Volume 11, Number 3 | Fall 2016

Integrating Kampo and Evidence-Based
Medicine (7) – From Reports of Medical
Cases from 200 Years Ago –The Effect of Maoto on Influenza
Hiromichi Yasui1), Tetsuhiro Yoshino2), Ryutaro Arita2),
Yuko Horiba2), Hiroshi Koike2), Takuya Hamaguchi2),
Miwako Ohgishi2) and Kenji Watanabe
1) Japan Institute of TCM Research2) Center for Kampo Medicine, Keio University
School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan

These records continued to be read even to thisday. Among them, the ailment that he wrote as"Shang-han lun" seems to be almost the same as the"Shang-han lun" which is listed in the " Shang-han
lun", the original text in which described maoto. And
seen from our modern eyes, this was probably
influenza.

Maoto is currently widely used for influenza. Thisis because this experience of Dr. Yodo ODAI wasearnestly recorded in his "Essay of Medical
Technique".

From medical cases about 200 years ago
This is a story of an experience by a boy born in adoctor's family in a rural area in Japan about 200
years ago.

The composition of maoto"Shang-han lun" lists the compounding anddosing method of maoto as follows.

One day, the people of the neighborhood came toMix ephedra (3 liang, remove stem node), apricot

this doctor’s house saying they wanted him to

seed (70 pieces, remove skin tip), cinnamon twig (2examine a patient. At this time, the doctor was notliang, remove skin), and liquorice (2 liang, scorch)at home, and the grandfather, who was alreadywith 9 sheng of water, first boil the ephedra, reduce

retired, told the doctor's younger brother to "go andby 2 sheng, remove foam, add the other medicines,

examine the patient". And so the boy went andboil down by 2.5 sheng, remove scum, and take 8

examined the patient. The grandfather asked thene warm. In other words, the boiled liquid will beboy what kind of sickness the patient had, and thedivided into 3 equal parts.

boy answered, "The patient's disease is Shang-han,Currently, the following crude drugs are boiled

he has splitting pain in his head, chills, fever,in the following gram amounts to prepare onelabored breathing, pain all over his body, and his

day's dose. The formulation divides this into 3

pulse was floating and strong." To this thetimes.

grandfather replied, "What kind of prescription do
you think to give him?” The boy answered, "howEphedra 3〜5g，apricot seed 4〜5g，cinnamon
twig 2〜4g，liquorice 1〜1.5g

about maoto?” Then the grandfather smiled and said,

Because the amounts are slightly different at"Good job", so he prop 3 doses of maoto and orderedeach pharmaceutical company, there is a range.

him to "give him these doses warm, and make him

Lactose is often used as an excipient, with somesweat a lot" and sent the messenger back. When heformulations using starch.

went back the next morning, the patient had sweat
a lot and said that his suffering had quickly been
alleviated. He still had a slight fever, so he changed
the prescription to shosaikoto, and he recovered inbarely more than a day.
This is a story experienced by Dr. Yodo ODAI(1799-1870) at age 13, who was praised as a great
doctor in his later years, and he wrote of this as being

Maoto as a remedy for influenza
Use of maoto is generally limited to the earlystages of acute fever such as influenza. As statedabove, the indication is the combination of symptoms
such as chills, fever, headache, joint pain, andfloating pulse, with no sweating.

his "first challenge" 1).

2

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

When administering maoto for influenza, I

be influenza or associated ailments. In recent years,

conduct the following dosing guidance based on the

research from this point of view has progressed anddescription in the "Shang-han lun".

there has been a great deal of clinical research

Patients take an extract formulation of maoto in
hot water. After taking, keep the body warm to help

produced showing that maoto is effective against
influenza.

induce sweating. After the first dose, take 1 dose

There are also many medical reports, theevery 2 hours taking 1 day's worth (3 doses) in 4

prototypical of which is published by Oribe in Vol.1

hours. Subsequently, take some every 3-4 hours, andNo. 1 of this journal.

continue until sweating onsets. After sweating starts,
stop taking at that point. In the original text it isCaution when usingstated that you must not induce too much sweating,Maoto is a formulation with ephedra as its main

but in actuality as long as you quickly change clothes,

ingredient, and the main component of ephedra is

keep warm, and intake an appropriate amount of

ephedrine. For this reason, use in combination withwater.

otherephedra-containing

compounds

and

In some cases the fever may temporarily risecatecholamine formulations requires caution. Side

before subsequently falling. For example, in someeffects caused by ephedrine can be seen includingcase a body temperature of 38.5℃ may rise to 39.3℃

coronary artery disease, arrhythmia, excessive

1 hour after dosing. Normally, the fever will go backperspiration and urinary retention. Also seen are

down after this. In rare cases, palpitation ordigestive symptoms such as a heavy feeling in thetachycardia may occur after dosing. In these cases

stomach and epigastric pain.

temporary stop taking the medicine.

It has also been shown that the absorption of

When the fever starts to go down, there is often

ephedrine raises in pH of the alimentary canal, solarge amounts of sweating, but in a few dozen

absorption is higher when taken internally after

percent of patients, the fever can go down withmeals, and it also has the potential to increase thefrequent urination (urination may occur about 5

likelihood of side effects due to sympathetic nerve

times in 2 hours). In these cases, there is not muchstimulation. For the same reason, taking together

sweating. In extremely rare cases, reduction of feverwith antacid drugs also requires caution 3).

may occur with nosebleeds. When effective, the fever
will drop to about 37.0℃ in 18-36 hours from thestart of dosing.
The amount to use for children depends on theirage and body weight or body surface area
Furthermore, in the series of maoto research
below, the standard method of dosing one day's
worth separated into 3 times is most common.
The diseases for which maoto is indicated in the
text of the "Shang-han lun" belong to taiyang
diseases among diseases called "Shang-han", andthey are "headache and fever, sheng teng lower backpain, bone pain, chills, and panting without sweat".
Thought of in the context of modern notions ofailments, these descriptions of "Shang-han" seem to

