U.S. patent application number 16/642189 was filed with the patent office on 2020-10-15 for kaempferol analog-containing composition.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO., LTD.. Invention is credited to Yasuhiro ABIRU, Minoru AKIYAMA, Yasutaka IKEDA, tsubasa MIZOKAMI, Ayuko OYAMA.
Application Number | 20200323816 16/642189 |
Document ID | / |
Family ID | 1000004971578 |
Filed Date | 2020-10-15 |
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United States Patent
Application |
20200323816 |
Kind Code |
A1 |
IKEDA; Yasutaka ; et
al. |
October 15, 2020 |
KAEMPFEROL ANALOG-CONTAINING COMPOSITION
Abstract
The present application provides a composition for improvement
in physical activity efficiency, a composition for reducing
fatigue, and a composition for improving dynamic/kinetic visual
acuity, comprising a kaempferol analog.
Inventors: |
IKEDA; Yasutaka; (Oaska-shi,
Osaka, JP) ; MIZOKAMI; tsubasa; (Oasaka-shi, Oasaka,
JP) ; ABIRU; Yasuhiro; (Oasaka-shi, Oasaka, JP)
; AKIYAMA; Minoru; (Oasaka-shi, Oasaka, JP) ;
OYAMA; Ayuko; (Oasaka-shi, Oasaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO.,
LTD.
Toyo
JP
|
Family ID: |
1000004971578 |
Appl. No.: |
16/642189 |
Filed: |
August 30, 2018 |
PCT Filed: |
August 30, 2018 |
PCT NO: |
PCT/JP2018/032104 |
371 Date: |
February 26, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A23L 29/30 20160801;
A61K 31/7048 20130101; A61K 31/353 20130101; A23L 29/035
20160801 |
International
Class: |
A61K 31/353 20060101
A61K031/353; A61K 31/7048 20060101 A61K031/7048; A23L 29/30
20060101 A23L029/30; A23L 29/00 20060101 A23L029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 30, 2017 |
JP |
PCT/JP2017/031214 |
Claims
1. A composition for improvement in physical activity efficiency,
comprising a kaempferol analog of Formula I: ##STR00013## or a
glycoside thereof, wherein: R.sub.1 is --OH, or --OCH.sub.3;
R.sub.2 is H, or --OH; R.sub.3 is H, --OH, or --OCH.sub.3; R.sub.4
is --OH, or --OCH.sub.3; R.sub.5 is H, or --OH; and R.sub.6 is H,
--OH, or --OCH.sub.3; excluding the following compound:
##STR00014##
2. The composition according to claim 1, wherein the improvement in
physical activity efficiency is improvement in endurance.
3. The composition according to claim 1, wherein the improvement in
physical activity efficiency is reduction of breathlessness.
4. A composition for reducing fatigue, comprising a kaempferol
analog of Formula I: ##STR00015## or a glycoside thereof, wherein:
R.sub.1 is --OH, or --OCH.sub.3; R.sub.2 is H, or --OH; R.sub.3 is
H, --OH, or --OCH.sub.3; R.sub.4 is --OH, or --OCH.sub.3; R.sub.5
is H, or --OH; and R.sub.6 is H, --OH, or --OCH.sub.3; excluding
the following compound: ##STR00016##
5. A composition for improving dynamic/kinetic visual acuity,
comprising a kaempferol analog of Formula I: ##STR00017## or a
glycoside thereof, wherein: R.sub.1 is --OH, or --OCH.sub.3;
R.sub.2 is H, or --OH; R.sub.3 is H, --OH, or --OCH.sub.3; R.sub.4
is --OH, or --OCH.sub.3; R.sub.5 is H, or --OH; and R.sub.6 is H,
--OH, or --OCH.sub.3; excluding the following compound:
##STR00018##
6. The composition according to claim 1, wherein the glycoside of
kaempferol analog is represented by Formula I, wherein: at least
one selected from R.sub.1, R.sub.2, R.sub.4, and R.sub.6 is
independently selected from --OR.sub.7, --OR.sub.7R.sub.8, and
--OR.sub.7R.sub.8R.sub.9; R.sub.7 is a glucose residue; and R.sub.8
and R.sub.9 are independently selected from a glucose residue, a
mannose residue, a galactose residue, a fucose residue, a rhamnose
residue, an arabinose residue, a xylose residue, a fructose
residue, a glucuronic acid residue, and an apiose residue.
7. The composition according to claim 1, wherein the kaempferol
analog or a glycoside thereof is selected from the group consisting
of the following: ##STR00019## ##STR00020## and a glycoside
thereof.
8. The composition according to claim 1, wherein the kaempferol
analog or a glycoside thereof is kaempferol or kaempferol
3-O-glucoside.
9. The composition according to claim 1, comprising 0.1 to 200 mg
(kaempferol analog equivalent value) of the kaempferol analog or a
glycoside thereof.
10. The composition according to claim 1, comprising 0.5 mg to 100
mg (kaempferol analog equivalent value) of the kaempferol analog or
a glycoside thereof.
11. The composition according to claim 1, wherein said composition
is for administration at a dose of 0.1 mg to 200 mg (kaempferol
analog equivalent value) of the kaempferol analog or a glycoside
thereof per administration.
12. The composition according to claim 1, wherein said composition
is for administration at a dose of 0.5 mg to 100 mg (kaempferol
analog equivalent value) of the kaempferol analog or a glycoside
thereof per administration.
13. The composition according to claim 1, wherein said composition
is for administration at a dose of 0.1 mg to 600 mg (kaempferol
analog equivalent value) of the kaempferol analog or a glycoside
thereof per day.
