Pediatr Allergy Immunol 2005: 16: 76–81. DOI: 10.1111/j.1399-3038.2005.00230.x
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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.
emphasis on symptom relief, the severity of
2. Hsieh KH, Shen JJ. Prevalence of childhood asthma in
problems including, coughing, wheezing, and
Taipei, Taiwan, and other Asian Pacific countries. J Asthma 1998: 25: 73–82.
breathlessness was alleviated in both mMMDT-
3. Bielory L, Lupoli K. Herbal interventions in asthma
treatment groups. The serum total IgE for the
and allergy. J Asthma 1999: 36: 1–65.
treatment groups showed a decreasing tendency
4. Hsieh KH. Evaluation of efficacy of traditional Chinese
after treatment but statistical difference was not
medicines in the treatment of childhood bronchial
noted. That was apparently due to the wide data
asthma: clinical trial, immunological tests and animalstudy. Pediatr Allergy Immunol 1996: 7: 130–40.
distribution. In addition, the treatment was quite
5. Hsu CH, Shyu YY, Li MH The mechanisms of anti-
safe in our sample population, with neither
asthma formulas in traditional Chinese medicine in the
severe side effects nor adverse events noted over
treatment of allergen-induced airway inflammation.
Previous studies have shown that glycyrrhizin
6. Orhan F, Sekerel BE, Kocabas CN, Sackesen C,
or glycyrrhetinic acid of licorice can influence
Adalioglu G, Tuncer A. Complementary and alter-native medicine in children with asthma. Ann Allergy
steroid metabolism (11). Additionally, immuno-
modulating effects have been demonstrated for the
7. Frew AJ, Plummeridge MJ. Alternative agents in
extract of American Ginseng, especially in terms
asthma. J Allergy Clin Immunol 2001: 108: 3–10.
of secretion of tumor necrosis factor alpha (12).
8. Szefler ST, Kamada AK, Hughes DM, Gelfand EW.
Ophiopogon contains substantial quantities of
Alternative treatments for asthma: assessing the need.
isoflavonoids, which possess anti-inflammatory,
9. Nestler G. Traditional Chinese medicine. Med Clin
antiallergic, antihistaminic and angioprotective
properties, as well as potent phosphodierterase
10. Huntley A, Ernst E. Herbal medicines for asthma: a
inhibitors (13). However, our previous animal
systematic review. Thorax 2000: 55: 925–9.
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.
composed of at least four different ingredients. As
Wessjohann LA. Homoisoflavonoids from Ophiopogon
well as reducing the possible side effects caused by
japonicus Ker-Gawler. Phytochemistry 2003: 62: 1153–8.
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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