Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02549570 2006-06-13
SPECIFICATION
Medicament for prophylactic and/or therapeutic treatment of cerebral
infarction
Technical Field
The present invention relates to a medicament for prophylactic and/or
therapeutic treatment of cerebral infarction.
Background Art
Among deaths of sickness in Japan, about twenty percent of people died from
cerebral apoplexy of which pathological conditions include cerebral
hemorrhage,
subarachnoid hemorrhage, and cerebral infarction. Cerebral infarction is a
state
where obliterations are generated in cerebral vessels to destroy brain
tissues, of which
causes are typically classified into two conditions, i.e., cerebral thrombosis
and
cerebral embolism. Cerebral thrombosis is a state where cerebral
arteriosclerosis
advances to narrow blood vessels" and as a result, blood flow becomes
insufficient and
blood cannot be brought beyond the lesion to cerebral tissues. Cerebral
embolism is a
state where clots of blood or lipid aggregates are transported to the brain to
plug
cerebral blood vessels. Although symptoms of the cerebral infarction vary
depending
on sites of infarction or causes, in patients with cerebral thrombosis, low
vision, speech
disorder, numbness of hand and foot, vertigo, and double vision appear
repeatedly for
several days, soon followed by paralysis to cause aphasia and mental disorder.
In
patients with cerebral embolism, a sudden attack appears to cause hemiplegia,
hemianesthesia, and speech disorder, and in a severe condition, coma continues
and
acroparalysis is caused.
As pharmacotherapy of cerebral infarction, glycerol is conventionally
administered for the purpose of the treatment of cerebral edema. For some
cases,
urokinase as a thrombolytic agent and a platelet aggregation inhibitor such as
ticlopidine and aspirin may also be administered. Meclofenoxate hydrochloride
and
the like may also be administered as a brain metabolism improving agent.
Further,
edaravone (Radicut, Mitsubishi Pharma Corporation) has been recently used as a
brain protective agent (free radical scavenger) for the purpose of improvement
of
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neurological symptoms, impaired activities of daily living, and functional
disorders in
an acute stage of cerebral infarction. However, even edaravone cannot provide
satisfactory therapeutic effect for cerebral infarction. Moreover, since acute
renal
failure including exacerbation of renal impairment caused by administration of
edaravone is reported and careful administration of edaravone is required, it
is desired
to provide a still safer medicament having higher efficacy.
It is known that platinum colloid decomposes hydrogen peroxide, which is one
of reactive oxygen species (for example, Japanese Patent Unexamined
Publication
(KOKAI) No. 10-68008, paragraph 0040). However, the above patent document 1
does
not teach efficacy of platinum colloid in therapeutic and/or prophylactic
treatment of
cerebral infarction.
Disclosure of the Invention
An object of the present invention is to provide a medicament for prophylactic
and/or therapeutic treatment of cerebral infarction. The inventors of the
present
invention conducted various researches to achieve the aforementioned object,
and as a
result, they found that symptoms of cerebral infarction could be improved, and
progress of that disease could be suppressed by administering metal colloid
such as
platinum colloid. The present invention was achieved on the basis of the
aforementioned finding.
The present invention thus provides a medicament for prophylactic and/or
therapeutic treatment of cerebral infarction, which comprises fineparticles o~
a noble
metal or an alloy containing a noble metal as an active ingredient. According
to
preferred embodiments, the present invention provides the aforementioned
medicament, wherein the noble metal consists of one or more kinds of noble
metals
selected from the group consisting of palladium, ruthenium, rhodium, and
platinum
the aforementioned medicament, wherein the noble metal is platinum and the
aforementioned medicament, wherein the ~ineparticles of a noble metal consist
of
platinum colloid having a mean particle size of 10 nm or smaller.
From another aspect, the present invention provides a method for prophylactic
and/or therapeutic treatment of cerebral infarction, which comprises the step
of
administering fineparticles of a noble metal to a mammal including human. The
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present invention also provides use of fineparticles of a noble metal for
manufacture of
the aforementioned medicament.
Brief Explanation of the Drawings
Fig. 1 shows six sections of rat brains. From the top, there are shown the
results of the control rat (0.9% physiological saline, single administration),
medicated
rat (0.5 a mol/kg, single administration), medicated rat (1.25 a mol/kg,
single
administration), and medicated rat (single administration of 1.25 a mol/kg
followed
by administration of 1.25 a mol/kg by drip infusion continued for 8 hours).
