診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

81 （245）

EFFICACY OF SUPPLEMENT CONTAINING ARGININE AND ORNITHINEON MALE SEXUAL FUNCTION IN HEALTHY JAPANESE― A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY ―Masatomo NAJIMA1), Mitsuhiko MUNEKATA2) and Ryo KOHIYAMA3)
1) JACTA (Japan Clinical Trial Association)
2) OZ Clinic3) INSPIRE CO. LTD.

Abstract
Objectives: The objective of this research was to investigate the effectiveness of daily
ingestion of a supplement, which contains arginine and ornithine on the male sexual function
improvement.
Methods: In this randomized, placebo-controlled, double-blind trial, 31 subjects wererandomized. To evaluate this objective, subjective reporting of sexual function (modified
International Index of Erectile Function), blood ﬂow velocity and Proﬁle of Mood States were
measured as the primary outcome.
Results: 7 subjects were withdrawn. 6 out of 7 were due to personal reasons (4; occupational
conﬂict, 2; a cold) and 1 subject revealed to have extremely high score of potassium in the 6th
week visit so that the physician in charge excluded. With 24 subjects, changes in values ofmodified IIEF were significant in the intergroup comparison after 12-week ingestion.
Moreover, in the Vigor and Fatigue questionnaire, the magnitude of change from baseline
was signiﬁcantly diﬀerent between the two groups after 12-week ingestion. 1 subject withextremely high score of potassium was examined as a sound individual overall by thephysician in charge.
Conclusion: We found out that the ingestion of the supplement containing arginine andornithine by healthy Japanese people for 12 weeks contributed to the improvement of themale sexual function. In addition, no safety-related matter occurred during 12-week test
period.
Key words: arginine, ornithine, male sexual function, erectile dysfunction

1. INTRODUCTION
For men, male sexual function (erectile function) is not
only an issue of sexual intercourse as the measure topreserve the species, but also an issue that relates to theself-conﬁdence or the eagerness for life, the relationshipbetween couples and ultimately the QOL (quality of life).
Erectile Dysfunction (ED) is deﬁned as a condition inwhich a man is unable to get or keep an erection firm
enough for sexual intercourse 1) (National Institute of
Health (NIH), 1993), and the same deﬁnition is applied inour country. In an epidemiological survey conducted inJapan in 1998, about 8.7 million people were estimated tosuﬀer from moderate ED (a condition in which a man cansometimes get or keep an erection ﬁrm enough for sexualintercourse), whereas about 2.6 million were estimatedto be suﬀered from complete ED (a condition in which a
man is always unable to get or keep an erection firm
enough for sexual intercourse): those add up to about
11.3 million people, which means one in four men aged 25
years old or older were reported to have an erectile

dysfunction problem 2), and the number is expected toincrease due to the countryʼs aging population.
It is commonly known that ED is brought by various
factors such as aging, psychological factors, adult
lifestyle-related diseases and/or a medicinal agent3).
The current mainstream medical treatment for ED is
the use of phos-phodiesterase5 inhibitor 4). In Japan theuse of Viagra became operational in 1999 and now threekinds of curative medicine are being used, all of which
are regarded as a highly eﬀective measure. However, it
is also reported that their use may cause adverse events
such as headache, variability in blood pressure or
palpitation, and there are some medicines that should not
be administered together with them5). In addition, it isrelatively expensive to purchase these three medicines
and they are only available on prescription. Therefore
purchasing them is somewhat a hurdle for the male whodoes not have a symptom of ED but just desires tostrengthen the male sexual function or the patients on
the borderline. This fact accelerates the needs among
men to strengthen their sexual function by taking the82 （246）

診療と新薬・第 53 巻

foods they eat regularly or the supplements which bothcontain the ingredients eﬀective for the revitalization of
the male sexual function.
Based on these needs, many kinds of supplement
products containing arginine are recently sold for men
who want to strengthen their sexual function. Arginine isa kind of non-essential amino acid contained in chicken,
soybean or Koya-dofu (freeze-dried bean curd), and it isreported to have functions such as increasing the
production of growth hormones and improving blood ﬂow
by causing blood vessels to dilate 6)7). Another reportillustrates the ingestion of arginine contributes to theimprovement of the sexual function8).
Ornithine, on the other hand, is also a kind of nonessential amino acid contained in Shijimi (freshwaterclam), cheese or ﬂatﬁsh, and is reported to be eﬀective
for fatigue recovery and growth promotion9). However,
although both arginine and ornithine have a great deal to
do with intravital behavior of human, there are only a few
reports about the relationship between the ingestion ofornithine and the sexual function, and as to therelationship between the use of both ingredients and thesexual function, we cannot ﬁnd any reports scrutinizingit.
I n t h i s s t u d y, w e e x a m i n e d t h e e f f e c t o f t h e
combination of arginine and ornithine for the male sexualfunction and the safeness of the combined use of them,excluding any deliberate effect of increasing vitality
achieved by medicine. The test targets were healthy
Japanese men, and the test method was a randomized,
placebo-controlled, double-blind study using the
supplement containing arginine and ornithine.

