**5. Chinese herbal formulas use in children with asthma**

TCM formulas have been used to treat asthma for centuries. A number of well-controlled clinical studies of several TCM formulas, including modified Mai-Men-Dong-Tang (mMMDT, five herbs), Ding-Chuan-Tang (DCT, nine herbs), and STA-1 (the combination of Mai-Men-Dong-Tang and Liu-Wei-Di-Huang-Wan, 10 herbs), and anti-asthma herbal medicine inter‐ vention (ASHMI, three herbs) provided evidence of clinical efficacy, safety, and immunomodulatory effects [24]. Typically, the traditional TCM formulas that are prescribed combine several single herbs to treat a specific disease. Recent research [25] from the National Health Insurance Research Database (NHIRD) in Taiwan has revealed the core herbal treat‐ ments for children with asthma. The most commonly used herbal formulas for the treatment of childhood asthma are Ma-Xing-Gan-Shi-Tang and Xiao-Qing-Long-Tang; the former is used for excess heat congested in the lung, whereas the latter is used for the exterior wind-cold with internal accumulation of retained fluid in the lung. These herbal formulas (shown in Table 1) and several single herbs commonly used for the treatment of childhood asthma are described below. The immunomodulatory effects of suppressing Th2 cells and decreasing subsequent cytokine secretion of these herbal remedies will also be investigated. Other commonly prescribed formulas that are used mainly to relieve asthma-related symptoms, such as productive cough (Xing-Su-San, Zhi-Sou-San), coughing with a sore throat (Yin-Qiao-San), and nasal congestion (Xin-Yi-Qing-Fei-Tang, Cang-Er-Zi-San, Shin-Yi-San), do not fall within the scope of this review.

#### **5.1. ASHMI**

ASHMI is the first herbal medicine to receive approval for phase I and II clinical trials as a US Food and Drug Administration investigational new drug (IND No. 71526) for treating asthma.


**Table 1.** Herbal formulas frequently used for asthmatic children

treatment of asthma and encompasses many therapies, including mind–body techniques, nutritional manipulation, dietary and herbal supplements, TCM (including acupuncture), exercise, manual therapies, and homeopathy [26]. Reportedly, CAM is commonly used in children who have mild or moderate persistent asthma, those receiving high-dose ICS, and patients who experience poor symptom control or require frequent physician visits, including emergency room visits [26]. One retrospective longitudinal cohort study showed that initiation of CAM treatment does not decrease future adherence to conventional asthma medications, suggesting that alternative or integrative medicine use does not necessarily compete with conventional asthma therapies [27]. As CAM use becomes more prevalent, it will become increasingly important for physicians attending to asthmatic children to be aware of CAM use. TCM is the major component of CAM therapies used in the United States and Taiwan. TCM is one of the oldest medical practices in the world and has played an important role in preventing and treating diseases in China for centuries, where it is still used as a monotherapy or as part of an integrated medicine approach. Evidence has increased showing the efficacy of TCM for the treatment of childhood asthma. Below, we explore complementary therapy,

TCM formulas have been used to treat asthma for centuries. A number of well-controlled clinical studies of several TCM formulas, including modified Mai-Men-Dong-Tang (mMMDT, five herbs), Ding-Chuan-Tang (DCT, nine herbs), and STA-1 (the combination of Mai-Men-Dong-Tang and Liu-Wei-Di-Huang-Wan, 10 herbs), and anti-asthma herbal medicine inter‐ vention (ASHMI, three herbs) provided evidence of clinical efficacy, safety, and immunomodulatory effects [24]. Typically, the traditional TCM formulas that are prescribed combine several single herbs to treat a specific disease. Recent research [25] from the National Health Insurance Research Database (NHIRD) in Taiwan has revealed the core herbal treat‐ ments for children with asthma. The most commonly used herbal formulas for the treatment of childhood asthma are Ma-Xing-Gan-Shi-Tang and Xiao-Qing-Long-Tang; the former is used for excess heat congested in the lung, whereas the latter is used for the exterior wind-cold with internal accumulation of retained fluid in the lung. These herbal formulas (shown in Table 1) and several single herbs commonly used for the treatment of childhood asthma are described below. The immunomodulatory effects of suppressing Th2 cells and decreasing subsequent cytokine secretion of these herbal remedies will also be investigated. Other commonly prescribed formulas that are used mainly to relieve asthma-related symptoms, such as productive cough (Xing-Su-San, Zhi-Sou-San), coughing with a sore throat (Yin-Qiao-San), and nasal congestion (Xin-Yi-Qing-Fei-Tang, Cang-Er-Zi-San, Shin-Yi-San), do not fall within

ASHMI is the first herbal medicine to receive approval for phase I and II clinical trials as a US Food and Drug Administration investigational new drug (IND No. 71526) for treating asthma.

involving TCM therapy for childhood asthma.

