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Pediatr Allergy Immunol 2005: 16: 76–81. DOI: 10.1111/j.1399-3038.2005.00230.x Printed in Singapore. All rights reserved Efficacy and safety of modifiedMai-Men-Dong-Tang for treatment ofallergic asthma Hsu CH, Lu CM, Chang TT. Efficacy and safety of modified Mai-Men- Dong-Tang for treatment of allergic asthma.
Pediatr Allergy Immunol 2005: 16: 76–81. Ó 2005 Blackwell Munksgaard 1Department of Pediatrics, China Medical UniversityHospital, 2TaiMont Biotec Inc., Tainan, 3Institute of The aim of this study was to evaluate the efficacy and safety of a Chinese Medical Science, China Medical University, Chinese herbal formula modified Mai-Men-Dong-Tang (mMMDT) for treatment of persistent, mild-to-moderate asthma. A total of 100 asth-matic patients were enrolled and assigned to three treatment groups inthis double-blind, randomized, placebo-controlled clinical trial. Over aperiod of 4 months, patients in groups A and B received 80 and 40 mg/kg/day of mMMDT, while those in group C received a placebo. Efficacyvariables included changes in forced expiratory volume in 1 s (FEV1),symptom score, serum total immunoglobulin E (IgE), and dust mite-specific IgE. Safety assessments included complete blood count, andliver and kidney function. Relative to baseline, significantly greaterincreases in FEV1 were demonstrated for both A and B groups incomparison with the placebo-treated analog (both p < 0.05). Further,similar improvements in symptom score were observed for both Key words: Mai-Men-Dong-Tang; allergic asthma; mMMDT treatment groups. The serum total IgE for group A showed a decreasing tendency after treatment but no statistical difference wasnoted. Furthermore, no drug-related adverse effects were reported.
Ching-Hsiang Hsu MD PhD, Department of Pediatrics, Blood test, and liver and kidney function were within normal range China Medical University Hospital, No. 2, Yuh-Der during the study, with no marked changes demonstrated over time. In Road, Taichung 404, TaiwanTel.: +886 4 2205 2121 (ext. 4163) conclusion, the Chinese herbal formula mMMDT provided improve- ments in lung function and relieved asthma symptoms in our sample of patients. Given its efficacy and safety, we consider mMMDT a credibletreatment regimen for persistent, mild-to-moderate asthma.
Allergen-induced, immunological disorders such disorders (3). The scientific literature supporting as asthma, have long been considered as one of the efficacy of herbal therapies is incomplete.
the most serious health problems in the world. In Further, there are few well-controlled studies recent years, statistics show earlier onset of supporting the efficacy of herbal remedies for allergic asthma. In Taiwan, the prevalence of treatment of, and clinical improvement in, childhood asthma has increased from 1.3% in patients with asthma. One of the most compre- 1974, to 5.07% in 1985 and 5.8% in 1991 (1, 2).
hensive anti-asthma clinical trials, a multi-center, Because of the pandemic proportions for both double-blind and placebo-controlled study, was the prevalence and morbidity of allergic asthma, reported in Taiwan (4). The results showed that usage of traditional Chinese herbal medicine the TCM treatments were beneficial in the (TCM) has become quite common because it is improvement of symptom scores. However, sta- often perceived as natural and, therefore, con- tistically significant differences were not demon- strated between treatment and placebo for many other clinical indicators. To further improve the are used to treat various chronic immunological efficacy of TCM treatment for allergic asthma, we studied the working mechanisms of several TCM formulas used for the treatment of bronchial For baseline measurement, lung function was asthma. From animal experiments, we found that assessed and reversibility of abnormalities in significantly decrease the concentration of inter- 1 established (if not previously determined).
Patients were randomly assigned to groups leukin-4 in bronchoalveolar fluid after inhala- tional allergen challenge. In addition, mMMDT day or placebo, in twice-daily doses. The appear- also significantly decreased airway inflammation ance of the placebo was almost identical to that compared with placebo groups (5). Therefore, a of mMMDT. Blood was taken for measurement clinical trial was conducted to prove the safety of total and allergen-specific IgE.
