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EFFICACY OF NATAMAME TEA CONTAINING CANAVANINEON THE NASAL CONDITION AND HALITOSIS IN HEALTHY JAPANESE― TWO RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES ―Masatomo NAJIMA1), Mitsuhiko MUNEKATA2) and Yoshifumi SOEDA3)
1) JACTA (Japan Clinical Trial Association)
2) OZ Clinic
3) Smile-Japan co., ltd.

Abstract
Objectives: Two clinical studies were done to investigate the eﬃcacy of daily ingestion of
Natamame Tea containing Canavanine on the nasal condition and halitosis.
Methods: Both studies were performed as randomized, placebo-controlled, double-blind
trials for 12 weeks.
Results: As the primary outcome, the study showed signiﬁcant diﬀerences in the subjective
assessment on the nasal condition and halitosis. On the other hand, no signiﬁcant diﬀerenceswere observed in the measurement of causative substances of the halitosis. In addition, as
the secondary outcome no abnormal change of safety had been triggered by the ingestion oftest drink.
Conclusion: The ingestion of Natamame Tea by healthy people for 12 weeks contributed tothe improvement of nasal condition centering on snivel and remediation of halitosis based on
self-evaluation. In addition, no safety-related matter occurred during 12-week test period.
Key words: Natamame, Canavanine, nasal condition, halitosis

1. INTRODUCTION
Canavalia gladiata (commonly called the sword bean) is
leguminous an annual grass which has a long husk
ranging from 25 cm to 30 cm. It is a native of South East
Asia and tropical Africa and therefore is tolerant of heatand dryness. From the very beginning of being
introduced to Japan, it has been actively cultivated in
Satsuma (Kagoshima-Prefecture). In China, the fruit has
been used as a Chinese herbal medicine for handlingmany kinds of symptoms, such as treating a cough,discharging pus, suppressing inflammation, preventing
swelling, increasing renal function, improving intestinal
environment, controlling vomiting or relieving pain 1). For
eating, on the other hand, its beans are cooked as
Nimame (boiled beans) or An (bean paste), and its young
husk is cooked as Fukujinzuke (sliced vegetables pickled
in soy sauce). The most typical way of ingestion,
however, is drinking as tea (i.e. Natamame tea) bygrinding and brewing its beans and husks.
In Japan, the prevalence rate of an allergic disease
exceeded 30％ in 2008, and the rate is increasing eachyear 2). Although it is not a life-threatening disease, many
patients are forced to suﬀer from some unpleasant nasal
symptoms such as sneezing, snivel and/or sniﬄes. These

symptoms interfere with daily activities, cause
impairment in concentration or disruption of sleep, andeventually result in a severe decrease of QOL (Quality ofLife). Physiological halitosis, on the other hand, is also amajor issue in Japan now: According to the health welfare
trend survey conducted by Health and Welfare Ministry(currently, Health, Labor and Welfare Ministry) in 1999,
there is a statistical data that about 10％ out of all
respondent to a survey (approximately 33 thousandpeople) answered as they mind their bad breath(halitosis) 3). Halitosis is a generic term of unpleasant odor
which comes through the mouth or nose, and about 90％
of it is said to be derived from mouth cavity 4). Its
causative substance is volatile sulfur compound (VSC)and especially, hydrogen sulfide and methyl mercaptan
account for about 90％ of the compound. It is thoughtthat these substances are produced through the activities
of bacteria in mouth cavity, and also thought that these
activities are accelerated by several factors such as lackof mouth cleaning, tongue coat, disease of the gums,
odontonecrosis, dry mouth and/or stress. Everybody hasa certain level of halitosis. Nowadays, there is a growinginterest in halitosis and many oral-care products such as
mouth wash or mouth spray aimed at preventing or
alleviating halitosis are sold in the market. The

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remediation of halitosis possibly improves the QOL since
it is said that due to the problem of their halitosis, agrowing number of young people tend to hesitate to talkin front of people or to go outside.
Since Natamame tea is expected to have the positiveeﬀects as explained above, many Natamame tea products
are sold in the market with the catch line of good for
empyema, rhinitis (nasal inflammation) or halitosis .
However, its pharmacological mechanisms are still
unclear, and there are few published reports that clearly
explain these effects of the tea. In this study, we
examined the eﬀect of Natamame tea on nasal symptoms
or halitosis, and also the safety of its ingestion. The test
targets were healthy person who are worried about theirnasal conditions or bad breath (halitosis), and the test
method was a randomized, placebo-controlled, doubleblind study.

2. METHOD
2.1. Eﬀect of Natamame tea on the nasal condition
2.1.1 Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from Smile-Japan co.,ltd. (Fukushima) at two centers, OZ clinic (Tokyo) and
JACTA (Tokyo).
The study period was 12 weeks, from August 27th toNovember 19 th, 2015. This study was conducted inaccordance with the ethical principles of the declarationof Helsinki. The study protocol was approved by theInstitutional Review Board of Pharmaceutical Law
Wisdoms (Tokyo). Written informed consent was
obtained from all subjects.
The allocation of the test product to the subjects was
carried out by the person in charge of allocation. The
allocation list was sealed and strictly controlled in a safe
deposit box of JACTA until the end of the study. The
clinical trial was registered at UMIN Clinical Trial
Registry (Trial ID: UMIN000018782).
2.1.2. Subjects
Healthy subjects participated in the present study. All of
the subjects in this study were public volunteers who had
enrolled in the monitor bank of CROee Inc. (Tokyo).
2.1.2.1. Inclusion criteria(1) Healthy people aged between 40 and 59 years;(2) People suffering from a running nose or nasal
congestion;(3) People suitable for the nasal problem questionnaire(Table 5).
2.1.2.2. Exclusion criteria(1) Individuals undergoing treatment of nasal problems;(2) Individuals on taking medication, including herbal
medicines;(3) Individuals judged to be unsuitable to participate in
the trial by the principle investigator
2.1.3. Randomization
Recruited subjects were 108 persons. Subjects who

