Original Article

診療と新薬 2018; 55: 936‑944

Eﬃcacy and Safety of Long-term Ingestion of
the Hyuga-touki Leaf on Blood Pressure in
Healthy Japanese:

診療と新薬 WebA Randomized, Double-blind, Placebo-controlled Study

Masatomo NA JIMA 1）／Akinobu MIYATA 2）／Masahiro YAMAMOTO 3）● Abstract
Objectives: The objective of this study is to examine how the ingestion of Hyuga-touki leaf containing YN-1
(isoepoxypteryxin) and isopteryxin contributes to the reduction of blood pressure.
Methods: A randomized, double-blind, placebo-controlled study was conducted to elucidate an eﬀect of foodingestion. In this study we measured systolic blood pressure (SBP) and diastolic blood pressure (DBP). We
also evaluated subjective reporting and biochemical analysis of blood and urine for safety as the secondary
outcome, and adverse events were collected by means of a written questionnaire during the study.
Results: 59 subjects were randomly assigned to two intervention groups, active and placebo, and made a startwith ingestion. 18 subjects discontinued due to personal reasons, and the remaining 41 subjects completed thestudy. 5 were eliminated because of an eﬃcacy eligibility (insuﬃcient intake of the food less than 80% of the
expected dose), thus data obtained with 36 subjects (Active; 16, Placebo; 20) was used for the analysis. In
addition, stratiﬁed analysis was applied with 31 subjects excluding 5 subjects with I degree high blood pressure(SBP 侒 140 or DBP 侒 90). As the result of an analysis of normotensive and high-normotensive healthy person,
the intergroup analysis showed a signiﬁcant diﬀerence in SBP. Regarding subjective reporting, there was no
signiﬁcant diﬀerence between the groups in all items. No adverse eﬀects were observed after the ingestion of
the test food.
Conclusion: We found out that the ingestion of Hyuga-touki leaf containing YN-1 and isopteryxin for 12 weeks
improved SBP. Additionally, no safety-related matter occurred during the 12-week of test period.
Key Words: Hyuga-touki, Angelica Furcijuga Kitagawa, YN-1, isoepoxypteryxin, isopteryxin, blood pressure,
SBP, high-normal, tablet

1. INTRODUCTION
Although the blood pressure of Japanese has declined
significantly in both males and females even in the pastten years, the proportion of hypertension with systolicblood pressure (SBP) more than 140 mmHg including
those taking antihypertensive medicine is still high as
38.6％ in males and 28.7％ in females over 40 years old(National Health and Nutrition Survey, 2016) 1) .
Hypertension is one of the most frequent diseases inJapan. The government declared Healthy Japan 21 (thesecond) in 2012 which also aims to improve hypertension
and to decrease dyslipidemia (risks manifesting
cerebrovascular disease and ischemic heart disease). By
2022, the government hopes to set an SBP goal of 134 inmales and 129 in females 2). In order to prevent andimprove hypertension and arteriosclerosis, it is said to be1) JACTA ( Japan Clinical Trial Association)2) Nihonbashi M s Clinic3) Meigen Inc.

important to improve lifestyle mainly with diet therapy
such as reducing salt and alcohol drinking and withphysical exercise.
Meanwhile, the traditional medicinal plant in northern
Miyazaki Prefecture named Hyuga-touki is called Nihonyamaninjin and has been eaten as it suppresses bloodpressure and blood glucose levels 3), prevent inﬂammation
and allergy 4). For modern Japanese, who tend to lead anirregular lifestyle and intake excessive calories, we thinkthat it is beneﬁcial to be able to prevent lifestyle diseases
by easily ingesting food as a supplement. In this study,
we examined the effect of Hyuga-touki leaf for bloodpressure and the safety by a randomized, double-blind,placebo-controlled study.

