Astragaloside IV: A Comprehensive Reference Article
1. Identity: Chemical Name, Botanical Source, and Physical Characteristics
Chemical Identity
Astragaloside IV (AS-IV) is one of the major compounds from the aqueous extract of Astragalus membranaceus and belongs to the cycloartane-type triterpene glycoside chemical class. More precisely, AS-IV is a tetracyclic triterpenoid saponin in the form of lanolin ester alcohol and exhibits various biological activities. Its full systematic chemical name is 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol, with the molecular formula C41H68O14.
AS-IV appears as a white crystalline powder (CAS: 83207-58-3; UNII: 3A592W8XKE). Its molecular weight is 784.97 Da. Its LogP value of 1.298 ± 0.00 (at 25°C) indicates moderate lipophilicity and hydrophilicity, providing a potential advantage for membrane permeability and drug delivery. AS-IV has a melting point range of 284°C–286°C and a high boiling point of 895.666°C ± 65.00°C, indicating excellent thermal stability and low volatility.
Botanical Source
AS-IV is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. Astragalus belongs to a group of medicinal plants in the Leguminosae family. The genus Astragalus includes over 2,000 species; however, Astragalus membranaceus (Fisch.) Bge. and Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao are the most commonly used medicinally.
Astragalus grows on mountainsides and in grasslands in Northeastern China, Siberia, and Central Mongolia. Four-to-five-year-old plants are harvested in spring and autumn; the rootlets and root head are removed, and the roots are laid out to dry in the sun. AS-IV is used as a quality control marker of Huangqi in the Chinese Pharmacopoeia (2015 version).
Key Related Compound: Cycloastragenol
Cycloastragenol (CAG) is another bioactive molecule derived from various species of the Astragalus genus. It is an aglycone derivative of AS-IV and a triterpenoid saponin compound formed through the hydrolysis of AS-IV. The active form of astragaloside IV is cycloastragenol, which is capable of activating telomerase, lengthening telomeres, and exhibiting immunomodulatory, antiviral, anti-fat accumulation, anti-ischemia and hypoxia, antioxidant, anti-apoptotic, neuroprotective, cardioprotective, hepatoprotective, and anticancer properties.
Common Forms and Preparations
Three main chemical compound classes are contained in Astragali Radix (Huangqi), including polysaccharides (heteropolysaccharide and dextran), saponins, and flavonoids. With the development of extraction and separation technologies, more than 40 constituents of astragalus saponins have been identified from dried astragalus roots using HPLC and GC-MS.
AS-IV is available in several supplemental forms for research and consumer use:
- Standardized root extracts: Dried root of A. membranaceus, standardized to a defined percentage of astragaloside IV, provided in capsule or tablet form.
- Isolated/purified AS-IV: White crystalline powder of high purity (≥98%), used principally in laboratory and preclinical research.
- Cycloastragenol (CAG) / TA-65: TA-65 is a patented, natural, encapsulated form of cycloastragenol that has gained attention as a dietary supplement for promoting healthy aging. Cycloastragenol is a compound derived from astragaloside IV that has been shown to promote telomerase activation in vitro; TA-65 is marketed as a nutraceutical whose function is to activate telomerase.
- Nanoparticle/nanocarrier formulations: The use of nanocarriers, such as nanoparticles, can significantly enhance the solubility of AS-IV and increase its absorption in the body.
- Intravenous preparations: Injectable formulations have been used in Chinese clinical settings, typically as infusion preparations.
2. Traditional and Historical Use
Origin in Traditional Chinese Medicine
Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2,000 years. Astragalus root was mentioned in the foundational Chinese text on herbal medicine, Shen-nong Ben-cao Jing, a body of work attributed to the creator of Chinese civilization and agriculture (Shennong).
TCM Classification and Therapeutic Roles
The root is traditionally classified as a superior herb because of its tonifying activity — meaning it is used to increase energy in certain parts of the body. In the language of TCM, it was seen to tonify both active energies (qi) and those that build resilience (xue or Blood), as well as supporting the Chinese concept of the Spleen — the function controlling assimilation in the body — thus being used where fatigue is linked to decreased appetite.