Fig. 2 shows cerebral infarction volumes and infarction ratios. The graph on
the left shows cerebral infarction volumes, and the graph on the right shows
infarction
ratios. The graphs show, from the left, the results of the control rat
(0.9°/
physiological saline, single administration), medicated rat (0.5 a mol/kg,
single
administration), medicated rat (1.25 a mol/kg, single administration), and
medicated
rat (single administration of 1.25 a mol/kg followed by administration of 1.25
a
mol/kg by drip infusion continued for 8 hours).
Best Mode for Carrying out the Invention
The medicament of the present invention is used for prophylactic and/or
therapeutic treatment of cerebral infarction, and is characterized to comprise
fineparticles of a noble metal as an active ingredient. Types of the noble
metal are not
particularly limited, and any of gold, ruthenium, rhodium, palladium, osmium,
iridium,
and platinum may be used. However, preferred noble metals are metals of
platinum
group, more specifically, ruthenium, rhodium, palladium, and platinum. The
fineparticles of noble metal may contain two or more kinds of noble metals.
Fineparticles of an alloy containing at least one kind of noble metal, or a
mixture
containing fineparticles of one or more kinds of noble metals and
fineparticles of one or
more kinds of metals other than noble metal can also be used. For example, an
alloy
comprising gold and platinum or the like may be used. Fine particles of two or
more
kinds of elements forming a core/shell structure may also be used. Moreover,
for
example, a single metal nanocolloid, binary nanocolloid, and the like may also
be used.
Among them, platinum or an alloy containing platinum is preferred, and
platinum is
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particularly preferred.
As the fineparticles of a noble metal, fineparticles that have a large
specific
surface area and can form a colloidal state of superior surface reactivity axe
preferred.
A particle size of the fineparticles is not particularly limited.
Fineparticles having a
mean particle size of 50 nm or smaller can be used, and fineparticles having a
mean
particle size of, preferably 20 nm or smaller, further preferably 10 nm or
smaller, most
preferably about 1 to 6 nm, can be used. Fineparticles having a smaller
particle size
can also be used.
Various preparation methods for noble metal fineparticles are known (for
example, Japanese Patent Publication (KOKOKU) Nos. 57-43125, 59-120249,
Japanese Patent Unexamined Publication Nos. 9-225317, 10-176207, 2001-79382,
2001-122723 and the like), and those skilled in the art can easily prepare the
fineparticles by referring to these methods. For example, as the method for
producing
noble metal fineparticles, a chemical method called precipitation method or
metal salt
reduction method, or a physical method called combustion method can be used.
Fineparticles prepared by any of the methods may be used as the active
ingredient of
the medicament of the present invention. It is preferable to use fineparticles
prepared by the metal salt reduction method from viewpoints of easiness of the
production and quality of the fineparticles.
In the metal salt reduction method, for example, an aqueous solution or
organic solvent solution of a water-soluble or organic solvent-soluble noble
metal salt
or noble metal complex is prepared, then a water-soluble polymer is added to
the
solution and pH of the solution is adjusted to 9 to 11, and the solution can
be refluxed
by heating in an inert atmosphere to reduce the metal salt or metal complex to
obtain
metal fineparticles. Types of the water-soluble or organic solvent-soluble
noble metal
salt are not particularly limited. For example, acetate, chloride, sulfate,
nitrate,
sulfonate, phosphate and the like can be used, and complexes thereof may also
be used.
Types of the water-soluble polymer used for the metal salt reduction method
are not particularly limited. For example, polyvinylpyrrolidone, polyvinyl
alcohol,
polyacrylic acid, cyclodextrin, amiropectin, methylcellulose and the like can
be used,
and two or more kinds of these polymers may be used in combination.
Polyvinylpyrrolidone can be preferably used, and poly(1-vinyl-2-pyrrolidone)
can be
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more preferably used. It is also possible to use various kinds of surface
active agents
such as anionic, nonionic or liposoluble surface active agents instead of the
water-soluble polymer or together with the water-soluble polymer. When an
alcohol is
used to perform the reduction, ethyl alcohol, n-propyl alcohol, n-butyl
alcohol, n-amyl
alcohol, ethylene glycol or the like is used. However, the methods for
preparing noble
metal fineparticles are not limited to the methods explained above.