2. METHODS
2.1. Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from Meigen Inc.

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Table 1 Schedule for the study

Term
Item
Informed consent
Selection and/or allocation
SBP/ DBP
Subjective reporting
Blood and urine test
Ingestion of test foods
Log

Screening●●●

Pretrial test●●●

Test period
6w

12 w

●
●
●

●
●
●

● : Implementation↔ : Daily practice during the test period(Kagoshima) at two centers (KUROSU HOSPITAL,Tokyo and Japan Clinical Trial Association; JACTA,Tokyo). The study period was 12 weeks, from September
2017 to January 2018, and divided into two groups withdifferent testing periods. This study was conducted inaccordance with the ethical principles of the declarationof Helsinki and the Ethical Guidelines for Medical and
Health Research Involving Human Subjects. The study
protocol was approved by the Institutional Review Boardof Pharmaceutical Law Wisdoms (Tokyo). Written
informed consent was obtained from all Subjects. This
trial was registered at UMIN Clinical Trial Registry (Trial
ID: UMIN000027204). The allocation of the test productto the subjects was carried out by the person in charge ofallocation. The allocation list was sealed and strictly
controlled in a safe deposit box of JACTA until the end of
the study.
2.2. Subject
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 TRIBELATECORPORATION (Tokyo), recruited from August throughOctober, 2017.
2.2.1. Inclusion criteria(1) Healthy Japanese aged between 30 and 59 years;(2) Subjects with normotensive, high-normotensive, and1 degree hypertension.
2.2.2. Exclusion criteria(1) Subjects with chronic hypertension;(2) Subjects with food allergies;(3) Subjects who are pregnant or lactating;(4) Subjects who consume medicinal products which may
inﬂuence the outcome of the study;(5) Subjects who consume foods which may inﬂuence theoutcome of the study;(6) Subjects who are judged as unsuitable for the study by
the principle investigator.

2.3. Randomization
From all 88 applicants, 29 were eliminated due to systolicblood pressure (SBP) or diastolic blood pressure (DBP).
The inclusion/ exclusion criteria were judged by theprinciple investigator. All subjects were sequentiallyallocated to Group A (n = 30, M; 14, F; 16) and Group B(n=29, M; 13, F; 16) using a random number table. In
the process of subject assignment, background factors
such as gender, age, SBP, and DBP were taken into
consideration to avoid biased distribution. Subjects inGroup A ingested the test sample of Angelica furcijuga
leaf and subjects in Group B ingested placebo for 12
weeks.
2.4. Description of test foods and blinding
The test product was NIHON-YAMANINJIN tablet(also called Hyuga-touki, hereinafter called Active )containing YN-1 (isoepoxypteryxin) and isopteryxin,
prepared by Meigen Inc. The amount of daily intake was
6 tablets (1 tablet weighs 240 mg), which include 8.0 mg
of YN-1 and 1.4mg of isopteryxin per day. The placebo( Placebo ) does not include Hyuga-touki, YN-1, nor
isopteryxin. Both tablets were indistinguishable in shape,
color, smell, and taste, and were managed by an
identiﬁcation symbol. All involved were blinded.
2.5. Experimental procedures
2.5.1. Experimental protocol
Subjects consumed 6 tablets of the supplement with hotor cold water before every supper for 12 weeks. Subjects
were instructed as follows: to take the assigned foods as
indicated; to maintain their usual lifestyles and habits; toavoid taking other supplements; to maintain their usual
lifestyles and habits; to avoid excessive amounts of food,drink, or alcohol; to avoid excessive intake of foods which
may inﬂuence blood pressure; to maintain a daily recordof every meal eaten and the number of steps measured bya pedometer during the test period; and to send the diary
to the study coordinator.

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Assessed for eligibility （n ＝ 88）

Enrollment〔M:40, F:48〕

Excluded （n＝29）〔M:13, F:16〕¨Did not meet inclusion criteria（n ＝ 29）¨¨SBP 侒 160 or DBP 侒 100（n ＝ 29）¨Declined to participate（n ＝ 0）

Randomized（n ＝ 59）〔M:27, F:32〕

Group AGroup B

Allocated to Active（n＝30）〔M:14, F:16〕¨Received allocated intervention（n＝30）¨Did not receive allocated intervention（n＝0）