Research into maoto for influenza
Influenza virus infection often shows evidence of
maoto, and there have been many reports regarding
the effects of administering maoto. Classified
broadly, we see studies which examine the effects
when adding maoto to commonly used anti-viral
medicines, studies which compare maoto alone with
anti-viral medicines alone, and also case series andcomparative studies which investigate the side
effects and administration methods in addition towhat

happens

before

and

after

maoto

is

administered.
In Japan, continuing from the rapid testing of
influenza viral antigens, in February 2001 theThe Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

3

Volume 11, Number 3 | Fall 2016

National

HealthInsurance

drug

pricesofNote: In Japan, the prices of medicines used with

oseltamivir (Tamiflu®) and zanamivir (Relenza®)

health insurance are controlled by the nation. The

were listed, after which their use expanded

drug price of oseltamivir phosphate is about 640 yen

explosively. In the case of oseltamivir especially, 7080% of its consumption in the world is in Japan, andas a unique phenomenon in Japan it as acquired thestatus of the standard treatment in a short period of

per one day's worth, while maoto is about 60 yen.
Arita et al. preliminarily calculated that using maoto
instead of oseltamivir would result in a reduction intime. Consequently, early-stage clinical researchhealth care costs of 3,000 yen per person or 9 billion

into the results of maoto against influenza virus

yen in Japan overall 5).

infection has no option to not administer the
standard treatment anti-viral medicine, and has

In recent years there have also been reports ofstarted generally as an examination of the effects ofviruses that are resistant to oseltamivir, andmaoto on top of the other medicine.

furthermore

oseltamivir-resistantviruseshave

As the use of oseltamivir expanded, in 2004 ashown cross-resistance with peramivir, a injectablepostscript was added to the package insert of

medicine, as well. There are no reports of resistanceoseltamivir regarding mental and nervous disorders,to maoto, and viewed from the point of view offurthermore about the abnormal behavior of theresistant virus control as well as from the point of

teenage patient, Japan’s Ministry of Health, Labour

view of drug assurance to prepare for pandemics, theand Welfare came to urgently perform a delivery ofsignificance of the existence of Kampo medicine such

safe information in 2007, and the report thatas maoto would seem to be great.

compared the independent groups given maoto withthe oseltamivir came to attract attention. In basic
researches

using

rats,

the

simultaneousadministration of ethanol and oseltamivir has beenreportedtopromoteexcitability,

andsimilarphenomena are predicted in ephedrine as well 4). For
this reason there are opinions that prudence isrequired when using oseltamivir and maoto together.
Furthermore, in 2009 the effectiveness of maoto
against new strains of influenza was investigated,
and this continues today. Compared to oseltamivir,
the National Health Insurance drug cost of maoto isoverwhelmingly low, and it is receiving attention interms of health economics as well regarding whether
or not administering maoto alone has the sameStudies of maoto with standard therapy
Research by Kuroki, et al.
In a comparative study by Kuroki, et al.,oseltamivir was administered to 83 children with
influenza, and in 44 of the 83 cases maoto 0.10.15g/kg/day x 3 was simultaneously administered.
In the group administered oseltamivir alone, nocomplications were seen except 1 case of febrile
convulsions. The time from the first day of fever until
the alleviation of fever was 3 days in the maoto +
oseltamivir group, and 2 days in the oseltamivir only
administration group. The reason maoto wasprescribed was not stated, and it is unclear what the
fever period indicates 6).

effects as oseltamivir.

4

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016(combined administration group) with the combined

Research by Kimoto, et al.
In an open labeled quasi-randomized-controlled

administration group being administered maoto

trial (RCT) conducted subsequently by Kimoto, et al.,(7.5g/day), and the number of days the patientswith the same group, 19 patients diagnosed with

continued to experience a fever of 38℃ or higher,

influenza through clinical condition and rapid

headaches, and full-body fatigue was investigated.

testing from January to March 2004 which did not

The method of assignment into the groups was notmeet exclusion criteria were divided into a group ofstated. The number of days the fever continued was

10 patients (4 men, 6 women, age 24.1±7.72) who

1.7±0.8 days in the single administration group and

were

maoto

1.9±0.6 days in the combined administration group,(7.5g/day×3 days) in the order of examination, and ashowing a significant difference. The number of days

group of 9 patients (5 men, 4 women, age 29.1±4.52)

the headache continued was 2.4±1.0 days in the

who were administered oseltamivir with Western

single administration group and 1.3±0.5 days in the

medicine

andcombined administration group, while the full-bodyclenbuterol hydrochloride or carbocysteine), andfatigue was 2.3±1.2 days in the single administration

their body temperature, appetite, fatigue, andgroup

dizziness after treatment were compared via aadministrationquestionnaire filled out by the patients. All of thedifference. It appeared to be clinical influenza, but incases were type-A influenza. 12 hours after the start

the 6 cases where maoto was administered withoutof treatment, their body temperature showed aa diagnosis via an influenza rapid testing kit, notendency to be lower in the maoto combination group

significant difference in number of days fever,than in the Western medicine combination group.

headache, and full body fatigue continued was foundThe date when the maoto group's fatigue, dizzinesscompared to the combined administration group. No

and lack of appetite scores improved significantly

serious side-effects were observed 8).

administeredoseltamivir(cyproheptadineandhydrochloride

compared to before treatment was sooner comparedto the Western medicine group. Not examples if
increased CRP were observed in the maoto group,
but in the Western medicine group 3 cases of CRP
increase were observed. In the Western medicinegroup reduced WBC, increased RBC, Hb, hematocritand significant increase in ALT and γ-GTP wereobserved. A decrease in albumin was also observedin the maoto group. Including 8 weeks of follow-up
observation,noseriousadverseeventswere

observed in either group 7).

and

1.3±0.5
group,

days

in

the

combinedshowingasignificant

Research by Kubo, et al.
In an open labeled RCT by Kubo, et al., 60 case ofpatients (5 months to 13 years of age) experiencing
fevers of 38℃ or higher, 2 or more of the symptoms
headache, chills, and fatigue, and coughing andnasal inflammation all appearing within 48 hours
were first classified into 2 groups: the group which
was 1 year old or older with a positive rapid testing
result, and the group which was 1 year or less witha positive rapid testing result or a negative rapid
testing result regardless of age. Additionally, thegroup of 1 year and older with positive rapid testing