2. METHOD
2.1. Trial Design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from INSPIRE CO. LTD.
(Tokyo) at two centers (OZ clinic, Tokyo and JACTA,Tokyo). The study period was 12 weeks, from July 18th toOctober 10th, 2015.
This study was conducted in accordance with the ethicalprinciples of the declaration of Helsinki. The study
protocol was approved by the Institutional Review Boardof LLP. 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.
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) andRabbits-coco (Tokyo).
2.2.1. Inclusion Criteria(1)Healthy males aged between 30 and 69 years;

第 3 号（2016 年 3 月）(2)Males who have a sexual decline;(3)Males who have a sexual partner.
2.2.2. Exclusion Criteria(1)Subjects who are allergic to food related to the test
material of this trial;(2)Subjects who have previous medical history of theserious diseases (heart, liver, kidney, blood, digestivesystem, metabolism system);(3)Subjects who are under treatment for hypertension, or
who untreated hypertension (not less than level 2);(4)Subjects who are under treatment for diabetes;(5)Subjects who contract, or are under treatment for
diseases of prostatic;(6)Subjects who are judged as inappropriate for this study
by the doctor in charge.
2.3. Randomization
Recruited subjects were 150 persons. Subjects who
fulﬁlled eligibility criteria were 31 persons. The inclusion
criteria were 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 sample: 16) and group P(Placebo: 15). The allocation was pre-assigned on thebasis of randomized numbers.
2.4. Description of test foods and blinding
The test food, Force ( FO ) and placebo were preparedby INSPIRE CO. LTD. The amount of daily intake is 9
tablets (1 tablet contains 400mg, therefore 9 tablets
contain 3600mg). The compositions of FO were arginine,ornithine, etc., while Placebo was mainly consisted ofcellulose. Both tablets were indistinguishable in shape,
color or taste. Tablets were managed by the identiﬁcation
symbol. All involved were blinded.
2.5. Experimental Procedures
2.5.1. Experimental protocol
Subjects consumed 9 tablets of the supplement with hotor cold water every day for 12 weeks. Subjects were
instructed as follows: to take the assigned foods as
indicated; to maintain their usual lifestyles and habits; toavoid excessive amounts of food, drink or alcohol; tomaintain a daily record of lifestyle factors during the test
period; and to send the diary to the study coordinator
every Friday by mobile email.
2.5.2. Outcome
The objective of this study is to verify the male sexualfunction improvement of ingesting food containing
arginine with ornithine. To evaluate this objective,
subjective reporting of sexual function was observed as
the primary outcome. The questionnaire is based on
International Index of Erectile Function (IIEF)10). Somequestions are eliminated or modiﬁed because they are thecriteria of Erectile Dysfunction (ED). This study isintended to exclude ED patients. The details areillustrated in Appendix 1.
Furthermore the blood flow velocity and Profile ofMood States ( POMS ) 11) were measured as the

診療と新薬・第 53 巻

Table 1

第 3 号（2016 年 3 月）

83 （247）

Schedule for the study.
Term

Item
Informed consent
Questionnaire on the treatment of sexual function
Selection and/or allocation
Modiﬁed IIEF
Blood ﬂow velocity
POMS
Biochemical analysis of the blood
Urine analysis
Ingestion of test foods
Log

Screening

Pre Trial

Test period (12 w)

Test

Week 6

Week 12

●
●
●
●
●

●
●
●
●
●

●
●
●
●
●

●
●
●

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

secondary outcome. The blood flow velocity was tested
by Bi-directional Doppler ES-100V3 (Hadeco, Inc.,Tokyo). For POMS, Vigor and Fatigue were questioned.
The details of questionnaire are listed in Appendix 2.
Blood biochemical and urine parameters were recorded toevaluate the safety of the test foods as the secondary
outcome.
These assessments were conducted upon entry into thestudy (pre-intervention), 6 weeks and 12 weeks (postintervention). To evaluate the safety of the test foods,
adverse events were collected by means of a written
questionnaire during the study.
According to the schedule shown Table 1, we
measured parameters on eﬃcacy and safety.
2.6. Data Analysis
All analyses were performed on the on-treatment
population in the study. The full analysis set principal was
adopted in the present study and no sample size design
was used.
Data were expressed as mean ± SD. For the modiﬁed
IIEF and POMS, changes from baseline in the same groupwere assessed using the Wilcoxon signed-rank test. The
Mann-Whitney U test was used for intergroupcomparisons of changes from the baseline. For blood ﬂow
velocity and biochemical analyses of blood and urine,changes from the baseline in the same group wereassessed using the paired t-test. Studentʼs t-test was used
for intergroup comparisons of changes from the baseline.
Studentʼs 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. RESULT
3.1. Participant Demographics
From all of 150 applicants, 119 were eliminated according

to questionnaire, Appendix 3.
The 31 subjects were randomly assigned tointervention groups and made a start with ingestion. 7
dropped out. Out of 7, 6 subjects were eliminated due topersonal reasons (4; occupational conflict, 2; a cold). 1
subject revealed to be extremely high score of potassiumin 6-week visit so that the physician in charge of this trial
excluded this subject. Thus, data obtained with 24
subjects was used for the analysis of eﬃcacy (Fig l).
There was no significant difference in the mean age
between the groups (Table 2).
3.2. Questionnaire of sexual function
Data obtained with respect to the scores of the modiﬁed
IIEF are summarized in Table 3.
Changes in values of the questionnaire were detected
as follows: The intake of FO resulted in a significant
increase in the score of #2, #3, #4, #5, #6, #7, #8, #9
and #10 after 12-week ingestion. For intergroupcomparison, the score of #2, #5, #6, #7, #8 and #10
showed signiﬁcant increase after 6-week ingestion, also
all 10 items represented significant increase after 12week ingestion.
3.3. Blood ﬂow velocity
Table 4 depicts changes in the blood flow velocity.
Significant upward changes were seen in the FO groupcompared to the Placebo group after 6-week and 12-weekingestion.
3.4. Vigor and Fatigue
Changes of values were also evaluated in Vigor andFatigue. The significant difference was found in theintragroup comparison with the FO group of 10 items
after 6-week ingestion, also 14 items after 12-weekingestion (Table 5). For the intergroup comparison, 1
item after 6-week ingestion and 8 items after 12-weekingestion revealed the signiﬁcant diﬀerence (Table 6).
3.5. Blood and Urine Test
Table 6 and 7 shows the blood biochemical and urine84 （248）

