Updated Research Report: Traditional Chinese Herbal Medicine for Allergic Diseases – newvita

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Research Update: Traditional Chinese Herbal Medicine for Allergic Diseases

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Chenyang Ai, Yi Zou, Hao Liu, Zheqiong Yang, and Jinlei Xi
https://doi.org/10.1142/S0192415X23500374

Abstract

The prevalence of allergic disorders has increased in recent years, lowering patients’ quality of life and increasing the demand for drugs to treat these diseases. Western drugs such as glucocorticoids, antihistamines, and leukotrienes are routinely utilized in clinics. However, drawbacks like high recurrence rates and adverse effects limit their use. As one of the most promising natural medicine systems, traditional Chinese medicine offers distinct benefits in treating allergic illnesses, such as maintaining long-term treatment, preventing disease recurrence, and producing fewer adverse reactions. We analyzed and discussed recent developments in traditional Chinese medicine used in allergic diseases from three perspectives: Chinese herbal formula, Chinese patent medicine, and active ingredients of traditional Chinese medicine, and explained their main components, efficacy, and mechanisms of action. We also reviewed the modification of Chinese herbal formulas and the combined application of Chinese medicine with Western medicine or non pharmaceutical therapies. Traditional Chinese medicines are becoming increasingly important in treating allergic disorders. Improving traditional Chinese herbal formulas and developing safe and effective Chinese patent medicines are currently the most pressing and important aspects of research on traditional Chinese medicine.

Introduction

Allergic diseases are a group of conditions caused by hypersensitivity of the immune system to normally harmless substances in the environment, known as allergens. These diseases include allergic rhinitis, asthma, atopic eczema, allergic purpura, anaphylaxis, and food allergies. Common allergic reactions primarily affect the respiratory tract, digestive tract, and body skin, manifesting as sneezing, a runny nose, shortness of breath, abdominal pain, an itchy rash, or swelling (Li, 2007Cardona et al., 2020). Allergic diseases are polygenic diseases influenced by genes, the environment, immunity, and other factors.

With the advancement of industrialization and the continuous pollution of the environment caused by human activities, the prevalence of allergic diseases continues to increase. According to a World Allergy Organization (WAO) report, the prevalence of allergic diseases has more than tripled in the last 30 years, with the current global prevalence standing at 22% (Warner et al., 2006). Over 4 billion people will have asthma and allergic rhinitis by 2050 (Lötval et al., 2014). WAO has identified allergic diseases as one of the three major diseases that must be studied and effectively prevented in the 21st century. The International Study of Asthma and Allergies in Childhood (ISAAC) announced that the number of children with allergic asthma and rhinitis continues to significantly increase worldwide (Asher et al., 2006). However, the overall control rate of allergic diseases is low. According to a survey, the global control rate of asthma is less than 50% (Haselkorn et al., 2010). The high prevalence of allergic diseases is attributed to genetic and environmental factors. (D’Amato et al., 2001Wong and Chow, 2008; Anderson et al., 2010). Allergic diseases cause patients not only physical pain but also mental stress. Adults and children with allergic diseases have varying degrees of impairment in health-related quality of life (HRQL). Adults are primarily affected by sleep disorders, dispersed attention, and lack of motivation, while the impacts on children are manifested in learning and emotional disorders (Meltzer et al., 2021). Raising public awareness of allergic diseases, optimizing dosing regimens, and disseminating standardized treatment are all necessary steps toward lowering the prevalence of allergic diseases.

Currently, the treatment of allergic diseases is primarily based on Western medicine, with standard treatment options such as allergens blocking and anti-allergic drug administration. Although western anti-allergic medicine has specific curative effects, it also shows substantial side effects and high recurrence rates (Wang et al., 2015). Therefore, available anti-allergic western medicines cannot fully meet the needs for treating allergic diseases. The commonly used anti-allergic western medicines include five categories, which were defined according to their mechanism of action: antihistamines, leukotriene receptor antagonists, mast cell stabilizers, corticosteroids, and vasoconstrictors (Table 1).

Table 1. Commonly Used Anti-Allergic Western Drugs

Category Drug Clinical Usage Common Adverse Effects
Antihistamines Olopatadine (Shah et al., 2009) Allergic conjunctivitis, allergic rhinitis, chronic asthma, urticaria Headache, debility, cold-like symptoms, pharyngitis, rhinitis, sinusitis, and dysgeusia
Bilastine (Okubo et al., 2017) Allergic conjunctivitis, allergic rhinitis, urticaria Headache, dizziness, fatigue, asthenia, anxiety, insomnia, sinus arrhythmia, vertigo, tinnitus, nausea, diarrhea, dry mouth, dyspepsia, gastritis, abdominal pain, pyrexia, oral herpes, somnolence, nasal dryness, dyspnoea, pruritus.
Leukotriene inhibitors Zafirlukast (Fish et al., 1997) Chronic asthma Headache, infection, nausea, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia, fever, back pain, vomiting, SGPT elevation, dyspepsia
Montelukast (Virchow and Bachert, 2006) Allergic rhinitis, chronic asthma Headache, abdominal pain, diarrhea, rhinitis, otitis media, cold-like symptoms, fever, cough, runny nose, pharyngitis, sinusitis, upper respiratory tract infection
Mast cell stabilizer Ketotifen (Greiner et al., 2003) Allergic conjunctivitis, allergic rhinitis, bronchial asthma, Weight gain, nasal dryness, drowsiness, lethargy, headache, dizziness, dry mouth, nausea, conjunctival hyperemia, corneal erosion, blepharitis
Sodium cromoglycate (Meltzer, 1995) Allergic rhinitis, allergic conjunctivitis, bronchial asthma Irritating cough, eye and nose irritation, allergic reaction
Glucocorticoids Budesonide (Szefler and Eigen, 2002) Bronchial asthma, allergic rhinitis Hoarseness, oropharyngeal candidiasis, urticaria, pruritus, depression, anxiety, restlessness, adrenal insufficiency and hyperactivity, bronchospasm, hypersensitivity reactions, anaphylactic shock, growth retardation
Prednisone (Rehrer et al., 2016Barniol et al., 2018) Bronchial asthma, acute urticaria Infections, diabetes, peptic ulcer, Cushing’s syndrome, insomnia, depression, headache, dizziness, hypokalemia, pancreatitis, weight gain
Vasoconstrictor Oxymetazoline (Baroody et al., 2011) Allergic rhinitis Rebound nasal congestion, drug-induced rhinitis, headache, dizziness, tachycardia
Pseudoephedrine (Sussman et al., 1999) Sinusitis, congestive rhinitis, bronchial asthma Insomnia, headache, tachycardia, increased blood pressure

