The application of mirabilite in traditional Chinese medicine and its chemical constituents, processing methods, pharmacology, toxicology and clinical research

Purpose: This study reviews the use of mirabilite in traditional Chinese medicine and various preparations by describing its chemical composition, processing methods, pharmacology, toxicology, and clinical research progress. Methods: The applications and processing methods of mirabilite are searched in traditional and modern Chinese medical writings, and the articles on chemical composition, pharmacological effects, toxicology, and clinical studies of mirabilite and its combinations in PubMed and China Knowledge Network are reviewed, sorted, and analyzed. Results: The main chemical component of mirabilite is sodium sulfate decahydrate (Na2SO4·10H2O), followed by small amounts of sodium chloride, magnesium sulfate, calcium sulfate, and other inorganic salts. This study systematically organizes the history of the medicinal use of mirabilite in China for more than 2,000 years. This mineral has been used by nine Chinese ethnic groups (Han, Dai, Kazakh, Manchu, Mongolian, Tujia, Wei, Yi, and Tibetan) in a large number of prescription preparations. The Pharmacopoeia of the People’s Republic of China (2020 edition) records stated that mirabilite can be used for abdominal distension, abdominal pain, constipation, intestinal carbuncle, external treatment of breast carbuncle, hemorrhoids, and other diseases. The traditional processing methods of mirabilite in China include refining, boiling, sautéing, filtration after hot water blistering, and firing. Since the Ming Dynasty, processing by radish has become the mainstream prepared method of mirabilite. Mirabilite can exhibit anti-inflammatory detumescence effects by inhibiting AMS, LPS, IL-6, IL-10, TNF-α, and NO levels and attenuating the upregulation of TNF-α and NF-κB genes. It can promote cell proliferation and wound healing by increasing the production of cytokines TGFβ1 and VEGF-A and gastrointestinal motility by increasing the release of vasoactive intestinal peptide, substance P, and motilin. It can increase the expression of low-density lipoprotein receptor and AKT phosphorylation in the liver by up-regulating bile acid synthesis genes; reduce TRB3 expression in the liver, FGF15 co-receptor KLB expression, and FGF15 production in the ileum, and JNK signal transduction; and increase the transcription of CYP7A1 to achieve a cholesterol-lowering effect. Mirabilite also has a variety of pharmacological effects, such as regulating intestinal flora, anti-muscle paralysis, anti-colon cancer, promoting water discharge, and analgesic. Only a few toxicological studies on mirabilite are available. External application of mirabilite can cause local skin to be flushed or itchy, and its oral administration is toxic to neuromuscular cells. The sulfur ions of its metabolites can also be toxic to the human body. At present, no pharmacokinetic study has been conducted on mirabilite as a single drug. This mineral has been widely used in the clinical treatment of inflammation, edema, wound healing, digestive system diseases, infusion extravasation, hemorrhoids, skin diseases, breast accumulation, muscle paralysis, intestinal preparation before microscopic examination, and other diseases and symptoms. Conclusion: Mirabilite has good application prospects in traditional Chinese medicine and ethnomedicine. In-depth research on its processing methods, active ingredients, quality control, pharmacokinetics, pharmacological and toxicological mechanisms, and standardized clinical application is needed. This paper provides a reference for the application and research of mirabilite in the future.


Introduction
Mirabilite is a salt sediment that mainly appears in the form of aqueous mirabilite and anhydrous mirabilite and combines with other compounds to form complex salts, such as calcium mirabilite, potassium mirabilite, and carbonate mirabilite (Li, 2020).More than 10 kinds of mirabilite exist in nature; among which, sodium mirabilite (i.e., ten water mirabilite and anhydrous mirabilite) and calcium mirabilite (Shen, 2003) have industrial utilization values.Ten water mirabilite is formed through the deposition of sulfate minerals in a dry and cold environment; the colder the climate, the easier the deposition and the thicker the deposit.Anhydrous mirabilite is deposited at temperatures >10 °warmer than those for natural mirabilite (Li, 2020).By conducting Aral Sea brine evaporation tests and Ferghana salt system studies, some researchers proposed that calcium mirabilite is crystallized directly from sulfate (Wei, 2001).
Mirabilite is a basic chemical substance commonly found in nature, and its formation is closely related to that of saline lake water, paleoclimate, paleoenvironment, and their related metallic and nonmetallic deposits (Ren, 2013).China has extremely rich mirabilite resources, and its total proven reserves of mirabilite are more than 20 billion tons (calculated by Na 2 SO 4 ), ranking first in the world.At the end of 2018, 167 mines with proven reserves and 256 mineral production sites were found across 18 provinces (regions) in China (Li, 2020).These reserves are relatively concentrated in various provinces, with greater than 1 billion tons found in Qinghai, Sichuan, Hunan, and Inner Mongolia, accounting for 90% of the national production (Ren, 2013).Sichuan has the richest resources of calcium mirabilite with high quality (the mass fraction of sodium sulfate in the ore is 30%-50%).Owing to its stable and reliable resources, simple geological structure, and good recoverability, it has gradually become the largest mirabilite producer and exporter in China.According to the type of mineralization, China's mirabilite ores are divided into modern inland salt-lake mirabilite deposits and ancient inland salt-lake calcium mirabilite deposits.The former are mostly distributed in the north of the Qinling Mountains, Xinjiang, Qinghai, Ningxia, Gansu, Inner Mongolia, Heilongjiang, Tibet, and other vast plateau or desert arid climate zones in the salt lake.Meanwhile, the majority of ancient inland salt-lake calcium mirabilite deposits are distributed in Sichuan, Yunnan, Hubei, Hunan, Anhui, Xinjiang, Gansu, and other provinces (regions).Sodium mirabilite is mostly distributed in modern salt-lake deposits, and calcium mirabilite is mostly obtained from ancient salt-lake deposits (Li, 2020).
Mirabilite (Latin name: Natrll Sulfas; Tibetan name: ) is a mineral in traditional Chinese medicine that shows a prismatic structure and appears as oblong or irregular lumps and grains that are colorless, transparent or off-white translucent, brittle, and friable, with glassy luster on the cross-section (Wang, 2014).Its main ingredient is aqueous sodium sulfate, which is salty, bitter, and characteristically cold and is mainly used for accumulation, and constipation, with the efficacy of clearing away heat and fire, resolving blood stasis, and dispersing knots (Huang and Zhang, 2008).Mirabilite has been used medicinally in China for more than 2,000 years.
As early as the Han Dynasty (202-220 BC), the name Poxiao (mirabilite) was documented and recorded in the upper class of medicines during the period of the Shen Nong Ben Cao Jing (Shang, 1981), and the efficacy of mirabilite was summarized in many subsequent books on ethnomedicine.Many preparations of mirabilite have been developed, the most common of which is Dachenqi decoction that has been studied in depth.Dachenqi decoction can inhibit the production of IL-1, IL-6, and TNF-α to achieve anti-inflammatory effects, rapidly reduce blood lipids by blocking the peroxisome proliferator-activated receptor γ pathway (Liu et al., 2020), and reduce blood lipids by lowering the levels of serum diamine oxidase (DAO), tumor necrosis factor-α (TNF-α), and interleukin-8 (IL-8) and elevating the gastric motility factor (MTL) for the treatment of intestinal obstruction (Gai et al., 2023).In addition, Dachenqi decoction has laxative (Zhao et al., 2013), antibacterial (Hu et al., 1999), anti-endotoxin (Tian et al., 1998;Sun et al., 2011), antipyretic (Zhang and Yang, 2009), detoxification (Liu, 2010) effects.It also has a significant effect on gastrointestinal (Zhang et al., 2011), immune (Yang et al., 2004;Guo and Bi, 2011), and digestive (Zhang, et al., 1998) functions and has a significant protective effect on the brain, lungs, and other important organs (Li et al., 2002).Owing to the similarity of efficacy between Rheum palmatum and mirabilite, their combination is the most commonly for treatments, such as for abdominal distension (Zhang, 2023), female pelvic inflammatory masses (Meng and Tian, 2023), constipation (Wan and Xiao, 2022), wound healing (Li, 2021), phlebitis (Sun Bobo and Pan, 2020), pneumonia (Xiao et al., 2019), and other diseases.
The modern biology of mirabilite production is relatively simple, that is, the natural mirabilite is dissolved in hot water, filtered, and cooled to precipitate crystals, which are commonly known as "Pixiao."The radish is washed, sliced, placed in a pot with water and Pixiao, and boiled.The upper layer of liquid is discarded, and the precipitation crystals are cooled down and named as mirabilite.Mirabilite prepared by weathering involves losing the water of crystallization into a white powder called Xuanming powder (Chen, 2012).In the modern industry, mirabilite is often produced by brine freezing and separation (Li, 1991).He and Wang (2020) prepared mirabilite particles by antisolvent recrystallization and concluded that the optimum onefactor conditions for the preparation of mirabilite particles were the solvent-antisolvent ratio of 1:4, stirring for 40 min, and droplet acceleration of 2 mL/min.Under these optimum conditions, mirabilite particles were obtained with about 5 m average size, complete hexahedral shapes, and uniform surfaces.Mirabilite has a wide range of uses and has traditionally been utilized in four main industries: paper, detergents, glass, and printing and dyeing.In the 18th century, mirabilite was used as a raw material for the industrial production of soda ash (sodium carbonate) (Li, 1991b).At present, its main use is for the synthesis chemical products such as Yuanming powder (anhydrous sodium sulfate with a purity of more than 99%), alkali sulfide, and sodium silicate.With the continuous progress of science and technology, mirabilite has widely been used in more than 20 industries, such as the chemical industry, light industry, textile, building materials, medicine, nonferrous metallurgy, and leather industry (Zhu, 2014).
With the continuous progress of science and technology, mirabilite has widely been used in more than 20 industries, such as the chemical industry, light industry, textile, building materials, medicine, nonferrous metallurgy, and leather industry (Zhu, 2014).
With the advancement of medical technology and the expansion of the scope of people's knowledge of traditional Chinese medicine, mirabilite has played an increasingly important role in medical treatment.Therefore, this study will further promote the global use of mirabilite by describing its application in traditional Chinese medicine and its processing methods, chemical composition, pharmacology, toxicology, and clinical studies for future research.