14. The composition according to claim 1, wherein said composition
is for administration at a dose of 0.5 mg to 200 mg (kaempferol
analog equivalent value) of the kaempferol analog or a glycoside
thereof per day.
15. The composition of claim 1, wherein said composition is for
administration to a subject who is hypoxic.
16. The composition according to claim 1, wherein said composition
is a food and drink.
17. The composition according to claim 1, wherein said composition
is a pharmaceutical composition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a National Stage of International
Application No. PCT/JP2018/032104 filed Aug. 30, 2018, claiming
priority based on International Application No. PCT/JP2017/031214
filed Aug. 30, 2017
TECHNICAL FIELD
[0002] The present application relates to a composition for
improvement in physical activity efficiency, a composition for
reducing fatigue, and a composition for improving dynamic/kinetic
visual acuity.
BACKGROUND ART
[0003] Improvement of physical activity efficiency, reduction of
fatigue, and improvement in dynamic/kinetic visual acuity are very
important not only in athletes with intense training but also in
ordinary people's daily work (e.g. housework, baggage handling,
stair climbing). Oxygen consumption is an indicator of energy
production, and improving oxygen consumption efficiency is key to
achieving a sustained "physical activity" in sports and daily life
without feeling tired or breathlessness.
[0004] Arterial oxygen saturation at rest is generally considered
normal at 96% or higher, but decreases to 93-88% during strenuous
exercise (Non-Patent Document 1). Arterial oxygen saturation (at
rest) is about 97% in people in their 20s, but this value decreases
with age, reaching about 93% in people in their 60s (Non-Patent
Document 2). In other words, in addition to the rapid decline in
oxygen status during intense sports, the decline in oxygen status
may also occur in the daily lives of ordinary people due to aging,
labor, bad weather (atmospheric depression), apnea syndrome and the
like.
[0005] Since the decline in the oxygen state can occur not only in
sports but also in the daily life of ordinary people, it is desired
to provide a preparation which can improve the oxygen consumption
efficiency, improve the physical activity efficiency, reduce the
fatigue, or improve the dynamic/kinetic visual acuity, at the
declined oxygen state in addition to at the normal oxygen state,
and which can be taken safely on a daily basis.
[0006] Kaempferol is a kind of natural flavonoid contained in
various edible plants, such as tea, broccoli, grapefruit, cabbage,
kale, beans, Cichorium endivia, leek, tomato, strawberry, grape,
Brussels sprouts, apple, quinua, and horseradish.
[0007] Natural flavonoids, including kaempferol, have been studied
with a focus on their diverse physiological effects, including the
involvement of kaempferol in mitochondrial function (Patent
Document 1, Patent Document 2, and Non-Patent Document 3) and the
effects of kaempferol on cellular energy expenditure and thyroid
hormone (Non-Patent Document 4), all of which relate to in vitro
studies.
[0008] Patent Document 3 discloses the effect of quercetin on
lactic acid concentration, but there is no specific disclosure
using other flavonoids.
PRIOR ART DOCUMENT
Patent Document
[0009] Patent Document 1: WO 2014/171333 [0010] Patent Document 2:
JP 2007-228855 A [0011] Patent Document 3: JP 2013-542924 A
Non-Patent Document
[0011] [0012] Non-Patent Document 1: Williams J H, Powers S K,
Stuart M K (1986) Hemoglobin desaturation in highly trained
athletes during heavy exercise. Med Sci Sports Exerc 18: 168-173
[0013] Non-Patent Document 2: Wilkins, R. L. et al. Clinical
assessment in respiratory care, (2004), Relationship between Age,
PaO, and Saturation [0014] Non-Patent Document 3: M. Montero, C. D.
Lobaton, E. Hernandez-Sanmiguel, et al., Direct activation of the
mitochondrial calcium uniporter by natural plant flavonoids,
Biochem. J. 384 (2004) 19-24. [0015] Non-Patent Document 4:
da-Silva W S, Harney J W, Kim B W, Li J, Bianco S D, Crescenzi A,
Christoffolete M A, Huang S A, Bianco A C 2007 The small
polyphenolic molecule kaempferol increases cellular energy
expenditure and thyroid hormone activation. Diabetes 56:767-776.
[0016] Non-Patent Document 5: "Oxygen uptake efficiency slope
(OUES): Sono seirigaku-teki kiso to rinsho y " [Oxygen uptake
efficiency slope (OUES): its physiological basis and clinical
application], The Tokai journal of sports medical science 11, 9-14,
1999-03, Tokai University (in Japanese).
[0017] The disclosures of the prior art documents cited herein are
hereby incorporated by reference in their entirety.
SUMMARY
Technical Problem
[0018] An object of the present application is to provide a
composition which can improve oxygen consumption efficiency (that
is, the ability to use oxygen can be enhanced.), and thereby can
suppress a decrease in physical activity efficiency, improve
physical activity efficiency, or reduce fatigue, or which can
suppress a decrease in dynamic/kinetic visual acuity, or improve
dynamic/kinetic visual acuity, even at the lowered oxygen state in
addition to the normal oxygen state.
Solution to Problem
[0019] The present inventors have been intensively studied to solve
the above problems, and have found that oral administration of a
kaempferol-containing composition to a human increases oxygen
consumption efficiency, improves physical activity efficiency,
reduces fatigue feeling, and improves dynamic/kinetic visual
acuity, in a wide range of an exercise ranging from mild exercise
of the level of daily work to an exercise of the level of intense
sports, thereby reaching the present invention.