Lost to follow-up（n＝0）
Discontinued intervention（n＝12）¨Personal reason（business trip, being unwell）（n＝12）〔M:8, F:4〕

Allocation
Allocated to Placebo（n＝29）〔M:13, F:16〕¨Received allocated intervention（n＝29）

Follow-Up

AnalysisAnalysed（n＝16）〔M:6, F:10〕¨Excluded from analysis（n＝2）¨¨Insuﬃcient intake（n＝2）
〔M:0, F:2〕

Analysed（n＝14）〔M:5, F:9〕
¨Excluded from analysis（n＝2））〔M:1, F:1〕¨¨SBP 侒 140 or DBP 侒 90（n＝2）

Stratiﬁed analysis

Lost to follow-up（n＝0）
Discontinued intervention（n＝6）¨Personal reason（business trip, being unwell）（n＝6）
〔M:2, F:4〕

Analysed（n＝20）〔M:10, F:10〕¨¨Excluded from analysis（n＝3）¨¨Insuﬃcient intake（n＝3）
〔M:1, F:2〕

Analysed（n＝17）〔M:8, F:9〕
¨Excluded from analysis（n＝3））〔M:2, F:1〕¨¨SBP 侒 140 or DBP 侒 90（n＝3）

Figure 1 Flow diagram of subject disposition

2.5.2. Outcome
The objective of this study was to elucidate the eﬀect onlowering blood pressure by consuming Hyuga-touki leaf
containing YN-1 and isopteryxin. To evaluate thisobjective, the blood pressure (SBP and DBP) was
measured as the primary outcome. As the secondary
outcome, subjective reporting about frequency ofurination, thirst, fatigue, headache, feeling heavy
headed, and dizziness were observed by a questionnaire.
Responses to each question were rated on an ordinalscale of 1 to 9, with higher scores indicating a better
result. Furthermore, blood and urine biochemicalparameters were recorded to evaluate the safety of
Hyuga-touki, and adverse events were collected bymeans of a written questionnaire during the study.
According to the schedule shown in Table 1, parameters
on eﬃcacy and safety were measured. These assessments
were conducted upon pre- and post- intervention.
At every clinical visit, the subjects were not allowed toeat or drink (except water) 12 hours prior to the visit andwere instructed to visit all at the same time. After taking
a 15 minute rest, the subjects had their blood pressure
measured. SBP and DBP were tested once via the rightarm of subjects by a clinical nurse using TAMANO
mercury sphygmomanometer (Sanden Medical Industry
Co., Ltd., Tokyo). Next, the subjects had their blood andurine taken, and evaluated the subject reporting
respectively.
2.6. Data analysis
A per protocol set (PPS) was adopted in the study and nosample size design was used. All statistics wereexpressed as mean ± SD. For SBP and DBP, the main
effects and interactions of the food and duration ofingestion were analyzed by two-way repeated measures
analysis of variance (ANOVA) and paired t-test was used
for intragroup analysis. For subjective reporting andbiochemical parameters, Student s t-test was used forintergroup comparisons, and paired t-test was used for
intragroup analysis. The Chi-square test and Student s

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Table 2 Subject demographics

Item

Unit

ActivePlacebo

Subjects

numbers

16

20

Male:Female *
Age *
SBP *
DBP *

numbers
years
mmHg
mmHg

6:10
45.9 ± 6.9
118.1 ± 17.8
67.7 ± 10.6

10:10
44.1 ± 8.9
116.8 ± 14.0
69.0 ± 7.4

mean ± SD* No signiﬁcant diﬀerence

Table 3 Results of blood pressure

Item

SBP

DBP

ValuesP-value（ANOVA）
Active（n ＝ 16） Placebo（n ＝ 20）

Unit

Time points

mmHg

0-week
6-week⊿ 0-6 w

118.1 ± 17.8
116.1 ± 16.4
− 1.9 ± 16.3

116.8 ± 14.0
114.1 ± 12.3
− 2.7 ± 10.1

12-week⊿ 0-12 w

111.1 ± 10.0
− 6.9 ± 12.3 *116.5 ± 12.8
− 0.3 ± 8.1

0-week
6-week⊿ 0-6 w

67.7 ± 10.6
66.1 ± 6.9− 1.6 ± 8.4

69.0 ± 7.4
66.2 ± 7.4− 2.8 ± 5.9 *12-week⊿ 0-12 w

67.6 ± 8.3− 0.1 ± 6.9

69.0 ± 7.6
0.1 ± 4.9

mmHg

0.108

0.788

Values are expressed as the mean ± SD.
* p ＜ 0.05 against 0-week.