Chemical composition of mirabilite
The main constituent of mirabilite is sodium sulfate decahydrate (Na 2 SO 4 •10H 2 O), followed by small amounts of inorganic salts such as sodium chloride, magnesium sulfate, and calcium sulfate (Wu et al., 2007).Japan preserved several Tang Dynasty medicines, one of which is "mirabilite," magnesium sulfate heptahydrate (MgSO 4 •7H 2 O) with the highest purity (Liu, 2001).According to the Japanese Han Fang Ye Wu Zhi Zhen (1981 edition), crystallized magnesium sulfate and aqueous sodium sulfate can be used as mirabilite (Xue, 1991).The Jing Zhu Ben Cao recorded mirabilite as Na 2 SO 4 •10H 2 O containing 19.3% Na 2 O, 3.2%-4.8%SO, and 55.9% H 2 O (Pontso, 2012).Ao (2023) measured the chemical fractions of natural mirabilite in the mirabilite ore of Zemubilite salt in Xinjiang as follows: Na 2 SO 4 , with a content of 16.34%-93.13%(AD 608) emphasized the constipation-curing effect of mirabilite and proposed for the first time that mirabilite solution can be used externally to treat skin diseases (Zhen, 1983).Su Jing's Xin Xiu Ben  and Tang Shenwei's Zheng Lei Ben Cao (AD 1082-1098) both inherited the record of Ben Cao Jing Ji Zhu.Zhang Yuansu's Jie Gu Zhen Zhu Nang (AD 1234) recorded the three major effects of mirabilite: "clear heat, treat constipation, and abdominal mass" (Li, 1991).Li Shizhen's Ben Cao Gang Mu (AD 1552-1578) summarized the characteristics, taste, main treatment, toxicity, source, and collection time of mirabilite in Shen Nong Ben Cao Jing, Ben Cao Jing Ji Zhu, and Yao Xing Lun (Li, 2014b).Jia Suoxue's Yao Pin Hua Yi (AD 1644) recorded that mirabilite has a significant effect on treating abdominal mass and clearing heat (Jia, 2015).According to Wang Ang's Ben Cao Bei Yao (AD 1694), "mirabilite can expel phlegm, unblock collaterals, induce abortions, and resolve stones.It can treat abdominal mass, typhoid fever, epidemic dysentery, accumulation, blood stasis, jaundice, gonorrhea, scrofula, and cataract" (Wang and Zheng, 2019).Tibetan medicine writing Jing Zhu Ben Cao (AD 1736-1796) recorded that mirabilite is a white nitrate salt that is produced in the deep valley of the cave and tastes sweet, similar to wheat flour.It has the functions of raising stomach Yang, helping digestion, and removing tumors.These findings emphasized the main effect of mirabilite on gastrointestinal and other digestive tract diseases (Pontso, 2012).In the modern times, the records of mirabilite have gradually been completed (Yiyu, 1956;Commission, 2019).

Application of mirabilite as a traditional Chinese medicine
Mirabilite is used in traditional Chinese medicine and in eight ethnic groups (Dai, Kazakh, Manchu, Mongolian, Tujia, Wei, Yi, and Tibetan) in China (Table 2).In traditional Chinese medicine and ethnomedicine, mirabilite is mainly used for the treatment of digestive diseases, urological diseases, dermatologic diseases, intestinal carbuncle, breast carbuncle, hemorrhoids, ulcers, abdominal distension, amenorrhea, mouth sores, and toothache with good results.Traditional Chinese medicine and eight ethnic groups of medicine all emphasize the therapeutic effect of mirabilite on constipation.In traditional Chinese and Wei medicine, it is used for the treatment of digestive system diseases and external treatment for breast carbuncle and hemorrhoids.In Mongolian and Tibetan medicine, it is used for the treatment of amenorrhea, indigestion, and edema.In Dai medicine, it is used for the treatment of skin and dental diseases.In Tujia and Yi medicine, it is used for the treatment of sores and eye redness.In Tibetan medicine, it has special application for heart disease and tumor.In Kazakh medicine, it has special application for bad breath.In Manchu medicine, it has special application for epistaxis.

Application and statistical analysis of mirabilite in Chinese traditional medicine preparations
According to statistics, mirabilite was used in 44 preparations, including 27 decoctions, 6 pulvis, 5 pills, 2 Dans, and 1 for each of the other dosage forms (e.g., external lotions, buccal tablets, mixtures, and granules).Table 3 shows the application of mirabilite in traditional Chinese medicine preparations, including the dosage form, preparation name, composition and dose of medicinal materials, method use, role of mirabilite in each preparation, and indications.21 According to our statistics and analysis, the internal use of mirabilite is mainly adopted in preparations.The main roles of mirabilite in each preparation are clearing heat and purgative.Other functions include removing dampness, expectorant, unblocking collaterals, dispelling blood stasis, antipruritic, and resolving stones.The indications of preparations containing mirabilite involve diseases of 12 systems (Table 4).The common disease types and frequencies in descending order are as follows: digestive system diseases (32.26%), mental and behavioral disorders diseases (16.13%), symptoms, signs and clinical and laboratory abnormalities that cannot be classified elsewhere (13.98%), circulatory system diseases (6.45%), infectious diseases (6.42%), traditional Chinese medicine (ethnic medicine) characteristic diseases (5.91%), respiratory system diseases (4.30%), eye and appendage diseases (4.30%), genitourinary system diseases (3.76%), some infectious and parasitic diseases (3.26%), musculoskeletal system and connective tissue diseases (2.15%), and skin and subcutaneous tissue diseases (1.08%).Owing to the significant effect of mirabilite, the preparations containing this mineral have great advantages in the treatment of certain diseases, such as gastrointestinal diseases (Gai et al., 2023) and mental and behavioral disorders (Wang, 2016).

Using method
The role of mirabilite in each preparation

Internal use
Purgative Heat trespass blood, heat and blood knot

Internal use
Purgative Insect accumulation

Internal use
Clearing heat Blood stasis caused by plague day and night fever; night heat day cool

Taohe Chengqi decoctions
Prunus persica (50pieces), Rheum palmatum (200 g), Cinnamomum cassia (100 g), Glycyrrhiza uralensis (100 g), mirabilite (100 g)   Note: The dose of some medicine preparations has not been found or disclosed.Shen Nong Ben Cao Jing recorded the processing of mirabilite as being "refined into paste" (Shang, 1981).Zhou Hou Bei Ji Fang (AD 266-420) proposed boiling (Ge, 2005).For the first time, Lei Gong Pao Zhi Lun adopted paper filtration after water flight and powder processing of mirabilite, and this method increased the cleanliness of mirabilite (Lei).Since the Han Dynasty, many medical writings have recorded that mirabilite needs to be sautéd (Lei; Zhao et al., 2022).In the Tang Dynasty, while following the method of refining and boiling, Xian Shou Li Shang Xu Duan Mi Fang (AD841-845) recorded filtering with paper after hot water blistering (Lan, 1957).In the Song Dynasty, Zheng Lei Ben Cao increased the utilization of firing (Tang, 1991).In the Ming Dynasty, Ben Cao Cheng Ya Ban Ji (AD 1647) first proposed the processing of mirabilite with radish and made a detailed record: mirabilite was decocted in water and boiled with radish (Lu, 2016).Ben Cao Meng Quan (AD 1565) divided the processing of mirabilite with and without excipients into weathered saltpeter and Yuanming powder (Chen, 1988).Ben Cao Gang Mu mentioned that licorice can be added to the processing of mirabilite to alleviate the cold characteristic and salty taste of mirabilite (Li, 2014).In the Qing Dynasty, the processing method of mirabilite excipients (radish and licorice) was followed.
After the founding of the People's Republic of China, the processing method of mirabilite was gradually standardized.For example, in the Pharmacopoeia of the People's Republic of China (AD 1963), the processing method of mirabilite, "take radish washed and sliced, placed in a pot with water and boiled through, add the , all of which do not include the addition of radish, is not stipulated.Second, the choice of auxiliary radish varieties is not clear.For example, most of the concoctions are recorded as radish, and a few select red radishes, white radish, and carrot as auxiliary materials.Third, the raw material is confusing, whether it is "natural mirabilite", "Poxiao", "crude mirabilite", or "Pixiao."Fourth, the effect of processing parameters such as the proportion of raw materials and auxiliary materials, the amount of water, cooking radish time, and adding raw materials after the total cooking time are not uniformly specified.
The above factors will affect the quality and clinical efficacy of mirabilite, resulting in the uncontrollable quality of radish-made mirabilite products.Therefore, the research on the processing method of mirabilite should be strengthened to clarify its scientific connotation.