224 Asthma - From Childhood Asthma to ACOS Phenotypes

the scope of this review.

**5.1. ASHMI**

**5. Chinese herbal formulas use in children with asthma**

ASHMI is composed of the aqueous extracts of Ling Zhi (*Ganoderma lucidum*), Ku Shen (*Sophora flavescens*), and Gan Cao (*Glycyrrhiza uralensis*) [24]. ASHMI improved lung function (FEV1), reduced symptom scores, and decreased beta-2-adrenoceptor agonist use, to a degree similar as that achieved by prednisone in adults with moderate to severe asthma, but without the adverse effect of prednisone on adrenal function and with no overall immune suppression. Individually, Ling Zhi, Ku Shen, and Gan Cao extracts and ASHMI (the combination of individual extracts) inhibited production of IL-4 and IL-5 by murine memory Th2 cells and that of eotaxin-1 by human lung fibroblast cells [28]. ASHMI synergistically inhibited eotaxin-1 production as well as Th2 cytokine production. In another mouse model of asthma, ASHMI also reduced the levels of ovalbumin (OVA)-specific IgE and Th2 cytokines, including IL-4, IL-5, and IL-13 in the lung, and increased IFN-γ secretion [29]. Moreover, ASHMI markedly reduced airway hyperresponsiveness (AHR), mucous production, neutrophilic inflammation, and TNF-α, IL-8, and IL-17 levels and also decreased eosinophilic inflammation and Th2 responses in vivo [30].

#### **5.2. Modified Mai-Men-Dong-Tang**

Mai-Men-Dong-Tang is a herbal TCM that has been used for the treatment of bronchitis, bronchial asthma, and cough. The compositions of Mai-Men-Dong-Tang are Mai Men Dong (*Ophiopogon japonicus*), Ban Xia (*Pinellia ternata*), Ren Shen (*Panax ginseng*), Gan Cao (*Glycyrrhiza uralensis*), Da Zao (*Ziziphus jujuba*), and Geng Mi (*Oryza sativa*). Mai-Men-Dong-Tang was shown to have an antitussive effect, based on improved airway clearance. The pharmacological effect of this antitussive effect is suggested to involve the inhibition of C-fibers, bronchodila‐ tion, anti-inflammatory effects, suppression of mucosal excretion, and augmentation of surfactant secretion [31]. Mai-Men-Dong-Tang was shown to potentiate beta-adrenergic function in ASM, which may reflect the efficacy on AHR and asthma [32]. mMMDT contains five herbs, including Mai Men Dong (*Radix Ophiopogonis*), Ban Xia (*Rhizoma Pinelliae*), Ameri‐ can Ren Shen (*Radix Panacis Quinquefolii*), Gan Cao (*Radix Glycyrrhizae*), and Lantern Tridax (*Herba Tridacis procumbentis*) [33]. mMMDT was shown to decrease serum total IgE and house dust mite-specific IgE significantly and downregulate the expression of IL-4 in allergensensitized mice. The effect of mMMDT on changes in FEV1 was studied as the first efficacy end point, given its validity for monitoring airway obstruction, which showed significant im‐ provement in FEV1 in patients treated with mMMDT [33]. Moreover, mMMDT also relieved asthma symptoms, including coughing, wheezing, and breathlessness [33].

#### **5.3. STA-1**

STA-1 is a combination of mMMDT (four herbs) and Lui-Wei-Di-Huang-Wan (six herbs) [34]. The four herbs of mMMDT comprise Mai Men Dong (*Radix Ophiopogonis*), Ban Xia (*Tuber Pinellia*), American Ren Shen (*Radix Panacis Quinquefolii*), and Gan Cao (*Radix Glycyrrhizae*) without Lantern Tridax (*Herba Tridacis procumbentis*). The six herbs of Lui-Wei-Di-Huang-Wan are Shu Di Huang (*Radix Rehmanniae Preparata*), Mu Dan Pi (*Cortex Moutan Radicis*), Shan Zhu Yu (*Fructus Corni*), Fu Ling (*Poria*), Ze Xie (*Rhizoma Alismatis*), and Shan Yao (*Radix Dioscor‐ eae*). STA-1 was able to inhibit mite-induced IgE synthesis, reduce inflammation-associated accumulation of eosinophils and neutrophils in the airway, and relieve AHR in a murine model [35]. Clinical evaluation of STA-1 in the treatment of mild-to-moderate chronic asthma revealed a significant reduction of symptom scores, systemic steroid dose, total IgE, and specific IgE in patients treated with STA-1 [34]. Furthermore, STA-1 also improved lung function (FEV1) as compared with placebo after 6 months' treatment and with only minimal side effects [34].