The medicament of the present invention can be used for prophylactic and/or
therapeutic treatment of cerebral infarction. The term of cerebral infarction
used in
the specification encompasses cerebral thrombosis and cerebral embolism, and
encompasses all diseases with brain ischemia including transient ischemic
attack
(TIA) and asymptomatic cerebral infarction. Various kinds of diseases
accompanying
cerebral infarction, for example, cerebral edema and the like are also
encompassed by
the term of cerebral infarction. Further, the term of "prophylactic and/or
therapeutic
treatment" should be construed in its broadest sense including prophylaxis of
onset of
cerebral infarction and therapeutic treatment of the aforementioned disease
after
onset, as well as suppression of advance of the aforementioned disease,
improvement
or amelioration of the aforementioned disease, prevention of relapse of the
aforementioned disease, and the like, and the term should not be construed in
any
limitative way.
Administration routes of the medicament of the present invention are not
particularly limited, and either route of oral administration or parenteral
administration may be chosen. As the medicament of the present invention,
noble
metal dispersion of a colloidal state or noble metal fineparticles in a dried
state
prepared by the methods explained above may be used without any treatment. The
metal fineparticles prepared in water, organic solvent, or mixture of water
and organic
solvent exist in a colloidal state. The aforementioned noble metal dispersion
in a
colloidal state, per se, can be used as the medicament of the present
invention. An
aqueous suspension in which the noble metal fineparticles associate to form
clusters
may also be used as the medicament of the present invention. Furthermore, when
it
is desirable to remove a solvent, the solvent can be removed by an operation
of heating
or the like to obtain fineparticles in a dried state, and the dried
fineparticles obtained
by the above operation can be used as the medicament of the present invention.
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Water containing platinum fineparticles, which is a soft drink (for example,
"Hakkin
Gensui", Inovex Co., Ltd.), platinum and palladium colloid preparation
("Paplal for
internal application", Toyo Kosei Seiyakusho) as a curative agent for acute
gastroenteritis or chronic esogastritis, intestinal catarrh and the like can
also be used
as the medicament of the present invention.
The medicament of the present invention can also be administered as a
pharmaceutical composition for oral or parenteral use that can be produced by
a
method well known to those skilled in the art. Examples of the pharmaceutical
composition suitable for oral administration include, for example, tablets,
capsules,
powders, subtilized granules, granules, solutions, syrups, and the like, and
examples
of the pharmaceutical composition suitable for parenteral administration
include, for
example, injections, drip infusions, suppositories, inhalants, eye drops,
nasal drops,
ear drops, ointments, creams, transdermal preparations, transmucosal
preparations,
patches, and the like. The aforementioned pharmaceutical compositions can be
produced by using one or more kinds of pharmaceutical additives together with
the
noble metal fineparticles as the active ingredient. Examples of the
pharmaceutical
additives include, for example, excipients, disintegrating agents or
disintegrating aids,
binders, lubricants, coating agents, dyes, diluents, bases, dissolving agents
or
dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants,
tackifiers, and
the like, and they can be suitably selected by those skilled in the art
depending on the
dosage form of the pharmaceutical composition.
Doses of the medicament of the present invention are not particularly limited,
and the dose can be suitably chosen depending on conditions such as a type of
disease,
a purpose of administration (prophylactic or therapeutic treatment), an age,
body
weight, symptoms and the like of a patient. The medicament of the present
invention
can be used by oral administration for adults in an amount in a range of, for
example,
about 0.001 to 1,000 mg per day on the basis of a weight of the noble metal
fineparticles.
Examples
The present invention will be explained more specifically with reference to
the
examples. However, the scope of the present invention is not limited to the
following
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examples.
Example 1
In a 100-ml 2-neck pear-shaped flask connected with an Allihn condenser and
a 3-neck joint, 0.1467 g of poly(1-vinyl-2-pyrrolidone) (Wako Pure Chemical
Industries)
was placed and dissolved in 23 ml of distilled water. This solution was
stirred for 10
minutes, then mixed with 2 ml of 1.66 x 10-2 M chloroplatinic acid solution
obtained by
dissolving hexachloroplatinic acid (HzPtCls ~ 6Hz0, Wako Pure Chemical
Industries) in
distilled water, and stirred for additional 30 minutes. The inside atmosphere
of the
reaction system was replaced with nitrogen gas. Twenty five ml of special
grade
ethanol was added to the reaction mixture and the resulting mixture was
refluxed at a
temperature of 100°C for 2 hours while the nitrogen atmosphere was
maintained. An
ultraviolet-visible light spectral scanning analysis of the reaction mixture
was
performed to confirm disappearance of the platinum ion peak and saturation of
the
peak due to scattering peculiar to metal solid and thereby confirm completion
of the
reduction reaction. The organic solvent was evaporated under reduced pressure
to
prepare a platinum colloidal solution containing platinum fineparticles (mean
particle
size: 2.4 ~ 0.7 nm).