Pharmacological actions of mirabilite
The pharmacological effects of mirabilite mainly focus on antiinflammatory detumescence; promotion of cell proliferation, wound healing, gastrointestinal motility, and water discharge; regulation of intestinal flora; anti-muscle paralysis; and analgesia.Recent reports also revealed the cholesterol-lowering function of mirabilite and its pharmacological effects on colon cancer (Table 6).Tseng et al. (2006) found that mirabilite has good antiinflammatory detumescence effects possibly because it can accelerate lymphatic circulation, enhance the phagocytic function of reticuloendothelial cells, and reduce local leukocyte infiltration and inflammatory response (Jin et al., 2016).The oral administration of mirabilite (Liu et al., 2012;Hu et al., 2018;Chen et al., 2021) or its external application (Zhu et al., 2004;Lu, 2017;Chen et al., 2020) can effectively inhibit the levels of serum AMS, LPS, IL-6, IL-10, TNF-α and NO in rats with acute pancreatitis and weaken the upregulation of TNF-α and NF-κB genes, thereby reducing the degree of pancreatitis and the level of inflammatory factors and protecting the pancreatic tissues (Ramudo et al., 2005;Malleo et al., 2007;Shen et al., 2017;Zeng et al., 2023).Liu et al. (2015) found that the gavage of mirabilite can significantly reduce the total number of eosinophils, lymphocytes, and serum IgE content in the bronchoalveolar lavage fluid of asthmatic mice to inhibit airway inflammation.Li et al. (2012) reported that mirabilite gavage shows an anti-inflammatory effect by significantly reducing the inflammatory response of PGE2 in the serum of colitis guinea pigs.Gou (2016) stated that mirabilite could stimulate the reticuloendothelial system, particularly the appendix and spleen, to enhance its phagocytosis and improve the anti-inflammatory effect.Gault (1993) suggested that the combination of mirabilite and R. palmatum can remove harmful substances such as oxygen free radicals and inflammatory factors in the intestine, relax the sphincter, accelerate intestinal peristalsis, increase intestinal mucosal blood flow, and benefit the early repair of pancreatic organs.

Promoting cell proliferation and wound healing
According to Traditional Chinese medicine, the bitter taste of mirabilite can remove heat, and its salty taste can soften hard substances.This mineral is good at eliminating blood stasis and can dredge all kinds of stases.Cell experiments revealed that mirabilite solution can promote the production of cytokines TGF β1 and VEGF-A, thereby accelerating the formation of endothelial cells, lymphocytes in the wound, and fibroblasts (Wei et al., 2011;Liu, 2015;Liu, 2018).Mirabilite can increase the blood flow under mechanical skin wounds and the exchange intensity of Na + and K + in vascular endothelial cells, promoting wound angiogenesis and significantly inhibiting wound tissue edema (Liu, 2015).Yu (2000) reported that mirabilite has good moisture absorption, strong permeability, low freezing point, and heat absorption, which can shrink capillaries and reduce congestion and swelling.Modern molecular biology studies found that sodium sulfate (the main component of mirabilite) can inhibit the outflow of Ca 2+ from vascular endothelial cells, activate Ras-ERK1/2 signaling pathway, upregulate the expression of VEGF, TGF β1 and PDGF mRNA, promote vascular tissue regeneration under mechanical skin wounds, and accelerate wound healing (Jiang, 1979).Rudge et al. (2007) found that sodium sulfate molecules can act on a variety of cell surface G protein-coupled receptors, initiate intracellular Ras/ ERK/Raf/MAPK and other signaling pathways related to tissue regeneration and inflammation inhibition, and promote the proliferation of vascular smooth muscle cells in vitro.Sodium sulfate solution can activate macrophages in the wound site and express a large number of Toll-like receptors (TLRs).Various lymphocytes can recognize the marker factors of various pathogenic microorganisms through TLRs, such as bacterial lipopolysaccharide (LPS), GpG-DNA, peptidoglycan, and PAMP molecules, providing a signal source for acquired immunity (Wang et al., 2020). Reginato et al. (2014) found that a low concentration of sodium sulfate has a significant effect on angiogenesis in the skin wounds of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit Rac2 knockout mice, greatly shortening the wound skin healing rate of mice.Stewart et al. (2013) found that sodium sulfate injection has a significant effect on the proliferation  Frontiers in Pharmacology frontiersin.orgdifferentiation of endothelial progenitor cells in vitro.Brown et al. (2010) found that mirabilite can significantly upregulate the mRNA and protein expression levels of insulin growth factor 1 and insulin growth factor 2 (IGF-2) in the skin wounds of type II diabetic mice, promoting the binding of IGF-2 to IGF-2/6-phosphate mannose receptor, the expression of TGF-β1, and wound repair.Castronuovo et al. (2011) also found that mirabilite can significantly increase the expression of PDGF protein in diabetic foot wound fluid and promote wound healing.Frank et al. (2006) found that mirabilite can significantly increase the expression of inducible nitric oxide synthase in fibroblasts and vascular endothelial cells in skin ulcers, promoting skin wound repair.

Effect on the digestive system
Mirabilite solution can play a role in the treatment of digestive system diseases, mainly by promoting the secretion of vasoactive intestinal peptide in the intestine (Liu, 2015).

Promoting gastrointestinal motility
The salty and bitter tastes and the cold characteristic of mirabilite are the main reason it can eliminate the food accumulation of gastrointestinal tri-jiao and abdominal fullness and pain.After the oral administration of mirabilite solution, its sulfate ions are not easily absorbed by intestinal mucosal villi.Thus, a hypertonic salt solution layer is formed on the upper layer of intestinal endothelium, and a large amount of water accumulates in the intestine.On the one hand, it can wet the intestine and internal moistening; on the other hand, it can relax the intestine, inhibit abnormal intestinal fermentation, restore normal intestinal peristalsis, and increase intestinal defecation ability (Ji, 2002).Yin et al. (2021) and Ying et al. (2003) found that compared with mirabilite, Poxiao (mirabilite) had more impurities and contained a large amount of Mg 2 + , so its promoting effect on gastrointestinal tract was stronger.Xiao et al. (1998) found that mirabilite can significantly increase the water content of the small intestine in mice, dilute feces, and promote diarrhea.Xie and Huang (1999) found that mirabilite solution can promote the release of vasoactive intestinal peptide, substance P, and motilin to promote gastrointestinal motility.SP is an extremely important gastrointestinal peptide widely distributed in the enteric nervous system and the entire gastrointestinal tract.It is the main excitatory neurotransmitter in the regulation of gastrointestinal motility and has a double contraction effect on the gastrointestinal longitudinal muscle and the circular muscle (Maake et al., 1999).Liu et al. (2006) found that after abdominal surgery in rats, the external application of mirabilite significantly increased the distribution of SP in the myenteric plexus of the gastric antrum and proximal colon, suggesting that this treatment may enhance the excitability of neurons in the gastrointestinal wall and thereby promote gastrointestinal motility by increasing the release of SP in the gastrointestinal tract.Yang (2021) found that mirabilite can promote the conversion of cholesterol to bile acid and accelerate the synthesis of bile acid, which can lead to diarrhea.Ruminococcus bacteria directly promote the secretion of short-chain fatty acids, especially butyric acid that helps regulate intestinal motility, mucus production, and other key functions.Oral mirabilite administration can increase the abundance of Ruminococcus in the intestinal flora of normal mice, thereby protecting the gastrointestinal mucosa and moistening the intestine (Tomova et al., 2019).

