Golden Pen Award | Pharmacological Effects and Clinical Applications of Sodium Aescinate

Sodium aescinate (SA) is a kind of ester-bonded triterpenoid saponin sodium salt extracted from the mature seeds of the plant Heptacodium miconioides, which belongs to the family of Hippocastanaceae. It appears as a white or nearly white crystalline powder and is easily soluble in water. Sodium aescinate possesses anti-exudation, anti-inflammatory, blood-stasis dissolving, and detumescence properties, making it valuable in the treatment of soft tissue injuries, cardiovascular and cerebrovascular diseases, and other exudative diseases. Currently, various formulations of sodium aescinate have been developed, including liniments, freeze-dried powder injections, tablets, and compound sodium aescinate gels, each with different pharmacological effects.

Pharmacological Effects of Sodium Aescinate

1. Anti-edema and Anti-exudative Effects

Sodium aescinate exerts its anti-edema effects through the following mechanisms: ① By inhibiting the activity of lysosomes in serum, it blocks protease metabolism, reduces the permeability of capillaries, and consequentially decreases the permeability of the blood-brain barrier. This inhibits water exchange, counteracts exudation, and achieves a detumescence effect. ② It acts on the cellular receptors of venous vessel endothelium, causing venous contraction and increasing venous return. ③ Sodium aescinate inhibits the activity of proteases in the blood, protects the collagen fibers of venous wall glycoproteins, and effectively restores the elastic strength of veins. ④ By regulating the absorption and release of K+ and Na+ in cells, it improves cell permeability and allows normal exchange of fluids inside and outside the cells. Studies have shown that sodium aescinate promotes sodium excretion in rats, inhibits the increase in capillary permeability, enhances venous tension, and reduces lymphatic permeability, thus achieving anti-edema effects. ⑤ Sodium aescinate may also alleviate cerebral edema by affecting the expression of serum P-substance receptors. Research reports indicate that sodium aescinate exerts anti-edema effects by acting on the adrenal glands to produce normal amounts of corticosteroids. Other reports suggest that the mechanism of sodium aescinate's treatment of cerebral edema is related to its ability to reduce arginine vasopressin in the brain. Additionally, studies have found that sodium aescinate can hydrolyze proteins into fragments, which are easier to leave damaged tissues, achieving anti-edema and anti-exudative effects by reducing colloid osmotic pressure.

2.Analgesic and Neuroprotective Effects

Research has reported that sodium aescinate exhibits analgesic effects in rats suffering from formalin-induced inflammatory pain, neuropathic pain caused by spinal nerve ligation, and chemotherapy-induced peripheral neuropathic pain. The mechanism of action involves sodium aescinate regulating the expression of autophagy-related proteins, increasing the expression of LC3Ⅱ and reducing the expression of p62, thus alleviating chemotherapy-induced peripheral neuropathic pain. Sodium aescinate can also achieve analgesic effects by stabilizing cell membranes, blocking the release of inflammatory mediators, and increasing capillary resistance.

Moreover, sodium aescinate possesses neuroprotective effects. It can reduce cortical neuron apoptosis induced by trauma in mice, effectively remove oxygen free radicals in a timely manner, and restore neural function. β-Aescin also inhibits neurological damage, cerebral infarction, and apoptosis caused by cerebral ischemia-reperfusion injury, as well as the release of proinflammatory factors TNF-α and IL-1β in brain tissue. It affects the expression of apoptosis-related proteins Bcl-2 and Bax. Studies have found that sodium aescinate exerts neuroprotective effects through the Nrf2-ARE pathway, protects spinal cord ischemic injury by inhibiting the activity of angiotensin II and antioxidant reactions, and improves no-reflow after myocardial ischemia-reperfusion in rats by inhibiting the p38MAPK pathway, inhibiting cell apoptosis and inflammatory responses, and reducing the area of myocardial infarction.

3.Synergistic Anti-tumor Effects

Studies have found that sodium aescinate can induce apoptosis in SH-SY5Y neuroblastoma cells by acting on NADPH oxidase and generating excessive ROS to exert tumor inhibitory effects. In research examining the effect and mechanism of sodium aescinate on the apoptosis of cancer cells in cervical cancer model rats, it was discovered that sodium aescinate can reduce the tumor volume of cervical cancer rats, improve their thymus and spleen indices, activate the PI3K-AKT signaling pathway, increase the expression of apoptosis proteins such as Caspase-3, Caspase-7, and Caspase-9, and promote cancer cell apoptosis. Furthermore, sodium aescinate can increase the number of cells in the G1 phase and inhibit the progression from G1 to S phase, thus inhibiting cell proliferation. Some studies have shown that sodium aescinate has synergistic anti-tumor effects, significantly enhancing the pharmacological effects of certain anti-tumor drugs.