Research by Fukutomi, et al.
In an open labeled RCT by Fukutomi, et al., 22

results was further assigned randomly into 2 groups,

patients diagnosed with influenza through rapid

with 19 patients being administered oseltamivir

testing within 24 hours of the onset of symptoms(4mg/kg/day) and 17 patients being administered

were

of

12

patients

oseltamivir and maoto (0.06g/kg/day). The group of

only

(the

single24 patients 1 year or less in age with a positive rapid

administration group) and a group of 10 patients

testing result or a negative rapid testing result

who were administered oseltamivir with maoto

regardless of age was administered maoto only.

dividedadministered

into

a

group

oseltamivir

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

5

Volume 11, Number 3 | Fall 2016

Antipyretics were requested not to be internallylack thereof, and the results of these were comparedadministered. The definitive diagnosis of influenza

with the patient information in the electronic charts

was conducted with viral culture or PCR, and among

to confirm the patient backgrounds such as age andthe negative rapid testing group those diagnosed

gender, fever period, and administration of anti-viralwith type A influenza were the only targets ofmedicine and antibiotics or lack thereof. The results

analysis. The method of randomization was notshowed that in the younger ages there was morestated. 3 of the patients with positive rapid testing

administration of maoto alone, while in the higher

resultsofages there was administration together with anti-

oseltamivir and maoto did not internally take maoto

influenza drugs. The average fever period by

and were therefore excluded from analysis. The 2

treatment method was 1.39±0.96 days in the maoto-groups which took maoto orally had significantly

only group and 1.60±1.20 days in the anti-influenza

shorter periods of fever after examination compareddrugs combined use group, with no significant

to those who did not take maoto orally. All patientsdifference observed between the 2 groups. Side

resumed their normal lives and no side effects from

effects were observed in 21 patients (13.1%), and a

maoto

breakdown observing duplicate responses was thatassigned

werecombined

observed.

administrationNo

patients

required13

hospitalization 9).

experienced

Research by Takeya, et al.
In RCT by Takeya, et al., the fever period fromstart of treatment until alleviation of fever wascomparedintwopatients

groups--a

group

that

was

administered both maoto and oseltamivir (23 type A
and 17 type B) and a group that was administeredexperiencedlacknausea/vomitingofappetite,(including

5

while

taking orally), 3 experienced rashes, 2 experienced
diarrhea/watery stools, and 1 each experienced badtemper and edema, respectively, with no significant
difference observed between the groups 11).
Research by Tsuji, et al.

only oseltamivir (59 type A and 86 type B)--targeting

Comparative research by Tsuji, et al. targeted 81

185 patients (age 0-14) selected from children

cases of child influenza patients whose families

examined at 7 hospitals and clinics in Shimane

consented in participation in the study. They wereprefecture

influenza

separated into 3 groups--an anti-influenza medicine

vaccination and who were shown to be type A or typeonly group (oseltamivir 4mg/kg/day or zanamivir

B influenza virus antigen-positive in rapid testing.

8mg/day), a maoto-only group (0.2g/kg/day), and an

The results showed a shorter trend in the combined

anti-influenza + maoto group--and investigated. The

administration group compared to the oseltamivir

method of assignment into the groups was not stated.

only group, but no significant difference wasNo significant difference was observed in the periods

observed 10).

of

who

had

not

receivedaretrospective

comparative

study

by

Yamamoto, et al., 167 cases were investigated via
responses to questionnaires out of 329 cases ofchildren where were diagnosed with new strains ofinfluenza

who

were

administeredmaoto.

A

questionnaire was administered to the guardians of
the target patients regarding the state of oral
ingestion, day of fever alleviation, and side effects or

6continuationorclinical

symptoms

continuation among the 3 groups, however the fever

Research by Yamamoto, et al.
In

fever

continuation

periodandclinical

symptoms

continuation period were both shortest in the
combinedtreatment

administration
withgroup.

anti-influenza

Furthermore,
medicine,clarithromycin (10mg/kg/day), and maoto combinedwith clarithromycin was conducted targeting a totalof 288 other child patients diagnosed with influenza(themaoto-onlygroup and antipyreticgroup

administered group were excluded due to a low

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

number of cases). The results showed no statisticallystart of ingestion was longer, so it is difficult to comesignificant difference between the groups in theto a conclusion based solely upon this report.

fever continuation or clinical symptom continuation

with almost the same contents targeting 129 childgroups 12).
Studies comparing maoto administered alone andanti-viral medicines administered alone
it

was

not

randomassignment,

Kawamura, who is proactively proceeding withcomparative research, has come to imply thepossibility that the differences in results and side
effects between maoto and oseltamivir are small. 139
child patients with influenza examined in the springof 2007 were divided into a maoto (0.08 ～0.19g/kg/day，maximum of 7.5g in 3 divided doses)
administration

group

and

an

(4mg/kg/day ， maximum 150 ㎎

influenza patients, in addition to similar contents tothe preceding study, the study also investigated thetime passed after onset of fever and after onset of