診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

Recruited (n ＝ 150)

Randomized (n ＝ 31)

FO (n ＝ 16)

Placebo (n ＝ 15)

Withdraw (n ＝ 4)
(personal reasons：3, blood
potassium extremity：1)

Withdraw (n ＝ 3)
(personal reasons)

Full analysis set

FO (n ＝ 12)

Placebo (n ＝ 12)

Fig. 1 Flow diagram of subject disposition

Table 2 Subject demographics
Item
Subjects

＊

Age
＊

Unit

FO

Placebo

−
Years

12
48.4 ± 11.3

12
48.8 ± 11.4

Number of subjects
mean ± SD

parameters. A signiﬁcant diﬀerence was observed in thechanges of Chloride, Potassium and Blood Sugar (Serum)of the FO group after 12 weeks of ingestion. The samedifference was observed with urine pH. However, theinvestigator judged it as the range of physiologicalvariation (or clinically safe).
3.6. Adverse Event
The subject whose blood potassium was extremely highwas examined as a sound individual overall by thephysician in charge of this study. Any other adverse
event was not depicted during this trial.

4. DISCUSSIONS
We conducted a randomized, placebo-controlled, doubleblind study for examining the efficacy of a supplement(FO) containing arginine and ornithine on the male sexualfunction improvement. As the primary outcome, thestudy showed the signiﬁcant diﬀerences in the scores ofmodified International Index of Erectile Function (IIEF)
on the questionnaire, which is designed to collect the
subjective evaluations against the FO among the study
subjects. In addition, the significant differences wereobserved in the blood ﬂow velocity. Furthermore, several

categories on the questionnaire of Proﬁle of Mood States(POMS) showed the significant differences, and thisresult indicates the improvement of QOL. At the sametime, as the secondary outcome of the observation ofclinical ﬁndings such as medical interview, the blood andurine test revealed no abnormal change had been
triggered by the ingestion of test products.
Main Findings
In this study we examined the male sexual function by
the questionnaire, designed based upon IIEF which
consists of ten items (the questions which presuppose ED
were excluded by the doctor handling this investigation).
Most items out of ten showed the signiﬁcant diﬀerences,indicating the improvement of male sexual function; theintake of FO resulted in the significant increase in thescore of #2, #3, #4, #5, #6, #7, #8, #9 and #10, andfor intergroup comparison, on the other hand, the scoreof #2, #5, #6, #7, #8 and #10 showed significant
diﬀerences. These results indicate that at least one out of
ten items, consisting of intercourse satisfaction (#1,
#2, #3), orgasmic function (#4, #5), sexual desire(#6, #7), overall satisfaction (#8, #9) and erectile
function (#10), showed the significant difference of診療と新薬・第 53 巻

Table 3

第 3 号（2016 年 3 月）

85 （249）

modiﬁed IIEF
Scores

1

2

3

4

5

6

7

8

9

10

Betweengroupdiﬀerence(P-value)

QuestionnaireTimepointsFO group (n ＝ 12)

Placebo group (n ＝ 12)

Over the past 4 weeks, howmany times have you
attempted sexual Intercourse?

Baseline
Week 6
ChangeWeek 12
Change1.6±1.0
1.9±0.7
0.3±1.3
2.1±0.5
0.5±1.1

2.1±1.4
2.2±1.3
0.1±0.7
1.7±0.9− 0.4±1.10.237Over the past 4 weeks, when you
attempted sexual intercourse,
how often was it satisfactory foryou?

Baseline
Week 6
ChangeWeek 12
Change1.8±0.6
3.2±1.2 *1.4±1.4
2.9±1.4 *1.2±1.4

3.3±1.2
2.9±1.3 †− 0.4±0.7
2.8±0.9 *− 0.5±0.70.001 ##

Over the past 4 weeks, howmuch have you enjoyed sexualintercourse?

Baseline
Week 6
ChangeWeek 12
Change2.2±0.6
2.9±0.5 *0.8±0.8
3.0±0.4 *0.8±0.72.8±1.0
3.1±0.7
0.3±1.0
2.6±0.7− 0.3±1.00.326Over the past 4 weeks, when you
had sexual stimulation orintercourse how often did you
ejaculate?

Baseline
Week 6
ChangeWeek 12
Change2.5±1.2
4.0±1.2 *1.5±1.3
4.0±1.0 *1.5±1.6

3.6±1.4
4.3±1.0 †0.7±1.2
2.9±0.9 †− 0.7±1.10.166Over the past 4 weeks, when you
had sexual stimulation orintercourse how often did you
have the feeling of orgasm or
climax?

Baseline
Week 6
ChangeWeek 12
Change2.4±0.9
3.7±1.0 *1.3±1.1
3.9±0.8 **1.5±1.1

3.7±1.2
3.0±0.9 †− 0.7±1.0
2.7±0.8 **− 1.0±0.7

Over the past 4 weeks, howoften have you felt sexual desire?