t-test were used to compare subject s backgrounds
between groups. Multiplicity according to the occasions
was not adjusted. Any subjects with missing values were
eliminated from the analysis. The subjects who cameunder the following criteria of exclusion were eliminatedbefore the allocation list was opened, 1; consumed lessthan 80％ of the expected dose, 2; without adequate
records, 3; fell under the exclusion criteria after
enrollment or had justiﬁable reason for exclusion.
Statistical analyses were performed using Statcel 4(Yanai, 2015) and Excel Tokei 2015 (SSRI). The results
were considered significant at a < 5％ level in the twosided test.

eliminated, thus data obtained with 36 subjects (Active;
16 [M 6, F 10], Placebo; 20 [M 10, F 10]) was used forthe analysis of efficacy (Figure 2). The subject s age
range was 31-58 years of age (mean age 44.9 ± 8.0 y.o.).
There was no signiﬁcant diﬀerence in gender, age, SBP,
and DBP between groups (Table 2).
3.2. SBP and DBP
Table 3 depicts the results of blood pressure. As for
SBP, there was no interaction of the food and duration ofingestion, though the Active showed a significant
decrease at week 12 in intragroup analysis. In regard to
DBP, a signiﬁcant diﬀerence was observed at week 6 ofPlacebo.

3. RESULTS
3.1. Participant demographics
The 59 subjects were randomly assigned to anintervention group and made a start with ingestion. 18
subjects were withdrawn due to personal reasons(business trip or being unwell), and the remaining 41
subjects completed the study. Due to an eﬃcacy eligibility(insufficient intake of the food less than 80％ of the
expected dose), 5 (Active; 2, Placebo; 3) were

3.3. Stratiﬁed analysis
According to the classiﬁcation of hypertension, 5 subjects(Active; 2, Placebo; 3) were excluded with I degree highblood pressure (Figure 2). 5 had exceeded 139 of SBP
and 1 had exceeded 89 of DBP (1 had exceeded both SBP
and DBP), so we applied stratified analysis of theremaining 31 subjects. The subject s age range was 31-58
years of age (mean age 45.0 ± 8.1 y.o.). There was no
significant difference in gender, age, SBP, and DBP

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Table 4 Subject demographics（stratiﬁed analysis）

Item

Unit

ActivePlacebo

Subjects

numbers

14

17

Male:Female *
Age *
SBP *
DBP *

numbers
years
mmHg
mmHg

5:9
45.1 ± 7.0
113.1 ± 12.3
65.6 ± 9.2

8:9
44.9 ± 9.1
112.4 ± 9.5
67.1 ± 6.3

mean ± SD* No signiﬁcant diﬀerence

Table 5 Stratiﬁed analysis

Item

SBP

DBP

Values 1）

P-value 2）

Unit

Time points

mmHg

0-week
6-week⊿ 0-6 w

113.1 ± 12.3
115.1 ± 13.8
2.1 ± 9.0

112.4 ± 9.5
111.4 ± 9.3− 0.9 ± 8.0

12-week⊿ 0-12 w

109.7 ± 9.9− 3.4 ± 7.6

113.8 ± 11.0
1.4 ± 6.7

0-week
6-week⊿ 0-6 w65.6 ± 9.2
65.6 ± 6.1− 0.1 ± 7.9

67.1 ± 6.3
64.7 ± 6.2 †− 2.4 ± 4.8

12-week⊿ 0-12 w

66.1 ± 7.7
0.5 ± 6.8

67.2 ± 6.6
0.1 ± 5.0

mmHg

Active（n ＝ 14） Placebo（n ＝ 17） （ANOVA）

0.023 #

0.495

Values are expressed as the mean ± SD.
1）† p ＜ 0.1 against 0-week.
2）# p ＜ 0.05 between-group diﬀerence