[0020] The present invention provides the following:
[0021] [1] A composition for improvement in physical activity
efficiency, comprising a kaempferol analog of Formula I:
##STR00001##
or a glycoside thereof, wherein:
[0022] R.sub.1 is --OH, or --OCH.sub.3;
[0023] R.sub.2 is H, or --OH;
[0024] R.sub.3 is H, --OH, or --OCH.sub.3;
[0025] R.sub.4 is --OH, or --OCH.sub.3;
[0026] R.sub.5 is H, or --OH; and
[0027] R.sub.6 is H, --OH, or --OCH.sub.3;
excluding the following compound:
##STR00002##
[0028] [2] The composition according to [1], wherein the
improvement in physical activity efficiency is improvement in
endurance.
[0029] [3] The composition according to [1], wherein the
improvement in physical activity efficiency is reduction of
breathlessness.
[0030] [4] A composition for reducing fatigue, comprising a
kaempferol analog of Formula I:
##STR00003##
or a glycoside thereof, wherein:
[0031] R.sub.1 is --OH, or --OCH.sub.3;
[0032] R.sub.2 is H, or --OH;
[0033] R.sub.3 is H, --OH, or --OCH.sub.3;
[0034] R.sub.4 is --OH, or --OCH.sub.3;
[0035] R.sub.5 is H, or --OH; and
[0036] R.sub.6 is H, --OH, or --OCH.sub.3;
excluding the following compound:
##STR00004##
[0037] [5] A composition for improving dynamic/kinetic visual
acuity, comprising a kaempferol analog of Formula I:
##STR00005##
or a glycoside thereof, wherein:
[0038] R.sub.1 is --OH, or --OCH.sub.3;
[0039] R.sub.2 is H, or --OH;
[0040] R.sub.3 is H, --OH, or --OCH.sub.3;
[0041] R.sub.4 is --OH, or --OCH.sub.3;
[0042] R.sub.5 is H, or --OH; and
[0043] R.sub.6 is H, --OH, or --OCH.sub.3;
excluding the following compound:
##STR00006##
[0044] [6] The composition according to any one of [1] to [5],
wherein the glycoside of kaempferol analog is represented by
Formula I, wherein:
[0045] at least one selected from R.sub.1, R.sub.2, R.sub.4, and
R.sub.6 is independently selected from --OR.sub.7,
--OR.sub.7R.sub.8, and --OR.sub.7R.sub.8R.sub.9;
[0046] R.sub.7 is a glucose residue; and
[0047] R.sub.8 and R.sub.9 are independently selected from a
glucose residue, a mannose residue, a galactose residue, a fucose
residue, a rhamnose residue, an arabinose residue, a xylose
residue, a fructose residue, a glucuronic acid residue, and an
apiose residue.
[0048] [7] The composition according to any one of [1] to [6],
wherein the kaempferol analog or a glycoside thereof is selected
from the group consisting of the following:
##STR00007## ##STR00008##
and a glycoside thereof.
[0049] [8] The composition according to any one of [1] to [7],
wherein the kaempferol analog or a glycoside thereof is kaempferol
or kaempferol 3-O-glucoside.
[0050] [9] The composition according to any one of [1] to [8],
comprising 0.1 to 200 mg (kaempferol analog equivalent value) of
the kaempferol analog or a glycoside thereof.
[0051] [10] The composition according to any one of [1] to [9],
comprising 0.5 mg to 100 mg (kaempferol analog equivalent value) of
the kaempferol analog or a glycoside thereof.
[0052] [11] The composition according to any one of [1] to [10],
wherein said composition is for administration at a dose of 0.1 mg
to 200 mg (kaempferol analog equivalent value) of the kaempferol
analog or a glycoside thereof per administration.
[0053] [12] The composition according to any one of [1] to [11],
wherein said composition is for administration at a dose of 0.5 mg
to 100 mg (kaempferol analog equivalent value) of the kaempferol
analog or a glycoside thereof per administration.
[0054] [13] The composition according to any one of [1] to [12],
wherein said composition is for administration at a dose of 0.1 mg
to 600 mg (kaempferol analog equivalent value) of the kaempferol
analog or a glycoside thereof per day.
[0055] [14] The composition according to any one of [1] to [13],
wherein said composition is for administration at a dose of 0.5 mg
to 200 mg (kaempferol analog equivalent value) of the kaempferol
analog or a glycoside thereof per day.
[0056] [15] The composition of any one of [1] to [14], wherein said
composition is for administration to a subject who is hypoxic.
[0057] [16] The composition according to any one of [1] to [15],
wherein said composition is a food and drink.
[0058] [17] The composition according to any one of [1] to [15],
wherein said composition is a pharmaceutical composition.
[0059] Furthermore, the present invention provides use of a
kaempferol analog or a glycoside thereof in the manufacture of a
composition for improvement in physical activity efficiency, a
composition for reducing fatigue, or a composition for improving
dynamic/kinetic visual acuity.
[0060] Furthermore, the present invention provides a method for
improvement in physical activity efficiency, a method for reducing
fatigue, or a method for improving dynamic/kinetic visual acuity,
comprising administering a kaempferol analog or a glycoside
thereof.
[0061] In addition, the present invention provides a kaempferol
analog or a glycoside thereof for use in improvement in physical
activity efficiency, reducing fatigue, or improving dynamic/kinetic
visual acuity.