Research by Kawamura
Although

In a subsequently published report by Kawamura

oseltamivirin 2 divided

doses)administration group as per their parents'
requests, the time of fever alleviation and fever
period, etc. were investigated. The administration
period was 2-8 days in the maoto group and 2-5 daysin the oseltamivir group, with fever alleviation or
improvement of symptoms as criterion in the case ofboth medicines. Antihistamine, antitussives, andexpectorants were also additionally administered asnecessary. In the type A patients no significant
difference was observed in age, maximum bodytemperature, ingested dose of maoto, time fromoutbreak of illness to start of ingestion, time fromingestion until alleviation of fever, time fromingestion until alleviation of general symptoms, andtime of continuation of general symptoms. In thetype B patients, the time of starting ingestion was
significantly later in the maoto group, the time fromingestion until alleviation of fever and time until
alleviation of general symptoms was significantly
faster in the maoto group, and the length of general
symptoms was significantly shorter in the maotogroup 13). In the B group patients, the time fromingestion until alleviation of fever and time until
alleviation of general symptoms was significantly
shorter in the maoto group, but the time until theillness until the start of ingestion, the fever period,
thesymptom

continuation

period,andthecorrelation between the amount of maoto ingested
and the fever period and symptom continuation
period. By and large no correlation was observed, but
a positive correlation between the time of starting
ingestion after onset of fever and fever period wasobserved in the type A influenza oseltamivir groupand in the type B influenza maoto group. No
significant difference in abnormal behavior such as
sleep-talking, auditory hallucinations, and visual
hallucinations was observed between these twogroups 14).
In comparative research conducted by Kawamura
conducted in the following season (2007/08), the timeof disappearance of the influenza virus form thepharynx with maoto and oseltamivir was examined,
and the study implied the efficacy of maoto. 172
patients with type A influenza in the 2007/2008
season were divided into 3 groups--64 patients with
Teikoku's maoto (0.16g/kg/day，maximum 7.5g/dayin 3 divided doses), 61 patients with Tsumura's
maoto (0.16g/kg/day，maximum 7.5g/day in 3 divided
doses), and 47 patients with oseltamivir (average 3.9
mg/kg/day，maximum 150 mg/day in 2 divided doses)by the request of the patients (their parents)--withmaoto administered with 1-6 days with fever
alleviation

as

the

target,andoseltamivir

administered with fever alleviation or 5 days being
the criterion. The average time after ingestion until
fever alleviation was 45.73±35.51 hours, 53.90±39.42
hours，and 30.36±20.96 hours, with the oseltamivirgroup being significantly shorter compared to the 2companies' maoto groups. Similarly, the average
fever

time

was

average

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

67.27±37.88

hours,

7

Volume 11, Number 3 | Fall 201669.57±39.76 hours, and 45.79±21.05 hours, and theA-type, the conservative was significantly younger

time from onset of illness until disappearance ofthan the maoto group. Also, although the fever

symptoms was 70.47±41.99 hours ， 73.95±43.01

period was significantly longer in the conservative

hours，and 48.47± 26.90 hours, significantly shorter.

compared to the maoto group, there was also no

No significant difference was observed in the 3

significant difference observed between the groups

groups in the time after onset of illness until thein the time until coming to the hospital and the time

influenza virus was removed, the time fromuntil alleviation of fever after ingestion. In Soviet A-

alleviation of fever was significantly shorter in the 2type, the time until coming to the hospital as well ascompanies'

thethe time after ingestion until alleviation of fever andoseltamivir group. In a comparison of the Teikoku

fever time were all significantly shorter in the

and Tsumura maotos, a significant difference wasoseltamivir group compared to the maoto group. Also,

observed in the fever alleviation time, fever time,

although the fever period was significantly longer ingeneral symptoms time, and elimination of A typethe conservative compared to the oseltamivir group,

influenza virus from the pharynx 15).

there was also no significant difference observed

maotogroupscomparedto

In comparative research by Kawamura, et al.

between the groups in the time until coming to the

conducted from January to March 2009, eachhospital and the time until alleviation of fever after

subtype of influenza was investigated. 147 patientsingestion. Furthermore, the Soviet A-type had

who came to a hospital within 48 hours of the onset

significantly longer fever time and time until feverof illness, were diagnosed with type A influenza via

alleviation after ingestion compared to the Hongrapid testing kits using nasal swabs and diagnosed

Kong A-type. No significant difference was observedwith a subtype (Soviet A-type H1N1, Hong Kong A-

between the groups in the time until general

type H3N2) were divided into the symptomatic

symptoms were alleviated after ingestion 16).

treatments of oseltamivir 4mg/kg/day and Teikoku
maoto extract 0.2g/kg/day as per the request of thepatients. 1-5 days of oral administration was
conducted depending on the continuing time of thesymptoms, and a comparative investigation of thecontinuation period of fever of 37.5℃ or higher andthe continuation period of general symptoms such as
headaches, fatigue, and lack of appetite wasconducted.

In

SovietA-type,

there

was

an

oseltamivir group of 15 patients (6 male patients，9female patients，age 11.20±16.22), an maoto groupof 63 patients (33 male patients, 30 female patients,
age 7.66±7.25), and a conservativeof 8 patients(1male patients，7 female patients, age 4.53±2.38),
and in Hong Kong A-type there was an oseltamivirgroup of 18 patients (9 male patients ， 9 female
patients, age 12.86±16.20), an maoto group of 34
patients (18 male patients，16 female patients，age
9.24±11.41),and a conservative of 9 patients (2 malepatients，7 female patients, age 7.86±9.40). In Soviet

8

Research by Fukutomi, et al.
In the preceding comparative study by Fukutomi,
et al. which reported the efficacy of combined
administration of maoto, 112 patients of less than 10
years of age diagnosed with influenza via rapid
testing within 24 hours after the onset of illness was
divided into 2 groups--54 patients (average age
4.7±2.1)

administered oseltamivir and 68 patients(average age 5.2±2.7) administered Tsumura maotoextract (7.5g/day) as per the request of the patients-and their body temperatures on consecutive days
were examined. In both groups, the 2nd day of illness
showed a significant decrease in body temperaturecompared to the 1st day of illness, and no difference
was observed between the groups. No serious sideeffects were observed

17).