第 5 号（2016 年 5 月）

Table 1 Nutritional content of the sample per 100 g
Item

Quantity

Moisture

1.4 gProtein
Lipid
Ash
Carbohydrates
EnergySodium27.3 g8.1 g
6.5 g
56.7 g409 kcal
5.5 mgfulfilled the eligibility criteria were 42 persons. The
questionnaire is listed in Table 5. The inclusion was
judged by the principle investigator. All subjects weresequentially assigned based on a random number table toone of the masked products and randomized to group T(Test sample: 22) and group P (Placebo: 20). The
allocation was pre-assigned on the basis of randomized
numbers.
2.1.4. Description of test drink and blinding
The test drink Natamame Cha ( NC ) is a tea
containing Canavanine. The method of making the tea
includes seeping a teabag in a tea pot of cold water andbringing to a boil. Drinking 1,000 ml of this tea per day isrecommended. The Placebo tea does not include
Canavanine. Table 1 shows the nutritional content of thetest sample (the Natamame bean). Both teas wereindistinguishable in color, flavor or taste. Teas weremanaged by an identification symbol. All involved wereblinded.
2.1.5. Experimental procedures
2.1.5.1. Experimental protocol
Subjects consumed almost 1,000 ml of boiled tea every
day for 12 weeks. In order to even out the contained
amount of Canavanine, the boiled tea is prepared from500ml of water and 3 g of tea-bag and contained in analuminum can. The subjects are asked to drink two cansof tea (500 ml x 2 = 1,000 ml) per a day.
Subjects were instructed as follows: to avoid excessive
amounts of food, drink or alcohol; to maintain a daily
record of lifestyle factors during the test period; and tosend the diary to the study coordinator every Friday bymobile email.
2.1.5.2. Outcome
The objective of this study was to verify the nasal
condition improvement by ingesting tea containing
Canavanine. To evaluate this objective, subjective
reporting of nasal conditions were measured as theprimary outcomes. The questionnaire covered: nasal
mucus buildup; throat mucus buildup; remaining mucus
after blowing nose; frequency of sneezing; throat ticklingsensation; smelling ability; nasal voice; running nose
symptom; and frequency of coughing. Responses to eachquestion were rated on an ordinal scale of 1 to 5, with
h i g h e r s c o r e s i n d i c a t i n g a b e t t e r r e s u l t . B l o od

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Table 2 Schedule for the study (nasal condition)
Term
Item

Screening

Informed consent
Selection and/or allocation
Subjective reporting of nasal condition
Biochemical analysis of blood
Urine analysis
Ingestion of test drinks
Log

●
●
●

Test period

Pre Trial
Test

4w

8w

12 w

●
●
●

●

●

●
●
●

←――――――――――――――――→←――――――――――――――――→● : Implementation↔ : Daily practice during the test period

biochemical and urine parameters were recorded toevaluate the safety of the test tea as the secondary
outcome. These assessments were conducted upon entry
into the study (pre-intervention) and after 12 weeks(post-intervention).
To evaluate the safety of the test drink, adverse eventswere collected by means of a written questionnaireduring the study. According to the schedule shown in
Table 2, we measured parameters on eﬃcacy and safety.
2.1.6. Data analysis
All analyses were performed on the on-treatment
population in the study. Data were expressed as mean ±SD. For subjective reporting of nasal condition, changes
from baseline in the same group were assessed using
Wilcoxon signed-rank test. Mann-Whitney U test wasused for intergroup comparisons of changes from thebaseline. For biochemical analyses of blood and urine,changes from the baseline in the same group wereassessed using the paired t-test. Student s t-test used forintergroup comparisons of changes from the baseline.
Student s t-test was used to compare subject backgrounds
between groups. Statistical analyses were performed
using Statcel 3 (Yanai, 2011). The results wereconsidered signiﬁcant at the < 5％ level in the two-sided
test.
2.2 Eﬀect of Natamame tea on halitosis
2.2.1. Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from Smile-Japan co.,ltd. (Fukushima) at three centers, Bio Clinic Tokyo(Tokyo), OZ clinic (Tokyo), and JACTA (Tokyo). The
study period was 12 weeks, from September 15 th toDecember 9 th , 2015. This study was conducted inaccordance with the ethical principles of the declarationof Helsinki. The study protocol was approved by theInstitutional Review Board of Pharmaceutical Law
Wisdoms (Tokyo). Written informed consent was
obtained from all subjects.
The allocation of the test product to the subjects was
carried out by the person in charge of allocation. The

allocation list was sealed and strictly controlled in a safe
deposit box of JACTA until the end of the study. The
clinical trial was registered at UMIN clinical Trial
Registry (Trial ID: UMIN 000018928).
2.2.2. Subjects
Healthy subjects participated in the present study. All of
the subjects in this study were public volunteers who had
enrolled in the monitor bank of CROee., Inc. (Tokyo).
2.2.2.1. Inclusion criteria(1) Healthy people aged between 40 and 59 years.
(2) People suﬀering from halitosis.
2.2.2.2. Exclusion criteria(1) Individuals undergoing treatment of halitosis.
(2) Individuals on taking medication, including herbal
medicines.
(3) Individuals judged to be unsuitable to participate in
the trial by the principle investigator.
2.3. Randomization
Recruited subjects were 116 persons. Subject who
fulﬁlled eligibility criteria were 41 persons. The inclusion
criterion was judged by the principle investigator. All
subjects were sequentially assigned based on a random
number table to one of the masked products andrandomized to group T (Test: 23) and group P (Placebo:
18). The allocation was pre-assigned on the basis ofrandomized numbers.
2.2.4. Description of test drinks and blinding
The test drink is a tea Natamame Cha ( NC ), and thePlacebo drink is a tea not including Canavanine as
explained in 2.1.4.
2.2.5. Experimental procedures
2.2.5.1. Experimental protocol
Subjects consumed almost 1,000ml of boiled tea every
day for 12 weeks as explained in 2.1.5.1.
2.2.5.2. Outcome
The objective of this study is to verify the effect of tea
containing Canavanine on halitosis. To evaluate thisobjective, concentrations of hydrogen sulﬁde and methyl
mercaptan in oral air were measured as the primary
outcomes. Questionnaire of halitosis was also observed as

