The efficacy of ma-huang-tang (maoto) against influenza

doi:10.4236/health.2011.35052

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Vol.3, No.5, 300-303 (2011)

doi:10.4236/health.2011.35052

Health

The efficacy of ma-huang-tang (maoto) against influenza

Mizue Saita, Toshio Naito, Soushin Boku, Yukiko Watanabe, Mai Suzuki, Fukuko Oka,

Miki Takahashi, Takako Sakurai, Eiichirou Sugihara, Tomomi Haniu, Yuki Uehara,

Kazunori Mitsuhashi, Hiroshi Fukuda, Hiroshi Isonuma, Keiko Lee, Hiroyuki Kobayashi*

Department of General Medicine, Juntendo University School of Medicine, Tokyo, Japan;

*Corresponding Aut hor: [email protected]

Received 1 February 2011; revised 20 April 2011; accepted 27 April 2011.

ABSTRACT

In this study, we compared Ma Huang Tang

(maoto), a traditional Jap anese medicine (Kampo),

with antiviral drugs to evaluate their respective

and combined effect on the duration of fever

and other subjective symptoms of influenza.

Forty-five patients enrolled in this randomized

control trial had positive type A influenza on

rapid influenza antigen test, provided written

consent, and sought treatment at Juntendo

University Hospital between November 2008

and March 2009. Using a computer-gen-erated

list, patients were randomly assigned to one of

the four intervention groups: 1): maoto (TJ-27),

9 subject s; 2): Tamiflu (o seltamivir), 13 subject s;

3): Relenza (zanamivir), 6 subjects; and 4):

maoto/oseltamivir combination, 9 subjects. Six

outcome measures were evaluated, including

fever, myalgia, headache, arthralgia, fatigue,

and cough. Statistical differences were deter-

mined by the Bonferroni-adjusted t-test for mul-

tiple comparisons. Our results showed that

there were no significant differences among the

four groups in the time-course profile of fever

and the number of days until fever resolution

since treatment was initiated. In addition, no

significant intergroup differences were detected

in the number of days until resolution of myal-

gia, headache, fatigue, and cough. However, the

maoto group reported a more rapid improve-

ment in joint pain than the oseltamivir group (P =

0.01). In conclusion, maoto showed comparable

efficacy as antiviral medications in reducing

fever and influenza symptoms. As serious con-

cerns over the indiscriminate use, adverse re-

actions, and resistance to current antiviral

drugs continue to grow, maoto may serve as an

elegant option for the treatment of influenza.

Keywords: Ma Huang Tang (Maoto); Influenza;

Joint Pain; Oseltamivir and Zanamivir

1. INTRODUCTION

The influenza virus was first isolated by Smith, An-

drews, and Laidlow in 1933. Six decades have passed

and influenza continues to circulate worldwide despite

substantial research and advances in early and effective

vaccination use [1]. In the wake of WHO Declaration of

“Pandemic Phase 6 for Novel Influenza A (H1N1)”, an

expedited search for potent antiviral agents was sum-

moned [2]. Antiviral drugs remain the mainstay of in-

fluenza treatment but their use has given rise to a num-

ber of problems. The widespread and often indiscrimi-

nate use of antiviral drugs has generated reports on ac-

celerated drug resistance in viruses [3-5] and adverse

drug reactions notwithstanding unclear causal relation-

ship [6,7].

Human influenza infection is predominantly an upper

respiratory tract infection, yet most patients present and

complain of various systemic symptoms. Despite em-

pirically demonstrated efficacy of Kampo medicines in

relieving systemic manifestations, such data often fall

short as clinical recommendation s. Of the two traditional

Japanese (Kampo) medicines-maoto and chikujyount-

anto—which are covered under the National Health In-

surance scheme for the treatment of influenza, we sought

to investigate the efficacy of maoto as the front-line

Kampo drug prescribed during the acute stage of influ-

enza.

During the 2008-2009 influenza season, we prospec-

tively compared the efficacy of maoto with antiviral

drugs in reducing fever and flu symptoms (myalgia,

headache, arthralgia, fatigue, and cough) in adult pa-

tients with seasonal influenza type A.

The Juntendo University School of Medicine Hospital

Institutional Review Board reviewed and approved all

study procedu r es (app roval number: 208-037).