Effect of Invention
[0062] The composition of the present invention may improve oxygen
consumption efficiency (an ability to utilize oxygen), thereby
allowing for increased efficiency in any "physical activity"
including daily activities and sports. For example, the composition
of the present invention may allow for an exercise with a reduced
breathlessness or an improved endurance. The composition of the
present invention may also be used as a composition for reducing
breathlessness or a composition for improving endurance. In
addition, the composition of the present invention may reduce
fatigue, and may allow for performing sports, daily housework, etc.
without feeling fatigue. Furthermore, the composition of the
present invention may improve dynamic/kinetic visual acuity and may
contribute to an improved outcome, for example in sports.
BRIEF DESCRIPTION OF DRAWINGS
[0063] FIG. 1 depicts a graph showing the oxygen consumption
(VO.sub.2) at each exercise intensity.
[0064] FIG. 2 depicts a graph showing the oxygen consumption
efficiency (VO.sub.2/VE) after initiation of incremental loading
exercise.
[0065] FIG. 3 depicts a graph showing the oxygen uptake efficiency
slope (OUES) for each of the dosages in incremental loading
exercise.
[0066] FIG. 4 depicts a graph showing the maximum oxygen
consumption (VO.sub.2peak) for each of the dosages in incremental
loading exercise.
[0067] FIG. 5 depicts a graph showing the maximum exercise load for
each of the dosages in incremental loading exercise.
[0068] FIG. 6-1 depicts a graph showing the exercise intensity (%
HR) and the rating of perceived exertion (RPE) at the oxygen
consumption equivalent to the level of climbing stairs.
[0069] FIG. 6-2 depicts a graph showing the exercise intensity (%
HR) and the rating of perceived exertion (RPE) at the oxygen
consumption equivalent to the level of jogging.
[0070] FIG. 7 depicts a graph showing the dynamic visual acuity
(DVA) before and after incremental loading exercise.
[0071] FIG. 8 depicts a graph showing the effect of each compound
on ATP production in a hypoxic environment.
[0072] FIG. 9-1 depicts a graph showing the ATP content in the
soleus muscle (Sol).
[0073] FIG. 9-2 depicts a graph showing the ATP content in the
whole brain.
[0074] FIG. 10 depicts a graph showing the time changes for the 1st
and 2nd 400 m runs.
[0075] FIG. 11 depicts a graph showing the respiratory rate during
400 m runs.
[0076] FIG. 12 depicts a graph showing the exercise intensity
during sprints.
[0077] FIG. 13 depicts a graph showing the changes in expiratory
mouth pressures.
[0078] FIG. 14 depicts a graph showing the changes in heart
rates.
DESCRIPTION OF EMBODIMENTS
[0079] The invention relates to a composition for improvement in
physical activity efficiency, a composition for reducing fatigue,
or a composition for improving dynamic/kinetic visual acuity,
comprising a kaempferol analog or a glycoside thereof.
[0080] In the composition of the present invention, a kaempferol
analog is a compound of Formula I:
##STR00009##
wherein:
[0081] R.sub.1 is --OH, or --OCH.sub.3;
[0082] R.sub.2 is H, or --OH;
[0083] R.sub.3 is H, --OH, or --OCH.sub.3;
[0084] R.sub.4 is --OH, or --OCH.sub.3;
[0085] R.sub.5 is H, or --OH; and
[0086] R.sub.6 is H, --OH, or --OCH.sub.3;
excluding the following compound:
##STR00010##
[0087] The composition of the present invention may comprise
glycoside(s) of the kaempferol analog(s). Since the glycoside(s) of
the kaempferol analog(s) may be converted into their aglycone(s) in
vivo, they may have the same activity as the aglycone(s).
[0088] In the composition of the present invention, a glycoside of
a kaempferol analogue means a compound in which a sugar chain
having at least 1 (preferably 1 to 3, more preferably 1) sugar
residue is glycosidically bonded to at least 1 (preferably 1 to 2,
more preferably 1) hydroxy group of the kaempferol analogue.
Preferred examples of the sugar residue(s) include a glucose
residue, a mannose residue, a galactose residue, a fucose residue,
a rhamnose residue, an arabinose residue, a xylose residue, a
fructose residue, a glucuronic acid residue, and an apiose
residue.
[0089] More preferred examples of the glycoside(s) of the
kaempferol analog(s) include compound(s) of Formula I, wherein
[0090] at least one of R.sub.1, R.sub.2, R.sub.4, and R.sub.6 is
independently selected from --OR.sub.7, --OR.sub.7R.sub.8, and
--OR.sub.7R.sub.8R.sub.9;
[0091] R.sub.7 is a glucose residue; and
[0092] R.sub.8 and R.sub.9 are independently selected from a
glucose residue, a mannose residue, a galactose residue, a fucose
residue, a rhamnose residue, a arabinose residue, a xylose residue,
a fructose residue, a glucuronic acid residue, and apiose
residue.
[0093] Preferred examples of the kaempferol analog(s) and
glycoside(s) thereof include the following kaempferol analog(s) and
glycoside(s) thereof:
##STR00011## ##STR00012##
[0094] More preferred examples of the kaempferol analog(s) include
kaempferol, and examples of its glycoside (s) include kaempferol
3-O-glucoside.
[0095] In the composition of the present invention, a kaempferol
analog or a glycoside thereof may be a combination of kaempferol
analog(s) and glycoside (s) of kaempferol analog(s).
[0096] In the composition of the present invention, a kaempferol
analog may be a single kind of kaempferol analog or a combination
of a plurality of kinds of kaempferol analog (s).
[0097] In the composition of the present invention, a glycoside of
a kaempferol analogue may be a single kind of glycoside of a
kaempferol analogue or a combination of a plurality of kinds of
glycoside(s) of kaempferol analog(s).
