U.S. patent application number 12/593053 was filed with the patent office on 2010-05-13 for medicament for prophylactic and/or therapeutic treatment of hepatic steatosis or non-alcoholic steatohepatitis.
This patent application is currently assigned to KOWA COMPANY, LTD.. Invention is credited to Naoto Ishibashi, Mami Seki, Megumi Yamamoto, Yuji Yoshikawa.
Application Number | 20100120914 12/593053 |
Document ID | / |
Family ID | 39863523 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120914 |
Kind Code |
A1 |
Yoshikawa; Yuji ; et
al. |
May 13, 2010 |
MEDICAMENT FOR PROPHYLACTIC AND/OR THERAPEUTIC TREATMENT OF HEPATIC
STEATOSIS OR NON-ALCOHOLIC STEATOHEPATITIS
Abstract
A medicament for prophylactic and/or therapeutic treatment of
hepatic steatosis or non-alcoholic steatohepatitis, which comprises
a polyprenyl compound (e.g.,
3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid) as an
active ingredient.
Inventors: |
Yoshikawa; Yuji; (Tokyo,
JP) ; Yamamoto; Megumi; (Tokyo, JP) ;
Ishibashi; Naoto; (Tokyo, JP) ; Seki; Mami;
(Tokyo, JP) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
KOWA COMPANY, LTD.
Aichi
JP
|
Family ID: |
39863523 |
Appl. No.: |
12/593053 |
Filed: |
March 27, 2008 |
PCT Filed: |
March 27, 2008 |
PCT NO: |
PCT/JP2008/000760 |
371 Date: |
January 21, 2010 |
Current U.S.
Class: |
514/560 ;
562/598 |
Current CPC
Class: |
A61K 31/201 20130101;
A61P 1/16 20180101 |
Class at
Publication: |
514/560 ;
562/598 |
International
Class: |
A61K 31/202 20060101
A61K031/202; C07C 57/03 20060101 C07C057/03; A61P 43/00 20060101
A61P043/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2007 |
JP |
2007-090114 |
Claims
1. A medicament for prophylactic and/or therapeutic treatment of
hepatic steatosis or non-alcoholic steatohepatitis, which comprises
a polyprenyl compound as an active ingredient.
2. The medicament according to claim 1, wherein the polyprenyl
compound is a polyprenylcarboxylic acid.
3. The medicament according to claim 1, wherein the polyprenyl
compound is 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid.
4. The medicament according to claim 1, wherein the polyprenyl
compound is
(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid.
5. The medicament according to claim 1, which is in the form of a
pharmaceutical composition containing a pharmacologically
acceptable pharmaceutical carrier.
6. The medicament according to claim 1, which is a preparation for
oral administration.
7. The medicament according to claim 2, which is in the form of a
pharmaceutical composition containing a pharmacologically
acceptable pharmaceutical carrier.
8. The medicament according to claim 3, which is in the form of a
pharmaceutical composition containing a pharmacologically
acceptable pharmaceutical carrier.
9. The medicament according to claim 4, which is in the form of a
pharmaceutical composition containing a pharmacologically
acceptable pharmaceutical carrier.
10. The medicament according to claim 2, which is a preparation for
oral administration.
11. The medicament according to claim 3, which is a preparation for
oral administration.
12. The medicament according to claim 4, which is a preparation for
oral administration.
13. The medicament according to claim 5, which is a preparation for
oral administration.
14. The medicament according to claim 7, which is a preparation for
oral administration.
15. The medicament according to claim 8, which is a preparation for
oral administration.
16. The medicament according to claim 9, which is a preparation for
oral administration.
Description
TECHNICAL FIELD
[0001] The present invention relates to a medicament for
prophylactic and/or therapeutic treatment of hepatic steatosis or
non-alcoholic steatohepatitis. More specifically, the present
invention relates to a medicament for prophylactic and/or
therapeutic treatment of hepatic steatosis or non-alcoholic
steatohepatitis, which comprises a polyprenyl compound as an active
ingredient, preferably a medicament comprising
(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid.
BACKGROUND ART
[0002] In recent years, consumption of fats has been increasing
every year in Japan with westernization of lifestyles including
eating habits. It is known that fats excessively taken up are
gradually accumulated in bodies, and become factors of inducing
various diseases. Mechanisms of the fat accumulation is roughly
classified into the following two classes. According to one of the
mechanisms, excessive fats existing in blood deposit on blood
vessel walls, which leads to stenosis of blood vessels to gradually
develops into arteriosclerosis, and some time later triggers the
onset of myocardial infarction, angina pectoris, cerebral
infarction, and the like. According to the other mechanism,
excessive fats similarly deposit in visceral organs. In particular,
so-called hepatic steatosis, in which a lot of fats deposit in the
liver, has recently been frequently observed, and some of hepatic
steatosis advance at some future to non-alcoholic steatohepatitis,
cirrhosis, and hepatoma (Gastroenterology, 116, 1413-1419 (1999)).