It was furthermore

reported in a comparative study conducted targeting
41 cases in a different season that no difference wasobserved between the groups. The oseltamivir groupwas 20 patients (average age 4.1±1.8, 10 type A

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

patients/10 type B patients ， fever of 39.0±0.3 ℃

desired maoto. Moreover, the patients who desired

when coming to hospital), and the maoto group was

maoto from among the group which desired

21 patients (4.1±2.6 age，12 type A patients・9type

neuraminidase

B patients，39.0±0.4℃). In a questionnaire regarding

administered maoto. Furthermore, an investigation

the results of maoto conducted 3 days after thewasadministration of maoto, 66% rated the results very

administered neither anti-viral medication nor

good or good. On the other hand, a large number ofmaoto. The amount of each drug administered was

respondents at 70% responded that it was difficult to

4mg/kg/day for oseltamivir，10mg/day for zanamivir，drink. In spite of the common opinion that it was

and 0.06g/kg/day for maoto. 16 patients weredifficult to drink, only about 3% responded that theyomitted, and only 70 patients were analyzed. No

could not drink it 18).

significant difference was observed in time fromIn a retrospective comparative study by Mori, 19
patients (12 men, 7 women, average age 11±11) out
of 22 patients from amount 291 patients diagnosed
with type A influenza between October andDecember 2009 were administered maoto extract,
and the time it took for their temperature to drop to
36.9 ℃ from examination was investigated. They
ingested 3 packets of Kampo medicine every 2 hours,
and subsequently ingested every 3 hours until
sweating was induced. By comparison, a group of 19
patients (7 men, 12 women, average age 16.5±16.1)
administered oseltamivir and a group of 21 patients
men,

10

women,

into

the

were

additionallypatients

who

were

ingestion to alleviation of fever or time from onset of

Research by Mori, et al.

(11

conducted

inhibitors

averageadministered the drugs in ANOVA. The time from
onset

of

illness

toalleviation

of

fever

was

significantly shorter in all the groups administereddrugs compared to the group administered no drugs.
All patients resumed their normal lives and noside effects from maoto were observed. No patientsrequired hospitalization. Although there were 2
patients in the oseltamivir-only and zanamivir-only
administration groups reported abnormal behavior
respectively, no serious side effects were observed 20).
Research by Saita, et al.

15.4±8.7)

In open labeled RCT by Saita, et al., 45 adult

administered zanamivir were also set up. Regarding

patients (average age 32.4±11.5) who tested positive

the time for the fever to drop to 36.9 ℃ after

for type A influenza in rapid testing were divided

administration,

droppedinto 3 groups--a group of 11 maoto patientssignificantly faster in the maoto group compared to(7.5g/day), a group of 14 oseltamivir patients, athe zanamivir group, no significant difference wasgroup of 9 zanamivir patients and a group of 11

observed between the maoto and oseltamivir

patients who took maoto in combination withgroups19).

oseltamivir. 2 patients in the maoto and combined

althoughtheageillness to alleviation of fever between the groups

fever

administration groups, 1 patient in the oseltamivir

Research by Toriumi, et al.
In the comparative research by Toriumi, et al., 86
patients (aged 5 months to 15 years) who wereobserved to have fevers of 37.5℃ or more and whotested positive for type B influenza were separated
into 3 groups--a group between 1 and 10 years of age
who desired oseltamivir, a group age 6 and older who
desired zanamivir, and a group age 1 year or younger
or who didn't desire neuraminidase inhibitors but

group, and 3 patients in the zanamivir group wereomitted. No significant difference was observed
between the groups in fever after coming to thehospital. The symptoms of joint pain, muscle pain,
headache, cough, and fatigue were evaluated on a 5point scale, with the product of the difference
between the maximum and minimum values of eachpatient and the number of days taken to reach theminimum value from the maximum value as the

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

9Volume 11, Number 3 | Fall 2016

symptom score, which when compared among theno significant difference in the virus isolationgroups was shown to be significantly lower in thepositive ratio or the serum cytokine concentration on

maoto group than the oseltamivir group. 1 patientthe 5th day after the start of administration amongdeveloped nausea due to the odor of the maoto, but

the 3 groups. Mild liver dysfunction was observed in

no serious side-effects were observed 21) 22).

1 patient from the maoto and oseltamivir groups
respectively, but this improved quickly 24).

Research by Nabeshima, et al.
In comparative research by Nabeshima, et al., 20
adult patients who developed a fever of 38 degrees or

Research by Yamagishi, et al.
Althoughretrospective,

Yamagishi,

et

al.,

higher within 48h and tested positive for type A

reported research comparing 130 pregnant women

influenza inrapid testing were divided into a group

who had contracted influenza by whether they hadof 12 patients who desired maoto (7.5g/day) and 8

been administered maoto or now. The assignment

patients who desired oseltamivir. No significant

was by the patients' requests, with 90 patients being

difference was observed between the maoto andadministeredoseltamivir groups in the fever continuation timeadministered no drugs. The group administeredafter coming to the hospital and the symptoms

maoto comprised 70 type A patients and 20 type B

continuation time. The average body temperature

patients, while the group administered no drugs

and headache score on the evening of the first day ofcomprised 32 type A patients and 8 type b patients.

treatment was significantly lower in the maoto

The maoto was administered at 7.5g/day in 3 divided

group

In open labeled RCT subsequently

doses (administration period not stated, antitussives

conducted by Nabeshima, et al., 33 adult patientsand expectorants administered in combination). In

age 20-64 who developed a fever of 38 degrees or

the maoto group, both the type A and type B patients

higher within 48h and tested positive in rapid

had their fevers alleviated significantly faster thantesting were randomly divided into a group of 11

the group administered no drugs. Furthermore theirpatients who were administered maoto (7.5g/day), a

symptoms such as headache, full-body fatigue andgroup of 10 patients who were administeredlackoseltamivir, and a group of 12 patients who weresignificantly faster 25).