[0098] A kaempferol analog or a glycoside thereof used in the
composition of the present invention is not limited in any way by
its form, method of production or the like. For example, when
kaempferol is selected, an extract from a plant known to contain a
large amount of kaempferol, prepared by a known method may be used
as it is, or a synthetic product may be used. The glycoside(s) of
the kaempferol analogue(s) derived from such plant may be used as
it is or may be converted into aglycone(s) (kaempferol
analogue(s)), by a known method (For example, by enzymatic
treatment). In the case of a food and drink or a pharmaceutical
composition, it is preferable to use a product with a higher
content obtained by a process (such as concentration or
purification) allowing for blending an effective amount. In such a
case, a known method of concentration or of purification can be
used.
[0099] In the present specification, "kaempferol analog equivalent
value" means a value obtained by converting the amount of the
glycoside of the kaempferol analog into the amount of the
kaempferol analog as its aglycone. Specifically, the kaempferol
analog equivalent value can be calculated by multiplying the amount
of substance of the glycoside, which is obtained by dividing the
amount of the glycoside by its molecular weight, by the molecular
weight of the aglycone.
[0100] The amount of kaempferol analog(s) or glycoside (s) thereof
contained in the composition of the present invention (food and
drink, pharmaceutical composition, etc.), the amount of kaempferol
analog(s) or glycoside(s) thereof administered per administration,
and the amount of kaempferol analog(s) or glycoside(s) thereof
administered per day are not particularly limited as long as they
are within the range in which the intended effect is exerted, and
may be selected according to the form of the composition, the
number of administrations, the health condition of the subject,
etc. The administration period of the composition of the present
invention is not particularly limited as long as it is within the
range in which the intended effect is exerted, and may be
administered as a single dose or continuously. In order to obtain a
continuous effect of improvement in physical activity efficiency,
reducing fatigue, or improving dynamic/kinetic visual acuity, the
composition of the present invention may be desirably administered
continuously over a long period of time, for example, 2 days, 3
days, 1 week, 10 days, 1 month, or 3 months or more.
[0101] Examples of the amount of kaempferol analog(s) or
glycoside(s) thereof comprised in the composition of the present
invention, as a kaempferol analog equivalent value(s), includes 0.1
mg to 200 mg, preferably 0.5 mg to 100 mg, more preferably 1 mg to
30 mg, and most preferably 2 mg to 10 mg, which may vary depending
on the total weight of the composition. Examples of the lower limit
of the amount of the kaempferol analog equivalent value include 0.1
mg, 0.5 mg, 1 mg, 2 mg, and 2.5 mg, and examples of the upper limit
include 200 mg, 150 mg, 100 mg, 50 mg, 30 mg, 25 mg, 15 mg, 10 mg,
5 mg, 3 mg, and 2.5 mg, and a preferred range of the amount of the
kaempferol analog equivalent value may be indicated by a
combination of the upper and lower limits.
[0102] The compositions of the present invention may be such that
kaempferol analog(s) or glycoside(s) thereof are administered, for
example, 0.1 mg to 200 mg per administration, preferably 0.5 mg to
100 mg per administration, more preferably 1 mg to 30 mg per
administration, and most preferably 2 mg to 10 mg per
administration, as a kaempferol analog equivalent value. Examples
of the lower limit of the dose of the kaempferol analog equivalent
value per administration include 0.1 mg, 0.5 mg, 1 mg, 2 mg, and
2.5 mg, and examples of the upper limit include 200 mg, 150 mg, 100
mg, 50 mg, 30 mg, 25 mg, 15 mg, 10 mg, 5 mg, 3 mg, and 2.5 mg, and
a preferred range of the dose of the kaempferol analog equivalent
value per administration can be indicated by a combination of the
upper and lower limits.
[0103] In the compositions of the present invention, kaempferol
analog(s) or glycoside(s) thereof may be administered, for example,
from 0.1 mg to 600 mg per day, preferably from 0.5 mg to 200 mg per
day, more preferably from 1 mg to 100 mg per day, as a kaempferol
analog equivalent value. Examples of the lower limit of the dose of
the kaempferol analog equivalent value per day include 0.1 mg, 0.5
mg, 1 mg, 2 mg, and 2.5 mg, and examples of the upper limit include
600, 300, 200 mg, 150 mg, 100 mg, 50 mg, 30 mg, 25 mg, 15 mg, 10
mg, 5 mg, 3 mg, and 2.5 mg, and a preferred range of the dose of
the kaempferol analog equivalent value per day may be indicated by
a combination of the upper and lower limits. The dose of kaempferol
analog(s) or glycoside(s) thereof which may be administered per
day, may be administered in a single dose or in multiple divided
doses (for example, twice, three times, four times, and five
times).
[0104] The composition of the present invention is preferably
formulated as oral dosage forms, and the form is not particularly
limited, but may be conventional food forms such as tablets,
granules, capsules, powders, chewable tablets, sweets (cookies,
biscuits, chocolate confectioneries, chips, cakes, gums, candies,
gummies, buns, yokan (sweet bean jelly), puddings, jellies, yogurt,
ice cream, sherbet, etc.), breads, noodles, rice, cereal foods,
beverages (liquid preparations, soft drinks, carbonated drinks,
nutritional drinks, powdered drinks, fruit drinks, milk drinks,
jelly drinks, etc.), soups (powder, freeze-dry), miso soups
(powder, freeze-dry), and the like.
[0105] The composition of the present invention may be a food and
drink or a pharmaceutical composition, and may be used as a food
and drink, for example Foods with Functional Claims, Food for
specified health uses, a health food, a nutritional supplement
(supplement), a food for medical use, etc.