Baseline
Week 6
ChangeWeek 12
Change3.2±0.9
3.8±0.9
0.6±1.0
3.9±0.5 *0.8±0.9

3.4±1.2
2.4±0.8 *− 1.0±1.1
2.3±0.5 **− 1.2±0.9

Baseline
Week 6
ChangeWeek 12
Change3.0±0.6
3.8±0.5 **0.8±0.5
3.8±0.6 *0.8±0.9

3.9±0.8
3.2±0.4 *− 0.8±1.0
2.7±0.7 **− 1.3±0.8＜ 0.001 ##Baseline
Week 6
ChangeWeek 12
Change2.3±0.6
3.2±0.6 **0.9±0.7
3.4±0.7 **1.2±0.9

3.3±1.3
3.0±0.90.3±1.1
2.6±0.5 *− 0.8±1.10.007 ##

Over the past 4 weeks, howsatisﬁed have you been with yoursexual relationship with yourpartner?

Baseline
Week 6
ChangeWeek 12
Change2.5±0.7
3.2±0.6 *0.7±0.7
3.3±0.7 *0.8±0.7

3.1±1.0
3.1±0.9
0.0±1.1
2.9±0.7− 0.2±0.80.126Over the past 4 weeks how often
have you experienced nocturnal
penile tumescence?

Baseline
Week 6
ChangeWeek 12
Change2.3±0.6
3.2±0.7 **0.9±0.7
3.2±0.4 **0.9±0.5

2.4±0.5
2.3±0.8− 0.2±1.0
2.0±0.6− 0.4±0.8

0.017 #

Over the past 4 weeks, howwould you rate your level ofsexual desire?

Over the past 4 weeks, howsatisﬁed have you been with you
overall sex life?

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

0.026 #

0.003 ##

0.013 #

0.001 ##

0.001 ##
＜ 0.001 ##0.004 ##
＜ 0.001 ##＜ 0.001 ##＜ 0.001 ##0.011 #

＜ 0.001 ##86 （250）

診療と新薬・第 53 巻

Table 4

unit

cm/s,
KHz

第 3 号（2016 年 3 月）

Blood ﬂow velocity
ValuesTime

Between-group

pointsFO group (n ＝ 12)

Placebo group (n ＝ 12)

Baseline
Week 6
ChangeWeek 12
Change5.3±2.5
7.0±3.4 *1.8±2.1
7.5±3.1 **2.3±2.2

7.5±4.7
6.0±3.2− 1.5±3.8
5.9±3.8 †− 1.7±3.0

diﬀerence(P-value)

0.017 #
0.001 ##

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

improvement. Although items #1, #3 and #9 did notachieve the satisfactory level of significant differences,these greatly relate to the relationship between thepartners, and therefore the improvement may not be
accomplished only by the improvement of subject s sexualfunction.
Based on the ﬁndings illustrated above, it can be said
that from a standpoint of IIEF score, the ingestion of FO
has improved all aspects of male sexual function.
Although IIEF was originally developed to examine astate change associated with treatment of ED, it has been
confirmed that the use of IIEF is available for theexamination of male sexual function of healthy people12)13).
Therefore it should be appropriate as an evaluation
criterion for the male sexual function of this study.
The main factor for evaluating the male sexual function
is an erection. It is considered that an erection isachieved based on the following mechanism 14)15); firstly,
sexual stimulation causes agitation on the sexual centerof the cerebrum, and the agitation passes through thepelvic nerve, pelvic plexus and cavernous nerves of thepenis. Then Nitrogen monoxide (NO) is secreted fromnerve terminals and it increases the level of cGMP in the
unstriated muscle of the corpus cavernosum penis. Thenthe unstriated muscle relaxes, and this relaxation lets the
blood ﬂow into the cavernous body. The ﬂow extends thetunica albuginea corporum cavernosorum, then thedraining vein is closed and ﬁnally an erection is achieved.
Arginine contained in FO produces NO, and it isreported that when the NO reaches the vascular smoothmuscle, it increases the level of cGMP and causes
dilatation of blood vessels16). There is also a report thathas shown a signiﬁcant subjective improvement in sexualfunction in men with organic ED who have the decreased
production of NO, as a result of the 5g/day ingestion of
L-arginine8).
On the other hand, ornithine reportedly has a functionof mitigating tiredness from having worked out9), and thisfunction possibly contributes to reducing the fatigue ofmen during sexual intercourse. In addition, ornithineconverts into arginine through the urea cycle17), therefore

the concurrent ingestion of arginine and ornithine is
expected to have a mutual influence. There is also areport that has shown the muscle strengthening functionof men as a result of the concurrent ingestion of bothingredients18) and this finding may affect the function of
unstriated muscle when an erection occurs. These
functions are diﬀerent from those of curative medicine for
ED (PDE5I) which has a function of inhibiting
biodegradation of cGMP. Therefore, FO containing botharginine and ornithine is expected to have an
improvement effect of male sexual function, while
excluding any deliberate effect of increasing vitality
achieved by medicine such as PDE5I
Secondary Findings
In this study we observed a signiﬁcant diﬀerence of theblood flow velocity in the FO group compared to thePlacebo group, after 6-week and 12-week ingestion. As
illustrated above, this result can be explained as thefunction of improving the blood ﬂow the amino acids suchas arginine or ornithine (contained in FO) reportedly
have16). The blood ﬂow of the subjects who ingested FO
has improved and its velocity has also increased. The
variation was within the standard level, and did notdeviate from the usual range.
At the same time, for evaluating the QOL of thesubjects the doctor conducted a questionnaire using
POMS. For POMS, vigor and fatigue were questioned.
After 12-week ingestion of FO, 14 items (of thequestionnaire) showed the signiﬁcant diﬀerences and thecomparison between the Placebo group indicated thesignificant differences on 8 items (Vigor Lively, Active,
Alert, Carefree, Fatigue worn out, Listless, Fatigued
and Exhausted). These include both items about thefatigue and the vigor, and although for the items of Vigor
Lively and Active , FO group answered as they felt
lively, at the same time they answered as they felt tiredon the items such as Fatigue worn out . It is possiblethat the fatigue is the result of intensity of their sexualintercourse after gaining some conﬁdence in their sexual
ability, but only this result is not sufficient to conclude
the improvement of QOL has been achieved by the