The aforementioned diseases are based on the different onset
mechanisms, and accordingly, a medicament suitable for prophylactic
and/or therapeutic treatment of each disease is needed.
[0003] As a therapeutic agent of hepatic steatosis,
polyenephosphatidylcholine has been clinically used. Further,
fibrate agents, of which typical examples include clofibrate as an
antihyperlipidemic agent, have also been clinically used as
therapeutic agents for hepatic steatosis. It is considered that the
fibrate agents improve lipid metabolism by acting on enzymes for
fatty acid .beta.-oxidation system in the liver (Ann. N.Y. Acad.
Sci., 386, 111-135 (1982)). However, side reactions such as liver
function failure are generally known for the fibrate agents
(Atherosclerosis, 92, 31-40 (1992)), and therefore a medicament for
prophylactic and/or therapeutic treatment of hepatic steatosis or
non-alcoholic steatohepatitis with less side effects has been
desired.
[0004]
(2E,4E,6E,10E)-3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid, which is one of polyprenyl compounds and has a chemical
structure totally different from those of
polyenephosphatidylcholine and the fibrate agents mentioned above,
is a acyclic retinoid having affinity for retinoic acid binding
proteins and retinoic acid receptors, and actions thereof for
inducing differentiation and inducing apoptosis in hepatocellular
carcinoma are known. Clinically,
(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid significantly inhibited recurrence of hepatoma after radical
treatment thereof by long-term administration for one year, and
thus suppressing action thereof on the recurrence of hepatoma was
suggested. Further, liver function failure or other adverse
effects, those caused by retinoids, were not substantially observed
during the administration thereof, and therefore the compound was
revealed to be a safe medicament (N. Eng. J. Med., 334, 1561-1567
(1996)).
[0005] However, it was not known that polyprenyl compounds had
prophylactic and therapeutic effectiveness on hepatic steatosis or
non-alcoholic steatohepatitis.
Non-patent document 1: Gastroenterology, 116, pp. 1413-1419 (1999)
Non-patent document 2: Ann. N.Y. Acad. Sci., 386, pp. 111-135
(1982) Non-patent document 3: Atherosclerosis, 92, pp. 31-40 (1992)
Non-patent document 4: N. Eng. J. Med., 334, pp. 1561-1567
(1996)
DISCLOSURE OF THE INVENTION
Object to be Achieved by the Invention
[0006] An object of the present invention is to provide a
medicament for prophylactic and/or therapeutic treatment of hepatic
steatosis or non-alcoholic steatohepatitis. More specifically, the
object of the present invention is to provide a medicament for
prophylactic and/or therapeutic treatment of hepatic steatosis or
non-alcoholic steatohepatitis with reduced side effects.
Means for Achieving the Object
[0007] The inventors of the present invention conducted various
researches to find a medicament for prophylactic and/or therapeutic
treatment of hepatic steatosis or non-alcoholic steatohepatitis. As
a result, it was found that polyprenyl compounds reduced an amount
of lipids in the liver. The present invention was accomplished on
the basis of the above finding.
[0008] The present invention thus relates to the followings.
[1] A medicament for prophylactic and/or therapeutic treatment of
hepatic steatosis or non-alcoholic steatohepatitis, which comprises
a polyprenyl compound as an active ingredient. [2] The medicament
according to [1], wherein the polyprenyl compound is a
polyprenylcarboxylic acid. [3] The medicament according to [1],
wherein the polyprenyl compound is
3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. [4] The
medicament according to [1], wherein the polyprenyl compound is
(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid. [5] The medicament according to any one of [1] to [4], which
is in the form of a pharmaceutical composition containing a
pharmacologically acceptable pharmaceutical carrier. [6] The
medicament according to any one of [1] to [5], which is a
preparation for oral administration. [7] Use of a polyprenyl
compound for manufacture of the aforementioned medicament. [8] A
method for prophylactic and/or therapeutic treatment of hepatic
steatosis or non-alcoholic steatohepatitis, which comprises the
step of administrating a prophylactically and/or therapeutically
effective amount of a polyprenyl compound to a mammal including
human.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a graph showing the amounts of H-TG (mg/g liver)
and the amounts of H-T-chol (mg/g liver) observed for the groups in
Example 1. In the graph, the symbol * means a significant
difference (P<0.05) compared with the normal control group.