The root has been used for many hundreds of years in TCM as a tonic in fatigue, especially with decreased appetite, spontaneous sweating, and diarrhoea. It has also been used to reduce blood loss and improve kidney function, as well as to recover from postpartum fever, organ prolapse, uterine bleeding, and other severe loss of blood.
In ancient China, Astragalus membranaceus was termed "Sacred medicine with the effects of tonifying Qi and consolidating exterior." It has been used as a herbal medicine for more than two thousand years, with traditional effects described as tonifying Qi and consolidating exterior, inducing diuresis to alleviate edema, expelling toxins and draining pus, promoting granulation, improving body immunologic function, protecting the liver, increasing secretion of urine, anti-aging, anti-stress, lowering blood pressure, and relatively broad-spectrum antibiosis.
Traditional Preparations
Decoctions prepared from the roots of Astragali Radix are known as "Huangqi" and are widely used in traditional Chinese medicine for treatment of viral and bacterial infections, inflammation, as well as cancer. In TCM, it is most common for the root to be taken in combination with other botanicals in complex multi-herb formulas. The root of A. membranaceus has a long history of use in traditional Chinese medicine and is often used along with other herbs as a tonic to increase stamina, strength, and vitality.
Introduction to the West
In 1925, Astragalus membranaceus was introduced to North America through the USDA's Plant Introduction Office via the Botanical Garden in St. Petersburg. It was not used in Western botanic practice until the tremendous East/West herbal blending that began during the 1960s, and is now one of the primary immune tonic herbs in the Western pharmacopoeia, widely available throughout the United States.
3. Key Constituents and Active Compounds
Chemical Constituents of Astragali Radix
The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. At present, more than 200 compounds have been isolated and identified from Astragalus membranaceus. Beneficial effects of astragalus are attributed to its polysaccharides and triterpenoid saponin compounds.
Astragaloside IV is the principal saponin of pharmacological interest. The molecular structure of AS-IV contains multiple hydroxyl and glycosyl groups, which enable it to interact with various biomolecules through hydrogen bonding and hydrophobic interactions, thereby imparting notable antioxidant, anti-inflammatory, and immunomodulatory properties.
Other Notable Astragalosides
More than 40 constituents of astragalus saponins have been identified from the dried astragalus roots, including astragalosides I, II, III, and IV, with AS-IV being the most extensively studied. Another active ingredient of Astragalus radix is astragalus polysaccharide (APS), a heteropolysaccharide with a complex chemical structure and water solubility.
4. Mechanisms of Action
Anti-Inflammatory Effects
AS-IV modulates the inflammatory response by suppressing inflammatory factors, increasing T and B lymphocyte proliferation, and inhibiting neutrophil adhesion-associated molecules. In vitro experiments have shown that AS-IV modulates the inflammatory response by regulating the balance of Th17/Treg cells, and studies have revealed an increase in IL-10 and a significant decrease in IL-6, IL-17, IgE, and TGF-β1 levels.
All glycosides and decoctions of AS-IV exert significant effects on the JAK/STAT signaling pathway, evidenced by decreased expression levels of JAK2, STAT1, STAT3, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) as well as reduced concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the aortic wall.
Antioxidant Effects
AS-IV can eliminate reactive oxygen species (ROS), increase superoxide dismutase (SOD) activity, and help cells resist oxidative damage, as well as regulate mitochondrial energy metabolism and ion homeostasis. Astragaloside IV improves oxidative stress-mediated endothelial dysfunction mainly by reducing the ROS that induce oxidative stress and enhancing endothelial nitric oxide synthase (eNOS) activity. The mechanism of action of AS-IV includes its capacity to enhance levels of eNOS and nitric oxide in animal models exhibiting glucose-induced endothelial dysfunction.