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Table 3

Schedule for the study (halitosis)

Term
Item

第 5 号（2016 年 5 月）

Screening

Informed consent
Selection and/or allocation
Medical Examination
Subjective reporting of halitosis
hydrogen sulﬁde and methyl mercaptan
Biochemical analysis of blood
Urine analysis
Questionnaire of halitosis
Ingestion of test drinks
Log

Test period

Pre Trial
Test

4w

8w

12 w

●
●
●
●
●
●
●

●
●
●
←――――――――――――――――→←――――――――――――――――→←――――――――――――――――→● : Implementation↔ : Daily practice during the test period

the primary outcome. The question was how do you feelyour halitosis? . The response was rated on an ordinalscale of 1 to 5, with lower score indicating a better
result. Subjects recorded this self-evaluation every day
during 12-week test period. The question asked for selfevaluation of halitosis:(1) Very low; (2) Low; (3) Moderate; (4) High; (5) Veryhigh.
Blood biochemical and urine parameters were recorded
to evaluate the safety of the test drinks as the secondary
outcome. These assessments were conducted upon entry
into the study (pre-intervention) and after 12 weeks(post-intervention). According to the schedule shown in
Table 3, we measured parameters on eﬃcacy and safety.
2.2.6. Data analysis
All analyses were performed on the on-treatment
population in the study. Data were expressed as mean ±SD. For Questionnaire of halitosis, changes from baselinein the same group were assessed using Wilcoxon signedrank test. Mann-Whitney U test was used for intergroupcomparisons of changes from the baseline. For theconcentrations hydrogen sulﬁde and methyl mercaptan inoral air, and biochemical analyses of blood and urine,changes from the baseline in the same group wereassessed using the paired t-test. Student s t-test used forintergroup comparisons of changes from the baseline.
Student s t-test was used to compare subject backgrounds
between groups. Statistical analyses were performed
using Statcel 3 (Yanai, 2011). The results wereconsidered signiﬁcant at the < 5％ level in the two-sided
test.

3. RESULTS
3.1. Eﬀect of Natamame tea on the nasal condition
3.1.1. Participant demographics
From all of 108 applicants, 66 were eliminated according
to the questionnaire (Table 5). 42 subjects wererandomly assigned to intervention groups and made astart with ingestion. 3 were withdrawn due to personalreasons (physical condition) and the remaining 39 subjects
completed the study. Thus, data obtained from 39
subjects (NC group; 19, Placebo group; 20) were used for
efficacy analysis (Fig. 1). There was no significant
diﬀerence in the mean age or gender ratio (Table 4).
3.1.2. Reporting of the nasal condition
Table 5 shows the results of questionnaire. No signiﬁcantdifference was observed between the two groups in all
nine items at the baseline. After 12 weeks ingestion, theNC showed a signiﬁcant diﬀerence in the items of nasal
mucus buildup , throat mucus buildup , remaining
mucus after blowing nose , frequency of sneezing ,throat tickling sensation , nasal voice , running nose
symptom and frequency of coughing , whereas thePlacebo only showed a signiﬁcant diﬀerence in the items
of frequency of sneezing , throat tickling sensation ,smelling ability and nasal voice . Furthermore thebetween-group analyses revealed that there was asignificant difference of changes in nasal mucus
buildup , throat mucus buildup , remaining mucus
after blowing nose , frequency of sneezing , running
nose symptom and frequency of coughing after
12-weeks ingestion.
3.1.3. Blood and urine test
Table 6 and 7 shows blood biochemical and urine
parameters. A signiﬁcant diﬀerence was observed in thechanges of CK (CPK) of females, Sodium, Chloride,
Potassium, Inorganic phosphorus, Urea nitrogen,
Creatinine of woman in the blood and urine specificgravity of the NC after 12 weeks ingestion. However,since the difference was within the standard value, theinvestigator judged it as the range of physiologicalvariation (or clinically safe).
3.1.4. Adverse event
No adverse event was reported during this trial.

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Recruited applicants(n ＝ 108) (M：43, F：65)

Eliminated (n ＝ 66)(M：29，F：37) ＜questionnaire＞

Randomized Applicants(n ＝ 42) (M：14, F：28)

NC (n ＝ 22)(M：8，F：14)

Placebo (n ＝ 20)(M：6，F：14)

NC (n ＝ 19)(M：6，F：13)

Placebo (n ＝ 20)(M：6，F：14)

Withdraw (n ＝ 3)
(M：2，F：1)＜physical condition＞

Fig. 1 Flow diagram of subject disposition (nasal condition)

3.2 Eﬀect of Natamame tea on halitosis
3.2.1. Participant demographics
From all of 116 applicants, 75 were eliminated according
to the subjective reporting of halitosis. The 41 subjects
were randomly assigned to intervention groups and madea start with ingestion. All subjects completed the study.
Thus, data obtained from 41 subjects (NC ; 23, Placebo;18) were used for eﬃcacy analysis (Fig. 2). There wereno significant differences in the mean age or genderratios. (Table 8)
3.2.2. Concentrations of hydrogen sulﬁde and methyl
mercaptan in oral air
Table 9 shows the results of test analyses. No signiﬁcantdiﬀerence was observed intragroup nor intergroup in thetwo items of concentrations of hydrogen sulfide andmethyl mercaptan in oral air.
3.2.3. Questionnaire of halitosis
The result of questionnaire of halitosis is described inTable 10. The number shows the mean of cumulativescores of subjective evaluation during 7 days. Signiﬁcantdiﬀerences were observed between two groups at week 4
and week 12. In the NC, week 4, week 8, week12
illustrated signiﬁcant changes compared to week 1.
3.2.4. Blood and urine test
Table 11 and 12 show the blood biochemical and urine
parameters. A signiﬁcant diﬀerence was observed in thechanges of potassium, creatinine of males in the blood,urine speciﬁc gravity of the NC after 12 weeks ingestion.