23).

administered zanamivir. Ischemic heart disease
patients,

patients

withhyperthyroidism,

enlargement of the prostate, and chronic infections,patients taking steroid/immunosuppressant drugs,
anti-viral drugs, or Kampo medicine, and patients
testing positive for new strains of influenza were
excluded. 1 patient from the maoto group, and 2
patients from the oseltamivir and zanamivir groups
respectively were omitted. The median value of thefever continuation time since coming to the hospital,
which was the primary outcome, was 29h in the
maoto group, 46h in the oseltamivir group, and 27hin the zanamivir group. A significant difference wasobserved between the maoto and oseltamivir groups.
No significant difference was observed between the
3 groups in the influenza symptoms score. There was
10

of

maoto

appetite

and

were

40

patients

observed

to

being

improve

Research by Yaegashi, et al.
In open labeled RCT by Yaegashi, 14 patients
aged 18 and older who had been diagnosed with type
A influenza within 48 hours of developing fever wererandomly

dividedinto

2groups--agroupadministered maoto and shosaikoto in combination(6 patients: 7.5g of maoto extract granules and 7.5gof shosaikoto granules/day in combination, taken for
3 days) and a group administered oseltamivir (8patients: 150mg/day, taken for 5 days). The fever
period from onset of illness, time from onset of illness
until start of treatment, time from start of treatment
until

alleviationoffever,

maximumbodytemperature, amount of antipyretics used, andamount of antitussives used were compared. The

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

method of assignment into the groups was not stated.

of bronchial asthma as well, the rate of use of

No significant difference was observed between theconcomitant drugs for respiratory organs was 34 out

groups 26).

of 107 (31.8％) in the anti-viral drug group and 9 outof 13.4 (13.4 ％ ) in the maoto group, significantly

Research by Yamauchi, et al.
In comparative research by Yamauchi, et al., childpatients aged 15 and younger diagnosed with
influenza were administered either anti-influenza
drugs (oseltamivir or zanamivir) (166 patients) or
maoto (80 patients) based mainly on the preferenceof their guardians, after which their frequency offollow-up treatment was investigated. The patientswere administered 4mg/kg/day of oseltamivir in 2
divided doses, 20mg of zanamivir in 2 divided doses,

lower in the maoto group. The rate of use ofconcomitant drugs for respiratory organs was lower
in the maoto group. Furthermore, in spite of the factthat the rate of use of concomitant drugs forrespiratory organs was significantly lower the maotogroup in patients without a history of bronchialasthma, the need for follow-up treatment for
respiratory organ complications was low 27).
Research by Suzuki, et al.

and 0.2g/kg/day of maoto in 2-3 divided doses. The

In an open labeled quasi RCT by Suzuki, et al.,anti-viral medicine group and maoto group werechild patients age 1-10diagnosed with type A

further stratified by age (younger than 10, andinfluenza were divided into a group administered

between 10 and 15), history of bronchial asthma or

maoto (0.15g/kg/day，in 3 divided doses) and a grouplack thereof, rate of follow-up treatment foradministered oseltamivir (4mg/kg/day，in 2 divided

respiratory organ complications, and rate of use ofdoses) for 5 days in alternating order of examination.

concomitantorgansFurthermore, the subjects of the study were limited(expectorants, bronchodilators, anti-allergy drugs,

to those with a maximum body temperature of 38.4

and antitussives). The rate of patients requiring～40.1℃ before administration, and who also could

follow-up

organ

be administered one of the drugs within 24 hours

complications was 34 out of 166 (20.5％) in the anti-

after the onset of fever. Child patients who could not

viral drug group and 9 out of 80 (17.8％) in the maoto

be administered maoto were also excluded. A

group, showing no significant difference. In thecomparison of the body temperatures was conducted

patients without a history of bronchial asthma, theat each 6 hour interval. The oseltamivir grouprate of patients requiring follow-up treatment wascomprised 46 patients, while the maoto group

19 out of 107 (17.8％) in the former group and 4 out

comprised 40 patients. No significant differences inof 67 (6％) in the latter group, significantly higher inage, gender, rate of vaccination before contracting

the anti-viral drug group. In the patients with athe illness, maximum body temperature before

history of bronchial asthma younger than age 10, thetreatment, and body temperature at the time ofrate of patients requiring follow-up treatment wasstarting administration were observed between the

15 out of 57 (26.3％) in the anti-viral drug group and2 groups. At 12-30 hours after the start of

4 out of 5 (80 ％ ) in the maoto group, showing aadministration, the temperature in the maoto group

significantly high rate requiring follow-up treatment

was on average 0.15 ～ 0.26 ℃ lower, showing a

in the maoto group, although the number of cases

significantly lower body temperature. Subsequently,

was small. The rate of use of concomitant drugs forthe median value of the body temperatures of the two

respiratory organs in all of the cases was 64 out ofgroups crossed at the 36th hour, after which the

166 (38.6％) in the anti-viral drug group and 12 out

oseltamivir group's body temperature converselyof 80 (15％) in the maoto group, significantly lower

became clearly lower. With having a fever is definedin the maoto group. In the patients without a historyas "37.5 ℃

drugs

treatment

for

for

respiratory

respiratoryor higher", the average ± standard

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

11

Volume 11, Number 3 | Fall 2016deviation of the fever period was 84.8±36.8 hours inreports, all symptoms showed improvement. Sidethe maoto group and 67.0±24.4 hours in theeffects appeared in 2 patients (4.9%), which wereoseltamivir group, showing a significant difference

diarrhea and rashes respectively 29). Iwaki also

between the 2 groups. With "a fever of 37.5℃ or

conducted a similar case series regarding the 2009higher continuing for 24 hours or more after apandemic, in which 12 type A influenza patients (4normal temperature for between 12 and 72 hours "men, 8 women, average age 21.9±11.6) were

defined as diphasic fever, the ratio becomes 4.3％ inadministered Tsumura maoto extract granules in

the oseltamivir group and 20.0％ in the maoto group,

doses of 7.5g per day for adults and 0.2g/kg per day

significantly higher in the former. The average value

for children for a period of 5 days. Results of virusof the number of days of administration was 5.3±1.59

examination via viral isolation and RT-PCR usingdays in the maoto group and 4.6±0.75 days in thenasal swabs and throat swabs as specimens showed

oseltamivir group. Depending on the progress, in thethat all cases were the 2009 pandemic virus (H1N1).

case of maoto, when the fever continued for 5 days or

The average time from onset of illness until initial

more,

there

were

also

cases

where

the

dosing was 15.7 hours, with temperatures at theadministration

waslonger.