Regulation of intestinal flora
Orally administered mirabilite can regulate intestinal population.Hu et al. (2022) found that mirabilite improved the abundance and diversity of intestinal bacteria in a dose-dependent manner and increased the beneficial bacteria in the intestine.Low-dose mirabilite only slightly increased the abundance of intestinal bacteria in mice and had minimal effect on the intestinal flora.This finding may be due to the different effects of mineral elements in different concentrations of mirabilite solution on the intestinal flora.Although it can improve the intestinal flora, mirabilite can also enhance the disorder of the intestinal flora.Yang (2021) found that after the gavage of mirabilite, the disordered intestinal flora of hypercholesterolemia mice was significantly improved because bile acids can inhibit the growth of specific bacteria in the intestine.Therefore, mirabilite affects the composition of intestinal microflora by promoting the production of bile acids.

Cholesterol-lowering effect
Orally administered mirabilite has a cholesterol-lowering effect.Yang (2021) found that after the intragastric administration of mirabilite, the cholesterol conversion and bile acid synthesis genes of hypercholesterolemic mice were upregulated, the expression of low-density lipoprotein receptor in liver was increased, the expression of TRB3 in liver was decreased, the phosphorylation level of AKT was enhanced, the production of FGF15 in ileum was decreased, the expression of FGF15 co-receptor KLB in liver was decreased, the JNK signal transduction was inhibited, and the transcription of CYP7A1 was increased.This finding proved that mirabilite can reduce the serum total cholesterol level of hypercholesterolemia mice and promote the conversion of liver cholesterol to bile acid.The mechanism may be through improving insulin resistance, reducing the expression of KLB on the surface of liver cell membrane, inhibiting the phosphorylation of downstream JNK, and promoting the transcription of CYP7A1, leading to the accelerated conversion of cholesterol to bile acid in the liver.

Anti-muscle paralysis effect
Barium ions can change the permeability of a variety of cell membranes so that a large number of potassium ions enter the cells, resulting in hypokalemia and causing significant muscle toxicity in smooth muscle cells, skeletal muscle cells, and myocardial cells.It can produce a stimulating effect, causing muscle paralysis, terminating the reaction, and inducing the clinical manifestations of heart rate disorders, atrial fibrillation, conduction block, ventricular fibrillation, cardiac arrest, decreased muscle tone, decreased muscle strength, tendon reflex disappeared, respiratory muscle paralysis, dyspnea, cyanosis, and asphyxia.10%-30% sodium sulfate solution has a strong antagonistic effect on barium ions and has a significant mitigation effect on limb paralysis, arrhythmia, and dyspnea (Frank et al., 2006).

Promoting the discharge of water in the body
Mirabilite promotes the discharge of water and liquid in the body.Zhang et al. (2018) statesd that the external application of mirabilite in the chest can form a high permeability state locally, absorb various effusions in the chest through osmotic pressure, and have a therapeutic effect on malignant pleural effusion.Chen and Xu (2008) and Zhang (2019) also statesd that the SO 4 2− in sodium sulfate, the main component of mirabilite, can locally form a high permeability state and thereby promote the discharge of local water.

Analgesic effect
Some scholars stated that the material basis of the analgesic effect of mirabilite may be related to its trace elements and other components (Ying et al., 2003).Pain is caused by the compression of traumatic hematoma or the stimulation of local peripheral nerves by inflammatory substances.Mirabilite can achieve analgesic effect through nerve reflex (Bo et al., 2006;Ye et al., 2013).

Toxicological effects of mirabilite
Shen Nong Ben Cao Jing lists Poxiao (mirabilite) as a nontoxic product (Shang, 1981).Mirabilite is refined from Poxiao (mirabilite).Most Chinese traditional medical works recorded that mirabilite is nontoxic, and some stated that mirabilite has small toxicity, such as Yao Xing Lun (Zhen, 1983).Yi Jing Xiao Xue recorded sulfur and Bolboschoenus yagara fear of Poxiao (mirabilite), one of the "Nineteen fears" songs in traditional Chinese medicine.This ideology means that sulfur and Bolboschoenus yagara are not suitable for combination with mirabilite because they will produce severe toxic and side effects or reduce and destroy the efficacy.However, Qingci Xiao and Xiaoping Mao (Mao et al., 1996;Qiao and Zhu, 2021) found that the combination of sulfur, Bolboschoenus yagara, and mirabilite only reduced the anti-inflammatory, analgesic, and purgative effects of mirabilite but had no toxic and side effects.With regard to the use of mirabilite, the Pharmacopoeia of the People's Republic of China only mentioned that "pregnant women should be cautious about using it, and should not be used with sulfur and Bolboschoenus yagara" (China, 1985).Some scholars proposed that mirabilite has a certain irritation to the skin (Tian et al., 2015).Zhou et al. (2015) found that patients who received the external application of mirabilite had local skin flushing or itching.Some scholars also stated that mirabilite is nontoxic, and umbilical application had no damage to local skin (Zhu et al., 2009;Lv, 2017).Qiao and Zhu. (2021) and Ying et al. (2003) found no stimulating effect on the external drip of mirabilite solution in the eyes of rabbits.Zhou (2012) applied 500 g of mirabilite external application combined with gastric tube injection of raw R. palmatum bubble solution to treat intraabdominal hypertension in patients with acute pancreatitis.Laboratory tests including blood routine, liver and kidney function, and coagulation function were performed.The results showed no adverse reactions and toxic and side effects during clinical treatment, indicating that mirabilite is nontoxic, side effects, safe to use, and has reliable efficacy.Zhou et al. (2007) reported that the oral administration of mirabilite solution caused chemical irritation to intestinal mucosa but had no significant biological damage to intestinal cells.Shen (2017) intraperitoneally injected mirabilite decoction at a dose of 6.738 g/kg in LD 50 mice, who died after 1 h of administration.The animals showed renal ischemia.Ying et al. (2003) also mentioned that increasing the dose of mirabilite or continuous use can cause a decline in health, and severe cases can cause dehydration.

Clinical applications of mirabilite
Mirabilite is widely used in clinical treatment of inflammation, edema, wound healing, digestive system diseases, infusion extravasation, hemorrhoids, skin diseases, breast accumulation, muscle paralysis, intestinal preparation before microscopic examination, and other diseases and symptoms (Table 7).

Inflammation
7.1.1Vein inflammation Tong et al. (2007) reported that the treatment of vein inflammation should be to clear heat, and remove blood stasis.68 patients with vein inflammation were treated with external application of mirabilite saturated solution, the results showed that the veins in 61 patients became soft and elastic.Huang and Zhang (2008) iced patients with vein inflammation with a 10% mirabilite solution, the effective rate was 85%, which was higher than the 72% of ordinary ice pack external application.Shi (2008) externally applied mirabilite and Borneolum syntheticum solution for the treatment of vein inflammation, and the efficacy was significantly better than the 50% magnesium sulfate solution external application.Lu et al. (2018) used New Zealand rabbits to test the effectiveness of mirabilite in preventing mechanical vein inflammation caused by vein indwelling needles, and the results showed that mirabilite can alleviate the inflammatory response of rabbit ear veins.Liu et al. (2006), Ma et al. (2012), andWu et al. (2007) proposed that pancreatitis belongs to the "spleen heat" of traditional Chinese medicine.Wu et al. (2017) stated that the treatment of acute pancreatitis should be to clear damp and hot.The treatment of pancreatitis with external application of Pixiao (mirabilite)+ Qingyi decoction for internal administration significantly improved the efficiency.Li et al. (2013) treated 89 patients with pancreatitis with the external application of mirabilite and internal administration of Dachengqi decoction, and the effective rate was 97.8%.Some patients with pancreatitis were treated with mirabilite plus raw R. palmatum soaking solution, the times for abdominal distension and abdominal pain to disappear and bowel sound to recover were shorter than those of the conventional treatment, and the complication rate was significantly lower than that of conventional treatment (Yu et al., 2019;Hu, 2022).Zeng et al. (2023) externally applied mirabilite to prevent postoperative pancreatitis (PEP) after endoscopic retrograde cholangiopancreatography.The incidence of PEP in the observation group was significantly reduced.

Arthritis
Li and Duan (2010) stated that using mirabilite externally could prevent the excessive crystallization and deposition of urate in joints, which could result in inflammation.Yi (2016) reported that combining mirabilite with Borneolum syntheticum was an effective treatment for gouty arthritis.Three cases of gouty arthritis were treated by applying hot compress with mirabilite.The results showed that the joint symptoms showed significant improvement.Zhong et al. (2021) treated 40 patients with arthritis by applying mirabilite ice treatment.The results showed that the CRP(C-reactive protein) and hospital stay at 72 h after surgery were significantly lower than those in the common ice pack group.