診療と新薬・第 53 巻

Table 5

第 3 号（2016 年 3 月）

POMS
ScoresQuestionnaire

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

87 （251）

Time points

Between-groupdiﬀerence(P-value)

FO group (n ＝ 12)

Placebo group (n ＝ 12)

Baseline
Week 6
ChangeWeek 12
Change1.6 ± 0.7
2.0 ± 0.6
0.4 ± 0.8
2.6 ± 0.7 **1.0 ± 0.6

1.8 ± 1.0
2.3 ± 1.1
0.4 ± 1.1
1.8 ± 0.8
− 0.1 ± 0.7

0.729

Baseline
Week 6
ChangeWeek 12
Change1.4 ± 0.7
2.3 ± 0.5 *0.9 ± 0.8
2.6 ± 0.7 **1.2 ± 1.0

2.1 ± 0.9
2.3 ± 1.1
0.3 ± 1.1
2.0 ± 0.7
− 0.1 ± 0.8

0.106

Energetic

Baseline
Week 6
ChangeWeek 12
Change1.2 ± 0.4
2.3 ± 0.9 **1.1 ± 0.7
2.4 ± 0.5 **1.3 ± 0.5

1.6 ± 1.1
1.7 ± 0.5
0.1 ± 0.9
2.6 ± 0.7
1.0 ± 1.0

0.011 #

Cheerful

Baseline
Week 6
ChangeWeek 12
Change1.4 ± 0.8
2.1 ± 0.7 *0.7 ± 0.7
2.3 ± 0.5 *0.8 ± 0.7

2.1 ± 1.1
2.3 ± 1.1
0.3 ± 1.4
3.1 ± 1.0 *1.0 ± 1.3

Baseline
Week 6
ChangeWeek 12
Change1.1 ± 0.9
2.2 ± 0.9 *1.1 ± 1.2
2.3 ± 0.7 *1.3 ± 1.1

1.9 ± 0.9
2.3 ± 0.8
0.3 ± 0.8
1.7 ± 0.7
− 0.3 ± 0.5

0.106

Baseline
Week 6
ChangeWeek 12
Change1.1 ± 0.7
2.0 ± 0.7 *0.9 ± 0.9
1.9 ± 0.8 *0.8 ± 0.8

1.5 ± 1.0
1.8 ± 1.2
0.3 ± 1.7
1.5 ± 0.8
0.0 ± 1.5

0.260

Baseline
Week 6
ChangeWeek 12
Change1.2 ± 0.6
2.0 ± 0.7 *0.8 ± 0.9
2.1 ± 0.5 *0.9 ± 0.8

1.8 ± 0.9
1.8 ± 1.6
− 0.1 ± 1.9
1.5 ± 0.7
− 0.3 ± 1.2

0.157

Baseline
Week 6
ChangeWeek 12
Change1.2 ± 0.7
1.9 ± 0.8 *0.8 ± 0.6
2.2 ± 0.7 **1.0 ± 0.7

1.6 ± 1.0
2.3 ± 1.1
0.7 ± 1.4
2.6 ± 0.9 *1.0 ± 1.4

0.795

Baseline
Week 6
ChangeWeek 12
Change1.8 ± 1.1
2.0 ± 1.0
0.3 ± 1.3
2.5 ± 0.8 *0.8 ± 1.1

1.9 ± 1.1
1.6 ± 1.4
− 0.3 ± 1.7
1.2 ± 0.9 †− 0.8 ± 1.3

0.525

Baseline
Week 6
ChangeWeek 12
Change1.5 ± 0.9
2.3 ± 0.6 *0.8 ± 0.9
2.5 ± 0.7 *1.0 ± 0.9

1.5 ± 1.1
1.3 ± 1.0
− 0.2 ± 1.5
1.3 ± 1.3
− 0.3 ± 1.9

0.126

Baseline
Week 6
ChangeWeek 12
Change1.8 ± 0.9
2.7 ± 0.8 *0.8 ± 0.8
2.7 ± 0.7 *0.8 ± 0.9

2.1 ± 1.0
2.0 ± 1.0
− 0.1 ± 1.4
1.8 ± 0.6
− 0.3 ± 1.2

0.073 ‡

Baseline
Week 6
ChangeWeek 12
Change1.1 ± 0.8
2.2 ± 0.7 **1.1 ± 0.7
2.3 ± 0.5 **1.2 ± 0.6

1.3 ± 1.3
1.5 ± 0.9
0.2 ± 1.3
0.8 ± 0.8
− 0.5 ± 1.2

0.069 ‡

SluggishBaseline
Week 6
ChangeWeek 12
Change1.4 ± 0.7
1.9 ± 1.0
0.5 ± 1.1
2.2 ± 0.9 *0.8 ± 1.1