Table 4 Subject demographics (nasal condition)
Item

Unit

NC

Placebo

Subjects *Male : Female *
Age

−
−
years

19
6 : 1348.7 ± 5.0

20
6 : 1448.2 ± 5.5* Number of subjects
mean ± SD

However, since the difference was within a range ofbaseline and a shade of diﬀerence, the investigator judged
it as the range of physiological variation (or clinicallysafe).
3.2.5. Adverse event
No adverse event was reported during this trial.

4. DISCUSSION
We conducted two randomized, placebo-controlled,
double-blind studies to verify the eﬀect of Natamame tea
containing Canavanine on the nasal condition andhalitosis. As the primary outcome, the study showedsigniﬁcant diﬀerences in the subjective assessment on thenasal condition and halitosis. On the other hand, we could
not ﬁnd any signiﬁcant diﬀerences in the measurement of
causative substances of the halitosis. At the same time,as the secondary outcome the observation of clinicalﬁndings such as medical interview, blood and urine test

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Table 5 Results of questionnaire analyses (nasal condision)
ScoresItem

Nasal mucus buildup

Throat mucus buildup

Remaining mucus after blowing nose

Frequency of sneezing

Throat tickling sensation

Smelling ability

Nasal voice

Running nose symptom

Frequency of coughing

Time points

P-valueNC (n ＝ 19)

Placebo (n ＝ 20)

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change2.0 ± 0.7
2.5 ± 1.0 †0.5 ± 1.0
3.4 ± 1.0 **1.4 ± 0.8
3.3 ± 0.9 **1.3 ± 1.1

2.0 ± 0.7
2.1 ± 0.9
0.2 ± 0.9
2.2 ± 0.5
0.2 ± 0.7
1.9 ± 0.5
− 0.1 ± 0.6

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change1.8 ± 0.8
2.7 ± 1.3 **0.9 ± 1.2
2.7 ± 1.2 **0.9 ± 1.1
3.3 ± 1.2 **1.4 ± 1.3

2.3 ± 0.9
2.2 ± 0.5
− 0.1 ± 0.7
2.4 ± 0.7
0.2 ± 0.9
1.9 ± 0.6
− 0.4 ± 0.9

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change1.7 ± 0.8
2.4 ± 1.3 *0.6 ± 1.0
2.7 ± 1.2 **1.0 ± 1.2
3.3 ± 1.3 **1.5 ± 1.2

2.4 ± 0.9
2.6 ± 1.0
0.2 ± 0.7
2.7 ± 0.9 †0.3 ± 0.7
2.5 ± 1.0
0.1 ± 0.7

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change1.7 ± 0.7
2.5 ± 1.2 **0.8 ± 1.1
2.6 ± 1.3 **0.9 ± 1.2
3.1 ± 1.1 **1.4 ± 1.1

2.0 ± 0.8
1.9 ± 0.6
− 0.1 ± 0.6
2.5 ± 1.1 *0.6 ± 1.0
2.6 ± 1.0 *0.7 ± 1.1

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change2.1 ± 0.6
2.7 ± 1.2 *0.7 ± 1.0
2.7 ± 1.1 †0.6 ± 1.3
3.3 ± 1.1 **1.3 ± 1.2

2.4 ± 1.1
2.9 ± 1.4 *0.6 ± 0.9
2.8 ± 1.3 †0.4 ± 0.9
3.0 ± 1.1 *0.6 ± 0.9

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change3.9 ± 1.0
4.3 ± 0.7 †0.4 ± 0.8
4.4 ± 0.7 *0.4 ± 0.8
4.3 ± 0.6 †0.4 ± 0.9

3.5 ± 1.2
4.3 ± 0.9 *0.8 ± 1.1
4.1 ± 0.9 †0.6 ± 1.2
4.5 ± 0.8 **1.0 ± 1.2

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change2.4 ± 0.8
2.8 ± 1.1 *0.4 ± 0.7
2.6 ± 1.0
0.2 ± 1.0
3.2 ± 1.3 **0.8 ± 1.1

2.7 ± 1.0
2.9 ± 1.1
0.2 ± 1.0
3.4 ± 1.3 *0.7 ± 1.2
3.5 ± 1.3 **0.9 ± 0.9

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change1.6 ± 0.7
2.1 ± 1.0 *0.5 ± 0.9
2.2 ± 1.1 *0.6 ± 1.0
2.6 ± 1.0 **1.1 ± 1.0

2.1 ± 0.7
2.0 ± 0.8
− 0.2 ± 0.8
2.1 ± 0.9
− 0.1 ± 1.1
1.9 ± 0.6
− 0.3 ± 0.9

Baseline
Week 4
ChangeWeek 8ChangeWeek 12
Change2.2 ± 0.6
3.1 ± 1.1 **0.9 ± 0.8
2.7 ± 1.1 †0.5 ± 1.1
3.0 ± 1.3 *0.8 ± 1.3

2.6 ± 0.9
2.6 ± 0.8
− 0.1 ± 0.9
2.6 ± 0.7
0.0 ± 0.7
2.5 ± 0.8
− 0.2 ± 0.7

Scores are expressed as the mean ± SD.
†
p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.
‡p ＜ 0.1, # p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerence in change from baseline.

