Therapeutic agent for cerebral infarction sequelae

Abstract

SOLUTION: To provide a therapeutic agent for cerebral infarction sequelae containing an ingredient selected from febuxostat and topiroxostat.EFFECT: Administering an ingredient selected from febuxostat and topiroxostat to a patient with cerebral infarction remarkably improves the ATP concentration in ischemic brain tissue, enhances the brain tissue after cerebral ischemic attack, and alleviates symptoms of various cerebral infarction sequelae.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a drug for treating sequelae of cerebral infarction. [Background technology]

[0002] Cerebral infarction is generally a disease characterized by cerebral ischemia caused by occlusion or stenosis of cerebral arteries, resulting in necrosis or near-necrotic state of brain tissue due to lack of oxygen or nutrients. Cerebral infarction includes disease types such as "lacunar infarction" caused by small intracerebral arterial lesions, "atherothrombotic cerebral infarction" caused by atherosclerosis of relatively large arteries in the neck or skull, and "cardiogenic cerebral embolism" caused by heart disease. Cerebral infarction is a disease with a high mortality rate, and once it develops, there is a high possibility of leaving sequelae, which is a major issue in terms of patients' QOL, welfare, and medical economy.

[0003] The first-choice treatment for cerebral infarction is thrombolysis in the hyperacute phase within 8 hours, and if this is not possible, physical removal of the clot is the treatment of choice. In the acute phase of 8 to 24 hours, the first priority is to prevent the progression of necrosis caused by swelling and free radicals. If thrombotic, cerebral edema is reduced by increasing plasma osmotic pressure with glycerin or mannitol in addition to anticoagulants, and free radical production is suppressed with edaravone within 24 hours of onset. After some time has passed since the onset of the disease, it is common to administer antiplatelet agents, anticoagulants, etc. to prevent recurrence.

[0004] The aftereffects of cerebral infarction include disorders of bodily movement such as cerebral palsy, spasticity, contracture, numbness, pain, dizziness, and swallowing disorders, as well as higher-level brain dysfunction resulting in declines in cognitive function, memory function, and language function. As such drugs for treating sequelae of cerebral infarction, sodium adenosine triphosphate, ifenprodil, nicergoline, etc., have been used. It has also been reported that when xanthine oxidase inhibitors allopurinol and oxypurinol were administered in large doses to rats and pigs with cerebral ischemia, the adenosine level in the brain increased (Non-Patent Documents 1 to 3). [Prior art documents] [Patent documents]

[0005] [Non-Patent Document 1] Neuroscience Letters,144(1992)103-106 [Non-Patent Document 2] Journal of Neurochemistry Vol.64,No5,1995, 2177-2184 [Non-Patent Document 3] BRAIN RESEARCH 1073-1074(2006)444-450 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the currently available drugs for treating the sequelae of cerebral infarction are not effective enough, and the development of new drugs is desired. [Means for solving the problem]

[0007] It is known that the energy required to maintain the structure and function of brain tissue is completely dependent on ATP, which is normally produced by the aerobic metabolism of glucose. Therefore, when cerebral blood flow is acutely reduced due to cerebral infarction, the ATP content of brain tissue decreases, lactate accumulates in the brain tissue, and cell death occurs. Therefore, the present inventors investigated the effects of xanthine oxidase inhibitors using a test system in which mice were placed under hypoxic conditions and then their brains were treated with microwaves. They found that febuxostat or topiroxostat had an extremely strong effect of improving ATP concentration in ischemic brain tissue at doses lower than the doses at which allopurinol was ineffective, and that the effect was further enhanced by the combined use of inosine, thereby completing the present invention.

[0008] That is, the present invention provides the following inventions [1] to [8]. [1] A drug for treating sequelae of cerebral infarction containing ingredients selected from febuxostat and topiroxostat. [2] The drug for treating sequelae of cerebral infarction according to [1], further comprising inosine. [3] A component selected from febuxostat and topiroxostat for use in treating sequelae of cerebral infarction. [4] A composition comprising an ingredient selected from febuxostat and topiroxostat, and inosine for use in treating sequelae of cerebral infarction. [5] Use of an ingredient selected from febuxostat and topiroxostat for the manufacture of a drug for treating sequelae of cerebral infarction. [6] Use of a composition containing an ingredient selected from febuxostat and topiroxostat, and inosine for the manufacture of a drug for treating sequelae of cerebral infarction. [7] A method for treating sequelae of cerebral infarction, comprising administering an ingredient selected from febuxostat and topiroxostat. [8] A method for treating sequelae of cerebral infarction, comprising administering a component selected from febuxostat and topiroxostat, and inosine. Effect of the Invention

[0009] When a component selected from febuxostat and topiroxostat, or these components together with inosine, are administered to a patient with cerebral infarction, the ATP concentration in ischemic brain tissue is significantly improved, brain tissue after a cerebral ischemic attack is improved, and various symptoms of sequelae of cerebral infarction are improved. [Brief description of the drawings]