Conversely,

intime of arrival at hospital of 38.2 ℃ and a post-

oseltamivir, there were many cases where the fevers

administration fever alleviation time of 18.5 hours.

were alleviated quickly, with a short administration

Regarding the symptoms, upon calculating theperiod not requiring 5 days of administration 28).

average symptom scores (0-3) from the patients'

Case series and comparative studies investigatingside effects, administration methods, etc.

comparingadministration

thesymptoms

preshowed

and

post-

significant

improvement in "sore throat", "muscle and joint

Research by Iwaki, et al.
In a case series by Iwaki, et al., 41 patients (17men, 24 women, age 40.5±13.6) age 20-72 diagnosed
influenza positive (type A and type B) via rapid
testing kits, who had fevers of 38.0 ℃ or higher
before or when coming to the hospital, and who had
been experiencing influenza symptoms for 48 hours
or less were administered maoto,

journals,

and the timefrom administration until alleviation of fever (fever
alleviation time), virus survival time and transitionof clinical symptoms were investigated. The resultspain", fatigue and tiredness" and "headache". An
examination of the virus survival rate conducted on
average on the 5th day after the start ofadministration showed 6 patients positive, for asurvival rate of 50.0%. Harmful events observed
were 1 case each of abnormal behavior and diarrhea,
with the abnormal behavior starting on the first dayof administration and ending the following day andbeing deemed "unrelated" to the maoto 30).
Research by Ihashi, et al.

showed that the overall average fever alleviation

Although it is not comparative research, the casetime was 27.4 hours, of which it was 25.9 hours withseries by Ihashi et al. contains reports of results oftype A and 33.7 hours with type B. Furthermore, theseriously ill child patients with new strains offever alleviation times of type A by subtype were 24.9

influenza and pneumonia requiring hospitalization

hours with H1N1 and 26.5 hours with H3N2. The

who were administered maoto in combination withsurvival

after

neurominidase inhibiters. The subjects were 70 childadministration was 22.6%, with type A H1N1 having

patients (average age: 7.3±3.7; gender: 46 male anda survival rate of 30.0%, type A H3N2 0%, and type24 female; bronchial asthma: 25 with and 45

B 20.0%. Regarding the progress of the clinicalwithout; administration of anti-influenza drugs as

symptoms, upon calculating the average body

outpatients: 21 yes and 49 no) who were hospitalized

temperatures and symptom scores from the patientwith new strains of influenza and pneumonia from

12

rate

of

the

viruses

5

days

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

June 2009 to January 2010 with no serious

time for group II's fevers to drop to 36.9℃ after

underlying illnesses. The anti-influenza drugs

administration. There are no statements regarding

selected for treatment after hospitalization werecomparisons between group Ⅰ

oseltamivir for 64 patients and zanamivir for 6

group, or between group Ⅰ and group II. No serious

patients. Regarding the administration of maoto, theside-effects

administration dose was 0.2g/kg in 3 divided doses,

observed32).

the administration method was every 2-3 hours on
the first day and 3 divided doses from the 2nd day
onwards (before or after morning, noon, and evening
meals), and the administration period was 5.0 dayson average (95％CI：4.7～5.2 days). The main subjectof the paper was to suggest the importance ofadministering

neuraminidase

inhibiters

beforehospitalization via multiple regression analysis, buteven regarding treatments where maoto wasadministered to seriously ill patients, no side effects
were observed 31).

due

to

Kampo

and the control
treatment

were

Research by Mori, et al.
In a case series by Mori, et al., where early-stage
administration of Kampo medicine was conducted
before seeing a doctor, treatment via early-stage
administration of Kampo medicine was conducted on
10 patients (5 men, 5 women, average age 13.2±12.1)
who exhibited flu-like symptoms between October toDecember 2009 and for whom treatment with the
Kampo internal medicine on hand was insufficient,
after which they went to hospitals and werediagnosed with type A influenza, and the results
thereof were examined. Upon arrival at the hospital

Research by MoriMori's open labeled quasi RCT, which examinedthe evidence was reconfirmed, and in cases where it

unique administration methods of maoto, divided

fit it was continued, while in cases where it differedcases of maoto administration from November 2007

the method was changed.

through March 2008 into 2 groups and examined the

1.5-2 times the normal does was administeredadministration(groupfrequently (every 2-3 hours), with the treatment

administered maoto every 3 hours): Patients withbeing ended at the point when the fever, generalevidence of maoto up to January 31were dosed withcondition, and respiratory tract symptoms improved.

methods.

Group

Ⅰ

maoto every 3 hours when the maoto administration
was started (no administration during sleep). GroupⅡ(group administered maoto every 2 hours):

Patients

with evidence of maoto After February 1

were dosed with maoto every 2 hours when the
maoto administration was started, taking 1 day
worth (3 packets) every 3 hours, and subsequently
continued to take it every 3 hours until the onset ofsweating(no administration during sleep). Afterthey started sweating, the dosing was halted(Hiromichi Yasui's method). Among those treatedwith Kampo, group Ⅰ was 17 patients (average age
6.7) and group II was 11 patients (average age 6.7).
Furthermore, 13 patients treated with oseltamivir
who did not use antipyretics served as the control
group. Examining group II and the group treatedwith oseltamivir shows that it took significantly lessDuring fevers, a dose of

The results showed that the time from coming to thehospital until alleviation of fever was 17.0±17.0
hours, the number of days from coming to thehospital until recovery was 1.8±0.6 days, and thenumber of days from early-stage administration
until recovery was 2.5±0.7 days. The early-stage
Kampo administered before going to the hospital
was keishi-to maoto for 4 patients, keishito for 3
patients, maoto for 2 patients, and saiko keishito
shoken-chu-tofor1

patient,

with

1-5

administrations, with 5 patients' Kampo fitting theevidence and 4 of the remaining 5 leaving earlystage administration prescriptions and combining
with

other

comparison

compounds.
oftheFurthermore,

Kampo

in

a

medicine/anti-viral

medicine combined administration group and the
Kampo-only group, no significant difference was

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

13

Volume 11, Number 3 | Fall 2016

observed in the number of days from start ofgroup from age 0 to 2, the good group was about 32

administration before going to the hospital until

hours while the poor group was about 48 hours,

recovery,ashowing a significant difference. In the type B

significantly shorter fever alleviation time andinfluenza, the fever alleviation time of the goodnumber of days from going to the hospital until

compliance group was about 28 hours while the poor

recovery 33).