0.332＜ 0.001 ##＜ 0.001 ##0.011 #
0.070 ‡
＜ 0.001 ##0.267
0.049 #
＜ 0.001 ##0.015 #
0.319
0.038 #

0.725
0.684
0.077 ‡

0.164
0.643
0.068 ‡

0.482
0.299
0.899

0.045 #
0.119
＜ 0.001 ##0.004 ##
0.140
0.012 #

診療と新薬・第 53 巻

Table 6

第 5 号（2016 年 5 月）

39 （407）

Biochemical blood test (nasal condision)
ValuesItem

Unit

Std. Value

GenderTime points

mg/dL

0.2-1.2

M/F

Baseline
Week 12
Change0.51 ± 0.18
0.49 ± 0.16
− 0.02 ± 0.16

0.57 ± 0.21
0.51 ± 0.15
− 0.06 ± 0.18

Total Protein

g/dL

6.3-8.3

M/F

Baseline
Week 12
Change7.4 ± 0.3
7.4 ± 0.3
0.0 ± 0.3

7.4 ± 0.4
7.4 ± 0.4
− 0.1 ± 0.3

Albumeng/dl

3.8-5.3

M/F

Baseline
Week 12
Change4.6 ± 0.3
4.5 ± 0.3
− 0.0 ± 0.3

4.5 ± 0.3
4.4 ± 0.3 †− 0.1 ± 0.2

AST (GOT)

U/L

8-38

M/F

Baseline
Week 12
Change23.4 ± 5.9
22.3 ± 4.9− 1.1 ± 5.1

21.5 ± 5.0
21.2 ± 5.2− 0.4 ± 3.8

ALT (GPT)

U/L

4-43

M/F

Baseline
Week 12
Change18.5 ± 7.7
18.4 ± 9.0− 0.2 ± 8.3

21.5 ± 9.4
21.8 ± 9.0
0.3 ± 7.9

ALP

U/L

110-354

M/F

Baseline
Week 12
Change200.6 ± 59.1
205.7 ± 75.0
5.2 ± 29.1

191.5 ± 54.2
198.9 ± 60.4
7.4 ± 27.8

LD (LDH)U/L

121-245

M/F

Baseline
Week 12
Change178.5 ± 22.5
175.1 ± 26.8
− 3.4 ± 13.4

169.7 ± 21.6
163.8 ± 29.5
− 5.9 ± 18.6

86 and underM

Baseline
Week 12
Change39.3 ± 22.3
50.3 ± 38.9
11.0 ± 43.8

43.8 ± 23.7
45.5 ± 26.4
1.7 ± 5.7

48 and underF

Baseline
Week 12
Change25.8 ± 15.7
24.6 ± 15.0
− 1.2 ± 9.0

29.8 ± 31.3
26.9 ± 25.7 *− 2.9 ± 6.3

38-196

M

Baseline
Week 12
Change117.8 ± 38.3
124.3 ± 36.4
6.5 ± 34.3

151.0 ± 77.3
162.5 ± 162.0
11.5 ± 109.9

30-172F

Baseline
Week 12
Change104.2 ± 41.6
82.4 ± 21.1 *− 21.8 ± 33.8

86.1 ± 21.9
87.7 ± 30.2
1.6 ± 19.3 #CK (CPK)

U/L

mg/dL

Total Cholesterol

mg/dL

130-219

M/F

Baseline
Week 12
Change210.4 ± 29.3
215.5 ± 28.9
5.1 ± 18.1

217.8 ± 30.7
216.3 ± 23.1
− 1.5 ± 17.9

Neutral Fat (TG)mg/dL

30-149M/F

Baseline
Week 12
Change194.8 ± 138.6
152.6 ± 103.2 †− 42.2 ± 102.5

144.3 ± 135.3
139.4 ± 87.6
− 4.9 ± 79.3 ‡Sodium

mEq/L

135-150

M/F

Baseline
Week 12
Change143.6 ± 1.6
141.4 ± 2.2 **− 2.2 ± 2.4

143.4 ± 2.2
141.6 ± 1.5 **− 1.9 ± 2.1

Chloride

mEq/L

98-110

M/F

Baseline
Week 12
Change104.7 ± 2.3
102.6 ± 1.9 **− 2.1 ± 2.7

104.4 ± 2.0
103.3 ± 1.4 *− 1.1 ± 2.1

Potassium

mEq/L

3.5-5.3

M/F

Baseline
Week 12
Change4.0 ± 0.3
4.3 ± 0.3 **0.3 ± 0.3

3.9 ± 0.3
4.2 ± 0.3 **0.3 ± 0.3

Calcium

mg/dL

8.4-10.2

M/F

Baseline
Week 12
Change10.0 ± 0.6
9.8 ± 0.6 †− 0.2 ± 0.4

9.8 ± 0.4
9.5 ± 0.3 **− 0.3 ± 0.2

Inorganic Phosphorus

mg/dL

2.5-4.5

M/F

Baseline
Week 12
Change3.7 ± 0.5
3.4 ± 0.5 *− 0.3 ± 0.5

3.4 ± 0.4
3.3 ± 0.4
− 0.1 ± 0.5

Urea Nitrogen

mg/dL

8.0-20.0

M/F

Baseline
Week 12
Change13.0 ± 3.3
11.6 ± 2.1 *− 1.4 ± 2.6

12.8 ± 2.3
13.9 ± 2.3 *1.1 ± 1.9 ##0.61-1.04

M

Baseline
Week 12
Change0.86 ± 0.25
0.76 ± 0.11
− 0.10 ± 0.24

0.81 ± 0.11
0.80 ± 0.10
− 0.01 ± 0.05

0.47-0.79

F

Baseline
Week 12
Change0.64 ± 0.06
0.60 ± 0.06 **− 0.04 ± 0.04

0.64 ± 0.07
0.63 ± 0.07
− 0.01 ± 0.05 #60-109M/F

Baseline
Week 12
Change73.7 ± 12.6
79.1 ± 16.9
5.4 ± 22.0

63.4 ± 10.1
74.9 ± 12.4 *11.5 ± 7.6

Creatinine

Blood Sugar (Serum)

mg/dL

mg/dL

Values are expressed as the mean ± SD.
p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.
p ＜ 0.1, # p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerence in change from baseline.