1.2 ± 1.2
1.8 ± 1.1 †0.6 ± 1.1
1.2 ± 0.9
0.0 ± 1.4

0.751

Weary

Baseline
Week 6
ChangeWeek 12
Change1.2 ± 0.8
1.6 ± 0.8
0.4 ± 1.2
1.8 ± 0.8 †0.6 ± 1.1

0.8 ± 1.0
1.8 ± 1.0 *1.1 ± 1.2
1.1 ± 0.9
0.3 ± 1.3

0.299

Baseline
Week 6
ChangeWeek 12
Change1.5 ± 0.9
1.9 ± 0.9
0.4 ± 1.2
2.3 ± 0.9 *0.8 ± 0.9

1.0 ± 1.3
1.3 ± 0.9
0.3 ± 1.8
1.1 ± 0.9
0.1 ± 1.4

0.817

Vigor Lively

ActiveAlert

Full of pep

CarefreeVigorous

Fatigue worn out

Listless

Fatigued

Exhausted

BushedScores 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 diﬀerences in change from baseline.

0.002 ##

0.007 ##

0.665

0.248
0.862

0.002 ##

0.0999 ‡0.0102 #1.000

0.006 ##

0.028 #

0.026 #

0.001 ##

0.194

0.583

0.166

88 （252）

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Table 6
Item

Total Bilirubin

Total Protein

AlbumenAST (GOT)

ALT (GPT)ALP

LD (LDH)

γ-GT (γGTP)CK (CPK)

Total Cholesterol

Unit

mg/dL

g/dL

g/dl

U/L

U/L

U/L

U/L

U/L

U/L

mg/dL

第 3 号（2016 年 3 月）

Changes in biochemical blood test ①
ValuesStd. Value

TimepointsFO group (n ＝ 12)

Placebo group (n ＝ 12)

0.2-1.2

Baseline
Week 6
ChangeWeek 12
Change0.71±0.32
0.69±0.34− 0.02±0.24
0.66±0.22− 0.05±0.22

0.61±0.32
0.45±0.16 †− 0.16±0.26
0.58±0.22− 0.03±0.39

6.5-8.3

Baseline
Week 6
ChangeWeek 12
Change7.4±0.4
7.4±0.3− 0.0±0.3
7.7±0.3 †0.2±0.4

7.4±0.5
7.4±0.4
0.0±0.3
7.5±0.4
0.1±0.4

3.8-5.3

Baseline
Week 6
ChangeWeek 12
Change4.6±0.3
4.7±0.3 *0.2±0.2
4.6±0.4
0.1±0.3

4.6±0.4
4.7±0.4
0.1±0.2
4.5±0.3 *− 0.1±0.2

8-38

Baseline
Week 6
ChangeWeek 12
Change20.3±3.1
20.8±4.6
0.5±3.0
22.1±4.6 †1.8±3.519.8±3.6
21.6±5.9
1.8±4.5
21.0±4.0 †1.3±2.0

4-43

Baseline
Week 6
ChangeWeek 12
Change19.7±9.3
20.3±11.4
0.6±3.923.3±13.2 †3.7±6.0

20.8±10.3
22.5±13.0
1.7±4.2
21.4±8.9
0.6±5.7

110-354

Baseline
Week 6
ChangeWeek 12
Change231.3±61.2
223.2±54.4− 8.1±24.7
234.0±42.1
2.8±45.9

231.2±69.6
219.8±53.1− 11.4±38.1
212.5±56.1 †− 18.7±34.2

121-245

Baseline
Week 6
ChangeWeek 12
Change180.2±17.9
168.0±19.0 *− 12.2±15.5176.9±22.5− 3.3±17.8

187.3±19.3
181.0±17.7− 6.3±17.2
173.3±18.3 **− 14.1±10.1 ‡86 andunder

Baseline
Week 6
ChangeWeek 12
Change42.0±48.7
43.9±47.2
1.9±6.550.9±51.8 †8.9±15.537.2±40.942.4±45.8 *5.3±6.341.8±43.9
4.7±10.8

38-196

Baseline
Week 6
ChangeWeek 12
Change132.5±34.1
138.3±54.1
5.8±39.6
146.3±80.8
13.8±73.3

148.7±74.8
107.8±27.6− 40.8±85.9
138.8±73.4− 9.8±114.6

130-219

Baseline
Week 6
ChangeWeek 12
Change210.7±29.0
201.7±26.3− 9.0±29.4
217.6±29.8
6.9±39.9

205.3±29.4
217.3±38.9
12.0±24.0 ‡214.7±39.9
9.4±26.3

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

診療と新薬・第 53 巻

Table 6
Item

Neutral Fat (TG)

SodiumChloride

Potassium

Calcium

Inorganic
Phosphorus

Urea Nitrogen

Creatinine

Blood Sugar(Serum)

Unit

mg/dL

mEq/L

mEq/L

mEq/L

mg/dL

mg/dL

mg/dL

mg/dL

mg/dL

第 3 号（2016 年 3 月）

89 （253）

Changes in biochemical blood test ②
ValuesStd. Value

TimepointsFO group (n ＝ 12)

Placebo group (n ＝ 12)

30-149Baseline
Week 6
ChangeWeek 12
Change161.3±75.8
178.8±136.0
17.4±112.5
179.2±101.8
17.8±91.2