Traditional Chinese medicine (TCM), one of the world’s oldest traditional medicine forms, has been used to treat allergic diseases for thousands of years, and many formulas are still in use today (Li, 2007). For example, Cassiabarktree Twigs and Ephedra Decoction from Treatise on Cold Damage, a well-known medical book from the Eastern Han Dynasty, is a Chinese classic herbal formula used for treating allergic diseases that is still widely used today in the treatment of urticaria and skin itching (Yu and Li, 2014). Unlike Western medicine, TCM emphasizes the overall concept of diseases and treats both symptoms and root causes with multi-level and multi-targeting actions, milder effects on internal organs, and less toxic side reactions.

Traditional Chinese Herbal Formulas for Allergic Diseases

Chinese classic herbal formulas are combinations of different herbs used in Chinese herbology to increase the efficacy of individual herbs. Traditional Chinese herbal formulas (TCHFs) are treatments tailored to the individual. Classic formulas can be adapted to meet the needs of each patient based on the differentiation of syndromes and diseases (Liu, 2010). TCHFs are widely used in anti-allergic therapy (Table 2). Minor Blue Green Dragon Decoction from Treatise on Cold Damage can effectively relieve asthma symptoms and improve pulmonary function (Zang et al., 2021). Coptis Toxin-Resolving Decoction from Arcane Essentials from the Imperial Library has an anti-allergic rhinitis effect. Its effects gradually increased as the dose increased in the 5–20

mg/kg range. The 20mg/kg dose reduced the behavioral score of allergic rhinitis mice from 6.49 to 2.18 and the amount of nasal secretions from 12.48mg/d to 4.18mg/d (Liu et al., 2021a). The Wind-Dispersing Powder recorded in Orthodox Lineage of External Medicine can significantly relieve atopic dermatitis symptoms. Over an 8-week course of treatment, Wind-Dispersion Powder reduced the overall symptom score of patients with atopic dermatitis by 79.7 points without causing significant side effects, compared with a drop of 13.5 points in the placebo group (Cheng et al., 2011). Jade Wind-Barrier Powder, included in Teachings of Dan-xi, not only reduced the allergy symptom score of mice with allergic rhinitis from 7.88 to 4.23 by effectively easing the inflammatory response, but also exhibited a significant therapeutic effect on cough variant asthma with a reduction in the ratio of CD4 to CD8

in patients from 1.68 to 1.04. Fluticasone propionate, a positive control, only reduced the ratio from 1.63 to 1.61. Furthermore, after undergoing treatment with Jade Wind-Barrier Powder, patients with cough variant asthma had a 14.29% recurrence rate, which was lower than the fluticasone-treated group’s 37.84% (Wang and Hu, 2016; Yang et al., 2018). Rhinoceros Horn and Rehmannia Decoction in Important Formulas Worth a Thousand Gold Pieces for Emergency was used to treat allergic purpura, potentially lowering the patient’s symptom score from 15.93 to 3.33 (Song et al., 2022).

Table 2. Commonly Used Anti-Allergic Chinese Herbal Formulas

Formulas Ingredients Generated Time Clinical Application Mechanism of Actions
Minor Green Dragon Decoction (Zang et al., 2021) Ephedrae Herba, Cinnamomi Ramulus, Paeoniae Radix Alba, Asari Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Zingiberis Rhizoma, Pinelliae Rhizoma, Schisandrae Chinensis Fructus Eastern Han Dynasty Bronchial asthma, allergic rhinitis
IgE level in the serum
IL-10 expression in the lung

Th1 and Th2 number in the lung

restore the balance between Th1 and Th2
Peony and Liquorice Root Decoction (Dong et al., 2014) Paeoniae Radix Alba, Glycyrrhizae Radix et Rhizoma Eastern Han Dynasty Bronchial asthma
Eosinophil number in lung
IL-13 level in the serum
STAT6 expression in airway epithelium
Mast cell granulation
Ephedra Decoction (He et al., 2018) Ephedrae Herba, Cinnamomi Ramulus, Armeniacae Semen Amarum, Glycyrrhizae Radix et Rhizoma Eastern Han Dynasty Allergic rhinitis

The level of TXB2, MMP-9, IL-2, IL-4, IL-5, and TNF-

in the serum
The expression of IL-21, IL-21R, STAT3, and p-STAT3
Histamine threshold
Ophiopogon Japonicus Decoction (Li, 2007) Ophiopogonis Radix, Pinelliae Rhizoma, Panacis Quinquefolii Radix, Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma Eastern Han Dynasty Bronchial asthma
IgE level in serum
Cassiabarktree Twig and Ephedra Decoction (Han et al., 2019Zhu, 2019Mou, 2021) Cinnamomi Ramulus, Paeoniae Radix Alba, Ephedrae Herba, Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum, Schizonepetae Herba, Saposhnikoviae Radix, Sophorae Flavescentis Radix,Dictamni Cortex, Kochiae Fructus, Portulaca oleracea, Liquidambaris Fructus, Zingiberis Rhizoma Recens, Jujubae Fructus, Eastern Han Dynasty Urticaria
IgE level in serum
Coptis Detoxification Decoction (Liu et al., 2021a) Coptidis Rhizoma, Phellodendri Chinensis Cortex, Scutellariae Radix, Gardeniae Fructus, Eastern Jin Dynasty Eczema