Lung function was assessed and recorded for each visit during treatment and at follow-up.
This study was a randomized, placebo-controlled, Lung function was measured at least 6 h after the double-blind study of children aged 5–18 yr who b-agonist was last given. Spirometry was per- had experienced episodes of dyspnea, coughing, formed using standardized equipment and pro- and wheezing, requiring intermittent or frequent cedures recommended by the American Thoracic bronchodilator treatment, and considered candi- Society. Predicted normal values for age and dates for continuous treatment for control of measured height were used for assessment of these symptoms. Inclusion criteria (as assessed in the month before randomization) were: forcedexpiratory volume in 1 s (FEV1) > 60% of the predicted value and reversibility ‡15% of baselinefollowing inhalation of a bronchodilator; two or During each visit, daily diary records of symptom more positive skin tests; total serum IgE scores and medication use were reviewed by a team titer > 95th percentile for age; and, family and of investigators unaware of treatment assignment.
personal histories of atopy. All patients were Asthma medications were provided gratis and instructed in asthma management, evaluated for adjusted in a stepwise fashion equally in all three compliance, and given radioallergosorbent and groups as follows: step 1, use of bronchodilator as skin prick tests. Exclusion criteria were: acute needed; step 2, regular use of brochodilator respiratory infection within 3 wk of study onset; (theophylline or albuterol); step 3, regular use of systemic glucocorticoid treatment in the 3 months two or three drugs (theophylline, albuterol and prior to the study, or for more than 30 days in the cromolyn); step 4, addition of beclomethasone preceding 2 yr; serious adverse reactions to the- delivered with a metered-dose inhaler or alternate- ophylline or glucocorticoids in the past; diagnosis day methylprednisolone; and, step 5, addition of of attention deficit disorder, behavioral disorder, oral corticosteroids (>0.5 mg/kg/day, with taper- mental retardation, alcohol or drug abuse, or ing). Acute exacerbation of asthma was treated as other psychological or emotional disorders requi- directed by the child’s physician using tapered ring treatment. Female candidates were also doses of oral methylprednisolone. Emergency excluded if they were pregnant, lactating, or room care and inpatient treatment were provided sexually active and not using reliable birth control. The study protocol was approved bythe Institutional Review Board. Before enroll- ment, oral consent was obtained from all children,and written informed consent from their parents.
All herbs were sourced as a dried powder andencapsulated. The standard herbal formulation(mMMDT) was designed by a doctor of Chinese medicine, and prepared by Sun-Ten Pharmaceu- Randomization was performed by selection of a tical Inc.(Taipei, Taiwan) (Table 1). The total sealed envelope from a closed bag. Forty sealed amount of medicine required for the entire study envelopes were prepared for each of the two was prepared at one time, aliquoted and pack- mMMDT groups, and 20 for the placebo group.
aged. The quality of each component herb was Patients were aware that there was a greater checked using high-pressure liquid chromatogra- chance of receiving active treatment.
Table 1. Components of herbal medicines in modified Mai-Men-Dong-Tang homogentisic acid,nicotine,aspartic acid,glutamic acid,arginine,b-sitosterol,cholesterol aspartate,homoserine,diaminobutyric acid,digitalis glycoside standards. The placebo was prepared and encap- diluted in 0.05% gelatin buffer, was added for an sulated to taste, smell, and look similar to the additional hour. Avidin-alkaline phosphatase (1:1000; Sigma Chemical Co., St Louis, MO, blinded primary research assistant managed all USA) was then added and incubated for 1 h at the questionnaires and was responsible for pro- 25°C, followed by six washes. The color reaction viding the capsules to the patients. All patients was developed with the addition of the phospha- were treated in an equivalent fashion.