between groups (Table 4).
Table 5 shows the results of the stratiﬁed analysis ofblood pressures. Significant difference was observed
between two groups in SBP, while DBP yielded nosigniﬁcant changes.
3.4. Subjective reporting
Table 6 shows the results of subjective reporting. After
12-weeks of ingestion, there was no signiﬁcant diﬀerenceof change between two groups. As for intragroup
analysis, about Fatigue of Active and Placebo (at week6), Headache of Active (at week 12), and Feelingheavy headed of Placebo (at week 12) depictedsigniﬁcant diﬀerences from baseline. Other questions did
not show any signiﬁcant diﬀerence.
3.5. Biochemical blood and urine test
Table 7 shows blood and urine biochemical parameters(data about week 6 were not shown). With respect to theblood test, significant differences were observed in
Potassium of Active and Creatinine (male) of Placebo
after 12-weeks ingestion, since there was no signiﬁcantdiﬀerence of change between two groups. As for urine,
no significant difference was observed in pH, and no

problematic findings were found in all items of uricprotein, sugar, urobilinogen, ketone bodies, occult blood,and bilirubin (data on urine qualitative analysis is notshown). The investigator judged diﬀerences as minor andwithin the range of physiological variation (or clinicallysafe).
3.6. Adverse Event
No adverse events associated with the test product wereobserved in the course of the reporting.

4. DISCUSSION
We conducted a randomized, double-blind, placebocontrolled study for examining the eﬀect of Hyuga-touki
leaf containing YN-1 and isopteryxin on blood pressure.
As the result of stratified analysis of normotensive andhigh-normotensive healthy subjects excluding 1 degreehigh blood pressure, Active showed a significant
decreasing in SBP compared to the Placebo after
12-weeks of ingestion. As for the secondary outcome,there was no significant difference between the groups
with regard to the subjective reporting, though it provedthat no abnormal change was triggered by the ingestion

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Table 6 Results of subjective reporting