The expression of IL-5, IL-4, mCLCA3, MUC5AC, TLR4, and NF-

B p65
Jade Wind-Barrier Powder (Yang et al., 2018) Astragali Radix, Atractylodis Macrocephalae Rhizoma, Saposhnikoviae Radix Yuan Dynasty Bronchial asthma, cough variant asthma, allergic rhinitis
Th1/Th2 ratio
Wind-Dispersing Powder (Yang et al., 2013) Angelicae Sinensis Radix, Saposhnikoviae Radix, Atractylodis Rhizoma, Anemarrhenae Rhizoma, Sophorae Flavescentis Radix, Schizonepetae Herba, Rehmanniae Radix, Arctii Fructus, Sesamum indicum, Gypsum Fibrosum, Cicadae Periostracum, Glycyrrhizae Radix et Rhizoma, Akebiae Caulis Ming Dynasty Bronchial asthma, eczema, Henoch-Schonlein purpura
IgA level in the serum
Guomin Decoction (Pang and Yang, 2019) Stellariae Radix, Saposhnikoviae Radix, Fructus Mume, Schisandrae Chinensis Fructus, Glycyrrhizae Radix et Rhizoma Modern time Eczema, Henoch-Schonlein purpura
NO level in the lung
Yangyin Zhixue decoction (Zheng et al., 2014) Rehmanniae Radix, Ophiopogonis Radix,Glycyrrhizae Radix et Rhizoma, Scrophulariae Radix Fritillariae Thunbergii Bulbus, Moutan Cortex, Menthae Haplocalycis Herba, Paeoniae Radix Alba Qing Dynasty Henoch-Schonlein purpura
IL-6 in the serum
IL-2 in the serum
Ephedra, Apricot Kernel, Licorice and Gypsum Decoction (Zheng and Qu, 2022) Armeniacae Semen Amarum, Ephedrae Herba, Glycyrrhizae Radix et Rhizoma, Gypsum Fibrosu Eastern Han Dynasty Allergic rhinitis
IgE expression Restore the disorder of T cell subsets
Blackberrglily Rhizome and Ephedra Decoction (He et al., 2021) Belamcandae Rhizoma, Armeniacae Semen Amarum, Asteris Radix et Rhizoma, Pinelliae Rhizoma, Ephedrae Herba, Bombyx Batryticatus, Pheretima, Flos Farfarae, Schisandrae Chinensis Fructus, Cicadae Periostracum, Glycyrrhizae Radix et Rhizoma, Asari Radix et Rhizoma, Eastern Han Dynasty Bronchial Asthma
Th2 and Th17 differentiation
Angelica Yinzi (Bao et al., 2020) Angelicae Sinensis Radix, Paeoniae Radix Alba, Chuanxiong Rhizoma, Rehmanniae Radix, Tribuli Fructus, Saposhnikoviae Radix, Schizonepetae Herba, Polygoni Multiflori Radix, Astragali Radix, Glycyrrhizae Radix et Rhizoma Song Dynasty Chronic urticaria
The level of LTB4 in the serum
Ephedra, Forsythia, and Rice Bean Decoction (Zuo et al., 2021) Vignae Semen, Mori Cortex, Fagopyri Dibotrydis Rhizoma, Forsythiae Fructus, Poria, Coicis Semen, Lophatheri Herba, Scutellariae Radix, Pinelliae Rhizoma, Citri Reticulatae Pericarpium, Aurantii Fructus, Talcum, Plantaginis Semen Eastern Han Dynasty Bronchial asthma

The level of IL-4, IL-8, CRP, and TNF- in the serum IFN-

level in the serum
Minor Bupleurum Decoction (Ning et al., 2021) Scutellariae Radix, Bupleuri Radix, Pinelliae Rhizoma, Changii Radix, Glycyrrhizae Radix et Rhizoma, phedrae Herba, Armeniacae Semen Amarum, Perillae Fructus, Jujubae Fructus, Eastern Han Dynasty Bronchial asthma

IL-4 level in the serum IFN-

level in the serum
Big Green Dragon Decoction (Lu et al., 2019) Ephedrae Herba, Gypsum Fibrosu, Cinnamomi Ramulus, Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum, Zingiberis Rhizoma Recens, Jujubae Fructus, Eastern Han Dynasty Pediatric asthma

the level of IgE, IL-4, and TNF-

in the serum
Rhinoceros Horn and Rehmannia Decoction (Song et al., 2022) Stapelia luxurians Dammann ex Rust, Rehmanniae Radix, Paeoniae Radix Rubra, Moutan Cortex Tang Dynasty Henoch-Schonlein purpura
GPIIb/IIIa expression in the serum
Magnolia and Ephedra Decoction (Hu et al., 2020) Magnoliae Officinalis Cortex, Ephedrae Herba, Armeniacae Semen Amarum, Gypsum Fibrosu, Pinelliae Rhizoma, Zingiberis Rhizoma, Asari Radix et Rhizoma, Schisandrae Chinensis Fructus, Triticum aestivum Eastern Han Dynasty Bronchial asthma
The levels of Th2-related cytokines
The expression of TRPA1 and TRPV1 in the lung
Ephedra, Aconite and Asarum Decoction (Wan, 2021Zhao, 2021) Ephedrae Herba, Aconiti Lateralis Radix Praeparata, Angelicae Sinensis Radix, Angelicae Dahuricae Radix, Paeoniae Radix Alba, Xanthii Fructus, Asari Radix et Rhizoma, Cinnamomi Ramulus Eastern Han Dynasty Allergic rhinitis

The levels of IL-10, IL-4, TNF-, IL-1

Cocklebur Fruit Powder (Hu and Zhou, 2021) Magnoliae Flos, Xanthii Fructus, Angelicae Dahuricae Radix, Menthae Haplocalycis Herba Song Dynasty Allergic rhinitis
The levels of IL-4, IgE, IL-5, IL-10, and HIS in the serum

IFN-

level in the serum
AQP5 expression in the nasal mucosa

Note:

: Decrease or downregulate;

: Increase or upregulate.