152.7±105.2
235.8±213.0
83.2±177.4
149.4±63.1− 3.3±98.6

135-150

Baseline
Week 6
ChangeWeek 12
Change144.3±1.7
143.7±1.8− 0.6±1.7144.0±2.0− 0.3±2.2144.1±1.8143.5±1.4− 0.6±2.1
143.9±1.7− 0.2±2.1

98-110Baseline
Week 6
ChangeWeek 12
Change104.8±2.3
104.5±1.0− 0.3±2.3103.5±1.9 *− 1.3±1.9105.0±2.2
103.3±2.1 **− 1.8±1.9 ‡103.4±1.1 *− 1.6±1.9

3.5-5.3

Baseline
Week 6
ChangeWeek 12
Change3.7±0.2
4.1±0.4 **0.3±0.3
4.0±0.2 **0.3±0.2

3.7±0.2
4.0±0.3 **0.3±0.2
4.0±0.4 *0.3±0.3

8.4-10.2

Baseline
Week 6
ChangeWeek 12
Change9.8±0.3
9.7±0.3
0.0±0.2
10.0±0.4
0.2±0.5

9.9±0.4
9.9±0.3
0.0±0.3
9.9±0.3
0.0±0.4

2.5-4.5

Baseline
Week 6
ChangeWeek 12
Change3.6±0.8
3.1±0.5 *− 0.5±0.7
3.3±0.4− 0.2±0.8

3.7±0.5
3.3±0.4 *− 0.4±0.5
3.6±0.4− 0.1±0.5

8.0-22.0

Baseline
Week 6
ChangeWeek 12
Change13.9±3.0
13.9±2.4
0.1±2.914.8±3.5 †0.9±1.715.1±1.914.4±2.2− 0.7±1.9
14.7±2.1− 0.4±2.3

0.61-1.04

Baseline
Week 6
ChangeWeek 12
Change0.90±0.13
0.83±0.13 **− 0.07±0.07
0.87±0.13− 0.03±0.06

0.89±0.15
0.82±0.13 **− 0.07±0.07
0.87±0.14− 0.02±0.06

60-109Baseline
Week 6
ChangeWeek 12
Change61.5±7.758.3±13.1− 3.2±12.1
73.0±19.7 *11.5±17.971.3±24.4
64.0±11.9− 7.3±15.1
66.5±14.2− 4.8±15.8 #Values are expressed as the mean ± SD.
†
p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.
‡p ＜ 0.1, # p ＜ 0.05 between-group diﬀerences in change from baseline.

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第 3 号（2016 年 3 月）

Table 7 Transition of Urinalysis
Item

Speciﬁc Gravity

pH

Unit

mg/dL

g/dL

Std. Value

1.010-1.025

4.5-8.0

Value

Time
pointsFO group (n ＝ 12)

Placebo group (n ＝ 12)

Baseline
Week 6
ChangeWeek 12
Change1.021±0.006
1.018±0.007 †− 0.003±0.005
1.022±0.005
0.001±0.006

1.023±0.007
1.020±0.006− 0.002±0.008
1.019±0.005 †Baseline
Week 6
ChangeWeek 12
Change5.6±0.6
6.0±0.6 †0.3±0.5
6.3±0.9 *0.6±0.7

5.7±0.4
6.0±0.7
0.3±0.8
6.4±1.0 *0.7±1.0− 0.003±0.006 ‡Values are expressed as the mean ± SD.
†

p ＜ 0.1, * p ＜ 0.05 against baseline.

‡p ＜ 0.1 between-group diﬀerences in change from baseline.

ingestion of the FO.
And in this study, it was observed that based uponclinical findings such as blood test and urine test, noabnormal change was triggered by ingestion of the test
product. In the blood test, significant difference wasobserved in the changes of Chloride, Potassium and Blood
Sugar (Serum) of the FO group after 12-week ingestion.
The same difference was observed with urine PH. In
either case, since the difference was minor one, theinvestigator judged it as the range of physiologicalvariation (or clinically safe).
During the test period seven subjects discontinued thetest. Six of them stopped the test because of theirpersonal reason such as impossibility of continuing thetest due to their business. As for the remaining one
subject, on the other hand, the measurement after
6-week ingestion showed an abnormal value of potassium,
but after the medical interview the doctor determined theabnormity was due to the backache and ruled out any
relationship with the test itself. Therefore, based upon
the medical interview, blood test and urine test, weobserved no harmful inﬂuence against biochemical and/or
physiological matters of the subjects which seem to havea causal relationship with FO.
These results indicated the safety of the ingestion of thetest product (FO) for the 12-week test period.
General Information
The male sexual function is a major factor of selfconﬁdence and vigor since it relates to the sexual desire,
which is one of three major desires. Therefore not only
the serious ED patients but also those who are not
suﬀering from ED desire to improve their sexual function.
Also, there is an opinion that the loss of confidence
toward their sexual function tends to decrease thefrequency of sexual intercourse and this tendency is oneof the causes of the decline in the birth rate19). If they areable to improve their sexual function by simple andconvenient methods such as obtaining supplements
instead of the prescription of medical drugs, they may
regain their conﬁdence, try to increase the frequency of
sexual intercourse, and eventually build a good
relationship with partners. The birth rate would also
increase.
The FO we used in this study contains the amino acids,
the foods such as chicken or Shijimi (freshwater clam)
plentifully have. The use of this supplement enables togain the amino acids such as arginine and ornithine
without selectively having plenty of these foods, and it
plays an important role in improving the quality of one's
sex life.
Limitations
In order to evaluate male sexual function it is necessary
to have both an erection (a condition) and sexualintercourse (an action), and for the evaluation of these
condition and action the subjective questionnaire plays animportant role since they are quite personal matters.
Although this study used the questionnaire based on IIEF
(which is internationally recognized), it is inevitable tohave some errors.
Although we found an improvement effect of malesexual function attained by the ingestion of arginine andornithine, there is also a report that points out arginine is
not functional for the mixed-type impotence20), and thisindicates that depending on the person the targeted
improvement by the supplement may not be achieved. In
addition, we have not yet discovered the mutual
influences among arginine, ornithine and the otheringredients contained in the FO, and this point should befurther scrutinized.
Conclusion
We found out that the ingestion of the supplement FO
containing arginine and ornithine by healthy Japanese