Item

1

2

3

4

5

6

Frequency of urination

ThirstFatigue

HeadacheFeeling heavy headed

Dizziness

Time point

Active（n ＝ 16） Placebo（n ＝ 20）

0-week

4.9 ± 0.3

4.8 ± 0.66-week⊿ 0-6 w

5.0 ± 1.0
0.1 ± 0.8

− 0.4 ± 0.9

12-week⊿ 0-12 w

4.9 ± 1.0
− 0.1 ± 0.9

5.0 ± 0.6
0.2 ± 0.7

0-week
6-week⊿ 0-6 w

4.9 ± 0.3
5.1 ± 0.8
0.2 ± 0.9

5.0 ± 0.0
5.0 ± 0.6
− 0.1 ± 0.6

12-week⊿ 0-12 w

4.8 ± 0.7
− 0.1 ± 0.7

4.8 ± 0.7
− 0.2 ± 0.7

4.5 ± 0.9

0-week
6-week⊿ 0-6 w

4.9 ± 0.3
5.4 ± 0.8 *0.5 ± 0.9

4.9 ± 0.3
5.1 ± 0.3 *0.2 ± 0.4

12-week⊿ 0-12 w

5.4 ± 1.2 †0.6 ± 1.3

5.2 ± 0.5 †0.3 ± 0.6

0-week

4.9 ± 0.3

5.1 ± 0.4

6-week⊿ 0-6 w

5.3 ± 0.5 *0.4 ± 0.6

5.4 ± 1.3
0.3 ± 1.1

12-week⊿ 0-12 w

5.3 ± 1.1
0.4 ± 1.1

5.6 ± 1.3 †0.5 ± 1.1

0-week
6-week⊿ 0-6 w

4.9 ± 0.3
5.4 ± 1.0
0.4 ± 1.0

5.0 ± 0.0
5.2 ± 0.7
0.2 ± 0.7

12-week⊿ 0-12 w

5.4 ± 1.0
0.4 ± 1.0

5.5 ± 0.9 *0.5 ± 0.9

0-week
6-week⊿ 0-6 w

4.9 ± 0.3
5.2 ± 1.1
0.3 ± 1.1

5.2 ± 0.9
5.2 ± 0.9
0.0 ± 0.0

12-week⊿ 0-12 w

5.3 ± 1.1
0.3 ± 1.1

5.4 ± 1.1
0.2 ± 0.7

Unit; score, Scores are expressed as the mean ± SD.
†

p ＜ 0.1, * p ＜ 0.05 against 0-week.

of the test food.
The Hyuga-touki used in this study is one of the
Apiaceae plants, which grows naturally from the northernpart of Miyazaki prefecture to the mountainous area ofKagoshima prefecture, and has been used as an
indigenous drug such as cordial medicine called the grassof God since ancient times. In 1971, it was announced asa new species, named Angelica Furcijuga Kitagawa ,and named Hyuga-touki as the Japanese name. The
Hyuga-toki is also called Nihon-yamaninjin, and it is said
that full-ﬂedged cultivation spreading activity had begun
since the 1980s. The Hyuga-touki contains YN-1 andisopteryxin, a type of coumarin-based compound, andcoumarin is said to have antibacterial effects 5) ,anticoagulant action 6) , and alleviating swelling 7) .
Moreover, there have been many reported effects of
coumarin on antihypertensive 8)9). In particular, it has beenshown that plant-derived coumarin compounds suppress
blood pressure increase by inhibiting angiotensin II 10).
Pickering in Britain (1955) described, essential
hypertension is one in which both DBP and SBP wererising 11). It is well known that hypertension causes
complicated diseases such as cardiac dysfunction,
cerebrovascular disorder, kidney impairment, and eyelesion. In actuality, according to the 18-year follow-up
study of Framingham Heart Study (FHS), it was reported
that the hypertensive group had incidence 7 times as
cerebral infarction, 3 times as coronary artery disease,38 （942）

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Table 7-1 Results of biochemical blood and urine test（1）