The Anti-Allergic Mechanism of Traditional Chinese Herbal Formulas

It has been demonstrated that TCHFs cure allergic diseases by regulating a variety of cytokines, and that the same formula regulates different cytokines in different allergic diseases. For example, in treating allergic rhinitis, Jade Wind-Barrier Powder alleviated symptoms by increasing the ratio of Th1 to Th2 in T helper cells by promoting IFN-

expression and inhibiting Th2 expression. The therapeutic effects of Jade Wind-Barrier Powder on atopic dermatitis were accomplished by lowering thymic stromal lymphopoietin (TSL) and IL-33 levels (Gu et al., 2006Zheng et al., 2019). On the other hand, cytokines regulated by different formulas in the same allergic disease differ. Minor Blue Green Dragon Decoction reduced the serum total IgE level to treat asthma (Wang et al., 2012). In contrast, Blackberrglily Rhizome and Ephedra Decoction treated asthma by increasing Treg cells, inhibiting Th2 and Th17 cell differentiation, and disrupting the mTOR and NF-

B signaling pathways (Lin et al., 2020). Aside from influencing cytokines, TCHFs can also exert therapeutic effects on allergic diseases in other ways. Ephedra Decoction alleviated allergic rhinitis symptoms by raising the histamine threshold (Ruan et al., 2002). By inhibiting mast cell degranulation, White Peony Root and Honey-Fried Licorice Decoction postponed asthma attacks (Cai et al., 2000).

Due to the large number of components in TCHFs, parallel effects may stem from different components in the same formula. Meanwhile, interactions between formula components are possible. The details of these processes are currently poorly understood, and they may impact the efficacy of TCHFs. More research into the anti-allergic mechanism of TCHFs is thus required.

Modification and Improvement of Chinese Classic Herbal Formulas

With the rise in the prevalence of allergic disorders and the widespread use of TCHFs in clinics, there have been increasing reports of TCHFs-related side effects. For instance, among 35 patients with cough variant asthma who used Jade Wind-Barrier Powder, two experienced throat irritation, and one developed an oral candida infection (Yang et al., 2018). Besides, Ephedra Forsythia Rice Bean Decoction caused side effects such as a sore throat when used to treat bronchial asthma (Zuo et al., 2021). The cumbersome pharmaceutical process of TCHFs and the multiple chemical components in the formulas make it challenging to ensure that various ingredients meet the standard. Meanwhile, the lengthy treatment period and the peculiar odor of some herbs make the TCHFs medication process unpleasant. So, modifying the composition to improve TCHFs has become a focus of traditional Chinese medicine research. Improved TCHFs with higher therapeutic efficacy and fewer side effects enhance the patient’s medication experiences while also making it easier for ingredients to meet quality standards.

Reducing the number of components in the MSSM-002 formula, which is comprised of 14 herbs, yields ASHMI (anti-asthmatic formula for traditional Chinese medicine interventions), which contains only three herbs and is used to treat patients with severe asthma. ASHMI significantly improved lung function, with an increase in FEV1 and peak expiratory flow value (from 64.9 to 84.2) and a decrease in clinical symptom scores (from 5.0 to 2.0), serum IgE levels (from 950 to 476 kU/L), and eosinophil number (from 0.52 to

/L). FAHF-2 (food allergy herbal formula, refined), obtained by removing Aconiti Lateralis and Herba Asari from the classic formula FAHF-1 (Food allergy herbal formula), has a longer-lasting effect on food allergies than FAHF-1. FAHF-2-treated mice were completely protected from anaphylaxis after the allergen challenge for up to five weeks posttherapy, and their IgE levels remained significantly lower than those of the comparison group (Li, 2007). The removal of ephedra from Minor Green Dragon Decoction greatly improved its therapeutic effects, yielding a treatment efficacy of 95%. The modified formula usually took effect in 2–3 days by relieving frailty symptoms in children with an allergic cough, and, on average, complete remission occurred in 3–5 days (Cong and Wang, 2012).

Jade Wind-Barrier Powder supplied with the wild mint herb is more effective than the original formula in alleviating nasal congestion and a runny nose. When used to treat allergic rhinitis mice, it can reduce the nasal symptom score to 2 and lower the mast cell count and histamine level, respectively, from 62.33 to 22.13 and 19.79 to 7.81

ng/mL (Chen et al., 2021a). In patients with cough variant asthma, adding Radix Asteris to Minor Green Dragon Decoction can better relieve the symptoms of excessive and thin phlegm, while adding Cicada Slough to this formula can help relieve throat itching and sneezing. The overall efficacy of improved Minor Green Dragon Decoction in short-term treatment reached 93.3%, and the recurrence rate was reduced to 13.3%, which is significantly lower than the 38.5% efficacy of the terbutaline-treated control group (Hu, 2011).

Traditional Chinese Herbal Formulas in Combination with Other Medicines

Jade Wind-Barrier Powder combined with modified Guomin Decoction can effectively alleviate patients’ multiple symptom scores in chronic urticaria. Pruritus, fatigue, and fever scores were reduced from 2.59 to 1.29, 2.53 to 1.11, and 2.45 to 1.01, respectively. This combination also had an effect on cytokine levels. Serum IFN-

levels rose from 4.49 to 15.96pg/mL, while IL-4 and IL-8 levels decreased from 23.95 to 15.62pg/mL and 24.23 to 13.33

pg/mL, respectively. The total efficacy of the combination was 96.55%, whereas the incidence of adverse reactions was only 3.45% (Zhang et al., 2020).

In addition to herbal formulas, TCHFs can be combined with western medicine. These combinations have also been proven to be effective against allergic diseases. For instance, Minor Dragon Decoction combined with fluticasone propionate in the treatment of allergic asthma can effectively reduce multiple symptom scores (cough: 5.29 to 1.34; expectoration: 5.34 to 1.99; wheezing: 5.41 to 1.29) and serum levels of IgG4 (128.3 to 52.6

g/L) and IgE (257 to 81 IU/mL), and reduced the recurrence rate to as low as 4% (Ran and Gao, 2020). Cassia Twig and Ephedra Decoction or Jade Wind-Barrier Powder can be combined with cetirizine to treat urticaria (efficacy: 91.67–96.7%; recurrence rate: 4.17–15.52%). These combinations can effectively ameliorate the symptoms and improve the patient’s quality of life. Multiple symptom scores and serum indices were improved (pruritus: 2.69 to 0.28; rash size: 2.79 to 0.46; abdominal pain: 2.71 to 0.69; serum IgE: 141.23 to 60.78 KIU/L) (Han et al., 2019Zhang, 2021).