‡

Placebo (n ＝ 20)

Total Bilirubin

γ-GT (γGTP)†

NC (n ＝ 19)

40 （408）

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第 5 号（2016 年 5 月）

Table 7 Transition of Urinalysis (nasal condision)
Item

Unit

Std. Value

GenderTime points

Speciﬁc Gravity

mg/dL

1.010-1.025

M/F

pH

g/dL

4.5-8.0

M/F

ValuesNC (n ＝ 19)

Placebo (n ＝ 20)

Week 12
Change1.019 ± 0.007
1.014 ± 0.007 **− 0.005 ± 0.006

1.018 ± 0.006
1.018 ± 0.007
0.000 ± 0.008 #Baseline
Week 12
Change6.0 ± 0.8
6.3 ± 0.8
0.3 ± 0.9

6.3 ± 0.8
6.5 ± 0.8
0.2 ± 0.7

Baseline

Values are expressed as the mean ± SD.
** p ＜ 0.01 against baseline.
#p ＜ 0.05 between-group diﬀerences in change from baseline.

Recruited applicants(n ＝ 116) (M：52，F：64)

Eliminated (n=75)(M：35，F：40)＜subjective reporting＞

Randomized applicants(n ＝ 41) (M：17，F：24)

NC (n ＝ 23)(M：10，F：13)

Placebo (n ＝ 18)(M：7，F：11)

NC (n ＝ 23)(M：10，F：13)

Placebo (n ＝ 18)(M：7，F：11)

Fig. 2 Flow diagram of subject disposition (halitosis)

revealed no abnormal change had been triggered by theingestion of test products.
Main Findings
In this study, we observed the significant differences inthe subjective assessment on the nasal condition andhalitosis, and therefore evaluated that the ingestion of
Natamame tea improved the conditions of the subjects.
At the same time, the study did not show any signiﬁcantdiﬀerences in the causative substances of the halitosis. As
for the nasal test, after 12-week test period the NC
showed the significant differences in 8 items out of 9
subjective items in total, whereas the Placebo showed in
4 items out of 9. In addition, the intergroup comparisons
showed signiﬁcant diﬀerences in 6 items. The items that
did not show the significant differences are such as

Table 8 Subject demographics (halitosis)
Item

Unit

NC

Placebo

Subjects *Male : Female
Age

−
−
years

23
10 : 1348.6 ± 6.0

18
7 : 1149.4±5.1* Number of subjects
mean ± SD

Throat tickling sensation , Smelling ability or Nasal
voice , and these items may have a close relationshipwith symptoms which are rather caused by factors otherthan allergic symptoms such as nasal inflammation. We
also found that the items showing the significant

診療と新薬・第 53 巻

第 5 号（2016 年 5 月）

41 （409）

Table 9Results of concentrations of hydrogen sulﬁde and methyl mercaptan in oral air

Item

ValuesP-value (between-group

Time points（unit）

diﬀerences in change
NC (n ＝ 23)

Placebo (n ＝ 18)

from baseline)

Hydrogen sulﬁde（ppb）

Baseline
Week 12
Change104.8 ± 176.8
133.9 ± 317.0
29.14 ± 187.5

64.0 ± 98.5
83.4 ± 165.3
19.37 ± 210.3

0.876

Methyl mercaptan（ppb）

Baseline
Week 12
Change42.4 ± 80.7
38.5 ± 90.6
− 3.91 ± 52.6

5.5 ± 17.7
7.9 ± 24.9
2.47 ± 31.8

0.647

Values are expressed as the mean ± SD.

Table 10 Results of questionnaire analyses (halitosis)
Time points

ScoresP-valueNC (n ＝ 23)

Placebo (n ＝ 18)

Week 1 (day 1-7)

51.9 ± 18.1

56.1 ± 14.8

Week 4 (day 22-28)
Change46.5 ± 115.2 *− 5.3 ± 9.5

58.0 ± 16.5
1.9 ± 4.9

0.118#

Week 8 (day 50-56)
Change43.7 ± 15.4 **− 8.1 ± 11.7

54.9 ± 14.5
− 1.1 ± 4.1

0.015

Week 12 (day 78-84)
Change41.9 ± 13.5 **− 10.0 ± 11.8

57.7 ± 15.6
1.7 ± 4.8

＜ 0.001##

Scores are expressed as the mean ± SD.
** p ＜ 0.01 against week 1.
#

p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerences in change from week 1.

differences in the Placebo are almost identical to those
without intergroup significant differences. Although thesymptoms such as sneezing or coughing are caused byseveral factors, we can say that mucus is one of the majorcausal factors for these symptoms. Based upon the above
discussions, it was indicated that the ingestion of
Natamame tea especially contributes to the remediationof symptoms pertinent to nasal inflammation such as
mucus or nasal congestion.
As for the halitosis test, the result of questionnaire ofhalitosis in the NC showed the significant differencesfrom 4-week, 8-week and 12-week. In the Placebo group,on the other hand, no signiﬁcant diﬀerence was observed
after 12-week ingestion of the test product. Theintergroup comparisons after 4-week and 12-week period
showed the signiﬁcant diﬀerences. The measurement of
the causative substances of the halitosis (hydrogen sulﬁdeand methyl mercaptan), which was conducted toobjectively assess the halitosis, did not show any
significant differences. The halitosis is caused by avariety of factors or ingredients, and their derivation also
varies 5). It is thought that among these ingredientshydrogen sulfide and methyl mercaptan are the maincausative substances 3): the former smells like a rotten

egg and has an odor threshold of 0.0047 ppm, and thelatter smells like a rotten onion and has an odor thresholdof 0.0021 ppm 6). Although the level of the obtained ﬁgurefrom the subject in this study was higher than thethreshold level, the ﬁgures vary widely, and therefore it
can be said that the number of the test subject in thisstudy was not enough to adequately understand thetendency. Generally, it is difficult to evaluate the odor
itself, and how to sense the halitosis varies widely
depending on relative relationship of the people. It is also
diﬃcult to judge it, and quite often the evaluation totallydifferent from the general evaluation of the odor ismade 7) . In addition, there are many patients withpsychogenic halitosis, who have been suﬀering from thememory in their childhood days that they were said You
have a bad breath! . In this study we could observe thatthe result of the self, questionnaire of halitosis showed
the ingestion of Natamame tea improved the condition.
Since this study adopted a double-blind study and there
was no signiﬁcant diﬀerence in the Placebo, it is unlikelythat this outcome was a result of placebo effect 8) .
Therefore it is reasonable to judge that certain level ofremediation of halitosis condition has been achieved froma viewpoint of subjective symptom.