[0106] The compositions of the invention may be formulated into
orally administered formulations by adding pharmaceutically
acceptable base(s), carrier(s), and/or additive(s) usable in foods,
etc., in addition to kaempferol analog(s) or glycoside(s) thereof.
It is desirable that ingredients other than kaempferol analog(s) or
glycoside (s) thereof used in the composition of the present
invention do not impair the stability of the kaempferol analog(s),
and that they do not impair the intended effect(s) of the
composition of the present invention (for example, improved oxygen
consumption, improved physical activity efficiency, reduced
fatigue, or improved dynamic/kinetic visual acuity).
[0107] In the present invention, "improvement of oxygen consumption
efficiency" means an increased ability to utilize oxygen. Specific
examples include an increase in the oxygen consumption efficiency
(VO.sub.2/VE) described in the present Examples, and under a given
exercise intensity an increase in oxygen consumption (VO.sub.2), an
increase in oxygen uptake efficiency slope (increase in OUES), and
an increase in maximum oxygen consumption (VO.sub.2peak).
[0108] As used herein, "physical activity" means a moving the body
and includes any movements, for example daily housework, baggage
handling, stair climbing, sports, and the like.
[0109] In the present invention, "improvement in physical activity
efficiency" means that the body can be moved more easily in any
kinds of physical activities. For example, improvement in physical
activity efficiency includes continuing a physical activity for a
long time in a more comfortable state by improving endurance, or
doing a physical activity more easily in a state of reduced
breathlessness. Examples of indices of improvement in physical
activity efficiency include under a given exercise intensity,
increased oxygen consumption (VO.sub.2), increased oxygen
consumption efficiency (VO.sub.2/VE), increased oxygen uptake
efficiency slope (increased OUES), increased maximum oxygen
consumption (VO.sub.2peak), increased maximum exercise load,
decreased exercise intensity at a given oxygen consumption
(VO.sub.2), or decrease in rating of perceived exertion (these
terms are described in Examples).
[0110] When the composition of the present invention is
administered to improve physical activity efficiency, the dosage
and the number of doses are not particularly limited, and the
composition may be administered in the dosage, the number of doses
and the period of administration exemplified above.
[0111] In the present invention, the term "reducing fatigue" means
that any physical activity can be done while suppressing fatigue.
Examples of indices of fatigue reduction include decreased exercise
intensity or decrease in rating of perceived exertion (these terms
are described in Examples). When the composition of the present
invention is administered for reducing fatigue, the dosage and the
number of doses are not particularly limited, and may be
administered, for example, at the dose, the number of doses and the
period of administration exemplified above.
[0112] In the present invention, improvement of dynamic/kinetic
visual acuity means prevention of reduction of dynamic/kinetic
visual acuity or improvement of dynamic/kinetic visual acuity. When
the composition of the present invention is administered for
improving dynamic/kinetic visual acuity, the dosage and the number
of doses are not particularly limited, and the composition may be
administered in the dosage, the number of doses and the period of
administration exemplified above.
[0113] The composition of the present invention may have an effect
of improving oxygen consumption efficiency (That is, the ability to
use oxygen increases.). Therefore, the composition of the present
invention may also be used for improving oxygen consumption
efficiency.
[0114] In the present invention, the "hypoxic" state means a state
in which oxygen level in the body is insufficient, for example, a
state in which arterial oxygen saturation is less than 95%. Since
the composition of the present invention may have an effect of
improving oxygen consumption efficiency even in a subject in a
hypoxic state, the composition of the present invention may
contribute to improvement of physical activity efficiency,
reduction of fatigue, and improvement of dynamic/kinetic visual
acuity even in the subject in the hypoxic state.
[0115] The subject of administration of the composition of the
present invention is not particularly limited, but is preferably
human. It is preferable to administer the composition before and
after sports, before and after outdoor work, before and after daily
work (going up and down stairs, doing housework, etc.), when the
subject feels that daily fatigue cannot be relieved, when the
subject wants to work efficiently, or when the subject feels that
the physical movement has become dull due to aging.
EXAMPLE
[0116] The present invention is explained in further detail with
reference to Formulation Examples and Test Examples. However, the
scope of the invention is not limited to these Examples.
Formulation Example 1
TABLE-US-00001 [0117] Cookies (kaempferol content: 2.5 mg) Quinua
extract* 37 wt % Maple syrup 22 wt % Milk 22 wt % Salted butter 15
wt % Granulated sugar 4 wt % Total 100 wt %
[0118] According to a conventional method, these were mixed and
baked at an oven temperature of about 140.degree. C. for 20 minutes
to produce cookies. The amount of kaempferol contained in one
cookie was 2.5 mg (HPLC).
[0119] Quinua extract*: an Quinua extract wherein kaempferol
glycosides were degraded into kaempferol aglycones by an enzymatic
treatment.
Formulation Example 2
TABLE-US-00002 [0120] Capsule-shaped food (kaempferol content: 2.5
mg) Ethanol-extracted and enzyme-treated quinoa powder** 48 wt %
Gelatin Capsule 52 wt % Total 100 wt %
[0121] Gelatin Capsule was filled with Ethanol-extracted and
enzyme-treated quinoa powder** to give the capsule food. The amount
of kaempferol contained in one capsule was 2.5 mg (HPLC).
[0122] Ethanol-extracted and enzyme-treated quinoa powder**:
prepared by process comprising: extracting quinua grains with a 50%
ethanol to give kaempferol glycosides, and then treating
enzymatically to degrade the kaempferol glycosides into kaempferol
aglycones.