Joint Application of Traditional Chinese Herbal Formulas with Nondrug Therapy

The combination of Minor Dragon Decoction and desensitization in treating allergic asthma can extend the duration of the curative effects and improve patient compliance. After one year of joint therapy, the cure rate for asthma was 72.4%, with a total efficacy of 100% (Hao et al., 2016). For allergic purpuras, the combination of Anti-allergic Purpura Decoction and laser acupoint irradiation produced an overall efficacy of 92%, effectively reducing the rate of renal impairment from 33% to 20% in the prednisone-treated control group (Chang et al., 2014). The combined use of Jade Wind-Barrier Powder and acupuncture in the therapy of allergic rhinitis resulted in a cure rate of 65.0% and a total effective rate of 92.5% (Dai, 2005).

Chinese Patent Medicines (CPMs) for Allergic Diseases

Chinese patent medicines are traditional Chinese herbal medicines modernized into a ready-to-use form such as tablets, oral solutions, or dry suspensions, as opposed to herbs that require cooking (hot water extraction) (Wang et al., 2021a). There are presently 1607 CPMs in the Chinese Pharmacopoeia 2020 edition, which is an increase from 207 in the 1985 edition (Nie et al., 2021). CPMs of various types are used to treat allergic diseases (Table 3). The dosage forms of CPMs include pills, capsules, tablets, granules, etc. For example, Compound Glycyrrhizin Tablets and Injections, Xinqin Granules, Jade Wind-Barrier Granules, and Keke Capsules are commonly used in treating various allergic diseases. Compound Glycyrrhizin is usually used to treat eczema and allergic purpura (Li et al., 2005). Shiduqing Capsules have significant curative effects on skin pruritus. It can relieve the symptoms of non-immune contact urticaria induced by dimethyl sulfoxide and suppress ear swelling and skin inflammation caused by croton oil in mice (Chen et al., 1999).

Table 3. Commonly Used Chinese Patent Medicines

Medicines Main Ingredients Clinical Application Mechanism of Actions
Tripterygium Glycosides Tablet (Meng et al., 2021Luo et al., 2022) Glycine, Glycyrrhizin, Methionine Eczema Reverse the increase of IL-2, IL-6, and CRP
Shi Du Qing Capsule (Li and Zhao, 2021) Rehmanniae Radix, Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix et Rhizoma, Cicadae Periostracum, Sophorae Flavescentis Radix, Dictamni Cortex, Glycyrrhizae Radix et Rhizoma, Smilacis Glabrae Rhizoma, Scutllariae Radix Senile pruritus

The level of IL-2 and INF-

The level of IL-4 and IL-10
Paeonol Ointment (Shi et al., 2016) Paeonol, clove oil Senile pruritus Restore the balance between Th1 cytokines (IL-2 and IFN-
) and Th2 cytokines (IL-4 and IL-10)
Compound Glycyrrhizin Injection (Wang et al., 2018aKang, 2020) Glycine, Glycyrrhizin, L-cysteine hydrochloride Henoch-Schonlein purpura
levels of IgA, IgM and IgG
The level of IL-10, IL-16, IL-18 and MMP-9

INF-

level
Xiqin Granule (Zou et al., 2015Li, 2019) Asari Radix et Rhizoma, Scutellariae Radix, Cinnamomi Ramulus, Xanthii Fructus Allergic rhinitis

The level of IL-4 and IgE

IL-10 level
Bishu Dripping Pill (Zhang et al., 2004) Scutellariae Radix, Notopterygii Rhizoma et Radix, Schizonepetae Herba, Asari Radix et Rhizoma Allergic rhinitis
levels of IgE and IL-4 in serum
the ratio of CD4 to CD8
IL-12 level in serum
Kang Min Ling Oral Solution (Li et al., 2000a, 2000b,Lin and Zhang, 2010) Sinapis Semen, Corydalis Rhizoma, Kansui Radix, Asari Radix et Rhizoma, Angelicae Dahuricae Radix, Aconiti Radix, Aconiti Kusnezoffii Radix, Cinnamomi Cortex, Zingiberis Rhizoma Recens Bronchial asthma

The activity of Na-K-ATPase on erythrocyte membrane

PLA2 activity
Fang Feng Tong Sheng Pill (Chen et al., 2022) Saposhnikoviae Radix, Ephedrae Herba, Schizonepetae Herba, Menthae Haplocalycis Herba, Rhei Radix et Rhizoma, Natrii Sulfas, Talcum, Gardeniae Fructus, Scutellariae Radix, ForsythiaeFructus, Gypsum Fibrosum, Platycodonis Radix, Chuanxiong Rhizoma, Paeoniae Radix Alba, Angelicae Sinensis Radix, AtractylodisMacrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma Eczema
the IgE level in the serum
Mast cell infiltration in the skin
Th2 cytokines expression in the skin (IL-4, IL-5, IL-9 and IL-13)
Epidermal thickening
Compound Xin Yi Oral Solution (Jiang et al., 2002Xu et al., 2007) Magnoliae Flos, Ephedrae Herba, Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum Allergic asthma

Eosinophil infiltration in the airway

Lymphocyte apoptosis in the peripheral blood
Fuyang Granule (Xu et al., 2014) Kochiae Fructus, Xanthii Fructus, Chuanxiong Rhizoma, Carthami Flos, Solanum lyratum Thunb Chronic urticaria

the level of IFN- and IL-18

IL-10 level
Runzao Zhiyang Capsule (Wang and Zhang, 2017) Rehmanniae Radix, Polygoni Multiflori Radix, Mori Folium, Sophorae Flavescentis Radix, Girardiana heterophylla Decne Chronic eczema

the levels of IL-4, TNF-

and IgE
Qufeng Zhiyang Granule (Wang et al., 2010) Saposhnikoviae Radix, Scutellariae Radix, Kochiae Fructus, etc. Chronic urticaria, eczema
The levels of IL-4 and IgE in the serum