[0010] FIG. 2 is a graph showing the hepatic steatosis scores and
the O.R. positive areas (mm.sup.2/mm.sup.2) observed for the groups
in Example 1. In the graph, the symbol * means a significant
difference (P<0.05) compared with the normal control group.
[0011] FIG. 3 is a graph showing the S-TG concentrations (mg/dL)
and S-T-chol concentrations (mg/dL) observed for the groups in
Example 1. In the graph, the symbol * means a significant
difference (P<0.05) compared with the normal control group.
[0012] FIG. 4 is a graph showing the S-ALT concentrations (U/L) and
the S-AST concentrations (U/L) observed for the groups in Example
1. In the graph, the symbols * and # mean a significant difference
(P<0.05) compared with the normal control group and the control
group, respectively.
[0013] FIG. 5 is a graph showing the S-TG concentrations (mg/dL)
observed for the groups in Example 2. In the graph, the symbol *
means that a significant difference (P<0.05) compared with the
control group.
[0014] FIG. 6 is a graph showing the testis weights (mg) observed
for the groups in Example 2. In the graph, the symbol * means a
significant difference (P<0.05) compared with the control
group.
BEST MODE FOR CARRYING OUT THE INVENTION
[0015] The polyprenyl compounds used for the medicament of the
present invention mean compounds having several linear isoprene
units in the chemical structure. Preferred compounds include
polyprenylcarboxylic acids having carboxy group at the end, and a
particularly preferred compound includes
(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic
acid (henceforth referred to as NIK-333). Other examples of the
polyprenyl compounds include conjugated polyprenylcarboxylic acids
(polyprenoic acids) such as
3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and
esters thereof described in Japanese Patent Publication (Kokoku)
No. 63-34855, and the like.
[0016] The polyprenyl compounds used in the present invention can
be synthesized by a known method (Japanese Patent Publication No.
63-32058; J. Chem. Soc. (C), 2154 (1966)).
[0017] When the polyprenyl compounds are used for the medicament
for prophylactic and/or therapeutic treatment of hepatic steatosis
or non-alcoholic steatohepatitis of the present invention, said
compounds can be administered by an appropriate administration
method such as oral administration or parenteral administration.
Examples of forms for oral administration include, for example,
tablets, granules, capsules, soft capsules, pills, powders,
solutions, and the like. Examples of forms for parenteral
administration include, for example, injections, suppositories, and
the like. These preparations can be prepared by a conventional
method using a polyprenyl compound or a pharmacologically
acceptable salt thereof and one or more kinds of ordinary
pharmaceutical carriers.
[0018] For example, in the case of preparation for oral
administration, desired administration forms can be prepared by
using excipients such as lactose, glucose, corn starch and sucrose,
disintegrating agents such as carboxymethylcellulose calcium and
hydroxypropylcellulose, lubricants such as calcium stearate,
magnesium stearate, talc, polyethylene glycol and hydrogenated oil,
binders such as hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl
alcohol, gelatin and gum arabic, and moistening agents such as
glycerin and ethylene glycol, as well as surfactants, flavoring
agents and the like as required.
[0019] Further, in the case of preparation for parenteral
administration, diluents such as water, ethanol, glycerin,
propylene glycol, polyethylene glycol, vegetable oil, agar and
tragacanth gum as well as dissolving aids, suspending agents,
emulsifiers, stabilizers, buffers, isotonic agents, preservatives,
soothing agents and the like can be used as required.
[0020] When the compounds are prescribed as the medicament for
prophylactic and/or therapeutic treatment of hepatic steatosis or
non-alcoholic steatohepatitis of the present invention, a dose may
be 1 to 2,000 mg, preferably 20 and 800 mg, in terms of the
compounds used for the present invention, per day for an adult in
the case of oral administration. In the case of parenteral
administration, the compounds are administered at a dose in the
range of 1 to 1,000 mg, preferably in the range of 10 to 100 mg.
Desired therapeutic effects can be expected by administering the
compounds 1 to 3 times per day as divided portions of the
aforementioned doses.
EXAMPLES
[0021] The present invention will be explained more specifically
with reference to the following examples. However, the scope of the
present invention is not limited to these examples.