M. Saita et al. / Health 3 (2011) 300-303

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2. MATERIALS AND METHODS

Adult patients ages 20 and over with a positive naso-

pharyngeal swab for influenza type A on rapid diagnostic

test (rapid flu test, Sekisui Medical Co., Ltd) and sought

treatment at the Department of General Medicine at

Juntendo University Hospital between November 2008

and March 2009 enrolled in the study. A total of 45 pa-

tients provided written consent (mean age 32.4 ± 11.5

years: 21 men, 24 women) upon full comprehension of

the study procedures. A computer-generated list was

used to assign patients to four different interventions (I:

maoto (TJ-27), II: Tamiflu (oseltamivir), III: Relenza

(zanamivir), and IV: maoto/oseltamivir combination

therapy), and the efficacy of each treatment was evalu-

ated as a randomized control study. Main outcome

measures included fever onset, arthralgia, myalgia,

headache, cough, and fatigue. Patients were instructed to

keep a record of their symptoms on an evaluation post-

card and to rate the intensity of their arthralgia, myalgia,

headache, cough, and fatigue on a 5-point scale (score

0-4). They were also advised to track their fever, medi-

cation schedule, and body temperature for five days after

their diagnosis. The time it took for the highest score to

drop to zero for a given symptom was defined as the

“number of days until symptom relief”; the symptom

severity was calculated as the difference between the

highest and lowest scores and termed “reduction in

symptom score”. The product of the “number of days

until symptom relief” and “red uction in symptom score”

was statistically analyzed using the Bonferroni-adjusted

t-test for multiple comparisons.

Eight out of 45 patients failed to return their evalua-

tion postcards (I: 2 subjects, II: 1 subject, III: 3 subjects,

IV: 2 subjects), resulting in a final analysis based on 37

patients (I: 9 subjects, II: 13 subjects, III: 6 subjects, and

IV: 9 subjects).

3. RESULTS AND DIS CUSSION

At the time of treatment allocation, no significant dif-

ferences were observed in age, onset and duration of

fever, and vaccination rate among the patients (Table 1).

Maoto-treated subjects (I and IV) had near-equivalent

reduction in fever (body temperature: fever duration)

relative to those of oseltamivir-(III) and zanamivir-(IV)

treated subjects, thus no significant differences in anti-

pyretic effects were found among the three groups (Fig-

ure 1) (p = 0.90). Further, all groups showed comparable

effects in alleviating headache, cough, fatigue, and myal-

gia (Figure 2), with an exception of a more rapid im-

provement in joint pain in the maoto grou p than th e osel-

tamivir group (Figure 3) (P = 0.02). However, without a

placebo group to compare against, we were unable to

determine whether maoto could alleviate joint pain bet-

ter than placebo. Nevertheless, Ito et al. previously dis-

covered that the duration of joint pain in the placebo

group without treatment was 2.8 days (± 1.7 SD) whereas

it was 3.5 days (± 2.0) in the amantadine group in a RCT

that evaluated the efficacy of amantadine against influ-

enza type A . Thus, a joint pain of 2 day (± 1.1) duration

in the maoto group in our study appears to be shorter

than the duratio n observ ed in the placebo group in Ito et

al.’s study [8].

With the H1N1 influenza outbreak, the shortage of

antiviral drugs has become a burgeoning public health

Figure 1. Time-course profiles of fever of the four treatment

groups.

Table 1. Demographics and medical history.

I Mao-to II OseltamivirIII Zanamivir IV Oseltamivir and Mao-to

Number n = 9 n = 13 n = 6 n = 9

Age (Mean age ± SD*) 31.2 ± 10.433.3 ± 14.8 34.3 ± 6.07 31.5 ± 8.5

Sex (n) Male: 2

Female: 7 Male: 7

Female: 6 Male: 3

Female: 3 Male: 4

Female: 5

Mean (SD) Duration of Fe v er before Medication 14.25 ± 7.6325.8 ± 15.59 21.0 ± 11.91 24.0 ± 14.36

Mean (SD) Baseline Temperature (˚C ± SD*) 38.0 ± 0.6638.7 ± 0.60 38.0 ± 0.61 38.4 ± 0.66

Number of Patients Immunized with Current I n fluen z a V a c c in e5 6 5 2

M. Saita et al. / Health 3 (2011) 300-303

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Figure 2. Severity of headache, muscle pain, cough and fatigue.