Appendix abscess
Appendix abscess belongs to the thermal stage of intestinal carbuncle in traditional Chinese medicine (Feng, 1998).Zhang (2001) tested the effectiveness of mirabilite in treating intestinal carbuncle.Mirabilite and R. palmatum were ground into a paste with vinegar and applied to the abscess of the appendix.The results showed that the effective rate was 100%, and the decrease rate of peripheral white blood cell level was significantly faster than that in the treatment with common antibacterial drugs.Jin and Gao (2015) and Liu (2018) treated appendix abscess with the topical application of mirabilite plus conventional antibiotics.The results showed that the effective rate was significantly higher than that of conventional antibiotics.The proportion of appendix abscess mass reduction, average length of stay, C-reactive protein, and white blood cell count were all better than those in the treatment using conventional antibiotics.Ma et al. (2012) mixed R. palmatum powder and mirabilite in a ratio of 2:1 with white vinegar into a paste to treat appendix abscess, and the results showed the effective rate was 100%.Yang (2010) treated 90 patients with appendix abscess by externally applying mirabilite and Dahuang Mudan decoction.the results showed the effective rate was 93.33%.

Edema
In combination with the conventional cisplatin treatment of patients with malignant pleural effusion, Zhang et al. (2021) employed the external application of mirabilite plus R. palmatum, the results showed the total effective rate of patients in the treatment group (66.67%) was significantly higher than that in the control group (54.76%).Zhang (2019) treated 90 patients with edema after hemorrhoid surgery with the ratio of R. palmatum and mirabilite mixed with 1:3 band and found that the effective rate and recovery rate were 93.09% and 27.58%, respectively.Chen and Xu (2008) treated 36 patients with upper limb edema after breast cancer surgery with the external application of mirabilite and the internal administration of Chinese herbs such as Astragalus membranaceus, Atractylodes macrocephala, Polyporus umbellatus, Coix lacrymajobi, and Alisma plantago-aquatica, the effective rate was 100%.Zhen (2016) mixed mirabilite and Borneolum syntheticum at a ratio of 100:1 and externally applied the mixture to patients with lower limb lymphedema.In the treatment group, the difference was (3.1 ± 0.62) cm on day 5, (4.5 ± 0.41) cm on day 7, and (5.0 ± 0.76) cm on day 14.The difference was (2.2 ± 0.48) cm on day 5, (4.0 ± 0.37) cm on day 7, and (4.3 ± 0.53) cm on day 14, indicating significant improvement compared with that in the control group.

Wound healing for trauma swelling and pain
Swelling is caused by capillary rupture, bleeding, increased permeability of blood vessel wall after trauma, and extravasation of intravascular fluid into tissue space (Qi, 2001).Pain is caused by the compression of traumatic hematoma or the stimulation of local peripheral nerves by inflammatory response substances (Ma and Ma, 2012).

Healing of diabetic foot ulcers
On the basis of routine treatment in the control group, Liu et al. (2011) applied 200 g of dry mirabilite to the ulcer wounds of patients with diabetic foot for 14 days.The results showed that the ankle brachial index and common peroneal nerve sensory conduction velocity of the treatment group was significantly better than that of the control group, and the average hospitalization days and average treatment costs were significantly lower than those of the control group.

Postoperative wound healing
Wang (2009) applied 500 g of mirabilite and 100 g of R. palmatum to the incision of patients with fat liquefaction after operation for 3 days.The cure rate and incision resection rate were significantly higher than those of the control group.Nie et al. (2022) and Zhao et al. (2021) externally applied R. palmatum and mirabilite to the incisions of patients with fatty liquefaction in cesarean delivery.The patients' nursing satisfaction, Chinese medicine symptom rating score, negative emotion score, economic stress score and other prognostic indicators were better than those in the conventional nursing group.Referring to Incision Management for Abdominal Surgery (Li, 2007), Xu et al. (2020), He (2019), Li (2019) and Zeng (2019) applied mirabilite and R. palmatum to the incision of patients after cesarean section and achieved ideal efficacy in wound healing.Zhao (2011) treated postoperative wound healing of perianal abscess with the topical application of Chinese medicine mirabilite gauze for 21 days.The results showed that the degree of wound edema, pain degree, and healing time of patients in the treatment group were superior to those in the control group.Li (2019) applied R. palmatum and mirabilite powder to the incision of patients undergoing double eyelid plasty and epicanthus correction.The results showed that the external application of mirabilite and R. palmatum powder was beneficial to incision healing and shortened postoperative recovery time.Ye and Lu. (2013) treated 23 cases of traumatic hematoma with wet hot compress with saturated solution of mirabilite and achieved satisfactory results.Bo et al. (2006) treated traumatic swelling pain by applying 10% mirabilite solution ice pack plus intravenous infusion of β-aescuin sodium.Compared with water ice pack, mirabilite ice pack had a significant effect on reducing pain degree within 72 h and swelling degree after 24 h.Zhang et al. (1990) found local bleeding, fluid seepage, or foreign body reaction in the skin bag embedded with the pacemaker or in the incision where the catheter electrode was inserted, resulting in local stasis and swelling, even the skin necrosis, secondary infection, with Pixiao (mirabilite) external treatment after all cured.Donghui Guan (Guan, 2009)used mirabilite + Borneolum syntheticum + raw R. palmatum + raw Phellodendron chinense powder was externally applied to treat 40 patients with traumatic lower limb swelling, and the clinical effective rate was 92.5%.Li (2014) used 25% mirabilite ice bag to treat 40 patients with perineal hematoma.The results showed that the degree of pain, swelling, and comfort at 1, 24, and 48 h after operation were better than those when using normal ice bag.
7.4 Digestive system disease 7.4.1 Functional disturbance of gastrointestinal tract "Six fu-organs keeping dredging," restoring gastric motility, and promoting gastrointestinal peristalsis are fundamental methods to solve gastrointestinal dysfunction (Gao, 2007).Wu et al. (2004) and Xu et al. (2016) treated 72 patients with gastrointestinal dysfunction caused by right heart failure with the external application of Pixiao (mirabilite) and oral R. palmatum powder solution or enema.The return time of intestinal sound to normal was significantly lower than that of patients treated by routine cardiology.Qin and Pan (2009) applied mirabilite paste to the lower abdomen of patients after abdominal surgery.The results showed that the time of anal exhaust and defecation was significantly shorter than that of the control group (conventional treatment), and the number of cases of abdominal distension 3 days after operation significantly decreased.Zhou (2011) treated 21 patients with umbilical cord around the abdomen with a mixed bag of R. palmatum and mirabilite at a ratio of 1:1.Within 12 h, 16 patients recovered bowel sounds and anal exhaust, accounting for 86%.The remaining 5 patients recovered bowel sounds and anal exhaust within 24 h, and the recovery time of gastrointestinal function was significantly shortened.Wu et al. (2017) smeared 200 g of mirabilite powder around the umbilicus of patients undergoing abdominal surgery while taking xylitol sugarfree gum.The results showed that the recovery time of bowel sounds, the first active anal exhaust time, and the first defecation time all improved in the treatment group.Lai et al. (2016) and Lin and Xu (2018) applied mirabilite powder to the navel, and Wang and Jinag (2014) applied mirabilite powder to the navel combined with Zusan-li and inner pass point massage to treat patients with gastrointestinal dysfunction in acute pancreatitis.The recovery of gastrointestinal function in the treatment group was significantly better than that in the conventional treatment.Lv (2017) treated patients with gastrointestinal dysfunction after colorectal cancer surgery by sticking mirabilite on the navel.The recovery time of bowel sounds, anal exhaust time, defecation time, and hospitalization time in the treatment group were significantly shorter than those in the conventional treatment group.Pan et al. (2021) used mirabilite combined with lactulose to treat gastrointestinal dysfunction in elderly patients after abdominal surgery.The recovery rate of bowel sounds in the experimental group (62.16%) was better than that in the control group (37.63%).70.27% of the patients in the experimental group finally had anal exhaust or defecation, and only 46.24% of the control group experienced this phenomenon.

Constipation
Xichun Zhang, one of the representatives of the modern school of Chinese and Western medicine, created XiaoFu TongJie decoction for the treatment of constipation.A large dose of radish was decocted and boiled with Pixiao (mirabilite) for the treatment of constipation (Peng et al., 2016).Tao (2022) and Yu (2014) used the external application of mirabilite and R. palmatum to treat orthopedic bedridden patients with constipation, and the symptoms of constipation were significantly improved.Wang (2021) applied mirabilite and R. palmatum powder to the umbilicus of patients with constipation, who also received orally administered powder of compound polyethylene glycol electrolyte.This study found that the defecation time of patients was significantly shorter than that of patients taking compound polyethylene glycol electrolyte powder alone.Li and Liao (2021) mixed mirabilite, R. palmatum, Astragalus membranaceus, Borneolum syntheticum, Houpoea officinalis, and ethanol into a sticky state and applied it to the navel of 35 patients with diabetes mellitus complicated with constipation.Combined with moxibustion, the treatment lasted for 7 days.The effective rate of the treatment group was 91.67%.Liu (2018) conducted enema on 30 patients with acute myocardial infarction complicated with constipation.The results showed that the efficacy and comfort of enema in the treatment group were better than those in the control group (Kaisailu enema).Song (2016) used mirabilite plus R. palmatum liquid to treat 39 patients with constipation after stroke, and the curative effect was 100%.Zhang et al. (2014) also stated the therapeutic effect of mirabilite on constipation.

