Asthma is a common chronic inflammatory disease of the airways that is responsible for significant morbidity, mortality, and healthcare costs [1,2]. Airway inflammation is a key pathophysiologic feature of asthma, leading to airway obstruction, airway hyperresponsiveness (AHR), and even remodeling of the airway. Recent guidelines for asthma management have therefore emphasized a need for the control of airway inflammation using inhaled corticosteroids (ICS) [3,4]. Chronic use of high-dose ICS, however, may result in serious side effects, including adrenal suppression and reduction in growth velocity, especially in children [5-7]. In addition, adequate ICS and other controller medications cannot achieve asthma control in some patients. Consequently, there is a pressing need for new alternative and/or complementary drugs with fewer side effects.

Recently, a number of clinical and laboratory studies have investigated the anti-asthmatic effects of Chinese herbal products. Some of these herbal remedies have been shown to be effective and safe alternatives or complements to standard therapy for asthma and other allergic diseases [8]. Magnoliae flos (Chinese name, 辛夷, Xin-yi) has a long history of clinical use in Asian countries, and is used to treat ulceration of the nasal mucosa, allergic rhinitis, sinusitis, bronchial asthma, and other conditions [9]. NDC-052 (Han Kook Sin Yak Pharmaceutical Co. Ltd., Nonsan, Korea) is a purified extract of M. fargesii and was developed to enhance and control bioactive lignan content, including magnolin and epimagnolin A [10]. These bioactive lignans have been shown to inhibit various inflammatory mediators, such as platelet-activating factor (PAF), cytosolic phospholipase A2, hexosaminidase, lipoxygenase, the complement system, and production of leukotriene C4 [11,12]. A recent study demonstrated that epimagnolin decreased nitric oxide (NO) levels by modulating inducible nitric oxide synthase (iNOS) in human respiratory epithelial cells [13]. In addition, oral administration of 50 mg/kg NDC-052 for eight weeks reduced airway resistance in a guinea pig chronic asthma model (unpublished data). Taken together, these reports suggest that concentrated NDC-052 extract might have anti-inflammatory, as well as anti-asthmatic effects.

Prior to the present study, the Korea Food & Drug Administration approved NDC-052 for clinical trials, and a phase II pilot study of NDC-052 in patients with persistent mild asthma found that a dose of 600 mg/day was effective and safe. We have evaluated the effects of NDC-052 as an add-on therapy to ICS in patients with persistent mild to moderate asthma symptoms.

We have shown here that the addition of NDC-052, an extract of an herbal remedy, to ICS may play a role in improving asthma control in patients with mild to moderate asthma. NDC-052 improved the results of pulmonary function tests, such as AM and PM PEFR and PEFR variation, as well as clinical parameters, including asthma symptom VAS, daytime and nocturnal asthma symptoms, the frequency of night-time awakening, and the frequency of β2-agonist use. In addition, NDC-052 was well tolerated and no severe adverse reactions were observed.

Traditional Chinese medicine (TCM) is one of the oldest types of medical practice in the world, and has played an important role for centuries in preventing and treating diseases in China and other Asian countries. Recently, TCM has been tested for the treatment of allergic diseases, including asthma, allergic rhinitis, and food allergy. The anti-asthma herbal medicines being evaluated include MSSM-002, modified Mai Men Dong Tang, Ding Chuan Tang, and STA-1, with clinical trials suggesting that these TCM remedies are efficacious and safe alternatives or complements to standard Western asthma therapy [8,17,18].