Figure 3. Severity of joint pain.

problem. Moreover, unequal dispensation and inade-

quate access to antiviral drugs have been speculated as

causing an aggravation of the disease in compromised

patients.

Much controversy exists over oseltamivir, the first-line

agent for influenza, regarding its dosage, development of

drug-resistant strains, and adverse drug reactions. Ac-

cording to published data, Japan comprises 77% of all

oseltamivir usage in the world, while the United States

occupies the 22% of world consumption. Between 2008

and 2009, the majority of H1N1 viruses isolated world-

wide were reportedly oseltamivir-resistant strains; in

Japan, the resistance rate reached 99.6% (1234/1239) by

March 2009 [9].

In contrast, maoto, which is composed of mao (Ephedrae

herba), annin (Armeniacae semen), keishi (Cinnamomi

cortex), and kanzo (Glycyrrhizae radix), has been long

touted as the leading prescription for early stages of

common cold in the ancient Chinese medical literature

Shang Han Lun. Influenza primarily affects the upper

respiratory tract, yet patients often present and suffer

from systemic symptoms. Kampo medicines have puta-

tive ability to address generalized symptoms thro ugh the

synergy of multiple botanical raw materials. For instance,

a preliminary investigation of antiviral properties of

Kampo medicines showed that keishi exerted a

dose-dependent antiviral effect [10]. Hattori et al. fur th er

suggested that the antiviral effect of keishi against mul-

tiple strains were associated with its suppressive effect

on various aspects of endocytosis [11].

In the present study, maoto showed comparable effi-

cacy as antiviral drugs in influencing the duration of

fever and subjective symptoms, including headache,

cough, fatigue, and myalgia. Also, maoto demonstrated

M. Saita et al. / Health 3 (2011) 300-303

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greater efficacy than oseltamivir or zanamivir in im-

proving joint pain . This finding is corroborated by Ku bo

and Nishimura who found that treatment with maoto or

maoto-oseltamivir combination was more effective than

oseltamivir alone in shortening the duration of fever [12].

If we take into account the fact that maoto has been his-

torically used to treat cold symptoms based on (symptom)

pattern diagnosis in Kampo medicine, it is not surprising

to discover its efficacy to be on par with antivirals which

are specifically designed to suppress viral replication.

Hence, our results are clinically significant, given the

scarcity of data on maoto’s efficacy in influenze from

prospective randomized trials.

Oseltamivir showed strong but statistically insignifi-

cant antipyretic effect. Figure 1 depicts the antipyretic

effect of both oseltamivir administered groups (II and

IV).

Zanamivir-treated group showed a rapid improvement

in cough than the other three group s. Though statistically

unremarkable, our results un dergird the trad itiona l use o f

Zanamivir as a potent respiratory agent.

While efforts to discover novel antiviral agents and

oseltamivir-related problems continue to attract attention,

maoto’s effect in influenza as endorsed by the NHI and

observed in our prospective study are useful information

for both healthcare practitioners and patients.

Except for one patient developing nausea from the

maoto’s distinct odor, no other serious adverse events

were reported during the study. Based on our observa-

tions, nine patients on maoto/oseltamivir combination

therapy, who were anticipated to achieve a greater over-

all symptom relief than patients in other treatment

groups, did not demonstrate apparent benefits of the

combination therapy.

The absence of a control group with inert placebo and

a control group without treatment due to insurance pur-

poses were two important caveats in this study. Addi-

tionally, we did not investigate the effect of maoto in

other influenza types because all patients recruited for

the study were uniformly infected with type A virus,

although Toriumi et al. had previously found that maoto

was as effective as oseltamivir and zanamivir in reduc-

ing fever in pediatric patients with type B influenza [13].

As the speed and routes of H1N1 propagation gain mo-

mentum, clinically-oriented studies based on isolated

strains may halt further global catastrophe.

In summary, we found that maoto improved systemic

influenza symptoms during the active disease phase as

effectively, if not, better than antiviral drugs. Moreover,

because none of the patients receiving maoto or maoto/

antiviral combination therapy suffered adverse drug re-

actions, maoto appeared to have a slightly wider safety

margin than antiviral drugs. Maoto may curb the devel-

opment of drug resistance to antivirals caused by their

misuse and overuse, and serve as an elegant option for

the treatment of influenza.

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