IFN-

level in the serum

the ratio of IFN-

to IL-4
Heqin Zhiyang Liniment (Zhao et al., 2013) Salvia kiaometiensis, Zingiber striolatum Diels, Scutellariae Radix Pruritus
IL-4 level
Capillary permeability
Xiaofengsan Granule (Li and Zheng, 2004) Angelicae Sinensis Radix, Rehmanniae Radix, Saposhnikoviae Radix, Cicadae Periostracum, Anemarrhenae Rhizoma, Sophorae Flavescentis Radix, Schizonepetae Herba, Atractylodis Rhizoma, Arctii Fructus, Sesamum indicum, Gypsum Fibrosu, Glycyrrhizae Radix et Rhizoma, Akebiae Caulis Eczema

The proliferation of T cells and B cells

the activity of IL-1, IL-2 and IL-4
Jade Wind-Barrier Granule (Duan et al., 2017) Astragali Radix

Atractylodis Macrocephalae Rhizoma

Saposhnikoviae Radix Henoch–Schonlein purpura

IL-17 level and Th17 number

Treg number
Ximin Capsule (Tang et al., 2003) Dictamni Cortex, Cnidii Fructus, Kochiae Fructus, Smilacis Glabrae Rhizoma, Sophorae Flavescentis Radix, Moutan Cortex, Rehmanniae Radix, Cicadae Periostracum, Schizonepetae Herba, Glycyrrhizae Radix et Rhizoma, Astragali Radix, Paeoniae Radix Rubra, Crataegi Fructus Allergic rhinitis

IL-4 in lymphocyte culture INF-

in lymphocyte culture
Chaihuang Tablet (Han et al., 2003) Bupleuri Radix, Scutellariae Radix Passive cutaneous anaphylaxis

Capillary permeability

Type I hypersensitivity reaction
Likemin Nasal Spray (Qian et al., 1999Tian et al., 2011) Astragali Radix, Saposhnikoviae Radix, Atractylodis Macrocephalae Rhizoma, Magnoliae Flos Allergic rhinitis
Substance P in the serum and lung
The number of mast cells
Capillary dilation
Xiaofeng Zhiyang Granule (Luo et al., 2006) Astragali Radix, Saposhnikoviae Radix, Schizonepetae Herba, Moutan Cortex, Tribuli Fructus, Herba Spirodelae, Atractylodis Macrocephalae Rhizoma, Stellariae Radix, Arnebiae Radix, Glycyrrhizae Radix et Rhizoma Chronic urticaria
IgE level in serum
Yinchen Wuling Powder (Jin et al., 1999Zhu et al., 2021) Artemisiae Scopariae Herba, Poria, Atractylodis Macrocephalae Rhizoma, Alismatis RhizomaPolyporus, Cinnamomi Ramulus Eczema
Histamine-induced skin vascular permeability enhancement
passive skin allergic reactions

Note:

: Decrease or downregulate;

: Increase or upregulate.

The application of CPMs in the therapy of allergic diseases is based on syndrome differentiation. It adheres to the fundamental principles of traditional Chinese medicine: adapting to individual conditions and seeking the root cause of diseases. CPMs function by regulating immune function, restoring self-stabilization, and correcting allergic constitution. CPMs have advantages over traditional Chinese herbal formulas (TCHFs) in that they are ready-to-use, easy to carry, convenient to store, odor-free, and only required in small dosages. In contrast to Western medicine, CPMs have fewer adverse reactions, lower recurrence rates, multiple targets, and a lower price. As a result, CPMs have become increasingly popular in treating allergic diseases in recent years.

CPMs exert anti-allergic and anti-inflammatory effects via comprehensive actions. The pharmacological mechanism of CPMs in anti-allergic reactions involves many interconnected aspects. They can inhibit mast cell degranulation and increase macrophage phagocytosis (Shen and Yang, 2008). Glycyrrhizin, one of the active ingredients of CPMs, can inhibit excessive T cell activation, resulting in anti-inflammatory and antipruritic effects. Furthermore, the liquiritigenin in glycyrrhizin is structurally similar to glucocorticoids and has hormone-like activity, which aids in the relief of allergic symptoms (Hao, 2001; Sun, 2018).

However, as the clinical application of CPMs grows, there have been reports of adverse reactions when treating allergic diseases. The survey found that drug-derived allergic reactions in hospitalized patients accounted for 15.38% of the total adverse reactions of CPMs. Compound Glycyrrhizin Injection, for example, caused a variety of side effects on multiple organs, most of which manifested as allergic reactions and, in severe cases, anaphylactic shock. Patients with rashes developed liver damage after being orally administered Shiduqing Capsules (Hao et al., 2020Liu et al., 2021b).

Active Ingredients of Traditional Chinese Herbal Medicines (TCHMs)

TCHFs are essential in the treatment of allergic diseases due to their multi-target action and efficacy. However, because the active ingredients of most TCHFs have not been identified, it is not easy to further investigate their anti-allergic mechanisms. In recent years, there has been some progress in studying the active ingredients of anti-allergic TCHMs (Table 4). According to current research, TCHMs primarily exert therapeutic effects by inhibiting mast cell degranulation and various pro-inflammatory factors release.