診療と新薬・第 53 巻

people for 12 weeks contributed to the improvement ofmale sexual function. In addition, no safety-related
matter occurred during the 12-week test period.
CONFLICT OF INTEREST
Ryo Kohiyama is a principal of INSPIRE CO. LTD. All remaining authors
have declared no conﬂicts of interest.

REFERENCES

第 3 号（2016 年 3 月）

91 （255）

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1) NIH Consensus Development Panel on Impotence: Impotence. JAMA.
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12) Momoi M, Sasaki F, Nibei F et al. Evaluation of Eﬃcacy and Safety of
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Appendix 1. Questionnaire of sexual function
Question #1: Over the past 4 weeks, how many times have you
attempted sexual Intercourse?
(0) No attempts(1) 1-2 attempts(2) 3-4 attempts(3) 5-6 attempts(4) 7-8 attempts(5) 11 or more attempts
NOTE: similar to IIEF #6
Question #2: Over the past 4 weeks, when you attempted sexualintercourse, how often was it satisfactory for you?
(0) Did not attempt intercourse(1) Almost never or never(2) A few times (much less than half the time)(3) Sometimes (about half the time)(4) Most times (much more than half the time)(5)Almost always or always
NOTE: similar to IIEF #7

Question #3: Over the past 4 weeks, how much have you enjoyedsexual intercourse?
(0) No intercourse(1) Not enjoyable(2) Not very enjoyable(3) Fairly enjoyable(4) Highly enjoyable(5) Very highly enjoyable
NOTE: similar to IIEF #8
Question #4: Over the past 4 weeks, when you had sexualstimulation or intercourse how often did you ejaculate?
(0) Did not attempt intercourse(1) Almost never or never(2) A few times (much less than half the time)(3) Sometimes (about half the time)(4) Most times (more than half the time)(5) Almost always or always
NOTE: similar to IIEF #9

92 （256）

診療と新薬・第 53 巻

Question #5: Over the past 4 weeks, when you had sexualstimulation or intercourse how often did you have the feeling oforgasm or climax?
(0) No sexual stimulation or intercourse(1) Almost never or ever(2) A few times (much less than half the time)(3) Sometimes (about half the time)(4) Most times (much more than half the time)(5) Almost always or always
NOTE: similar to IIEF #10
Question #6: Over the past 4 weeks, how often have you felt
sexual desire?
(0) Almost never or never(1) A few times (much less than half the time)(2) Sometimes (about half the time)(3) Most times (much more than half the time)(4) Almost always or always※ Question #6 and #7 ask about sexual desire. Letʼs deﬁne sexual desire
as a feeling that may include wanting to have a sexual experience (forexample, masturbation or intercourse) thinking about having sex or
feeling frustrated due to a lack of sex.
NOTE: similar to IIEF #11
Question #7: Over the past 4 weeks, how would you rate your levelof sexual desire?
(0) Very low or none at all(1) Low(2) Moderate(3) High(4) Very high
NOTE: similar to IIEF #12
Question #8: Over the past 4weeks, how satisﬁed have you beenwith you overall sex life?
(0) Very dissatisﬁed(1) Moderately dissatisﬁed(2) About equally satisﬁed and dissatisﬁed(3) Moderately satisﬁed(4) Very satisﬁed
NOTE: similar to IIEF #13

第 3 号（2016 年 3 月）
(6) Full of pep(7) Care free(8) Vigorous
Fatigue(1) Worn out(2) Listless(3) Fatigued(4) Exhausted(5) Sluggish(6) Weary(7) Bushed
The scores of answers are as follows:
Vigor(0) Not at all(1) A little(2) Moderate(3) Quite a bit(4) Extremely
Fatigue(0) Extremely(1) Quite a bit(2) Moderate(3) A little(4) Not at all

Appendix 3. Questionnaire for screening

Q1. Over the past 4weeks,have you taken some medication
for your sexual function improvement?

YES
Question #9: Over the past 4 weeks, how satisﬁed have you beenwith your sexual relationship with your partner?
(0) Very dissatisﬁed(1) Moderately dissatisﬁed(2) About equally satisﬁed and dissatisﬁed(3) Moderately satisﬁed(4) Very satisﬁed
NOTE: similar to IIEF #14
Question #10: Over the past 4 weeks how often have you
experienced nocturnal penile tumescence?
(0) No attempts(1) 1-2 attempts(2) 3-4 attempts(3) 5-6 attempts(4) 7-8 attempts(5) 11 or more attempts
NOTE: original

Appendix 2. POMS
Vigor
(1) Lively(2) Active(3) Energetic(4) Cheerful(5) AlertNO

EliminatedQ2. Over the past 4weeks,have you had a medical
examination for your sexual function improvement?

YES

NO

EliminatedRamdomized