 months showed fibrosis reversal rates of 36.67% vs. 30.0% respectively; evidence is preliminary and requires replication in larger multicenter trials.
Neurological (preclinical): Robust animal and cell data supporting neuroprotection in ischemic stroke, Alzheimer's, and Parkinson's models. No large randomized human trials.
Cancer (preclinical): In vitro evidence of antiproliferative, pro-apoptotic, and chemosensitizing effects. No human randomized controlled trials.
Fibrosis in other organs (preclinical): Animal model evidence across pulmonary, cardiac, and renal fibrosis. No completed clinical trials.
Diabetes and metabolic disease (preclinical + early clinical): Phase 1 clinical trials of salvianolic acid A for diabetic complications were initiated in China; outcomes of efficacy trials have not yet been widely published.

References

Health Conditions

Health conditions that Salvianolic acid may help support.

AnginaScientific
Salvianolic acid is the major hydrophilic phenolic constituent of Danshen (Salvia miltiorrhiza) with potent antioxidant and antiplatelet properties. Meta-analysis evidence shows Danshen depside salts (primarily salvianolic acids) are superior to conventional treatment alone in improving angina symptoms. Salvianolic acids A and magnesium tanshinoate B specifically inhibit LDL oxidation, a key mechanism in coronary artery disease pathogenesis.
Arterial HealthScientific
Salvianolic acids (A and B) from Danshen (Salvia miltiorrhiza) protect against arterial endothelial dysfunction by increasing NO production, inhibiting inflammatory macrophage responses, reducing LDL oxidation, and attenuating atherosclerotic plaque formation in diabetic models. Salvianolic acid B showed vasoprotective effects via HO-1 modulation and arginase inhibition in peer-reviewed research.
Blood Clot PreventionScientific
Salvianolic acids (A and B) are water-soluble active components of Danshen (Salvia miltiorrhiza) with documented antiplatelet activity. Salvianolic acid A inhibits platelet aggregation via ERp57 protein disulfide isomerase inhibition. Multiple studies confirm salvianolic acids as key antithrombotic constituents of danshen.
Blood PressureScientific
Salvianolic acids (A and B) from danshen (Salvia miltiorrhiza) have documented ACE-inhibitory and endothelium-protective antihypertensive properties. They protect NO from oxidative degradation, inhibit ACE, and reduce vascular inflammation. Both in vitro and animal evidence supports these effects, with clinical evidence from danshen preparations.
Kidney HealthScientific
Salvianolic acids (A and B) are the primary water-soluble bioactive components of danshen (Salvia miltiorrhiza) with documented nephroprotective effects including reduction of renal fibrosis, anti-inflammatory activity, and antioxidant protection in the kidney. They are identified in authoritative reviews as key active components of one of the five TCM herbs with the strongest clinical evidence for CKD.

Body Systems

Body systems that Salvianolic acid may help support.

No body systems available.