Table 4. Common Anti-Allergic Active Ingredients of TCHMs

Crude Drugs Active Ingredients Pharmacological Effects Indications
Scutellaria baicalensis Baicalin
The secretion of IL-17, IL-6, and IgE Allergic rhinitis, allergic asthma, urticaria, eczema, atopic dermatitis
STAT3 expression

The expression IL-10 and FOXP3

restore the balance between Treg and Th17
(Xu et al., 2017)
Magnoliae Flos Ethanol extract
Histamine release from mast cells activated by antidinitrophenyl (DNP) IgE (Shin et al., 2001) Allergic rhinitis
Glycyrrhizae Radix et Rhizoma Glycyrrhizin
The activation-inducing effect of HMGB1 on mast cell degranulation Atopic dermatitis, urticaria, eczema

The expression of NF-B, TNF-

, and IL-6
(Wang et al., 2018b)
Sophorae Flavescentis Radix Matrine Restore the balance between Th1 and Th2 Eczema, atopic dermatitis, urticaria
Levels of IL-4, IL-5, IL-13
The expression of leukocyte
Differentiation antigen CD40
The number of eosinophils
(Sun et al., 2016)
Coptidis Rhizoma Berberine
The release of pro-inflammatory factors Atopic dermatitis, allergic rhinitis
B cell transformation

Mast cell degranulation through Fc

RI-mediated signaling and MAPK signaling
(Fu et al., 2019)
Paeoniae Radix Alba Total glucosides of Paeoniae Radix Alba

IFN-

secretion by Th1 Urticaria, eczema, atopic rhinitis
The secretion of IL-4 and IL-5 by Th2
IgE expression
(Song et al., 2017)
Saposhnikoviae Radix Polysaccharide of Saposhnikoviae Radix
histamine release Allergic asthma
Anti-inflammation
(Yang et al., 2020)
Artemisia argyi Volatile oil of Artemisia argyi
The release of histamine Urticaria
Anti-inflammation
(Kim et al., 2005)
Dictamni Cortex Aqueous extract of Dictamni Cortex
Histamine release Urticaria, eczema, tinea corporis
Capillary permeability
(Zhao and Ma, 2019)
Astragali Radix Astragaloside
The ratio of Treg to Th17 Allergic rhinitis, allergic asthma
(Wang et al., 2019)
Lonicerae Japonicae Flos Ethanol extract
Histamine release Food allergy
The expression of pro-inflammatory factors
IgE level
(Ran and Li, 2007)
Houttuyniae Herba Flavonoids of Houttuyniae Herba

The expression of FoxP3/ROR

T Allergic asthma
Restore the balance between Treg and Th17
(Wang et al., 2022)
Xanthii Fructus Phenolic acids of Xanthii Fructus
Mast cells degranulation Allergic rhinitis
Intracellular calcium release
cAMP level
(Cheng et al., 2019)
Centipeda minima Volatile oil of Centipeda minima
The release of pro-inflammatory factors (Jia and Zhang, 2018) Allergic rhinitis
Cnidii Fructus Osthole
Histamine release (Wu and Xu, 2011) Eczema, scabies, allergic asthma
Schizonepetae Herba Volatile oil of Schizonepetae Herba

The release of IFN-, TNF-

, IL-4 and IL-6 (Lin et al., 2018) Urticaria, atopic dermatitis
Perillae Folium luteolin

Fc

R1 and MRGPRX2-mediated mast cell activation through calcium signaling (Hao et al., 2022) Eczema, urticaria
Lophatherum Herba Medick sativa
Histamine release Allergic asthma
Focal eosinophilic infiltration
(Liu et al., 2018)
Ephedrae Herba Ephedrine Induce IgE receptor, Fc

RI, internalization in mast cells

antigen-induced IgE-dependent degranulation (Nagata et al., 2021) Allergic rhinitis, allergic asthma
Tussilago Farfarae Flos Tussilagone

Lyn/Syk, NF-B and p38 MAPK signaling pathways in activated mast cells

mast cell degranulation (Jin et al., 2020) Eczema, urticaria

Note:

: Decrease or downregulate;

: Increase or upregulate.

Examples and Mechanisms of Active Ingredients of TCHMs in Treating Allergic Diseases

The allergy mediator theory and the Th1/Th2 balance theory are now widely accepted in modern pharmacology. Astragaloside from Astragali Radix alleviated allergic reactions by restoring the balance between Tregs and Th17 cells (Fu et al., 2014Wang et al., 2019). While treating allergic rhinitis and asthma, astragaloside increased the Th1 cytokines and decreased the Th2 cytokines in the serum (Deng, 2017). Matrine, the active allergic ingredient in Sophorae Flavescentis Radix, lowered IL-4 and IL-13 levels while increasing IFN-

expression to restore Th1/Th2 balance (Sun et al., 2016), inhibited the expression of the leukocyte differentiation antigen CD40, and reduced the number of eosinophils (Zhang et al., 2015). Luteolin is a natural flavonoid found in many plants, including Reseda luteola, and is used to treat allergic skin diseases. It has been shown to reduce allergic reactions by inhibiting mast cell degranulation through a calcium-regulated pathway (Hao et al., 2022).

The same active ingredients of TCHMs treat different allergic diseases via different mechanisms of action. In the treatment of children with atopic dermatitis, total glucosides of Paeoniae, the active ingredient extracted from Paeoniae Radix Alba, primarily increased the level of IFN-

secreted by Th1 cells, suppressed the secretion of IL-4 and IL-5 by Th2, and inhibited the expression of IgE (Liu et al., 2017). On the other hand, total glucosides of Paeoniae achieved the treatment goal of eczema by lowering serum levels of IL-17 and IL-23 (Wang, 2015). Different active gradients produce therapeutic effects via different mechanisms while treating the same allergic disease. As previously stated, in treating allergic rhinitis, astragaloside regulated the ratio of Treg to Th17 cells to reduce allergic reactions, promoted Th1 cell differentiation, and inhibited Th2 cell differentiation (Deng, 2017). On the other hand, berberine, obtained from Coptidis Rhizoma, significantly inhibited the synthesis and release of pro-inflammatory factors stimulated by IgE, thereby alleviating allergic rhinitis symptoms (Fu et al., 2019). Some active ingredients from different TCHMs have similar pharmacological effects when treating the same allergic disease, but their therapeutic efficacy varies. Glycyrrhizin and baicalin can both be used to treat eczema by stabilizing the mast cell membrane and inhibiting degranulation (Su and Zhang, 2010; Zhou, 2019). Nonetheless, glycyrrhizin’s efficacy in the conventional comprehensive treatment of chronic urticaria is only 84.8% (Su and Zhang, 2010), while the overall efficacy of baicalin in combination with conventional comprehensive therapy can reach 95.65% (Zhou, 2019).