#### **5.4. Ma-Xing-Gan-Shi-Tang**

ASHMI is composed of the aqueous extracts of Ling Zhi (*Ganoderma lucidum*), Ku Shen (*Sophora flavescens*), and Gan Cao (*Glycyrrhiza uralensis*) [24]. ASHMI improved lung function (FEV1), reduced symptom scores, and decreased beta-2-adrenoceptor agonist use, to a degree similar as that achieved by prednisone in adults with moderate to severe asthma, but without the adverse effect of prednisone on adrenal function and with no overall immune suppression. Individually, Ling Zhi, Ku Shen, and Gan Cao extracts and ASHMI (the combination of individual extracts) inhibited production of IL-4 and IL-5 by murine memory Th2 cells and that of eotaxin-1 by human lung fibroblast cells [28]. ASHMI synergistically inhibited eotaxin-1 production as well as Th2 cytokine production. In another mouse model of asthma, ASHMI also reduced the levels of ovalbumin (OVA)-specific IgE and Th2 cytokines, including IL-4, IL-5, and IL-13 in the lung, and increased IFN-γ secretion [29]. Moreover, ASHMI markedly reduced airway hyperresponsiveness (AHR), mucous production, neutrophilic inflammation, and TNF-α, IL-8, and IL-17 levels and also decreased eosinophilic inflammation and Th2

Mai-Men-Dong-Tang is a herbal TCM that has been used for the treatment of bronchitis, bronchial asthma, and cough. The compositions of Mai-Men-Dong-Tang are Mai Men Dong (*Ophiopogon japonicus*), Ban Xia (*Pinellia ternata*), Ren Shen (*Panax ginseng*), Gan Cao (*Glycyrrhiza uralensis*), Da Zao (*Ziziphus jujuba*), and Geng Mi (*Oryza sativa*). Mai-Men-Dong-Tang was shown to have an antitussive effect, based on improved airway clearance. The pharmacological effect of this antitussive effect is suggested to involve the inhibition of C-fibers, bronchodila‐ tion, anti-inflammatory effects, suppression of mucosal excretion, and augmentation of surfactant secretion [31]. Mai-Men-Dong-Tang was shown to potentiate beta-adrenergic function in ASM, which may reflect the efficacy on AHR and asthma [32]. mMMDT contains five herbs, including Mai Men Dong (*Radix Ophiopogonis*), Ban Xia (*Rhizoma Pinelliae*), Ameri‐ can Ren Shen (*Radix Panacis Quinquefolii*), Gan Cao (*Radix Glycyrrhizae*), and Lantern Tridax (*Herba Tridacis procumbentis*) [33]. mMMDT was shown to decrease serum total IgE and house dust mite-specific IgE significantly and downregulate the expression of IL-4 in allergensensitized mice. The effect of mMMDT on changes in FEV1 was studied as the first efficacy end point, given its validity for monitoring airway obstruction, which showed significant im‐ provement in FEV1 in patients treated with mMMDT [33]. Moreover, mMMDT also relieved

asthma symptoms, including coughing, wheezing, and breathlessness [33].

STA-1 is a combination of mMMDT (four herbs) and Lui-Wei-Di-Huang-Wan (six herbs) [34]. The four herbs of mMMDT comprise Mai Men Dong (*Radix Ophiopogonis*), Ban Xia (*Tuber Pinellia*), American Ren Shen (*Radix Panacis Quinquefolii*), and Gan Cao (*Radix Glycyrrhizae*) without Lantern Tridax (*Herba Tridacis procumbentis*). The six herbs of Lui-Wei-Di-Huang-Wan are Shu Di Huang (*Radix Rehmanniae Preparata*), Mu Dan Pi (*Cortex Moutan Radicis*), Shan Zhu Yu (*Fructus Corni*), Fu Ling (*Poria*), Ze Xie (*Rhizoma Alismatis*), and Shan Yao (*Radix Dioscor‐ eae*). STA-1 was able to inhibit mite-induced IgE synthesis, reduce inflammation-associated

responses in vivo [30].