Ileus
Xie et al. (2007) and Zhang et al. (2007) applied Pixiao (mirabilite) externally to the abdominal wall of patients with intestinal obstruction.The time to relief of abdominal pain, time to anal exhaustion, and number of hospitalization days were all significantly reduced.Shan Jing stated that intestinal obstruction belongs to Chinese medicine abdominal pain, the treatment should be based on relieving constipation by purgation.Mirabilite of 500 g was applied to the navel and combined with traditional Chinese medicine (such as Atractylodes macrocephala, Cynanchum otophyllum, Bupleurum longiradiatum, Houpoea officinalis, and R. palmatum) for the treatment of simple intestinal obstruction.The first defecation time, abdominal pain relief time, first anal exhaust time, white blood cell recovery time, and hospitalization time in the treatment group were significantly shorter than those in the conventional treatment group (Jing and Gu, 2015).Tian et al. (2015) used mirabilite external application combined with R. palmatum liquid gavage or enema to treat patients with acute pancreatitis abdominal distension.The results showed that the relief time of abdominal distension in the observation group was significantly shorter than that in the conventional treatment group.Zhang (2013) applied mirabilite to patients with abdominal distension after abdominal surgery, and the duration of abdominal distension and anal exhaust time was significantly improved.Hou and Yan (2016) applied mirabilite to the periumbilical area of patients with liver cirrhosis and abdominal distension.The abdominal distension relief index of the treatment group was better than that of the conventional treatment group, and the effective rate was 90%.The effective rate of abdominal distension relief in patients with damp-heat cirrhosis was 100%.For patients with abdominal hypertension, Cao and Wang (2004) Xu and Wei (2008) externally applied Pixiao (mirabilite) to 120 patients with infusion extravasation, and the control group received gauze soaked with 50% magnesium sulfate.Swelling subsidence and pain relief were recorded every 2 h, and the treatment group was observed for 24 h.The cure rate of the treatment group was 81.82%, which was significantly higher than the 45.46% of the control group.Sun et al. (2009) applied mirabilite and Taraxacum mongolicum solution to the puncture site of 30 patients with infusion extravasation, and the control group applied 50% magnesium sulfate wet and hot compress.The effective rate was 40% in 14 cases, 46.7% in 12 cases, and 13.3% in 4 cases, all of which were significantly higher than that in the control group.

Hemorrhoid
The external application of mirabilite can locally soften hemorrhoids, allowing them to easily peel off (Su et al., 2015).Wei. (2007) decocted, fumigated, and hot-applied the traditional Chinese medicine Pixiao (mirabilite) to hemorrhoids.Among the 1002 patients, 890 were cured, 106 experienced drug efficacy, and 6 experienced no drug effect.The total effective rate was 99.40%.Wang and Xu (2013) applied mirabilite to the wound surface of patients with mixed hemorrhoids after external stripping and internal ligation, and the clinical effect was significant.

Skin diseases
As early as in the Tang Dynasty, Sun Simiao's Bei Ji Qian Jin Yao Fang (AD 652) had records of using mirabilite to treat dermatitis and skin diseases.The external application of mirabilite decoction in the treatment of children with erysipelas was also recorded in Zi Mu Mi Lu.

Herpes
Herpes belongs to the category of snake strand trauma in traditional Chinese medicine, which is mostly caused by heat toxin.The application of mirabilite can lead the heat toxin to dissipate rapidly from the stool (Liu and Lu, 2021).Fu (2011) tested the effectiveness of mirabilite solution in treating genital herpes, the results showed good therapeutic effects.Peng et al. (2018) also stated that the external wet compress of mirabilite and alum in the treatment of herpes has the characteristics of multicomponent, multitarget, definite curative effect, and less adverse reactions.

Acne
Acne belongs to the category of comedone in traditional Chinese medicine.The purpose of applying mirabilite is to clear heat and detoxification, disperse blood stasis, and eliminate acne.Bai. ( 2012) treated 72 cases of acne with external washing of mirabilite solution combined with the oral administration of Yeju Qushi Decoction, and 39 cases were cured.Among them, 20 cases were markedly effective, 10 cases were effective, and 3 cases were ineffective.The total effective rate was 95.8%.Li et al (2011) has achieved good results in the treatment of dampheat acne by external washing with Xiaofan pulvis (mirabilite preparation) combined with the oral administration of Cuochuang decoction or Longdan mixtures.Wu et al. (2007) achieved positive outcomes by immersing verruca vulgaris in a saturated mirabilite solution for 1 month.

Breast accumulation, breast distention, mastitis
The accumulation of breast, which cannot be excreted, can lead to breast distension and mastitis (Xu and Li, 2011).A possible reason why the external application of mirabilite is effective for postpartum milk return is that its main component can absorb the surrounding water with the help of osmotic pressure in a hypertonic environment (Shen, 1997).In addition, the salty taste of mirabilite softens the breasts, and its cold character lowers the temperature of the skin, normalizes the body temperature, opens the mammary ducts, and promotes the discharge of milk, which plays a role in the return of milk (Zou and Li, 2008).Li et al. (2022) applied mirabilite and raw R. palmatum to prevent breast accumulation in parturient.The results showed that postpartum milk lactation time in the observation group was significantly better than that in the control group, and the treatment in the observation group could effectively prevent the incidence of breast congestive swelling, milk stasis and acute mastitis.Shuhui Yu (Yu et al., 2006) applied fermented dough to the right breast in the observation group and Pixiao (mirabilite) to the left breast, while the control group treated the right breast with traditional methods and applied fermented dough to the left breast.Results, the effective rate of the group was 93%, which was significantly higher than that of the group and the traditional treatment group.Dai and Liu (2004) used the external application of mirabilite for the treatment of patients with postpartum breast distension and recorded a clinical effectiveness rate of 96.67%.Ye et al. (2013) used the traditional technique of lactation and applied 1000 g of mirabilite external compresses on the breasts for 3-5 days; 22 patients were successfully treated.Jiang (2013) externally applied mirabilite to the breasts and combined it with internal administration of Mianhuai pulvis for 3-5 days.The total effective rate was 100%.Liu (1993) treated postpartum patients with lactation deficiency by externally applying mirabilite, and the clinical effective rate was 88.9%.In the study of Xu and Li (2011), the hot compress of mirabilite and Gualou Niubang decoction showed a total effective rate of 97.9% for the treatment of mastitis.Liao reported that the topical treatment of mastitis with mirabilite plus Jinhuang pulvis could quickly eliminate silting and control infection.

Intestinal preparation before microscopic examination
Mirabilite is a purgation drug, and its purgative effect has been exploited by some scholars for intestinal preparation before microscopic examination (Wu et al., 2009).Yang and Zhang (2019) applied polyethylene glycol electrolyte pulvis combined with 20% mirabilite solutionm, and the results showed that the effective rate of intestinal cleaning before colonoscopy was 100% and the incidence of adverse reactions was 2.12%, which was significantly lower than 17.78% in the control group.She et al. ( 2014) randomly divided 44 subjects into experimental group and control group.The experimental group was orally given mirabilite solution, and the control group was orally given polyethylene glycol electrolyte pulvis.Before colonoscopy, the amount of residual fecal water in the treatment group was significantly less than that in the control group, and the intestinal foam was significantly less than that in the control group.Zhu et al. (2013) divided 462 subjects into four groups (mirabilite group, polyethylene glycol electrolyte pulvis group, mannitol group, magnesium sulfate group).Before colonoscopy, no significant difference in the excellent and good rate of intestinal cleaning, the incidence of adverse reactions, and the excellent and good rate of comfort during medication was observed in the four groups.

Muscle paralysis
Qing Liu (in Frank et al., 2006) found that sodium sulfate injection has a significant recovery effect on Na + -K + pump dysfunction and can treat periodic muscle paralysis.Shuhua Zhu (in Frank et al., 2006) found that mirabilite combined with electric shock had a good effect on myocardial fibrosis.Br Med J (Vecht et al., 1989) found that sodium sulfate solution has a certain remission effect on polio patients.Chengguo Yang (in Frank et al., 2006) confirmed that sodium sulfate solution had a significant remission effect on patients with toxic muscle paralysis, and the effective rate was 93.5%.