4.Anti-inflammatory, Antioxidant, and Anti-free Radical Effects

Sodium aescinate can promote the secretion of corticosteroid compounds from the adrenal cortex in the body, exerting an anti-inflammatory effect. In a study investigating the impact of sodium aescinate on ischemia-reperfusion injury in rat skeletal muscle, it was found that at 8 hours after reperfusion, the expression levels of inflammatory proteins such as iNOS, IL-1, IL-6, and TNF-α decreased, antioxidant protein levels increased, inflammatory cell infiltration was reduced, and tissue morphology improved. Furthermore, sodium aescinate, with its phenolic hydroxyl structure, can effectively resist oxygen free radicals. Research has reported that sodium aescinate injection has functions such as antioxidant damage and immune enhancement.

Additionally, sodium aescinate also exhibits anti-epileptic, blood lipid regulation, and hypoglycemic effects. When administered to young epileptic rats, sodium aescinate was observed to inhibit cell apoptosis in the hippocampus and improve cognitive function. The molecular mechanism may involve inhibiting the activation of p38MAPK in the hippocampus. Sodium aescinate can increase the excretion of triacylglycerol (TG) by inhibiting pancreatic lipase, thereby reducing TG levels. The acyl group of sodium aescinate can inhibit the absorption of ethanol and Na+-dependent active transport, exerting a hypoglycemic effect. However, sodium aescinate did not inhibit non-oral glucose activity, indicating that its hypoglycemic effect is achieved through the digestive tract.

Clinical Combination of Sodium Aescinate with Other Drugs

1. The Combined Use of Sodium Aescinate and Other Drugs in Treating Cerebral Hemorrhage

The therapeutic mechanism of sodium aescinate for cerebral hemorrhage is multifaceted. Firstly, it clears free radicals, increases venous tension, improves blood circulation, and reduces cerebral edema. Secondly, it upregulates anti-inflammatory factors, inhibits inflammatory reactions, reduces brain injury, and improves cerebral neurological function. When sodium aescinate is combined with urapidil, it can reduce the volume of cerebral edema and residual blood volume in patients with hypertensive cerebral hemorrhage, maintain stable blood pressure, effectively lower the levels of inflammatory proteins such as C-reactive protein (CRP), TNF-α, and IL-6, and reduce brain tissue damage. Studies have reported that the combined use of mannitol, glycerin fructose, and β-sodium aescinate in treating cerebral hemorrhage patients shows significantly better total effectiveness, intracranial pressure reduction, neurological function, and cerebral edema improvement compared to using them individually. Additionally, the total incidence of adverse reactions is also reduced. Therefore, when using mannitol alone, the combined use of sodium aescinate for treating cerebral edema has the advantages of fewer adverse reactions and lower total treatment costs in terms of clinical effectiveness and economic benefits.

2.The Combined Use of Sodium Aescinate with Other Drugs in Treating Edema

Sodium aescinate can reduce cerebral edema by inhibiting the expression of aquaporins, which controls water influx and efflux from cells. The combined use of sodium aescinate injection and glycerin fructose in treating cerebral edema caused by cerebral hemorrhage can significantly reduce hematoma volume. The combination of sodium aescinate and bone peptide injection can effectively improve limb swelling after calcaneal fracture surgery and promote fracture healing. Additionally, the combination of sodium aescinate and Danhong injection in treating limb swelling caused by tibiofibular fractures can accelerate the disappearance of swelling.

3.The Combined Use of Sodium Aescinate with Other Drugs in Treating Cerebral Infarction and Deep Vein Thrombosis of the Lower Extremities

The combined use of sodium aescinate and clopidogrel in treating acute ischemic stroke can significantly improve the patient's neurological function and increase cerebral blood supply. The combination of sodium aescinate and butylphthalide in treating acute cerebral infarction can reduce the body's inflammatory response, significantly improve the patient's cerebral neurological function, and the combined use of these drugs is relatively safe. The combination of sodium aescinate and heparin calcium for patients undergoing thrombolysis for deep vein thrombosis of the lower extremities can effectively reduce the level of inflammatory mediators after thrombolysis, improve the hypercoagulable state of the blood, and alleviate lower limb swelling.