tase substrate, p-nitrophenyl phosphate, disodium(Sigma Chemical Co.). Readings were referencedto a standard serum pooled from five patients who were newly diagnosed and had high IgE titers. The The patients were issued a diary card and asked standard serum was calculated as 100 ELISA to make twice daily entries of albuterol usage, and the severity of symptoms, if any. A 4-pointscale was used to assess the extent of cough, wheeze, and breathlessness, with the score indi-cating the absence of symptoms, and mild, The primary outcome measure was percentage moderate, and severe symptoms, respectively; change in FEV1 from baseline at each measured time point following treatment. Secondary out-come measures included asthma symptom score,and changes in total and specific IgE. A sample Determination of allergen-specific IgE antibodies size of 100 patients provided sufficient power The amount of total and Dermatophagoides pter- (90%) to detect a difference of a 10% difference onyssinus (Dp)-specific IgE was determined using in FEV1 between treatment and placebo groups ELISA. Protein high-binding plates were coated (a ¼ 0.05). Nonparametric statistics were used with 100 ll of purified allergen or recombinant to determine p-values for group comparisons mouse anti-human IgE diluted in coating buffer for all outcome measures. All reported p-values (0.1 m NaHCO3; pH 8.2) to a concentration of are two-sided and calculated using Prism soft- 5 lg/ml. After overnight incubation at 4°C, plates ware. Symptom scores are expressed as median were washed three times and blocked with 3% with range. Serum total and allergen-specific (wt/vol) BSA-PBS buffer for 2 h at 25°C.
IgE are expressed as mean ± SE. Wilcoxon’s Sera were used at 1:10 dilution, with duplicate measurement. After overnight incubation at 4°C, were used for intra- and inter-group analysis, biotin-conjugated mouse anti-human IgE mAb, Table 2. Demographics, baseline characteristics and reasons for patient withdrawal Table 3. Clinical assessments of therapeutic efficacy the placebo group. The mean PEF values for the 800-mg mMMDT group were 63.17 ± 17.64%and 72.36 ± 20.81% before and after treatment, A total of 100 patients were enrolled in this study respectively (p < 0.05; Wilcoxon’s signed-rank and randomized into three treatment groups test). The PEF also improved from 46.76 ± 16.99% (p < 0.001) in the 400-mg mMMDT controls) with similar patient demographics and group. Mean FEV1 also improved for the 800-mg baseline characteristics (Table 2). The AAS score and 400-mg treatment groups from 77.66 ± was used to represent asthma severity, with no 12.43% to 77.73 ± 12.62%, and from 64.62 ± 9.72% to 73.76 ± 12.43%, respectively. The ences. Approximately 80% of the patients com- symptom score for the 400-mg group decreased pleted the study. Withdrawals included seven of 40 (17.5%) patients from the 800-mg mMMDT group, 11 of 40 (27.5) from the 400-mg mMMDT improvement was observed over time for both group, and three of 20 (15%) from the placebo mMMDT groups (Fig. 1), with the majority of group (Table 2). Reasons for withdrawal were patients showing an improvement of more than 10 similar across treatment groups. There was no compared with baseline (Fig. 2). The serum total patient withdrawal due to adverse effects.
IgE and Dp-specific IgE levels for the 800-mgmMMDT groups showed a decreasing tendencyafter treatment, however, no statistically signifi- cant difference was demonstrated, apparently due After 4 months of treatment, significant improve- to the wide data distribution. The serum IgG4 for ments in lung function were achieved for both the all three groups did not change in spite of 800-mg and 400-mg mMMDT groups, but not for blood tests, were within normal reference values, with no significant differences demonstrated relative to the placebo-treated patients (Table 4).