42 （410）

診療と新薬・第 53 巻

第 5 号（2016 年 5 月）

Table 11 Biochemical blood test (halitosis)
ValuesItem

Unit

Std. Value

GenderTime points

mg/dL

0.2-1.2

M/F

Baseline
Week 12
Change0.59 ± 0.18
0.58 ± 0.19
− 0.01 ± 0.21

0.64 ± 0.29
0.61 ± 0.30
− 0.03 ± 0.15

Total Protein

g/dL

6.3-8.3

M/F

Baseline
Week 12
Change7.5 ± 0.4
7.4 ± 0.3
0.0 ± 0.3

7.5 ± 0.4
7.4 ± 0.4
0.1 ± 0.3

Albumeng/dl

3.8-5.3

M/F

Baseline
Week 12
Change4.6 ± 0.2
4.6 ± 0.3
0.0 ± 0.2

4.6 ± 0.3
4.6 ± 0.3
0.0 ± 0.3

AST (GOT)

U/L

8-38

M/F

Baseline
Week 12
Change22.9 ± 8.5
24.0 ± 7.5
1.2 ± 8.6

19.6 ± 4.6
22.4 ± 5.1 †2.8 ± 5.8

ALT (GPT)

U/L

4-43

M/F

Baseline
Week 12
Change22.8 ± 14.3
22.6 ± 12.2
− 0.2 ± 14.3

19.4 ± 10.2
21.3 ± 9.5
1.9 ± 7.8

ALP

U/L

110-354

M/F

Baseline
Week 12
Change205.0 ± 50.2
197.9 ± 54.5
− 7.1 ± 30.3

204.3 ± 60.8
210.2 ± 70.2
5.8 ± 24.3

LD (LDH)U/L

121-245

M/F

Baseline
Week 12
Change198.3 ± 68.6
188.9 ± 51.4 †− 9.4 ± 26.0

176.6 ± 22.4
180.5 ± 30.5
3.9 ± 15.2 ‡86 and underM

Baseline
Week 12
Change32.4 ± 17.2
40.3 ± 33.2
7.9 ± 18.0

43.1 ± 18.6
38.7 ± 12.1
− 4.4 ± 10.7

48 and underF

Baseline
Week 12
Change21.0 ± 8.5
22.2 ± 9.8
1.2 ± 8.6

20.5 ± 6.6
18.9 ± 5.5− 1.5 ± 3.9

38-196

M

Baseline
Week 12
Change260.3 ± 195.0
223.7 ± 179.1− 36.6 ± 67.8

155.7 ± 38.1
210.4 ± 158.7
54.7 ± 169.3

30-172F

Baseline
Week 12
Change90.8 ± 29.5
101.2 ± 46.3
10.4 ± 45.1

104.9 ± 54.4
95.3 ± 23.0
− 9.6 ± 45.7

212.1 ± 25.3
218.6 ± 29.5 †6.5 ± 17.0

231.0 ± 50.2
242.8 ± 58.2 *11.8 ± 18.1

CK (CPK)

U/L

mg/dL

Total Cholesterol

mg/dL

130-219

M/F

Baseline
Week 12
ChangeNeutral Fat (TG)mg/dL

30-149M/F

Baseline
Week 12
Change128.3 ± 73.8
112.0 ± 84.2
− 16.2 ± 84.9

128.1 ± 61.6
139.2 ± 83.4
11.2 ± 60.1

Sodium

mEq/L

135-150

M/F

Baseline
Week 12
Change143.4 ± 2.0
143.3 ± 2.0− 0.1 ± 2.0

143.2 ± 2.8
143.4 ± 2.0
0.2 ± 2.6

Chloride

mEq/L

98-110

M/F

Baseline
Week 12
Change103.8 ± 2.1
103.9 ± 1.9
0.1 ± 1.7

104.5 ± 2.5
103.8 ± 2.6− 0.7 ± 2.4

Potassium

mEq/L

3.5-5.3

M/F

Baseline
Week 12
Change4.1 ± 0.4
4.5 ± 0.4**
0.4 ± 0.4

4.0 ± 0.4
4.3 ± 0.4**
0.3 ± 0.3

Calcium

mg/dL

8.4-10.2

M/F

Baseline
Week 12
Change9.6 ± 0.2
9.6 ± 0.3
0.0 ± 0.3

9.6 ± 0.3
9.6 ± 0.2
0.0 ± 0.3

Inorganic Phosphorus

mg/dL

2.5-4.5

M/F

Baseline
Week 12
Change3.5 ± 0.6
3.4 ± 0.5
− 0.1 ± 0.3

3.4 ± 0.6
3.3 ± 0.6
− 0.1 ± 0.4

Urea Nitrogen

mg/dL

8.0-20.0

M/F

Baseline
Week 12
Change13.1 ± 2.9
13.1 ± 2.7
0.0 ± 2.3

13.9 ± 3.7
13.3 ± 3.3− 0.6 ± 2.7

0.61-1.04

M

Baseline
Week 12
Change0.87 ± 0.11
0.83 ± 0.10 *− 0.04 ± 0.05

0.47-0.79

F

Baseline
Week 12
Change0.64 ± 0.05
0.61 ± 0.04
− 0.02 ± 0.05

0.59 ± 0.10
0.57 ± 0.11
− 0.02 ± 0.04

60-109M/F

Baseline
Week 12
Change75.6 ± 14.8
71.7 ± 12.4
− 3.9 ± 16.1

78.1 ± 14.5
72.4 ± 10.5
− 5.7 ± 14.1

Creatinine

Blood Sugar (Serum)

0.93 ± 0.14
0.96 ± 0.19
0.03 ± 0.06 #

mg/dL

mg/dL

Values are expressed as the mean ± SD.
p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.
p ＜ 0.1, # p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerence in change from baseline.