Cardiovascular Mechanisms
AS-IV can protect the myocardium through antioxidative stress, anti-inflammatory effects, regulation of calcium homeostasis, improvement of myocardial energy metabolism, anti-apoptosis, anti-cardiomyocyte hypertrophy, anti-myocardial fibrosis, regulation of myocardial autophagy, and improvement of myocardial microcirculation. It can protect vascular endothelial cells through antioxidative stress and anti-inflammatory pathways, relax blood vessels, stabilize atherosclerotic plaques, and inhibit the proliferation and migration of vascular smooth muscle cells.
AS-IV also plays a protective role against ischemia-hypoxic damage by regulating multiple pathways such as the MAPK, PI3K/AKT, Notch1, and NF-κB pathways. It can act on ion channels or reduce the inflammatory response to inhibit myocardial hypertrophy, and also inhibits FAS/FASL and TGF-β/Smads pathway activation and reduces the level of collagen and collagen volume fraction to counter myocardial fibrosis.
Antifibrotic Mechanisms
AS-IV can effectively alleviate fibrosis-induced dysfunction of major tissues or organs, including the heart, lungs, kidneys, and liver, by regulating the signal transduction of reactive oxygen species/caspase-1/gasdermin D, transforming growth factor-β/Smads, Wnt/β-catenin, and sirtuin 1–nuclear factor-κB pathways.
Telomerase Activation
Modern research has focused on two of its active compounds: astragaloside IV and cycloastragenol (CAG). Both are classified as triterpenoid saponins and both have been identified as potent activators of telomerase. Telomerase is composed of a protein called telomerase reverse transcriptase (TERT) and several telomere-associated proteins. Telomeres are repetitive DNA sequences at the end of chromosomes; these end regions shorten during cell division, and their presence protects from the degradation of coding chromosomal DNA. By extending these regions, telomerase protects against telomere shortening, a common feature of aging.
Autophagic Regulation
AS-IV not only promotes but also inhibits autophagic activity through a variety of signaling pathways to improve various diseases. The autophagic effects are associated with multiple signaling pathways in experimental models, including the PI3KI/Akt/mTOR, PI3K III/Beclin-1/Bcl-2, PI3K/Akt, AMPK/mTOR, PI3K/Akt/mTOR, SIRT1–NF-κB, PI3K/AKT/AS160, and TGF-β/Smad signaling pathways.
Multi-Pathway Summary
These pharmacological effects are associated with multiple signaling pathways, including the Raf-MEK-ERK pathway, EGFR-Nrf2 signaling pathway, Akt/PDE3B signaling pathway, AMPK signaling pathway, NF-κB signaling pathway, Nrf2 antioxidant signaling pathways, PI3K/Akt/mTOR signaling pathway, PKC-α-ERK1/2-NF-κB pathway, IL-11/STAT3 signaling pathway, Akt/GSK-3β/β-catenin pathway, JNK/c-Jun/AP-1 signaling pathway, PI3K/Akt/NF-κB pathway, miRNA-34a/LDHA pathway, Nox4/Smad2 pathway, JNK pathway, and NF-kB/PPARγ pathway.
5. Pharmacokinetics
Absorption and Oral Bioavailability
The absolute bioavailability of AS-IV after oral administration was only 2.2% in a rat intestinal perfusion model. This low bioavailability may be attributable to its high molecular weight and poor solubility in water and lipids. The absolute bioavailability of AS-IV in beagle dogs was reported to be approximately 7.4%. The binding rate of AS-IV to plasma proteins was approximately 90% in the concentration range of 250–1,000 ng/mL.
AS-IV exhibits a solubility of 30 mg/mL in DMSO, which decreases significantly to 0.5 mg/mL in PBS buffer, and this low solubility limits its bioavailability, thereby affecting clinical efficacy.
Distribution and Metabolism
The pharmacokinetics characterization revealed that AS-IV was detected in 12 tissues, including the liver and kidney. Glycosyl hydrolysis can occur through the transformation of intestinal flora, and AS-IV is hardly metabolized in the liver.