Recently, the usage of complementary prepara- tions for asthma, especially herbal medicine, has prevailed (6–9). Nevertheless, lack of blinding,description of adverse effects, and withdrawal rates are frequent limitations to a number ofrandomized clinical trials investigating these herbal medicinal products. In addition, outcome Fig. 1. Percentage change in FEV1 from baseline after Mai- measures are variable and, in several cases, of Men-Dong-Tang treatment over time. Data shown are doubtful relevance (10). Therefore, we designed mean ± s.d. Changes in FEV1 were measured as described this randomized, placebo-controlled, double- in Materials and methods. Patients receiving 400 and800 mg/10 kg/day of mMMDT and placebo are depicted by blind study to investigate the efficacy and safety lines marked with triangle, solid circle and square, respect- of the modified herbal formula, Mei-Man-Do-Tan (mMMDT), for the treatment of mild-to-moder-ate persistent asthma. MMDT was originally formulated by Zhang Zhong-Jjing, an outstanding physician who lived during the Han Dynasty Chinese medicine believed that MMDT could treat various lung disorders, especially bronchial asthma. Although its pharmacological action has not been fully clarified, for centuries it has been widely prescribed, marketed and used to treat The modified MMDT consists of five herbs, ophiopogon, pinellia, licorice, American ginseng, Fig. 2. Magnitude of improvement in FEV1 from baseline and Lantern Tridax. In our previous animal after Mai-Men-Dong-Tang treatment. Solid bar indicatesFEV study, the mMMDT decoction significantly 1 improvement of 5–10%; blank bar indicates FEV1 decreased serum total IgE and house dust mite-specific IgE, and downregulated the expression ofthe IL-4 gene in allergen-sensitized mice (5).
Therefore, we considered that mMMDT was a Adverse effects were reviewed by investigators good candidate for a new treatment regimen for during each visit. No patient experienced a allergic asthma. We studied changes in FEV1 as serious adverse event during treatment. All the first efficacy end point on account of their laboratory measurement values obtained during validity for monitoring of airway obstruction. By the study, including liver, kidney function and the end of the study, FEV1 was significantly Table 4. Laboratory assessments for safety by treatment group patients (Table 4). Moreover, a marked progres- 1. Tang RB, Tsai LC, Hwang HM, Hwang BT, Wu KG, sion in lung function of more than 10 compared Hung MW. The prevalence of allergic disease and IgE with baseline was achieved for most patients antibodies to house dust mite in school children in Taiwan. Clin Exp Allergy 1990: 20: 33–8.
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Ophiopogon contains substantial quantities of Alternative treatments for asthma: assessing the need.
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studies have demonstrated that individual herbs 11. Mackenzie MA, Hoefnagels WH, Jansen RW, could not downregulate IgE synthesis or improve lung function in murine models (unpublished glycyrrhetinic acid on plasma cortisol and cortisone inhealthy young volunteers. J Clin Endocrinol Metab data). On the basis of the results of this study, however, it seems reasonable to suggest that the 12. Aubry A, Mullin J, Lemaire I. Extractable polysac- combination of these five herbs may improve lung charides of Panax quinquefolius L. (North American function and ameliorate clinical symptoms. The ginseng) root stimulate TNFalpha production by original Chinese herbal formulation was typically alveolar macrophages. Phytomedicine 2002: 9: 398–404.
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one or more of the herbs in the formula, these 14. Li XM, Zhang TF, Huang CK, Srivastava K, combinations frequently exhibit a therapeutic Teper AA, Zhang L. Food Allergy Herbal Formula-1 synergy (14, 15). Thus, further research is needed (FAHF-1) blocks peanut-induced anaphylaxis in a to clarify the mechanisms that underlie these murine model. J Allergy Clin Immunol 2001: 108: 639–46.
15. Dipaola RS, Zhang H, Lambert GH, et al. Clinical synergistic effects. In conclusion, the results of our and biologic activity of an estrogenic herbal combina- investigation suggest that due to its efficacy, tion (PC-SPES) in prostate cancer. N Engl J Med 1998: safety, low cost and favorable compliance char- acteristics, mMMDT can be considered aneffective treatment regimen for persistent, mild-to-moderate asthma in addition to currenttherapies.
AcknowledgmentsThis work was supported by grants from the Committee onChinese Medicine and Pharmacy, Department of Health(CCMP 92-RD-002), China.

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