Only a subset of TCHMs has been used to treat allergic diseases. Numerous TCHM active ingredients with potential medicinal value have yet to be discovered. Furthermore, some TCHMs contain more than one active ingredient, and the same active ingredient obtained through different extraction methods has varying efficacy. With the advancement of clinical trials, our understanding of the strengths and weaknesses of active ingredients in TCHMs has become clearer.

Advantages of Active Ingredients of TCHMs in Treating Allergic Diseases

The active ingredients have more specific effects on allergic reactions caused by allergens than herbs, and the active ingredients are more effectively absorbed after oral administration than the original TCHMs or TCHFs. Therefore, the total dosage of the drugs can be reduced to avoid adverse reactions, and the therapeutic effects of the active ingredients are equal to or even stronger than that of the original TCHMs. For example, Jade Wind-Barrier Powder, used to treat chronic urticaria, contains up to 12 TCHMs (Astragalus, Nepeta, Paeonia, etc.), and the total dose is high. Nonetheless, using the total glucosides of Paeonia in a combination therapy significantly reduced the total dosage while improving the overall efficacy (Chen and Lei, 2021b). Research on the active ingredients of TCHMs is far less complex than that on TCHFs. So, compared to the TCHFs, the adverse reaction induced by the active ingredients of TCHMs can be easier to detect and predict, potentially reducing or eliminating drug harm. Glycyrrhizin is the active ingredient in licorice, and glycyrrhetinic acid is the primary hydrolytic metabolite of glycyrrhizin. The chemical structure of glycyrrhetinic acid is similar to that of adrenocortical hormones. Thus, it frequently causes adverse symptoms such as nausea, vomiting, diarrhea, and gastrointestinal ulcer bleeding. Hence, glycyrrhizin should not be taken with aspirin to avoid aggravating aspirin’s gastrointestinal side effects (Tang, 2014).

Disadvantages of Active Ingredients of TCHMs in Treating Allergic Diseases

Compared with TCHFs, the active ingredients of TCHMs may have weakened pharmacologic effects, their compatibility with the entire formulas may be greatly reduced, and they may even produce new side effects that the original TCHMs do not have. Glycyrrhizae Radix is widely used in various TCHFs to reconcile drugs in the same formula. It has been used as medicine in China for over 2000 years with no apparent toxicity. In contrast, its active ingredient, glycyrrhizin, can cause hyperaldosteronism (Rongyi et al., 2016). In comparison with single herb processing, extracting active ingredients from TCHMs necessitates a higher extraction standard. The ultrasonic extraction method of perilla oil has strict requirements on many factors, including the extraction solvent, solid–liquid ratio of drug and solvent, ultrasonic power, extraction temperature, and time, but the extraction rate is only 23.78% (Li et al., 2020). Silver ion complexation, molecular distillation, or column chromatography are required for further extraction of

-linolenic acid from perilla seed oil. Because of their high cost of production, time consumption, and proneness to product contamination, the use of these active ingredients is limited. (Wang et al., 2021b). Therefore, large-scale industrial production remains impossible even after accumulating a large amount of laboratory extraction experience with the aforementioned active ingredients. Furthermore, some of the active ingredients in TCHMs have poor efficacy when used alone and thus must be combined with other drugs to achieve effective anti-allergic effects.

Summary and Perspectives

For thousands of years, Traditional Chinese medicine has been used to treat a wide range of diseases in China. Traditional Chinese herbal formulas, Chinese patent medicines, and active ingredients of traditional Chinese medicines are becoming increasingly important in treating allergic disorders. Modern pharmacological research in traditional Chinese medicine has primarily focused on respiratory, skin, and food allergies, while little work has been done on life-threatening anaphylaxis (Li et al., 2021aWang et al., 2021c). The study of traditional Chinese medicines’ anti-allergic mechanism concentrates on the inflammatory process and allergic mediators (Fig. 1). Improving traditional Chinese classic herbal formulas is an efficient way to improve therapeutic effects while decreasing toxic and side effects. Paying attention to the rational compatibility of the ingredients in the formulas and encouraging the use of TCHFs in combination with other treatment methods can help to shorten the treatment period and relieve patients’ pain. In terms of information sharing, several bilingual databases (Chinese and English) of TCHMs, TCHFs, and active ingredients of TCHMs have been established. Researchers can easily share recently discovered pharmacologic effects and adverse reactions of TCHMs and their active ingredients in real-time via these websites, which will greatly promote the improvement of TCHFs.

Figure 1.

Figure 1. Mechanism of TCMs in allergic diseases. TCMs exert anti-allergic effects by modulating inflammation, signaling pathways, lymphocyte apoptosis, oxidative stress, and axis balance.

The 2021 version of China’s national medical insurance drug list contains 1374 CPMs, accounting for 48% of the total number of drugs covered by the list (http://www.nhsa.gov.cn/art/2021/12/3/art_104_7438.html). CPMs, compared with TCHFs, are gaining market share in treating allergic diseases due to their clearer quality control standards and convenient dosage forms. The safety, efficacy, and controllability of preparations for Chinese patent medicines are the critical elements of current concern. Feng et al. developed an evidence-based clinical practice guideline for diagnosing and treating allergic rhinitis in children to address these concerns (Feng et al., 2021). Yu et al. conducted a large number of clinical studies on drug safety evaluation using the Adverse Drug Events Active Surveillance and Assessment System-2 (ADE-ASAS-2) (Yu et al., 2020). Regarding TCHM active ingredients, the current focus is on improving the extraction process to extract high-quality active ingredients. Similar to TCHMs, there are also mutual complementarity and inhibition between the active ingredients of TCHMs. Therefore, improving efficacy while reducing side effects when using active ingredients in combination is a pressing issue that must be addressed.

TCHMs have the advantages of a wide range of sources, sound curative effects, and few side effects. However, our current understanding of TCHMs is still limited. Hence, more research is needed to discover the targets of TCHMs, reveal their adverse reactions, and support the development of new anti-allergic drugs to serve more people.

Acknowledgment

This work is supported by Natural Science Foundation of Hubei Province (No. 2021CFB340), National Natural Science Foundation of China (No. 82003593) and Innovation and Entrepreneurship Training Program for College Students in Hubei Province (No. S201910488063).

 


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