Human Pharmacokinetics
In humans administered astragaloside IV intravenously at doses of 200, 300, 400, and 500 mL, the corresponding mean AUC values were 4.38, 9.75, 13.59, and 18.22 μg·h·mL−1, respectively, with mean elimination half-lives of 2.14, 2.59, 2.62, and 2.69 hours, respectively. Cumulative urinary excretion of AS-IV was 3.91% within 24 hours after administration of 500 mL. AS-IV did not accumulate in human plasma after seven consecutive days of intravenous astragaloside injection and was safe and well tolerated after single doses of 200–600 mL and multiple doses of 500 mL over 7 days.
Strategies to Overcome Low Bioavailability
Several strategies have been proposed to improve the solubility and bioavailability of AS-IV, including the use of nanocarriers such as nanoparticles, which can significantly enhance solubility and increase absorption in the body. Currently, one AS-IV derivative, astragalosidic acid, has been synthesized; it has better water solubility, twice the oral bioavailability of AS-IV, better clinical efficacy, and mainly exerts cardioprotective effects.
6. Scientific Evidence by Area of Use
6.1 Cardiovascular Disease
AS-IV has been reported to be effective in treating various diseases such as cerebral ischemia/reperfusion lesions, cardiovascular diseases, lung disease, liver cirrhosis, and diabetic nephropathy.
Astragalus has been studied in clinical trials of patients with cardiopulmonary bypass, ischemic heart disease, angina pectoris, and chronic heart failure, with positive results. However, astragalus was not found to improve clinical outcomes in viral myocarditis, and the quality of studies included in a Cochrane review was reported to be poor.
One clinical study showed significant improvements in left ventricular diastolic function after 12 months, and concluded that astragalus was effective when combined with conventional treatment at a dose of 10 g/day in the treatment of left ventricular diastolic dysfunction, acting as a cardioprotective agent.
Preclinical and early clinical data suggest notable anti-inflammatory and anti-atherosclerotic effects, with AS-IV demonstrating effects on blood lipid profiles, inflammatory pathways, and adhesion molecules, indicating an anti-inflammatory and anti-atherosclerotic role and underscoring its pivotal role in cardiovascular health regulation.
Evidence strength: The majority of cardiovascular evidence for AS-IV specifically derives from in vitro and animal model studies. Human clinical trials have tested broader astragalus preparations or extracts rather than isolated AS-IV. Evidence is preliminary and mechanistically well-characterized at the preclinical level, but robust randomized controlled trials in humans specifically for AS-IV remain limited.
6.2 Telomere Biology and Anti-Aging
Two human cell line studies demonstrated that cycloastragenol (CAG), a saponin compound synthesized from astragaloside IV, reduces telomere shortening and promotes telomerase activity.
A randomized, double-blind, placebo-controlled clinical trial published in 2024 tested the ASTCOQ02 supplement complex in 40 healthy middle-aged volunteers over 6 months. The telomerase activator complex tested was ASTCOQ02, a blend of Astragalus extracts (including astragaloside IV and cycloastragenol), olive fruit extract (including hydroxytyrosol), zinc oxide, and grape seed extract. The dosage form was an oral capsule taken twice a day for 6 months. The daily dose delivered by the two capsules included astragalus extract: 250 mg; astragaloside IV: 40 mg; cycloastragenol: 25 mg; zinc oxide: 14.46 mg; grape seed extract: 160 mg; olive fruit extract: 140 mg; and hydroxytyrosol and its derivatives: 28 mg.
A one-year TA-65 clinical study demonstrated that treatment significantly enhanced telomerase activity in immune cells, resulting in a marked reduction in systemic inflammatory markers such as IL-6 and TNF-α. Additionally, it improved lymphocyte proliferation and decreased signs of immune senescence.
In one crossover trial examining TA-65, HDL cholesterol was higher while body mass index, waist circumference, and the LDL/HDL ratio were lower during TA-65 treatment compared to placebo. Plasma tumor necrosis factor-α (TNF-α) was also lower during the TA-65 period.