Rats (Japan SLC, Inc., Sle:Wistar (SPF) rats, 170 to 210 g, 8-week old) were
weighed and observed for general conditions during a preliminary breeding
period
provided for more than five days, and animals exhibiting no abnormality in the
general
conditions and body weight change were used for the experiment. The animals
were
bred with ad libitum feeding of pellets (CRF-1, Oriental Yeast Co., Ltd.)
under
conditions of a room temperature of 20 to 26°C, humidity of 40 to 70%,
and light and
darkness of 12 hours each. According to the method of Koizumi et al. (Cerebral
Apoplexy, 8, pp.l-8, 1986 Memezawa, H. et al., Exp. Brain Rew., 67-78, 1992),
middle
cerebral artery obstruction-recanalized animals were prepared. One hour after
the
middle cerebral artery occlusion and immediately before blood reperfusion, the
medicament of the present invention (1.25 ~ mol/kg or 0.5 ~ mol/kg) was
administered from the femoral vein as single administration, and then the
embolus
was removed for recanalization of blood. The administration fluid volume was 2
mL/kg. Further, another test group was prepared where the animals were
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administered with the medicament of the present invention at 1.25 ~ mol/kg by
drip
infusion over 8 hours after the single administration (1.25 a mol/kg). The
medicament of the present invention was administered as an isotonic solution.
A
physiological saline-administered group was used as a control.
About 24 hours after the end of recanalization of the middle cerebral artery
occlusion, each animal was decapitated under anesthesia, and then the skull
was cut
open from the cerebellum side, and the brain was extracted. The brain was put
into
physiological saline cooled with ice water, sufficiently cooled, and put into
Brain
Matrix for preparation of rat brain sections made from metal zinc (Bioresearch
Center)
with the hypothalamus side up. A portion between the olfactory bulb and the
brain
stem was fixed with a stainless steel blade, and the brain was divided into 6
sections
with a thickness of about 2 mm (three sections for the portion in the front of
the
hypothalamus, and three sections for the portion behind the hypothalamus). The
sections were stained with 2°/ 2,3,5-triphenyltetrazonium chloride (in
physiological
saline). The image of each brain section captured with a digital camera was
entered
into image analysis software (Win Roof Ver. 4.51, Mitani Corp.) to obtain
infarction
area, and infarction volume was calculated from this area. The appearance of
each
section is shown in Fig. 1.
Right brain volume (mm3) = 2 (mm) X E Mn
= 2 (mm) X M1 (mm2) + 2 (mm) X Mz (mm2) + 2 (mm) X Ms (mm2) + 2 (mm) X M4
(mm2) + 2 (mm) X Ms (mm2) + 2 (mm) X Ms (mm2)
Right brain infarction volume: The sum of the calculated right brain
infarction lesion
areas ( E Mn, mm2) was multiplied by the thickness, 2 mm, to obtain the right
brain
infarction volume (mm3). The right brain infarction volume (mm3) is obtained
in
accordance with the following equation.
Right brain infarction volume (mm3) = 2 (mm) x E Sn
= 2 (mm) X Si (mm2) + 2 (mm) X S2 (mm2) + 2 (mm) X Ss (mm2) + 2 (mm) X S4
(mm2) + 2 (mm) X Ss (mm2) + 2 (mm) X Ss (mm2)
Infarction ratio: The infarction ratio is obtained in accordance with the
following
equation.
Infarction ratio (%) = E Sn - E Mn X 100
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_ (Si infarction area + Sz infarction area + Ss infarction area + S4
infarction area + Ss
infarction area + Ss infarction area) - (Mi area + Mz area + Ms area + M4 area
+ Ms
area + Ms area) X 100
Averages and standard deviations were calculated for the cerebral infarction
volume, the infarction ratio, and the right brain volume in each group. As for
significant test, a multiple test was performed between the medium group and
the test
substance administration group for the cerebral infarction volume and the
infarction
ratio in one section and six sections. As the significant test, a
homoscedasticity test
was performed by the Bartlett method. When homoscedasticity was observed, the
test was performed by the Tukey method in a parametric manner, and when
heteroscedasticity was observed, the test was performed by the Tukey method in
a
non-parametric manner. A significance level of less than 5% is considered
significant,
and the results are shown as significance level less than 5% (p < 0.05) or
less than 1%
(p < 0.01). The result are shown in Fig. 2.
Industrial Applicability
The medicament of the present invention is useful as a medicament for
prophylactic and/or therapeutic treatment of cerebral infarction such as
cerebral
thrombosis and cerebral embolism.
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