Test Example 1: Incremental Loading Exercise Test with Bicycle
[0123] For 25 healthy adult males, 3 dosages of
kaempferol-containing cookie-shaped foods (containing 2.5 mg, 10
mg, or 25 mg of kaempferol, respectively) and a placebo
cookie-shaped food (kaempferol-free) were used as test foods, and a
once-a-day ingestion for consecutive 8 days were repeated four
times by the crossover method. 3 hours after a test food ingestion
on day 1 (Single ingestion) and on day 8 (Consecutive ingestion),
an incremental loading exercise with bicycle was performed while
sampling the exhaled gas to determine the oxygen consumption. The
Heart rate and the rating of perceived exertion were monitored
during exercise. Dynamic/kinetic visual acuity was measured before
and after the exercise. Details of each endpoint are given
below.
<1: Evaluation of Oxygen Consumption (VO.sub.2)>
[0124] Oxygen consumption (VO.sub.2) (mL/min/kg) was calculated
from the difference between the amount of oxygen in the inhaled gas
(atmosphere) and the amount of oxygen in the exhaled gas. When a
weight of the pedal approaches a subject's limit during incremental
loading exercise with bicycle, a heart rate (HR) is maximized. The
increase in heart rate from the resting heart rate to the maximum
heart rate was defined as 100% of exercise intensity, and the
oxygen consumption (VO.sub.2) was plotted at each exercise
intensity.
[0125] That is, for example, an exercise intensity of 50% HR is
calculated by the following equation:
100.times.(x-Resting heart rate)/(Maximum heart rate-Resting heart
rate)=50% HR,
and the oxygen consumption (VO.sub.2) in which the heart rate is
the "x" means "oxygen consumption (VO.sub.2) at an exercise
intensity of 50% HR".
[0126] The results are shown in FIG. 1.
[0127] As shown in FIG. 1, in both of the single ingestion and the
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the increased oxygen consumption at
all exercise intensities (50%, 60%, 70%, 80%, 90%, and 100%).
<2: Evaluation of Oxygen Consumption Efficiency
(VO.sub.2/VE)>
[0128] Oxygen consumption efficiency was calculated by the
following equation.
Oxygen consumption efficiency (VO.sub.2/VE)=oxygen
consumption/ventilation
[0129] As shown in FIG. 2, in both of the single ingestion and the
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the increased oxygen consumption
efficiency (VO.sub.2/VE).
<3: Evaluation of Oxygen Uptake Efficiency Slope (OUES)>
[0130] The oxygen uptake efficiency slope (OUES) was calculated
using the ventilation and VO.sub.2 every 1 min from the beginning
of the incremental loading exercise. Specifically, a graph of
linearity was obtained by plotting "logarithmic value of
ventilation (VE)" on the horizontal axis and "VO.sub.2" on the
vertical axis, and the slope of the linear function graph was
defined as OUES. For details, see Non-Patent Document 5.
[0131] As shown in FIG. 3, in both of the single ingestion and
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the increased oxygen uptake
efficiency slope (OUES), which indicates that oxygen was more
efficiently utilized during incremental loading exercise.
<4: Evaluation of Maximum Oxygen Consumption
(VO.sub.2peak)>
[0132] As shown in FIG. 4, in both of the single ingestion and
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the increased maximum oxygen
consumption (VO.sub.2peak) (mL/min/kg).
<5: Evaluation of the Maximum Exercise Load>
[0133] As shown in FIG. 5, in the both of the single ingestion and
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the increased maximum exercise load
(Pedal Weight (watt))
<6: Effects on Exercise Intensity of the Level of Daily
Work>
[0134] Oxygen consumption (VO.sub.2) during stair climbing and
jogging has been reported to be generally 14 mL/min/kg and 24.5
mL/min/kg, respectively.
[0135] Exercise intensity (% HR) and rating of perceived exertion
(RPE) at the oxygen consumption (VO.sub.2) of 14 mL/min/kg and 24.5
mL/min/kg in incremental loading exercise (the levels of stair
climbing and jogging, respectively) were evaluated.
[0136] The calculation methods for oxygen consumption (VO.sub.2)
and exercise intensity (% HR) are the same as those described
above. The perceived exertion was rated by the subject according to
the following table at 1-minute intervals from the beginning of the
incremental loading exercise, and the scales rated by each subject
were averaged to give the rating of perceived exertion (RPE). As
shown in FIGS. 6-1 and 6-2, in the both of the single ingestion and
consecutive ingestion, compared with the no intake of kaempferol,
the intake of kaempferol showed the decreased exercise intensity
and the decreased rating of perceived exertion, at the both oxygen
consumption (VO.sub.2) levels (stair climbing and jogging).
TABLE-US-00003 Scale Perceived exertion 20 Maximally hard 19 Very
very hard 17 Very hard 15 Hard 13 Somewhat hard 11 Fairly light 9
Very light 7 Very very light 6 Comfort
[0137] As indicated in the results of the above 1 to 6, ingesting
the kaempferol-containing food increased the oxygen consumption and
the oxygen consumption efficiency at the same exercise intensities.
In addition, the maximum exercise load increased. In addition,
comparing the exercise intensities at the same oxygen consumption,
it is found that the heart rate was decreased, which suggests that
the subjects could exercise more comfortably with less
breathlessness due to increased endurance. This improvement in
physical activity efficiency may also reduce the fatigue of the
subject. In fact, the ingestion of kaempferol-containing foods
reduced perceived exertion and reduced breathlessness and fatigue.
Therefore, it is suggested that the composition may be used for
reducing breathlessness, and/or an enhancing endurance and/or
improving oxygen consumption.