Example 1
Evaluation of Action of NIK-333 for Decreasing Hepatic Lipid
Amount
[0022] For the experiment, 6-week old SD male rats (Charles River
Japan) were used. HFD32 (Clea Japan) was used for the high fat diet
group, and CE-2 (Clea Japan) was used for the normal control group.
The feeding was restricted to 25.+-.3 g for both of the groups. The
feed ingredients are shown in Table 1. Administration of NIK-333
was started at the same time as the start of the loading of the
high fat diet, and the drug was given once a day for 8 weeks by
forcible continuous oral administration. After completion of the
test, each liver was extracted, and triglyceride (H-TG) amount and
cholesterol (H-T-chol) amount in the liver were measured. The
results are shown in FIG. 1. Hematoxylin-eosin (H.E.) and Oil Red O
(O.R.) staining samples were prepared from the extracted liver, and
histopathological examination was performed. Degree of fatty
degeneration of the liver was graded into five categories on the
basis of the examination of the H.E. staining sample, and scores
were assigned. Further, from the O.R. staining sample, O.R.
positive area in the liver sample area was calculated by using an
image analyzer. The results are shown in FIG. 2. Furthermore,
triglyceride (S-TG), total cholesterol (S-T-chol), alanine
aminotransferase (S-ALT), and aspartate aminotransferase (S-AST)
levels in serum were measured. The results are shown in FIGS. 3 and
4.
TABLE-US-00001 TABLE 1 Contents in 100 g of feed Common ingredients
CE-2 HFD32 Moisture (g) 9.2 6.9 Crude protein (g) 25.8 25.0 Crude
fat (g) 4.0 32.4 Crude fiber (g) 3.8 2.9 Crude ash (g) 6.9 4.0
Soluble non-nitrogen substance (g) 50.5 28.8 Energy (kcal) 340.4
506.8
[0023] As shown in FIGS. 1 and 2, NIK-333 decreased the amount of
lipids in the liver, and therefore, it was revealed that the
compound has effectiveness on prophylactic and/or therapeutic
treatment of hepatic steatosis or non-alcoholic steatohepatitis. It
can be also understood that NIK-333 decreases the amount of lipids
in the liver without affecting lipid concentration in blood as
shown in FIG. 3. Generally, retinoids are pointed out to have a
problem of inducing hypertriglyceridemia as a side effect in
clinical use (N. Engl. J. Med., 313, 981-985 (1985)). However,
NIK-333 does not show such increase in lipid concentration in
blood. It can be recognized that NIK-333 has an suppressing effect
on the increase of blood transaminase as shown in FIG. 4, and has
an action of protecting the liver. From the above, it is clearly
understood that NIK-333 has effectiveness on prophylactic and/or
therapeutic treatment of hepatic steatosis or non-alcoholic
steatohepatitis.
Example 2
Evaluation of NIK-333 and ATRA for Toxicity
[0024] 7-Week old C57BL/6N mice (Charles River Japan) were given
with NIK-333 or ATRA once per day for 2 weeks by forcible
continuous oral administration. After completion of the test, S-TG
concentrations and testis weights of individual mice were measured.
The results are shown in FIGS. 5 and 6, respectively. To the
control group, soybean oil was administered.
[0025] As shown in FIG. 5, it can be understood that ATRA increases
the S-TG concentration, whilst NIK-333 does not affect the
concentration. It can be also recognized that ATRA markedly
decreases testis weight, whilst NIK-333 does not affect the weight
as shown in FIG. 6. It was observed that ATRA decreased testis
weight in mice (Fundam. Appl. Toxicol., 8, 517-530 (1987)) and rats
(Toxicology, 30, 115-124 (1984)), whilst the aforementioned action
is not observed for NIK-333. From the above results, it is clearly
understood that toxicity of NIK-333 for S-TG and testis is lower
than that of ATRA.
[0026] From the above results, it can be concluded that the
medicament of the present invention is useful as a novel medicament
for use in prophylactic and/or therapeutic treatment of hepatic
steatosis or non-alcoholic steatohepatitis.
INDUSTRIAL APPLICABILITY
[0027] The medicament for prophylactic and/or therapeutic treatment
of hepatic steatosis or non-alcoholic steatohepatitis provided by
the present invention has an action of decreasing lipid amount in
the liver and improving liver functions. The medicament has less
effect on triglyceride (S-TG) concentration in blood serum and
testis weight as compared with all-trans-retinoic acid (henceforth
abbreviated as ATRA) as a cyclic retinoid, and thus a medicament
with reduced side effects.
* * * * *