compliance group was about 56 hours, showing a

but

the

Kampo-only

group

had

significant difference. In (2), the fever alleviation time
Research by Nishimura, et al.

of the maoto administration group was about 26

In a case series by Nishimura, et al., wherein

hours, which was significantly shorter than in (1)there is a unique report of using a maoto suppository,

where it was about 40 hours. In the zanamivir

a comparison is conducted on the body temperatures

administration group it was about 32 hours. However,before administration and until 24 hours afterin (2), a pharmacist proactively conducted interfusedadministration of a maoto suppository in pediatrics

flavoring agent guidance for the maoto. The results

department between June 2006 and April 2007 on 21

were that milk coffee, cocoa, orange juice, Calpis andpatients (from 10 days old to 9 years and 9 months

other flavors resulted in good medication compliance,old) with fevers of 38.9℃ or greater. There were 17

with (2) being the good medication compliance grouppatients whose body temperature were possible tosignificantly increasing from (1)'s 69.9% to 93.9%,

track. The temperature of these patients decreased

while in the age 0 to 5 group the good medication

significantly. No side-effects were observed 34).

compliance group significantly increased from (1)'s
59.4% to 100% 35).

Research by Tabata, et al.
In open labeled comparative research by Tabata,This concludes the discussion of the state of

et al., in addition to the clinical results of maoto andmaoto's use in Japan as a treatment for influenza

zanamivir, the influence of interfused flavoring

and the current state of its research. It is currently

agent guidance by pharmacists as an idea to increase

commonly used in combination with anti-viralpatient compliance in taking medicine was compared

medications, but in some circumstances it is also

over 2 seasons. (1) In the 2006-2007 season, maotoused alone. It is used especially often in the field of

was administered to 63 child influenza patients (37pediatrics.

type A, 26 type B). (2) In the 2007-2008 season, maoto

The fact that the text cited in the first paragraph

was prescribed for all cases of children 5 years or

which was written in "Shang-han lun" is connectedyounger, while for children of 5 years or older either

to the treatment by a 13 year old boy almost 200

maoto or zanamivir were administered after informed

years ago is a testament to the very high level ofconsent and the parents choosing one of them, with 49

research that "Shang-han lun" was in Japan. The

patients (all type A patients) being administeredKampo medicine of Japan even today continues tomaoto and 32 patients (31 type A patients and 1 type

carry on this tradition.

B patient) being administered zanamivir. The time
until alleviation of fever was scored, and theNote: One way of looking at maoto is that veterinary

compliance with taking the medicine was also

surgeons are focusing on the prescription. They

examined split into a good group and poor group.

discovered maoto’s effect on avian influenza during

maoto was taken 0.18g/㎏/day in 3 divided doses for 3

their research. Currently they are aggressively

days, and zanamivir was inhaled 2 blisters (10mg) per

proceeding with the study 36). A vast amount of researchtime, twice per day for 5 days. In the good medication

reports in future.

compliance group of type A influenza in (1) in the
14

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 11, Number 3 | Fall 2016

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therapy for pediatric influenza, Science of Kampo
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Kawamura,
Yoshinobu
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Investigation of the effectiveness of oseltamivir
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1391-1396, 2009. (in Japanese)17) Osamu Fukutomi, Hideo Kaneko, Hidenori Onishi,
et al.: Investigations of the effects of maoto forpediatric influenza and the choice of therapy,
Kampo and Immunology / Allergy, vol. 22, pp. 2333, 2008. (in Japanese)18) Osamu Fukutomi, Takahide Teramoto, Michio
Koseki, et al.: Investigations of the usefulness of
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Journal of Japan Pediatric Oriental Medicine
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Medicine, vol. 57, no. 10, pp. 1655-1662, 2010. (inJapanese)20) Yoshitaka Toriumi, Kohji Murata, Tsutomu
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influenza, Kampo and Immunology / Allergy, vol.
23, pp. 17-26, 2010. (in Japanese)23) Nabeshima S, Kashiwagi K, Ajisaka K, et al.: A
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Effects of maoto in women suffering from influenza
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no. 27, pp. 89-92, 2010. (in Japanese)
26) Hironobu Yaegashi: Efficacy of Coadministrationof maoto and Shosaikoto, a Japanese Traditional
Herbal Medicine (Kampo Medicine), for theTreatment of Influenza A Infection, In Comparison
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28) Eitaro Suzuki, Kiyoshi Ichihara: Comparison of
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14, no. 3, pp. 248-253, 2011. (in Japanese)29) Norio Iwaki, Naoki Kawai, Osamu Tanaka, et al.:The Japanese Journal of Clinical andExperimental Medicine, The Japanese Journal of
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Experimental Medicine, vol. 87, no. 12, pp. 17891793, 2010. (in Japanese)31) Mai Ito, Takehisa Yamamoto, Katsusuke
Yamamoto, et al.: The influence of a combination
therapy with oseltamivir and maoto duringhospitalization because of influenza pneumonia on
the clinical course in children after discharge,
Kampo and Immunology / Allergy, vol. 24, pp. 6068, 2011. (in Japanese)32) Yoshio Mori: Experiences with Kampo therapy
over the period from 2003 until 2008, Kampo &Newest therapy, vol. 18, no. 4, pp. 313-320, 2009.
(in Japanese)33) Katsumi Mori, Mizuaki Miyazaki: Early initiationof Kampo monotherapy for a new influenza type,
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34) Nishimura N, Doi N, Uemura T, et al.
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pediatric influenza infection;
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2219-2225, 2009 (in Japanese)36) Miyazaki T.: Pathogenesis of Influenza and Effects
of Herbal Medicines on the Inhibition of Influenza
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Medicine, vol. 86, no. 12, pp. 1713-1718, 2009. (inJapanese)30) Norio Iwaki, Yutaka Wakasa, Osamu Tanaka, etal.: Investigation of the therapeutic effectivenessand safety of maoto during the pandemic (H1N1)
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16

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)