<7: Effect on Dynamic/Kinetic Visual Acuity>
[0138] The effect on dynamic/kinetic visual acuity was examined by
measuring dynamic visual acuity (DVA) and kinetic visual acuity
(KVA) before and after (within about 1 min after exercise) the
incremental loading exercise.
(1) Measurement of Dynamic Visual Acuity (DVA) Measurement
Equipment:
[0139] Dynamic vision tester HI-10 Dynamic Vision Tester (Kowa
Company, Ltd.)
Measurement Method:
[0140] The fastest visible speed of Landolt's ring moving
horizontally on the arc was measured with the subject as the
center. The target automatically decelerated gradually as it
rotated, and when the subject detected the break in Landolt's ring,
the subject pressed a switch on his/her hand to indicate the
direction (up and down, and left and right) of the break. The
number of revolutions at the time of the digital display was
recorded on the recording paper and used as the inspection result.
The results are shown in FIG. 7.
Test Example 2: Effect on ATP Production in Hypoxic Environment
[0141] C.sub.2C.sub.12 skeletal muscle cells differentiated with
horse serum were obtained, and various compounds (Final
concentration of 20 .mu.M) or dimethyl sulfoxide (DMSO) as a
negative control were added thereto. After incubation in a hypoxic
incubator (3% O.sub.2) for 24 hours, the ATP content in the cells
was determined using a kit (luciferase luminescence assay)
manufactured by TOYO B-Net Co., Ltd. The ATP content of the
negative control treated with DMSO was defined as 100%, and the
activity value of the test compounds was calculated as a percentage
based on the value of DMSO.
[0142] The results are shown in FIG. 8.
Test Example 3: Effect of Kaempferol or Kaempferol 3-O-Glucoside in
Rat
[0143] Male Sprague-Dawley rats at 9 weeks of age were orally
administered kaempferol (KMP; 1.0 mg/kg body weight) or kaempferol
3-O-glucoside (K3G; 0.1, 0.2, or 1 mg/kg body weight (KMP aglycone
equivalent value)) once a day for 8 consecutive days at 9 AM
(reared in 21% oxygen). On day 8 of administration, the control
group was exposed to 21% oxygen for 1 hour, and the other groups
were exposed to 12% oxygen for 1 hour. Then, the soleus muscle
(Sol) and whole brain were excised, and the ATP contents in the
tissues were measured. The results are shown in FIGS. 9-1 and
9-2.
Test Example 4: Effect on Performance in 400 m Run
[0144] A two-group and two-phase crossover study (single ingestion)
was conducted for 13 healthy male adults. In the study, a
kaempferol-containing capsule-shaped food (SNR 14) wherein the
aglycone equivalent value is 10 mg; and a placebo capsule-shaped
food: Placebo (kaempferol free) were used as test foods.
[0145] Three hours after taking the test food, the subjects
sprinted 400 m, and sprinted 400 m again after a 90 minute
interval. Respiratory rate and heart rate were monitored during the
sprint. The expiratory mouth pressure was measured by the maximum
mouth pressure method, before and after the 400 m runs, using an
electronic spirometer, autospyro (Minato Medical Science Co.,
Ltd.).
[0146] The subjects inhaled to the limit after three deep breaths
in a standing position and then exhaled with full force into the
mouthpiece for measurement while preventing air leakage from the
nose to determine expiratory mouth pressure.
[0147] FIG. 10 depicts a graph showing the time change between the
1st and 2nd 400 m runs. The mean time change of the placebo group
was -0.11 seconds and the mean time change of the
kaempferol-Ingestion group was -0.77 seconds.
[0148] FIG. 11 depicts a graph showing the respiratory rate during
the run.
[0149] In the 2nd run, the total number of breaths during the run
was significantly lower in the kaempferol-containing food group
compared with the placebo food group, and the respiratory rate
(times per minute) every 50 m was also significantly lower in the
kaempferol-containing food group.
[0150] FIG. 12 depicts a graph showing the exercise intensity
during the runs. For the second run, the exercise intensity during
the run was significantly lower in the kaempferol-containing food
group compared with the placebo food group.
[0151] FIG. 13 shows a graph showing the changes in expiratory
mouth pressure. As shown in FIG. 13, the decrease in expiratory
mouth pressure was significantly suppressed in the
kaempferol-containing food group compared with the placebo food
group.
[0152] FIG. 14 depicts a graph showing the changes in heart rate.
As shown in FIG. 14, the heart rate was significantly lower at
200-250 m during the 1st run and at 0 (start)-150 m in the 2nd run
in the kaempferol-containing food group compared with the placebo
food group.
[0153] Compared with the placebo group, more participants in the
kaempferol-containing food group commented that they felt
"comfort", "recovered quickly", "body moved easily".
[0154] The kaempferol-containing food may improve exercise
performance while giving the feeling of "comfort", "recover
quickly" etc.
[0155] As shown in the results of Test Example 4, ingestion of
kaempferol-containing food decreased the exercise intensity.
Furthermore, the ingestion of kempferol-containing food suppressed
the respiratory muscle weakness and the heart rate increase,
thereby it is considered that the improvement of breathlessness
improves physical activity efficiency and relieves fatigue. In
fact, the participants' comments which was that exercise intensity
was reduced by the ingestion of kaempferol-containing food suggests
that physical activity efficiency was improved, and fatigue was
reduced, due to ingestion of kempferol-containing food. Therefore,
it has been suggested that the composition can be used for
inhibiting heart rate elevation, reducing breathlessness
composition, and/or improving endurance.
* * * * *