In this context, NDC-052 extracted from M. flos using ethanol, is a well-known natural herbal remedy in East Asian countries, including Korea, China, and Japan. M. flos refers to the flower buds of M. denudata and other plants belonging to the same genus, including M. fargesii (also known as M. biondii), M. denudata, M. liliflora, M. salicifolia, and M. kobus. Extraction yields many compounds, including oils, lignan compounds, and sesquiterpenes [10,19,20]. Some of the compounds extracted from both M. fargesii and M. denudata were shown to be calcium antagonists, inhibiting the activity of PAF and serum complement, and reducing tumor necrosis factor-alpha (TNF-alpha) production [11,12,20-23]. Using an anaphylaxis model in mice, M. flos was shown to inhibit immediate-type allergic reactions by inhibiting mast cell degranulation, both in vivo and in vitro [24]. Moreover, epimagnolin, a major lignin of NDC-052, was shown to inhibit the expression of iNOS and the production of NO via extracellular signal-regulated kinase (ERK) pathway in cytokine-stimulated human respiratory epithelial cells [13]. Thus, NDC-052 may have both anti-inflammatory and antioxidant effects, and the pathway by which NDC-052 reduces inflammation may differ from that of steroids. Therefore, NDC-052 may provide additional benefits to asthma patients using ICS.

We found that treatment with add-on NDC-052 did not noticeably increase FEV1. Most of our subjects, however, had mild persistent asthma, with FEV1 > 80% of the predicted value. Nevertheless, NDC-052 improved AM and PM PEFR and other clinical indicators of asthma control, such as the need for β-agonist relief therapy and both day and night asthma symptom scores. In recent guidelines, these clinical outcomes were regarded as important characteristics for evaluating asthma control. Therefore, our data indicate that patients with close-tonormal FEV1 levels may be symptomatic and require additional control of asthma symptoms. In addition, our results were similar to those of previous studies showing that addition of ICS to leukotriene receptor antagonists, currently used as alternatives to ICS in patients with mild persistent asthma, improved various measurements of asthma control, despite failing to cause a significant improvement in FEV1 [25,26]. Pharmacologically, NDC-052 has anti-inflammatory, rather than bronchodilating, effects. Therefore, NDC-052 may not directly affect FEV1 level. We did not measure inflammatory markers in these patients, suggesting the need for additional clinical studies involving measurements of inflammatory markers, such as induced sputum analysis or exhaled NO, to determine the mechanisms by which NDC-052 affects airway inflammation. Further clinical trials are necessary to determine if the addition of NDC-052 to ICS is effective in patients with more severe or refractory asthma, or if it can decrease the frequency of asthma exacerbation.

ICS has been shown to improve both asthma-related symptoms and pulmonary function in many patients, although a subset of patients required additional medications to achieve asthma control. Updated GINA guidelines suggest that symptoms can be improved by: 1) increasing the dose of ICS, 2) adding inhaled long-acting β2-agonists (LABA), or 3) adding other controller medications, such as leukotriene modifiers and sustained-release theophylline. Since ICS has a plateau effect, such that increased doses are not matched by further increases in efficacy [27,28], the updated GINA recommends the addition of a controller, preferably LABA, rather than increasing the dose of ICS. LABA, however, does not have anti-inflammatory effects, raising concerns that it may enhance airway remodeling [29]. In addition, inhaled agents may fail to reach the small airways, i.e., the site of inflammation in asthma. Theophylline, a currently available oral controller, has a narrow therapeutic window and many side effects, limiting its utility as an add-on therapy in asthmatics suboptimally controlled with ICS. These findings indicate the need for novel alternative agents that can improve airway inflammation and asthma symptoms in patients who cannot be controlled by ICS alone.

However, the design of this study imposes some limitations on the interpretation of the results. First, the absence of a placebo group precluded assessment of any placebo effect on asthma symptoms; thus, improvements in outcome measures may have been influenced by the expectation of a benefit from treatment. Secondly, the increased compliance to ICS may have affected the results. However, we strongly suggested that participants use their ICS regularly during the whole study period, including run-in periods, and enrolled symptomatic patients despite regular ICS usage. Finally, eight weeks was a relatively short period to evaluate the long-term effects of therapeutic drugs on asthma control. Further clinical trials are necessary to address these issues.

In conclusion, we have shown that add-on NDC-052 was well tolerated and shows potential for improving asthma control in patients with persistent symptoms treated with ICS. Further clinical trials are needed to test the efficacy and safety of NDC-052 in patients with severe and/or refractory asthma.