Discussions
Mirabilite is a natural mineral medicine with simple chemical composition (Wang, 2022).Its main component is sodium sulfate decahydrate (Na 2 SO 4 •10H 2 O), and it contains small amounts of sodium chloride, magnesium sulfate, calcium sulfate, and other inorganic salts (Wu, R. et al., 2007).Owing to the lack of knowledge of mineral composition, the ancient Chinese often confused mirabilite with saltpeter.Compared with mirabilite, which refers to the mineral with sodium sulfate as the main component, saltpeter is the mineral with potassium nitrate as the main component (Wei et al., 2022).The pharmacological effect of mirabilite is closely related to its chemical composition.When SO 4 2− in sodium sulfate is applied externally, a hypertonic salt solution is formed locally and prompts the tissues to exudate water in vitro (Liu, 2019).It is not easy to be absorbed by the intestinal mucosa when taken orally and forms a hypertonic salt solution in the intestine.While adsorbing a large amount of water, it can expand the intestine, causing mechanical stimulation, promoting intestinal peristalsis, and thus causing a defecation effect (Yu, 2000).Sohn et al. (2009) found that mirabilite solution can also relax the surrounding blood vessels, increase absorption, reduce exudation, promote blood circulation, achieve the effect of removing blood stasis, dispersing knots, detumescence and promoting wound healing through the special reaction of sodium salt and sulfate in mirabilite solution.The physical and chemical properties of mirabilite are also one of the reasons for its pharmacological effects.Mirabilite has good moisture absorption, a low freezing point, and its characteristics of absorbing heat.External application of 10%-20% mirabilite solution can accelerate lymphatic circulation, enhance the phagocytic function of reticular endothelial cells, reduce local leukocyte infiltration, and reduce inflammatory response.At the same time, it can expand local blood vessels, accelerate blood flow, improve microcirculation, enhance the phagocytic ability of monocytes, and promote the absorption and dissipation of inflammation.It has anti-inflammatory and analgesic effects and prevents infection (Wu et al., 2007).Qiao Yin and Zhu (2021) and Ying et al. (2003) added 40% mirabilite solution to the medium containing common pathogenic bacteria, and found that the common pathogenic bacteria were not inhibited, indicating that mirabilite did not have a bacteriostatic effect.Recent studies also found that mirabilite has cholesterol-lowering, anti-colon cancer, regulating intestinal flora, anti-muscle paralysis, and analgesic effects.Despite the many pharmacological studies on mirabilite, some problems remain to be solved and improved.For example, current pharmacological experiments of mirabilite lack studies on its active ingredients, which must be a breakthrough in future experiments.Part of the pharmacological mechanism of mirabilite remains unclear.For example, how mirabilite stimulates the reticuloendothelial system, promotes the proliferation of endothelial cells enhances the phagocytosis of cells, and then improves the mechanism of human immune function is still not fully understood (Fu et al., 2023).The mechanism of mirabilite in regulating intestinal flora, increasing the abundance of intestinal flora, and exerting analgesic effects is still less studied.Relevant technologies such as ICP-MS, LC-MS, and GC-MS can be used to analyze the active components in mirabilite to clarify its pharmacological mechanism.Given that most pharmacological research results are obtained through animal models, their effectiveness cannot be fully proved; therefore, additional clinical trials with confirmatory results are needed (Ning et al., 2016).For example, the cholesterol-lowering and anti-colon cancer effects of mirabilite are still only in the experimental stage and have not been applied in clinical practice.
At present, the processing methods and processing indexes of mirabilite in China have not been unified.Taking the yield of mirabilite as the index, Zhang et al. (1998) used the orthogonal design test method to obtain the best process parameters as follows: per 100 kg of Poxiao (mirabilite), 10 kg of radish, 250 kg of water, decoct for 10 min, filter, and crystallize the filtrate at 2 °C-4 °C.Zheng et al. (2015) took the mass fraction of magnesium ions in mirabilite as the index and obtained the optimum processing technology by orthogonal test: natural mirabilite powder was dissolved in fivefold volume of water at 40 °C water bath, allowed to stand for 30 min; afterward, 0.1-fold of the amount of radish was added to the supernatant for decoction for 60 min and crystallized at < 4 °C for 12 h.In terms of temperature, Zhou (1987) showed that the crystallization rate of mirabilite was the highest at 2 °C-4 °C.Mao (1984) used the solubility curve of mirabilite to calculate that the optimum crystallization temperature of mirabilite, which was 0 °C.The research also focused on how to make the drug clean and moderate the nature of the medicine.Li (1999) proposed that the sweet taste and warm character of radish can neutralize the salty taste and cool character of mirabilite and enhance its effect of purging and softening through the work of radish.According to traditional Chinese medicine, boiling radish, which processes mirabilite, is a warm character, so it can alleviate the cool character of mirabilite.The character and taste here originate from the theory of four characters and five tastes in the traditional Chinese medicine properties.The theory was first recorded in the preface of Shen Nong Ben Cao Jing (Wang and Xue, 2008), stating that medicine has four character: cold, hot, warm, and cool.In general, cold and cool medicine have functions such as clearing heat, detoxifying, cooling blood, and nourishing Yin and are mainly for treating heat diseases.Warm and hot medicine have functions such as warming the spleen and stomach, dispersing cold, and aiding Yang and are mainly for treating cold diseases (Zhao, 2008).The theory of character and taste can reflect the inherent attributes of medicine and guide clinical medication (Li and Zhang, 2023), which is an important attribute of traditional Chinese medicine.When the character of traditional Chinese medicine is too much, which will have an adverse effect on the body.Processing traditional Chinese medicine with opposite properties can effectively solve this problem (Deng, 2017).Jiang et al. (2011) found that after the processing of Coptis chinensis by Tetradium ruticarpum juice, which has a hot character, the phenolic acids, and alkaloids were increased, alleviating the cold character of C. chinensis.The study on the changes of chemical components and the mechanism of action before and after the processing of mirabilite is limited.Tibetan medicine work Jing Zhu Ben Cao (Pontso, 2012) stated that the mechanism of adding radish for co-cooking during mirabilite processing is that radish can adsorb the salt of mirabilite, reduce the amount of Na + , recrystallize mirabilite, reduce the taste of salty and bitter, and increase the taste of sweet and the character of cool (Tibetan medicine stated that radish is cool character, so it can enhance the cool character of mirabilite).Lu (1993) also reported that processing mirabilite with radish could reduce the content of Na + and the side effects of pure sodium sulfate, which was beneficial to detumescence.Yongxue Zhou (Zhang et al., 2018) proposed that the content of sodium in mirabilite after radish processing decreased slightly, that of calcium and magnesium decreased significantly, and that of potassium increased significantly; no heavy metal lead was detected.Mirabilite absorbs zinc, manganese, and iron in radish, which in turn adsorbs copper, lead, and chromium, in mirabilite.Some scholars questioned the processing of radish with mirabilite.Xu (1986) took the yield of mirabilite as the investigation index and found that the crystallization yield of mirabilite without radish was higher than that of radish itself.The coarse grain of mirabilite is also entrained with toxic impurities, which will affect the effect of treating diseases and cause damage to the human body (He and Wang, 2020).In view of these findings, the processing of mirabilite is extremely important.Advanced analytical methods such as UPLC-Q-TOF-MS should be used to analyze the changes of various inorganic salts and active ingredients before and after the processing of mirabilite.The pharmacodynamic comparative study on the effects of purgation and detumescence before and after the processing of mirabilite deeply reveals the scientific connotation of processing mirabilite with radish, providing the basis for optimizing the processing technology of mirabilite, further standardizing the traditional processing technology of mirabilite, establishing the operation rules of production technology, refines the technical parameters, and formulating the quality standard of radish-made mirabilite.
To date, no pharmacokinetic studies have been performed on mirabilite as a single drug.The absorption, distribution, metabolism, and excretion of mirabilite in the body and the changes in blood concentration with time after taking mirabilite remain unclear.Although pharmacokinetic studies were conducted on mirabilite preparations, such as Dachengqi decoction (Yang, 2012), Dahuang Mudan decoction (Nong et al., 2019), Taohe Chengqi decoction (Fan et al., 2001), these investigations are enough to replace the study of mirabilite as a single drug.Preparations contain many medicinal materials and complex components, and distinguishing which metabolite belongs to mirabilite is difficult.Therefore, the pharmacokinetics study of mirabilite must be strengthened.The chemical composition of mirabilite is not toxic, but its main component sodium sulfate will be metabolized in the body as a small amount hydrogen sulfide that will be hydrolyzed to sulfur ions.Sulfur ions are easily absorbed by digestive tract epithelial cells, reducing the levels of peroxidase horseradish (HRP), catalase (CAT), and dopa oxidase (DO) in the body, causing sulfur poisoning, and affecting the level of oxidative metabolism in the body.Sulfides have a paralytic effect on vascular arteries.The combination of sulfides and heme produces thiohemoglobin, which reduces the oxygen load capacity of the blood and induces severe dyspnea (Liu, F., 2018).Murray et al. (1998) found that 30% sodium sulfate solution can significantly cause Ca 2 + outflow and K + influx in neuromuscular cells, which is toxic to neuromuscular cells.In general, the clinical application of mirabilite should not focus on its biological therapeutic effect but also consider the toxic and side effects caused by its metabolism in vivo.Therefore, the clinical and experimental research on the toxicology of mirabilite must be strengthened.
The clinical application of mirabilite is highly consistent with the records of traditional Chinese medical works.According to the first record of mirabilite in Shen Nong Ben Cao Jing to the Qing Dynasty, mirabilite was widely used in various internal prescriptions, mainly for the treatment of various heat syndromes and constipation, such as abdominal fullness and pain, stool dryness, intestinal carbuncle swelling, and pain.External application is less used and only sporadically adopted for the treatment of breast carbuncle and skin diseases.In the Shen Nong Ben Cao Jing, Poxiao (mirabilite) can transform 72 kinds of stones.In the Tang Dynasty Shi Yao Er Ya (AD 806), mirabilite was called "Huajinshi;" however, it was less mentioned in clinical reports.Recent research on the external application of mirabilite has gradually increased.Mirabilite has been widely used in various types of inflammation, edema, wound healing, skin, breast, and gastrointestinal diseases.External application is one of the characteristic therapies of traditional Chinese medicine, allowing the drug components to be absorbed through the skin so they can directly reach the disease and perform their role.Relevant literature showed that the external application of mirabilite is common in clinical usage.Mirabilite can externally applied alone or in combination with other treatments.For example, Mao (2023) utilized a single external application of mirabilite for the treatment of foot swelling after closed calcaneal fracture.For combined external applications, Zhang et al. (2022) used mirabilite combined with Borneolum syntheticum to treat the early swelling of the middle and lower 1/3 fracture of the closed tibia and fibula.Zhang et al. (2022) employed mirabilite and Tetradium ruticarpum to treat pancreatitis and abdominal distension.The external application of mirabilite is also combined with traditional Chinese medicine, such as traditional Chinese medicine prescription (Miao et al., 2023), auricular point pressing (Zhang et al., 2022), acupoint massage (Lin et al., 2023), and warm needle (Gulishaera et al., 2015).With the prevalence of external application of mirabilite, the production of external application bags is gradually reaching perfection (Lu et al., 2012;Wang, 2015).Owing to the barrier effect of the stratum corneum of the skin, the traditional external application method has a low absorption efficiency for the drug.Ultrasonic drug introduction is clinically used to improve the penetration of topical drugs (Yang et al., 2017).At present, the hot and cold methods of mirabilite external application of are not uniform.In China, ice packs combined with mirabilite are known to reduce posttraumatic swelling and pain (Wang et al., 2020;Yu et al., 2009), so the traditional external application is ice compress.For example, Li (2014) proposed that cold compress therapy is one of the commonly used treatments in the early stage of acute trauma.Some scholars also stressed that the external application of mirabilite should be a hot compress, such as Qingyun Ye treatment with mirabilite hot and humid compress for hematoma (Ye and Lu, 2013).Li and Duan (2010) used a mirabilite hot compress to treat gouty arthritis, Xu and Li. (2011) used a mirabilite hot compress to treat acute mastitis, and Wang et al. (2017) used R. palmatum combined with mirabilite hot compress to reduce the occurrence of pancreatic leakage in severe acute pancreatitis.They proposed that a hot compress of mirabilite can accelerate the movement of mirabilite molecules according to the thermal principle, promote the absorption of intraabdominal exudate, increase local blood circulation, and improve the therapeutic effect and comfort (Liu et al., 2022).An increasing number of scholars have begun to pay attention to the therapeutic effect of mirabilite on colon cancer.For example, Grosso et al. (2014) found that the occurrence of colon cancer in Mediterraneans is closely related to their diet.Mirabilite can treat colorectal cancer by regulating bile acid metabolism and lipid metabolism.However, no clinical report is available on the treatment of colon cancer with mirabilite.Mirabilite has a strong defecation effect.Some scholars proposed that laxatives promote the excretion principle.Mirabilite should have a good therapeutic effect on various infectious diseases in modern medicine and metabolic diseases such as fatty liver, diabetes, and obesity (Liu et al., 2016).In clinical use of mirabilite, its internal use should not be decoction because the main component of mirabilite is the sulfate of 10 crystal waters, which is easily soluble in water and will hydrolyze under boiling conditions.Its composition changes, altering its activity (Fan et al., 2001;Nong et al., 2019).Mirabilite is also an inorganic salt.It is fried with other drugs, which can reduce the solubility of saponins, alkaloids, and other active ingredients.In addition, the oral administration of mirabilite easily causes nausea (Wu et al., 2009).At present, only a few studies are available on whether different administration methods such as external application and internal administration of mirabilite affect the clinical efficacy of the disease.Only Yuemei Liu proposed the treatment of constipation with mirabilite.Compared with oral or external administration, the effect of enema with mirabilite solution is more evident.In addition, only a few studies focused on the optimal duration of external application of mirabilite.Only Zhidong Zhang mentioned that the external application of mirabilite for 8 and 12 h had minimal treatment effect.The dose-effect relationship of mirabilite efficacy remains unclear.Liu (2018) found that the external application of high-dose mirabilite solution in the treatment of acute myocardial infarction with constipation sometimes has inferior efficacy over the medium and low doses.The number and frequency of clinical use of mirabilite by many doctors are not the same.At present, no basic consensus has been reached on the optimal dosage and frequency of clinical use of mirabilite.The dose, frequency, and mode of administration of mirabilite affect its dissolution and absorption in the gastrointestinal tract and tissue skin, which largely determine its efficacy in the treatment of diseases (He and Wang, 2020).These subjects must be the focus of further studies on mirabilite.