[0010] [Figure 1]The results of the effect of allopurinol and febuxostat on improving ATP concentration in ischemic brain tissue were examined using a test system in which mice were placed under hypoxic conditions and then microwaved on the mouse brain. The vertical axis shows the ATP concentration, ADP concentration, and AMP concentration in the ischemic brain tissue. The horizontal axis shows the white squares for the untreated group under normal oxygen conditions, the light gray squares for the febuxostat group under normal oxygen conditions, the dark gray squares for the allopurinol group under normal oxygen conditions, the dotted white squares for the untreated group under hypoxic conditions, the dotted light gray squares for the febuxostat group under hypoxic conditions, and the dotted dark gray squares for the allopurinol group under hypoxic conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] One aspect of the present invention is a therapeutic drug for sequelae of cerebral infarction, comprising an ingredient selected from febuxostat and topiroxostat. Another aspect is a therapeutic drug for sequelae of cerebral infarction, comprising an ingredient selected from febuxostat and topiroxostat, and inosine.

[0012] The active ingredient of the therapeutic agent for sequelae of cerebral infarction of the present invention is Febuxostat or Topiroxostat. Febuxostat is a compound with the chemical name 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid. Topiroxostat is a compound with the chemical name 4-[5-(4-pyridinyl)-1H-1,2,4-triazol-3-yl]-2-pyridinecarbonitrile. These compounds suppress uric acid production by selectively inhibiting xanthine oxidase without affecting the activity of purine and pyrimidine metabolic enzymes. Therefore, these ingredients are commercially available or under development as hyperuricemia treatments. It is also known that these ingredients are clearly different from allopurinol in that they do not affect the activity of purine and pyrimidine metabolic enzymes. These ingredients can be produced by known methods, for example, as described in Japanese Patent No. 2725886 and Japanese Patent No. 3600832, and are also available as commercial products. Inosine can also be produced by known methods and is also available as a commercial product.

[0013] As shown in the Examples below, when the above-mentioned component was tested using a test system in which mice were placed under hypoxic conditions and then their brains were subjected to microwave treatment, it was found that the component exerted an extremely strong effect of improving ATP concentration in ischemic brain tissue at a lower dose than the dose at which allopurinol was ineffective, and the effect was further enhanced by the use of inosine in combination. Therefore, a composition containing the above component, or a composition containing the above component and inosine, is useful as a therapeutic agent for sequelae of cerebral infarction.

[0014] In the present invention, the aftereffects of cerebral infarction include disorders of the function of moving the body or parts of the body, such as cerebral palsy, spasticity, contracture, muscular atrophy, numbness, pain, dizziness, and swallowing disorders, as well as higher brain dysfunction resulting in impaired cognitive function, memory function, language function, and the like. As mentioned above, cerebral infarction is a disease characterized by cerebral ischemia caused by occlusion or stenosis of cerebral arteries, resulting in necrosis or near-necrotic state of brain tissue due to lack of oxygen or nutrients. Cerebral infarction is classified into three types according to the mechanism of vascular occlusion: thrombotic, embolic, and hemodynamic. The 1990 NIND-III (NINDS: National Institute of Neurological Disorders and Stroke) classification is well known as a clinical disease type. In the NIND-III classification, focal brain dysfunction is classified into TIA (transient ischemic attack) and stroke. Stroke is classified into cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage associated with cerebral arteriovenous malformation, and cerebral infarction, and cerebral infarction is classified into four types: atherothrombotic cerebral infarction, cardiogenic cerebral embolism, lacunar infarction, and other cerebral infarction. According to the TOAST classification, it is classified into five types: large vessel atherosclerosis (=atherothrombotic cerebral infarction), small vessel occlusion (=lacunar infarction), cardiac embolism (=cardiogenic cerebral embolism), other causes, and unknown causes.

[0015] The administration route of the pharmaceutical of the present invention is not particularly limited, and it can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, subcutaneous or intradermal injection, inhalation, rectal administration, intranasal administration, topical administration, etc. The medicament of the present invention may be administered to a patient as the active ingredient or the active ingredient and inosine as is, but should preferably be administered in the form of a pharmaceutical composition containing the active ingredient and a pharmaceutical acceptable additive. Examples of the pharmaceutical acceptable additive include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilization aids, isotonicity agents, pH regulators, stabilizers, propellants, and adhesives.