‡

Placebo (n ＝ 18)

Total Bilirubin

γ-GT (γ GTP)†

NC (n ＝ 23)

診療と新薬・第 53 巻

第 5 号（2016 年 5 月）

43 （411）

Table 12 Transition of Urinalysis (halitosis)
Item

Unit

Std. Value

GenderTime points

Speciﬁc Gravity

mg/dL

1.010-1.025

M/F

Week 12
ChangepH

g/dL

4.5-8.0

M/F

Baseline

Baseline
Week 12
ChangeValuesNC (n ＝ 23)

Placebo (n ＝ 18)

1.019 ± 0.006
1.020 ± 0.007
1.013 ± 0.008 **1.014 ± 0.007**− 0.006 ± 0.007− 0.006 ± 0.008
6.0 ± 0.8
6.2 ± 0.8
0.2 ± 1.1

5.7 ± 0.5
6.6 ± 0.7 **0.9 ± 0.7 #Values are expressed as the mean ± SD.
* p ＜ 0.05, ** p ＜ 0.01 against baseline.
#p ＜ 0.05 between-group diﬀerences in change from baseline.

Natamame reportedly contains a plenty of concanavalin
A (a type of lectin) 9), canavanine (a type of amino acid),
phenols, tannin, flavonoid and several types ofminerals 10)11). Especially, canavanine is an ingredientextracted from Natamame for the first time, and it has
functions such as antiviral action, antimycotic action,
anti-inﬂammatory eﬀect, and discharging pus 12)13). Thereis a report that the sword bean extract (Natamame
extract) containing canavanine inhibits the growth ofPorphyromonas gingivalis or Fusobacterium nucleatum(which are an oral bacteria and periodontopathic
bacteria) 14), and also a report that showed inhibiting eﬀect
of isolation of histamine by using KU812 cells 15). In
addition, it is reported that the use of the tooth paste
containing Natamame contributed to the remediation ofmild degree of gingivitis and halitosis 16). Tannin andflavonoid, on the other hand, also reportedly own
functionalities such as depressive eﬀect on allergic nasal
inflammation and/or halitosis 17)18) , therefore thosecontained in Natamame expectedly achieve the samefunctionalities. In sum, the ingestion of Natamame tea inthis study likely led the functions of canavanine and theother ingredients, and contributed to the improvement of
nasal condition centering on mucus and the remediationof halitosis.
Secondary Findings
In this study, it was observed that based upon clinicalﬁndings such as blood and urine test, no abnormal change
was triggered by ingestion of the test product. In thenasal test, signiﬁcant diﬀerences were observed in someblood parameters and urine speciﬁc gravity, whereas in
the halitosis test significant difference was observed inurine speciﬁc gravity; however, since the diﬀerence waswithin a range of baseline, the investigator judged it as
the range of physiological variation (or clinically safe).
During the test period three (3) subjects discontinued thenasal test, but it was because of their personal reasons
such as impossibility of continuing the test due to a cold.
Therefore, we observed no harmful influence against
biochemical and/or physiological matters of the test

subjects which seem to have causal relationship with thetest product. These results indicated the safety of theingestion of the test product (NC) for the 12-week test
period.
General Information
In Japan, the number of people who suﬀer from allergic
symptoms (such as hay fever) is growing with eachpassing year. Among the allergic symptoms, thesymptoms related to nasal inﬂammation such as mucus or
nasal congestion force the patient to take breaths throughthe mouth, and this way of breathing triggers off the
discomfort such as a feeling of oppression or difficulty
sleeping. In addition, this way of breathing only using
mouth may cause the dryness of oral cavity and/or
pharyngeal region, and the dryness can lead tosusceptibility to viruses such as the flu virus orworsening of halitosis in the oral cavity. The halitosis
negatively aﬀects the relationship with others, and at thesame time, the actions such as blowing nose or sniffing
tend to build a feeling of discomfort among the people
around them. The awareness of building such discomfort
leads to the excess attention to others and they are
eventually forced to bear a huge psychological burden.
Tea is a type of drink Japanese has been drinking
regularly since old times, and there are a wide variety oftea products sold in the market now. Switching the typeof tea in their daily life from green tea to Natamame tea
can contribute to the solution of problems of nasal
conditions or halitosis existing among contemporary
people. In addition, the ingestion of Natamame tea may
alleviate the physical and/or mental burden without any
botheration such as going to the hospital or taking
medicine , and is eventually expected to improve the
QOL of the user.
Limitations
Although in this study, we found the significant
diﬀerences in the result of questionnaire of halitosis, themeasurement of its causative substances did not show thesignificant differences. It is generally said that it isdiﬃcult to recognize their own halitosis since an olfactory44 （412）

診療と新薬・第 53 巻

sensation is a sensation that tends to accept an adaptation
easily 19). This study employed the self- assessment of thetest subjects at their home in order to let them monitor
the changes sequentially. This may be effective for the
remediation of halitosis in the sense of the improvementof QOL, but it does not connect to the objective
assessment of the test result. In order to obtain theadequate and sound test result, it should be required tocongruously shape the design of further study, which
includes an organoleptic examination with intermediationof a third party, or expanding the number of test subjects
and measuring the causative substances of halitosis froma perspective of stratiﬁed analysis (such as comparison ofphysiology-oriented halitosis and pathology-oriented
halitosis) 19). In addition, as for the improvement of thenasal condition the further study should scrutinize therelationship between ingredients contained in Natamame
and allergic material more closely.

5. CONCLUSION
In conclusion, we found out that the ingestion of
Natamame tea by healthy people for 12 weeks
contributed to the improvement of nasal condition
centering on snivel and remediation of halitosis based on
self-evaluation. In addition, no safety-related matteroccurred during 12-week test period.
CONFLICT OF INTEREST
Yoshifumi Soeda is the principal of Smile-Japan co., ltd.. All remaining
authors have declared no conﬂicts of interest.

ACKNOWLEDGEMENT
We appreciate the assistance and support of Kazuhiro Kurashima, M.D.,
Sanno Hospital and International University of Health and Welfare.

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