**5.3. STA-1**

**5.2. Modified Mai-Men-Dong-Tang**

226 Asthma - From Childhood Asthma to ACOS Phenotypes

Ma-Xing-Gan-Shi-Tang, a TCM, has been used in the treatment of bronchial asthma for several centuries. Ma-Xing-Gan-Shi-Tang consists of Ma Huang (*Herba Ephedrae*), Xing Ren (*Semen Armeniacae Amarum*), Shi Gao (*Gypsum Fibrosum*), and Gan Cao (*Radix Glycyrrhizae*). A murine cough model, induced by sulfur dioxide gas, was used to investigate the antitussive effect of Ma-Xing-Gan-Shi-Tang [36]. Both Ma Huang and Xing Ren inhibited cough induction in a dose-dependent manner. However, Ma-Xing-Gan-Shi-Tang, which contains Ma Huang and Xing Ren, showed stronger antitussive effects than the individual crude drugs [36]. In a guinea pig model of allergic asthma, Ma-Xing-Gan-Shi-Tang was efficacious in stimulation of beta-2 adrenoceptors on bronchial smooth muscle and had an anti-inflammatory effect, involving inhibition of neutrophil infiltration into the airway [37]. Ma-Xing-Gan-Shi-Tang is typically indicated in syndromes involving wind-heat on the lung or stagnated wind-cold that has turned into heat and that stayed in the lung. In Taiwan, asthma triggered by respiratory tract infection among asthmatic children is much more common than that triggered by cold exposure and weather change. Asthma triggered by respiratory tract infection is the most important indication for Ma-Xing-Gan-Shi-Tang [25].

#### **5.5. Xiao-Qing-Long-Tang**

Xiao-Qing-Long-Tang (XQLT) has been widely used clinically for the treatment of allergic diseases, including bronchial asthma and allergic rhinitis. XQTL consists of Ma Huang (*Herba Ephedrae*), Gui Zhi (*Ramulus Cinnamomi*), Ban Xia (*Rhizoma Pinelliae*), Gan Jiang (*Rhizoma Zingiberis*), Xi Xin (*Herba Asari*), Wu Wei Zi (*Fructus Schisandrae*), Bai Shao Yao (*Radix Paeo‐ niae*), and Gan Cao (*Radix Glycyrrhizae*).

XQLT was shown to reduce bronchial inflammatory cell infiltration and airway remodeling in repetitive *Dermatogoides pteronyssinus-*challenged mouse model of chronic asthma [38]. XQLT inhibited *D. pteronyssinus*-induced total IgE and *D. pteronyssinus*-specific IgG1 in serum and changed the Th2-bios in bronchoalveolar lavage fluid (BALF) by inhibiting the activation of nuclear factor-Kappa B (NF-κB). The same study also showed that XQLT treatment increased the protein levels of IL-12, but decreased that of TNF-α, TGF-β1, IL-5, IL-6, and IL-13 by inhibiting expression of the genes including IL-10, IL-13, eotaxin, RANTES, and MCP-1 in the lung. Moreover, collagen assays and histopathology indicated that XQLT reduces airway remodeling in the lung [38]. XQLT treatment could inhibit the secretion of IL-5 in the serum and downregulate mRNA expression of genes encoding eotaxin, RANTES, and MCP-1 in lung tissues, which may contribute to a reduction in eosinophils and monocytes recruited to the airway.

Studies on the OVA-sensitized allergic airway inflammation model in mice revealed that XQLT significantly inhibited the antigen-induced immediate asthmatic response and late asthmatic response in actively sensitized mice. XQLT was shown to reduce the production of Th2-associated cytokines, IL-4 and IL-5, and to restore the production of the Th1 cellassociated cytokine, IFN-γ [39]. Anti-OVA IgE antibody levels were reduced in the BALF of sensitized mice after oral administration of XQLT [39]. Furthermore, XQLT was shown to have an anti-asthmatic effect, which is partly mediated by stimulation of beta-2-adrenocep‐ tors, leading to bronchorelaxation; furthermore, XQLT inhibits the infiltration of eosino‐ phils into the airway [40].

#### **5.6. Ding-Chuan-Tang**

Ding-Chuan-Tang (DCT), another TCM, has been used in the treatment of bronchial asthma for several centuries. DCT is composed of nine herbs, including Ma Huang (*Herba Ephedrae*), Gan Cao (*Radix Glycyrrhizae*), Ban Xia (*Rhizoma Pinelliae*), Bai Guo (*Semen Ginkgo*), Kuan Dong Hua (*Flos Farfarae*), Sang Bai Pi (*Cortex Mori*), Su Zi (*Fructus Perillae*), Xing Ren (*Semen Arme‐ niacae Amarum*), and Huang Qin (*Radix Scutellariae*). According to TCM principles, this decoction is frequently prescribed for children with coughing, wheezing, and chest tightness.

One study of a murine OVA-sensitized allergic airway inflammation model revealed that DCT significantly inhibited the increase of eosinophils in the airway and caused concentrationdependent bronchorelaxation via a beta-2 adrenergic effect [41]. A randomized, double-blind clinical trial [42] conducted to assess the add-on effect of DCT showed that AHR significantly improved after weeks of DCT treatment compared with that after placebo use. In addition, patients in the DCT group also showed superior clinical improvement and used less medica‐ tion than in the placebo group. This study suggested that addition of DCT to conventional treatment could further improve AHR, even in patients with well-controlled asthma. How‐ ever, this study did not find a significant reduction in IgE levels and FEV<sup>1</sup> with DCT treatment, as compared to placebo [42].