4.Anti-Inflammatory, Analgesic, and Neuroprotective Effects of Sodium Aescinate Combined with Other Drugs

Research reports indicate that the combined use of sodium aescinate and iressa in assisting arthroscopic debridement for knee osteoarthritis, the combination of sodium aescinate and febuxostat in treating acute gouty arthritis, and the use of sodium aescinate and Bactroban in caring for chemical phlebitis can all accelerate postoperative recovery, enhance patient comfort, and provide a new nursing direction for clinical medication. The combination of sodium aescinate and diosmin tablets can significantly reduce postoperative edema and pain symptoms after mixed hemorrhoid stapler hemorrhoidectomy, improving clinical treatment effects. Injectable sodium aescinate can alleviate pain in patients with lumbar disc herniation, reduce the levels of pain-controlling factors such as serum substance P and calcitonin gene-related peptide. Injectable sodium aescinate can effectively relieve clinical symptoms in patients with lumbar disc herniation, improve lumbar function, reduce inflammatory reactions, promote neural function recovery, enhance clinical treatment effects, and has high safety.

Dosage contraindications and adverse reactions of Sodium Aescinate

Sodium aescinate has a very high binding rate with plasma proteins, which can reach over 90%. Therefore, sodium aescinate should not be used simultaneously with drugs that have a high binding rate with plasma proteins, as it would compete with other drugs for serum proteins, leading to excessively high blood drug concentrations and potential harm to the body. Sodium aescinate has certain nephrotoxicity, and its use with nephrotoxic drugs requires special caution. Drugs containing alkaline groups may produce precipitation when combined with sodium aescinate, so it is generally not recommended to use these two drugs together. Sodium aescinate can promote the secretion of adrenocorticotropic hormone, so its combination with hormone drugs such as prednisone requires careful consideration.

The most common local adverse reaction of sodium aescinate in clinical practice is venous inflammation of varying degrees, which is mainly manifested as local pain, redness, and swelling, with cord-like blood vessels. The onset time and severity of the reaction vary, and in the most severe cases, it may lead to necrosis of the extremities. The possible causes of venous inflammation include: ① different drug concentrations producing different side effects; ② the pH value of the solution; ③ sodium aescinate significantly increasing plasma osmolarity, which also affects the metabolism and function of vascular endothelial cells; ④ possible damage to the vascular endothelium by the puncture needle; ⑤ excessive infusion speed; ⑥ limited purity of sodium aescinate; ⑦ patient-specific factors, etc.

Sodium aescinate may also cause liver damage, kidney damage, and myogenic damage. Most liver damage occurs 7 to 12 days after starting medication, with main clinical manifestations including fatigue, jaundice, poor appetite, nausea, as well as enlarged liver, tenderness in the liver area, and elevated transaminase levels. The kidney damage caused by sodium aescinate is mainly manifested as acute kidney injury symptoms such as hematuria, oliguria, and renal dysfunction. When used concurrently with nephrotoxic drugs, the kidney damage effect is more pronounced. Myogenic damage is primarily manifested as elevated creatine kinase, severe muscle pain, visible hematuria, rhabdomyolysis, and myoglobinuria, and the reaction typically occurs around 5 days after starting medication. Research shows that sodium aescinate can cause hemolysis both in vivo and in vitro, increasing the concentration of free hemoglobin. This effect has a significant correlation with the drug concentration. Therefore, when using high doses of sodium aescinate, one should be vigilant for myogenic damage.

Additionally, as a plant extract, sodium aescinate contains a small amount of impurities that can serve as allergens, easily triggering allergic reactions after administration. These allergic reactions are primarily manifested as localized or generalized skin rashes, laryngeal edema, and blisters on the extremities, typically occurring within 3 to 7 days after medication. Therefore, it is crucial to thoroughly understand the patient's allergy history before administration, and cautious medication should be considered for patients with allergic tendencies.

References

[1] Tian Weigang. Research Progress on the Pharmacological Mechanism of Sodium Aescinate [J]. New Education Times Electronic Journal (Student Edition), 2017.

[2] Zheng Xueyan, Li Xinnan. Research Progress of Sodium Aescinate [J]. International Medicine and Health Guide News, 2017, 23(20):3.

[3] Xu Fei, Guo Dongkai, Ji Shiliang, et al. Pharmacological Effects and Clinical Drug Combination of Sodium Aescinate [J]. China Pharmaceutical Sciences, 2022, 12(10):5.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.