Item

Unit

Std. Value

GenderTime
pointsValuesActive（n ＝ 16） Placebo（n ＝ 20）〔M 6, F 10〕〔M 10, F 10〕

Total Bilirubin

mg/dL

0.2-1.2

M/F

0-weeke
12-week⊿ 0-12 w

0.76 ± 0.23
0.76 ± 0.31
0.00 ± 0.32

0.76 ± 0.26
0.82 ± 0.24
0.07 ± 0.23

Total Protein

g/dL

6.7-8.3

M/F

0-weeke
12-week⊿ 0-12 w

7.4 ± 0.4
7.3 ± 0.4
− 0.1 ± 0.3

7.2 ± 0.3
7.1 ± 0.3
− 0.1 ± 0.3

4.5 ± 0.2
4.4 ± 0.2
− 0.1 ± 0.2

4.5 ± 0.3
4.4 ± 0.3
− 0.1 ± 0.2

Albumeng/dL

3.8-5.2

M/F

0-weeke
12-week⊿ 0-12 w

AST（GOT）

U/L

10-40

M/F

0-weeke
12-week⊿ 0-12 w

22.1 ± 7.1
23.8 ± 8.8
1.6 ± 3.8

20.8 ± 4.1
21.4 ± 7.4
0.6 ± 5.8

ALT（GPT）

U/L

5-45

M/F

0-weeke
12-week

19.1 ± 9.0
20.6 ± 11.4

19.1 ± 11.6
19.3 ± 12.5

⊿ 0-12 w

1.4 ± 7.4

− 0.4 ± 5.8

ALP

U/L

100-325

M/F

0-weeke
12-week⊿ 0-12 w

200.4 ± 47.5
210.0 ± 51.2
9.6 ± 20.0

190.5 ± 45.4
187.4 ± 49.1
− 3.1 ± 20.8

LD（LDH）

U/L

120-240M/F

0-weeke
12-week⊿ 0-12 w

183.7 ± 22.6
191.1 ± 28.4
7.4 ± 24.5

185.2 ± 30.3
196.5 ± 43.4
11.3 ± 41.4

80 and underM

0-weeke
12-week⊿ 0-12 w

49.8 ± 48.4
55.7 ± 49.2
5.8 ± 20.0

35.7 ± 16.0
34.8 ± 14.1
− 0.9 ± 6.9

30 and underF

0-weeke
12-week⊿ 0-12 w

17.8 ± 4.1
19.6 ± 7.1
1.8 ± 4.1

21.1 ± 9.5
18.8 ± 9.8− 2.3 ± 10.7

60-270M

0-weeke
12-week⊿ 0-12 w

126.2 ± 30.4
160.8 ± 94.9
34.7 ± 87.1

133.8 ± 39.1
130.8 ± 34.6
− 3.0 ± 17.7

40-150F

0-weeke
12-week⊿ 0-12 w

85.1 ± 21.1
93.7 ± 35.2
8.6 ± 24.8

84.9 ± 48.0
81.6 ± 33.7
− 3.3 ± 30.7mg/dL

120-219M/F

0-weeke
12-week⊿ 0-12 w

206.3 ± 36.9
212.7 ± 34.7
6.4 ± 16.9

207.5 ± 27.6
204.3 ± 36.5
− 3.2 ± 22.2

Neutral Fat（TG） mg/dL

30-149M/F

0-weeke
12-week⊿ 0-12 w

81.1 ± 42.5
84.6 ± 94.3
3.5 ± 78.2

94.0 ± 45.5
110.3 ± 145.5
16.3 ± 141.8

M/F

0-weeke
12-week⊿ 0-12 w

142.3 ± 1.9
141.9 ± 2.3− 0.4 ± 1.4

141.6 ± 1.6
141.3 ± 1.8− 0.3 ± 1.7

γ-GT（γGTP）

CK（CPK）

Total Cholesterol

Sodium

U/L

mg/dL

mEq/L

137-147

Values are expressed as the mean ± SD.

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Table 7-2 Results of biochemical blood and urine test（2）