Conclusion
The medicinal history of mirabilite in China and its chemical composition, processing methods, pharmacology, toxicology, and clinical application were comprehensively described for the first time.As a natural mineral medicine, mirabilite has a simple chemical composition, mainly containing sodium sulfate decahydrate (Na 2 SO 4 •10H 2 O) with a small amount of sodium chloride, magnesium sulfate, calcium sulfate, and other inorganic salts.Mirabilite is widely used in nine ethnic groups (Han, Dai, Kazak, Manchu, Mongolian, Tujia, Uygur, Yi, Tibetan) and a large number of prescription preparations in China.Since the Ming Dynasty, radish processing has become the mainstream processing method of mirabilite in China.The pharmacological effects of mirabilite include antiinflammatory detumescence, promoting cell proliferation, wound healing, gastrointestinal motility, and water discharge, regulating intestinal flora; lowering cholesterol, anti-muscle paralysis, anti-colon cancer, and analgesic.External application of mirabilite can cause local skin to become flushed or itching.Its oral administration is toxic to neuromuscular cells, and the sulfur ions of its metabolites will also be toxic to the human body.Mirabilite is widely used in the clinical treatment of inflammation, edema, wound healing, digestive system diseases, infusion extravasation, hemorrhoids, skin diseases, breast accumulation, muscle paralysis, intestinal preparation before microscopic examination, and other diseases and symptoms.
Mirabilite is rich in reserves, easy to obtain, widely used in clinical practice, and has a good application prospect.However, its processing methods, active ingredients, quality control, pharmacokinetics, pharmacology and toxicology mechanisms, and standardized clinical application require further studies.In the future, the following three aspects of research on mirabilite should be strengthened.The first is to standardize the processing of mirabilite and provide a basis for formulating the quality standard of mirabilite.The second is to strengthen the discovery of active components in mirabilite and clarify the mechanism of its pharmacological effects.The third is to carry out standardized dose-effect relationship research to lay the foundation for its clinical application.
treated them with nasal feeding mirabilite plus raw R. palmatum powder, Wang (2009) treated them with mirabilite plus external application of R. palmatum, Xu. (2010) treated them with external mirabilite application, and Sun et al. (2010) treated them with external application of mirabilite combined with nasal feeding Liqi Tongbian decoction.Leng et al. (2016) stated that mirabilite can achieve satisfactory results in controlling IAP (intraabdominal pressure) in critically ill patients.

TABLE 2
Application of mirabilite in Chinese traditional medicine.

TABLE 3
Application of mirabilite in traditional Chinese medicine preparations.

TABLE 3 (
Continued) Application of mirabilite in traditional Chinese medicine preparations.

TABLE 3 (
Continued) Application of mirabilite in traditional Chinese medicine preparations.

TABLE 4
Classification statistics of mirabilite preparation indications.

TABLE 5
Processing methods of mirabilite in Chinese Pharmacopoeia and local standards.
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