CA2549570A1 - Medicament for prophylactic and/or therapeutic treamtent of cerebral infarction - Google Patents

Abstract

A pharmaceutical for the prevention and/or treatment of cerebral infarction, comprising as an active ingredient a noble metal or an alloy containing a noble metal, preferably fine particles of platinum (preferably platinum colloid of 10 nm or less average particle diameter).

Description

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 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 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 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 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.

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 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 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 _ (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.

Claims (4)

1. A medicament for prophylactic and/or therapeutic treatment of cerebral infarction, which comprises as an active ingredient fineparticles of a noble metal or an alloy containing a noble metal.

2. The medicament according to claim 1, wherein the noble metal consists of one or more kinds of noble metals selected from the group consisting of ruthenium, rhodium, palladium, and platinum.

3. The medicament according to claim 1, wherein the noble metal is platinum.

4. The medicament according to claim 1, wherein the fineparticles of a noble metal consist of platinum colloid having a mean particle size of 10 nm or smaller.