Item

Unit

Std. Value

GenderTime
pointsValuesActive（n ＝ 16） Placebo（n ＝ 20）〔M 6, F 10〕〔M 10, F 10〕

102.9 ± 2.4
103.7 ± 2.2
0.8 ± 4.0

102.9 ± 2.9
103.1 ± 2.4
0.2 ± 3.9

Chloride

mEq/L

98-108M/F

0-weeke
12-week⊿ 0-12 w

Potassium

mEq/L

3.5-5.0M/F

0-weeke
12-week⊿ 0-12 w

9.4 ± 0.3
9.3 ± 0.3
− 0.2 ± 0.4

9.3 ± 0.3
9.1 ± 0.4
− 0.2 ± 0.4

4.2 ± 0.3
4.5 ± 0.4 *0.3 ± 0.5

4.2 ± 0.3
4.4 ± 0.5
0.3 ± 0.6

Calcium

mg/dL

8.4-10.4

M/F

0-weeke
12-week⊿ 0-12 w

Inorganic
Phosphorus

mg/dL

2.5-4.5

M/F

0-weeke
12-week⊿ 0-12 w

3.3 ± 0.4
3.5 ± 0.4
0.2 ± 0.5

3.3 ± 0.4
3.3 ± 0.5
0.1 ± 0.5

Urea Nitrogen

mg/dL

8.0-20.0

M/F

0-weeke
12-week

12.3 ± 2.8
13.9 ± 3.1

12.2 ± 2.1
13.3 ± 4.3⊿ 0-12 w

1.6 ± 3.7

1.1 ± 3.40-weeke
12-week⊿ 0-12 w

0.77 ± 0.10
0.76 ± 0.07
− 0.00 ± 0.11

0.87 ± 0.08
0.81 ± 0.09 *− 0.06 ± 0.07

Creatinine

0.61-1.04

M

0.47-0.79

F

0-weeke
12-week⊿ 0-12 w

0.58 ± 0.05
0.59 ± 0.06
0.01 ± 0.04

0.63 ± 0.08
0.60 ± 0.07
− 0.03 ± 0.05

mg/dL

Blood Sugar（serum）

mg/dL

70-109M/F

0-weeke
12-week⊿ 0-12 w

83.1 ± 8.9
83.4 ± 8.3
0.3 ± 8.0

87.3 ± 8.9
85.5 ± 9.8− 1.8 ± 6.9

pH（urine）−

5.0-7.5

M/F

0-weeke
12-week⊿ 0-12 w

6.5 ± 0.7
6.6 ± 0.8
0.1 ± 0.5

6.3 ± 0.8
6.4 ± 0.8
0.1 ± 1.0

Values are expressed as the mean ± SD.
* p ＜ 0.05 against baseline.

and 4 times as congestive heart failure, compared to thenormotensive group 12). It is important for us to suppress
hypertension in order to extend healthy life expectancy
and to maintain and improve QOL. Hyuga-touki has beenused as an indigenous medicine so far, while its part of
the root was acknowledged as medicine by the Ministryof Health, Labour and Welfare in 2002 13). On the other
hand, there are reports that the leaves and stems of
Hyuga-touki also contain YN-1 and isopteryxin similar to
the root 14). The test food used as an intervention in thistrial is a tablet made from dried leaves of Hyuga-touki
into powder, so it was thought that the similar eﬀect toroot was obtained.
As the secondary outcome, we evaluated the subjective
eﬀects of the Hyuga-touki leaf in this study, though there
was no significant difference between the groups in all

items. In this study, the screening was performed tochoose subjects with normal level of blood pressure or
slight hypertensive (normotensive, high-normotensive,
and I degree high blood pressure). Actually, the majorityof subjects analyzed were normal or high-normal, so it isconsidered that the subjective eﬀect did not appear. Dueto these conditions, the effect of Hyuga-touki leaf
observed in this study would have been limited, anddiﬀerent study designs in the future would be expected.
In addition, we examined the safety of the test food by
the biochemical analysis of blood and urine. A signiﬁcantdifference was observed in Potassium of Active andCreatinine (Male) of Placebo after 12-weeks of ingestion,
while there was no significant difference of change
between two groups. The principle investigator judged
the differences as minor and within the range of40 （944）

診療と新薬・第 55 巻

physiological variation (or clinically safe). During the test
period 18 subjects discontinued the test. The reasons fordiscontinuance were personal circumstances such abusiness trip or being unwell. 5 subjects were withdrawn
from analysis due to insuﬃcient consumption of the test
food and had nothing to do with the ingestion of the test
product. Therefore, based upon the blood and urine test,
and the diaries of the subjects, we observed no harmful
influence against biochemical and/or physiologicalmatters of the subjects, and this result indicated thesafety of ingestiing of the test product for 12 weeks of thetest period.
In recent years, hypertension has been found to aﬀect
the occurrence or progression of dementia. It is supposedthat hypertension leads to atherosclerosis,
arteriosclerosis, and cerebrovascular lesion. In addition,
the presence of cerebrovascular lesion lowers thethreshold of cognitive dysfunction, and amyloid β -protein
is advanced in the brain from disorders of ischemic andendothelial, or increased vascular permeability. Thus
Alzheimer s lesion accelerates with obstruction ofclearance 15). Conversely, there is also a report that YN-1
and isopteryxin contained in Angelica shikokiana reducesamyloid β-proteins 16), therefore, future studies are
expected on this.

5. CONCLUSION
In conclusion, we found out that the ingestion of
NIHON-YAMANINJIN tablet containing YN-1
(isoepoxypteryxin) and isopteryxin for 12 weeks
decreased SBP in normotensive and high-normotensive
healthy subjects. In addition, no safety-related matteroccurred during the test period.
CONFLICT OF INTEREST
All parts of this study were funded by Meigen Inc. Masahiro Yamamoto is
the principal. All authors state that the study was conducted in theabsence of any other relationships that could be interpreted as a conﬂict of

第 12 号（2018 年 12 月）
interest.

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