[0016] Examples of formulations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups, while examples of formulations suitable for parenteral administration include injections, drips, suppositories, inhalants, and topical preparations (including patches, ointments, creams, gels, lotions, sprays, and the like). Preparations suitable for oral administration may contain, as additives, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat. Preparations suitable for injection or infusion may contain additives for formulations, such as dissolving agents or solubilizing aids capable of constituting aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, propylene glycol, etc.; isotonicity agents, such as glucose, sodium chloride, D-mannitol, glycerin, etc.; and pH adjusters, such as inorganic acids, organic acids, inorganic bases, or organic bases. Preparations suitable for suppositories can use, for example, bases such as polyethylene glycol, lanolin, cacao butter, fatty acid triglycerides, and, if necessary, additives such as surfactants, such as nonionic surfactants. Preparations suitable for ointments may contain commonly used bases, stabilizers, wetting agents, preservatives, etc. as necessary. Examples of bases include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin, etc. Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, etc. Preparations suitable for use as patches include those prepared by applying the above-mentioned ointments, creams, gels, pastes, etc., to a common support in a conventional manner. Suitable supports include woven or nonwoven fabrics made of cotton, staple fiber, or chemical fibers, and films or foam sheets made of soft polyvinyl chloride, polyethylene, polyurethane, etc.

[0017] The dosage of the pharmaceutical of the present invention can be appropriately selected depending on various conditions such as the progression of the disease or the severity of the symptoms, and the age and weight of the patient. For example, in the case of oral administration, 1 mg to 1000 mg can be administered in one to three divided doses per day.

[0018] Another aspect of the present invention includes an ingredient selected from febuxostat and topiroxostat for use in treating sequelae of cerebral infarction. Another aspect of the present invention includes a composition containing an ingredient selected from febuxostat and topiroxostat, and inosine, for use in treating sequelae of cerebral infarction. Another aspect of the present invention is the use of an ingredient selected from febuxostat and topiroxostat for the manufacture of a therapeutic agent for sequelae of cerebral infarction. Another aspect of the present invention includes use of a composition containing an ingredient selected from febuxostat and topiroxostat, and inosine for the manufacture of a therapeutic agent for sequelae of cerebral infarction. Another aspect of the present invention is a method for treating sequelae of cerebral infarction, which comprises administering a component selected from febuxostat and topiroxostat. Another aspect of the present invention includes a method for treating sequelae of cerebral infarction, comprising administering a component selected from febuxostat and topiroxostat, and inosine. EXAMPLES

[0019] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0020] Example 1 In the conventional cerebral infarction model, lesions were created by blocking the arteries that supply oxygen to the mouse brain, and the effects were evaluated by observing the pathological images of brain slices. However, because ATP decomposition is rapid, this method does not allow the evaluation of the ATP increase effect in brain tissue. Therefore, the inventor developed a new method to create a cerebral ischemia model by placing mice in a hypoxic environment. Furthermore, while maintaining this condition, the inventor devised and implemented an experimental model of cerebral infarction treatment that allows the quantification of cerebral ATP concentration, which was previously difficult, by instantly denaturing the brain tissue with electromagnetic wave irradiation and stopping ATP metabolism.

[0021] (method) After a one-week acclimation period, 6-8 week-old C57BL / 6 male mice were orally administered 0.5% methylcellulose, febuxostat (5 mg / kg), or allopurinol (10 mg / kg). Thirty minutes after administration, the mice were exposed to hypoxia as follows: Two tubes were drawn from a 5% oxygen gas cylinder into a glove bag, one of which was fixed in a beaker, and the other was connected to the tip of an animal holder for microwave irradiation. After placing the mouse in the beaker and closing the glove bag, gas flow was started, and after 3 minutes, the mouse was transferred to the animal holder. The animal holder was removed from the glove bag and immediately irradiated with 5 kW microwaves for 0.94 seconds using a microwave irradiation device. The extracted mouse brain was homogenized with 60% perchloric acid to remove proteins, neutralized with potassium carbonate, and the supernatant was subjected to HPLC to measure adenine nucleotides. The results were expressed as mean ± SD. A significant difference test was performed using the Tukey's , The sHSD method was used. (*p<0.05,**p<0.01,n=5,5,5,6,6,5,respectively)

[0022] (result) The results are shown in Figure 1. Under normoxic conditions, there were no differences in ATP, ADP, or AMP among the three groups. Hypoxic treatment significantly decreased intracerebral ATP levels and increased AMP, an ATP decomposition product, in the untreated group, suggesting that ATP decomposition was occurring. On the other hand, in the febuxostat group, ATP did not decrease even under hypoxic conditions, and AMP was unchanged from normoxic conditions, suggesting that ATP decomposition was suppressed. In the allopurinol group, ATP was significantly decreased by hypoxic treatment, as in the untreated group. Therefore, it is clear that febuxostat does not inhibit ATP decomposition even under hypoxic conditions, does not reduce ATP in brain tissue under hypoxic conditions, protects brain tissue after cerebral infarction, and is effective in treating the aftereffects of cerebral infarction.

Claims

1. A therapeutic drug for the aftereffects of cerebral infarction, comprising an ingredient selected from febuxostat and topiroxostat.

2. 2. The therapeutic agent for sequelae of cerebral infarction according to claim 1, further comprising inosine.

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