Evidence strength: Evidence for telomere lengthening from astragalus-derived compounds has been rated as not statistically significant in some independent analyses, sample sizes in trials are small, and long-term human data are limited. The field remains active but inconclusive for definitive anti-aging claims.
6.3 Renal Protection and Diabetic Nephropathy
There is increasing evidence that AS-IV is protective against focal cerebral ischemia/reperfusion injury, central nervous system disease, cardiovascular disease, diabetic nephropathy, pulmonary fibrosis, and hepatic fibrosis, and that it regulates bone metabolism and exerts antiviral effects.
In a db/db mouse model of type 2 diabetic nephropathy, administration of AS-IV reduced albuminuria, ameliorated changes in glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity.
AS-IV can attenuate diabetic nephropathy progression through coordinated modulation of renal AMPK/PI3K/AKT signaling, intestinal microenvironment restoration, glucose–lipid metabolism regulation, and mitochondrial protection.
Kidney diseases for which AS-IV has been tested include chronic glomerulonephritis (CGN) and glomerular diseases. As an immune-mediated disease, CGN is the most common glomerular disease. AS-IV protects against CGN through autophagy activation via the PI3K/AKT/AS160 pathway, demonstrated by improved kidney function and ameliorated kidney lesions.
Evidence strength: Preclinical evidence from rodent models of diabetic nephropathy is extensive and mechanistically detailed. Human clinical data specifically for AS-IV in renal disease are currently lacking; AS-IV is a potential therapeutic agent for diabetes and its complications, but preclinical toxicity studies indicate the safe human dose limit is yet to be determined, and formal assessments of adverse drug reactions among humans need further investigation.
6.4 Liver Protection (Hepatoprotection)
AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant, and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis, and liver cancer.
In the field of liver protection, AS-IV shows therapeutic potential through various mechanisms such as inhibition of inflammatory responses, reduction of oxidative stress, amelioration of insulin and leptin resistance, modulation of gut microbiota, suppression of HCC cell proliferation, and induction of tumour cell apoptosis.
Evidence strength: Predominantly preclinical (cell line and animal model) evidence. Well-characterized mechanisms. Human clinical data specifically for isolated AS-IV in liver disease are limited.
6.5 Pulmonary and Respiratory Protection
AS-IV exhibits pleiotropic pharmacological activities, including anti-inflammatory, immunomodulatory, antioxidant, and antifibrotic properties as well as cardioprotective, antimicrobial, and antiviral effects.
AS-IV inhibited fibroblast collagen production and myofibroblast transformation via the TGF-β1/Smads signaling pathway. AS-IV at 10 mg/kg/day (i.p.) reduced blood levels of type III collagen, laminin, and hyaluronic acid and hydroxyproline in lung tissues of bleomycin-induced pulmonary fibrosis rats.
AS-IV has been reported to exert protective effects in various diseases, including non-small cell lung cancer (NSCLC), lung toxicity caused by fine particulate matter (PM2.5), and acute respiratory distress syndrome (ARDS).
Evidence strength: The existing research remains fragmented and consists mainly of isolated experimental investigations without a systematic, evidence-based evaluation from human trials. A 2025 systematic review and meta-analysis of preclinical pulmonary fibrosis studies is underway but human trials are not yet available.
6.6 Neuroprotection
The neuroprotective mechanism is probably related to the inhibition of NF-κB and JAK1/STAT1 signaling pathway activation upon cerebral ischemia and the regulation of endoplasmic reticulum stress. These findings signify that AS-IV has potential therapeutic value for neuroprotection.
AS-IV counters the radiation-induced senescence of brain cells by regulating the p53-p21 and p16-RB senescence-regulated signaling pathways and JNK-p38 phosphorylation. Furthermore, the combination of AS-IV and ginsenoside Rg1 augments the protective effects against cerebral ischemic injury via antiapoptotic and anti-inflammatory effects.
Evidence strength: Limited to in vitro and animal model data. No robust human clinical trials specifically isolating AS-IV for neuroprotective endpoints have been identified in the peer-reviewed literature.
6.7 Anti-Cancer (Antitumor) Effects
Astragalus membranaceus Bunge is widely used in TCM to treat various cancers. AS-IV is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion, and metastasis in various cancer types.
AS-IV has been assessed in different cancer types, including lung, colon, liver, gastric, and breast cancers, through in vitro cultured cancer cell lines and in vivo animal models with xenografted tumors. Accumulating evidence suggests that the antitumor effects of AS-IV are mainly conferred via mechanisms that increase apoptosis and autophagy, inhibit cell proliferation, invasion, and migration.
In non-small cell lung cancer (NSCLC) specifically, AS-IV inhibited the migration and proliferation of NSCLC cells and caused a noticeable increase in cell death. The expression of Bax (a marker of cell death) was increased, whereas the expression of Bcl-2 (an antiapoptotic protein) was reduced. AS-IV also promoted cleavage of caspase-3, another indication of apoptosis; the Akt/GSK-3β/β-catenin axis was suppressed in response to AS-IV.
A systematic review and meta-analysis explored the efficacy and safety of TCM containing astragalus when combined with chemotherapy in patients with gastric cancer, including analysis of electronic databases and both oral and injection forms of astragalus, with treatment duration varying from up to eight weeks.
Evidence strength: Anti-cancer evidence for AS-IV is primarily from in vitro cell line experiments and animal xenograft models. While mechanistically suggestive, this type of evidence does not establish clinical efficacy. No completed phase II or III randomized controlled trials specifically evaluating isolated AS-IV as a monotherapy in human cancer populations have been identified. Adjuvant use of broader astragalus preparations alongside chemotherapy has shown some signal in meta-analyses, but the quality of the underlying studies is variable.
6.8 Diabetes and Metabolic Effects
As a metabolic disorder, diabetes is marked by high levels of glucose, which can damage the kidneys, heart, eyes, gastric mucosa, and even cause coma and death. AS-IV can lower blood glucose levels and can alleviate diabetic complications in diabetic mice.
AS-IV is a potential drug for the treatment of diabetes and its complications, including diabetic vascular disease, cardiomyopathy, retinopathy, peripheral neuropathy, and nephropathy.
One of the chronic diabetes complications is diabetic peripheral neuropathy (DPN), whose prevention and treatment have become an active research topic. Several studies have shown that AS-IV protects against DPN through an autophagic mechanism.
Evidence strength: Primarily preclinical (animal model). Evidence is mechanistically rich but awaits translation to adequately powered human clinical trials.
6.9 Immune Modulation
Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects.
In traditional Chinese medicine, Astragali Radix was used in patients with chronic diseases and healthy persons who want to improve their body vital functions. Modern immunological research has corroborated some of these traditional claims. AS-IV provides therapeutic benefits in the early stages of acute kidney injury, regulates Th1/Th2 imbalance, reduces renal tubular damage, and plays a vital role in protecting the kidneys.
7. Dosage Forms and Doses Reported in Studies
The following dosages are reported as used in specific published studies and do not constitute recommendations:
- Oral capsule (human, RCT, telomere study): An oral capsule taken twice daily for 6 months. The daily dose delivered included astragalus extract: 250 mg; astragaloside IV: 40 mg; cycloastragenol: 25 mg; zinc oxide: 14.46 mg; grape seed extract: 160 mg; olive fruit extract: 140 mg; and hydroxytyrosol and its derivatives: 28 mg.
- Oral dose in animal models (diabetic nephropathy): AS-IV was administered to db/db mice by adding it to standard feed at a dose of 1 g/kg for 12 weeks.
- Intraperitoneal injection in animal models (pulmonary fibrosis): AS-IV at 10 mg/kg/day (i.p.) was used to reduce markers of lung fibrosis in bleomycin-induced pulmonary fibrosis rats.
- Intravenous (human pharmacokinetics study): A study determined the average maximum concentration of AS-IV in human plasma in healthy patients by administering astragaloside IV extract intravenously in doses of 200, 300, 400, and 500 mL.
- Cardiovascular (human, adjuvant therapy): Astragalus was effective when combined with conventional treatment at a dose of 10 g/day in the treatment of left ventricular diastolic dysfunction.
- TA-65 (cycloastragenol, human): TA-65MD® is available at a dose of 100U or 250U. The most commonly tested doses in clinical studies that show evidence of effects on biomarkers are 250U once or twice per day.
Preclinical toxicity studies indicate that AS-IV appears to be safe, but the safe human dose limit is yet to be determined, and formal assessments of adverse drug reactions among humans need to be further investigated. Additionally, formulation or structural modifications are required to improve the pharmacokinetic parameters and facilitate the clinical use of AS-IV.
8. Safety Considerations and Drug Interactions
General Safety Profile
A study on rats and dogs injected with Astragalus extract (mainly composed of Astragalus polysaccharides and Astragalus saponins) for 3 months found no obvious side effects. In addition, no significant adverse effects such as hepatotoxicity and nephrotoxicity were observed in rats after oral administration of AS-IV at 10 mg/kg/day for 14 weeks.
No hepatotoxicity or nephrotoxicity was found in young and adult animals at safe doses equivalent to 35 times and 70 times the safe dose in humans (570 mg/kg), respectively.
AS-IV did not accumulate in human plasma after seven consecutive days of intravenous astragaloside injection and was safe and well tolerated after single doses of 200–600 mL and multiple doses of 500 mL over 7 days.
Reproductive and Maternal Toxicity
Maternal toxicity of astragaloside IV has been observed to be dose-dependent. In rats receiving doses ranging from 0.25 to 1.0 mg/kg, no maternal toxicity was observed. However, at the dose of 1.0 mg/kg/day, significant maternal toxicity was manifested, leading to delays in fur development, eye opening, and cliff parry reflex of the pups. Caution should therefore be exercised when pregnant women consider using astragaloside IV, as high doses may have adverse effects on maternal health and the development of offspring.
AS-IV exhibits maternal toxicity (intravenously 1.0 mg/kg) and foetal toxicity (≥0.5 mg/kg) in rats, but there are no teratogenic effects in rats or rabbits. Toxicology indicates that AS-IV is safe, but should be used cautiously in pregnant women.
High-Dose Rodent Findings
Adverse effects such as nephrotoxicity and hepatotoxicity were observed in rodents after the oral administration of a dose of 10 mg/kg per day over a period of 14 weeks. This finding stands in some tension with reports of safety at similar doses, reflecting that precise dose ranges and study conditions differ across publications.
Drug Interactions
The inhibitory effect of astragaloside IV on the activity of CYP3A4 has been demonstrated in previous studies, and it has been reported to induce interaction with other drugs or herbs when co-administered. For its metabolite cycloastragenol, cycloastragenol has been shown to inhibit P450 3A4 (CYP3A4) and induce the CYP2E1 subunit. It has also been shown to competitively inhibit UDP-glucuronosyltransferase (UGT) 1A8 and noncompetitively inhibit UGT2B7. Therefore, it may interact with drugs that are metabolized by these enzymes.
The adverse interaction between drugs and herbs is common in the clinic. Drug-drug interactions are a recognized consideration, and strong CYP3A4 inhibitors or inducers such as verapamil, phenytoin, and ketoconazole are examples of classes subject to interaction warnings in pharmacological practice. Given AS-IV's and cycloastragenol's CYP3A4 inhibitory activity, co-administration with CYP3A4-metabolized medications warrants attention.
Current Limitations and Research Gaps
The transition from preclinical findings to clinical applications remains a critical need. Future studies should focus on designing and conducting well-organized clinical trials to evaluate the safety, efficacy, and optimal dosing regimens of AS-IV in human populations suffering from chronic inflammatory diseases, neurodegenerative disorders, and various cancers.
The safe human dose limit is yet to be determined, and formal assessments of adverse drug reactions among humans need to be further investigated. Additional formulations or structural modifications are required to improve the pharmacokinetic parameters and facilitate the clinical use of AS-IV.
References
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