JP2012046543A - Prevention and/or treating method of neurodegenerative diseases - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug for treatment of neurodegenerative diseases.SOLUTION: Provided are a prevention and/or a parenteral drug containing (2R)-2-propyl octanic acid or its salt for treatment of a neurodegenerative disease, a nervous disorder, and a disease requiring a nerve regeneration. This therapy is characterized by dosing parenterabout 100 mg or more of the drug per each administration, and is useful for the prevention and/or treatment of neurodegenerative diseases including cerebral infarction, since it has an improvement effect on the nervous disorder and an increase suppressing effect on S 100 βin cerebral infarction cases. Moreover, the drug is useful also as a nerve regeneration agent after transplantaton.

Description

  The present invention is administered parenterally for the prevention and / or treatment of neurodegenerative diseases, for the prevention and / or treatment of neurological disorders, or for the prevention and / or treatment of diseases requiring nerve regeneration (2R). The present invention relates to a pharmaceutical comprising 2-propyloctanoic acid or a salt thereof. In particular, it relates to a method of parenterally administering a high dose of (2R) -2-propyloctanoic acid or a salt thereof exceeding about 100 mg at a time for the prevention and / or treatment of cerebral infarction.

  Cerebral infarction is a disease cited as a cause of stroke along with cerebral hemorrhage and subarachnoid hemorrhage. Cerebral infarction is caused by cerebrovascular obstruction due to cerebrovascular arteriosclerosis or a thrombus that has been carried, and the blood flow beyond that is disrupted, resulting in the loss of nutrient supply to the brain cells, and ultimately the death of neurons Is a neurodegenerative disease Even if patients with cerebral infarction escape from sudden death, they often have serious sequelae due to neuronal dysfunction such as hemiplegia and aphasia. In general, in the treatment of cerebral infarction, it is said that after cerebral blood flow is blocked, the blood flow must be resumed before the cerebral tissue undergoes irreversible changes and falls into necrosis. On the other hand, cerebral infarction has a therapeutic time window (therapeutic time window: hereinafter abbreviated as TTW) that can be treated with almost no sequelae of cerebral infarction. ing. Although TTW is considered to vary depending on the development of collateral circulation and individual cases, it is generally considered to be about 3 hours after stroke and about 6 hours at the latest.

  Currently, the drugs mainly used as a therapeutic agent for cerebral infarction are thrombolytic agents, tissue plasminogen activator (t-PA), urokinase, anticoagulants, warfarin, heparin, and the like. Radicut (Edaravone), which is a radical scavenger. However, t-PA is effective only within 3 hours from the onset of cerebral infarction, ie, within TTW, and anticoagulants take several days to develop anticoagulant action, It is not enough for the effect. Furthermore, since Radicut may cause side effects such as severe kidney damage, it should be used with caution. Thus, since the currently used therapeutic agents for cerebral infarction have problems in terms of effectiveness or toxicity, and there are many restrictions on the usage, development of useful therapeutic agents is eagerly desired.

In recent years, the involvement of S100 protein in various neurodegenerative diseases has been revealed. For example, in stroke, measurement of blood S100 protein has been reported to be used for diagnosis of brain lesions and neurological damage (Stroke, 28, 1956-60, 1997). S100β, one of the S100 proteins, is a protein known to exist in high concentrations in glial cells and Schwann cells in the central and peripheral nervous systems, as well as in anterior pituitary cells and Langerhans cells. is there. It is known that S100β in cerebrospinal fluid or blood is elevated in cerebral infarction, subarachnoid hemorrhage, head trauma, various neurodegenerative diseases, neurological complications after cardiopulmonary bypass surgery, etc. .
On the other hand, (2R) -2-propyloctanoic acid has the effect of reducing intracellular S100β content, so it improves the function of abnormally activated astrocytes and becomes a therapeutic or preventive agent for various cranial nerve diseases including stroke. The possibility to obtain is reported (for example, refer nonpatent literature 1).

In addition, pentanoic acid derivatives including (2R) -2-propyloctanoic acid are known to be effective for various diseases such as stroke since they have an astrocyte function improving action. In addition, the dose is orally administered once to several times a day in the range of 1 to 1000 mg per adult, or parenterally once to several times a day in the range of 0.1 to 100 mg per adult. It is described as being administered (see, for example, Patent Document 1).
Furthermore, a method is known in which (2R) -2-propyloctanoic acid or a salt thereof is used as a therapeutic agent for cerebral ischemic disease together with a thrombolytic agent such as tissue plasminogen activator (for example, Patent Document 2). reference).
However, the treatment methods described in these publications only describe a method of parenterally administering 100 mg at a time at most. In particular, it is not known at all that doses exceeding 100 mg per dose are administered parenterally and are safe and effective in patients.

European Patent No. 0632008 International Publication No. 03/007992 Pamphlet

Tateishi.N, 8 others, Journal of cerebral blood flow & metabolism, 2002, Vol. 22, p. 723-734

  In general, when a pharmaceutical is administered at a high dose or even at a low dose for a long period of time, side effects and the like occur, and the treatment of the intended patient is limited, and a sufficient therapeutic effect is often not obtained. Among them, there has been no report on a clinically satisfactory pharmaceutical so far as a method for treating neurodegenerative diseases, particularly cerebral infarction. For example, since Radicut, a free radical scavenger, has serious side effects such as acute renal failure, it is necessary to perform a renal function test during and after administration.

  As a result of diligent investigations to find a therapeutic agent for neurodegenerative diseases, particularly cerebral infarction, the present inventors have found that a high dose of (2R) -2-propyloctanoic acid, which has not been conventionally known, exceeds 100 mg per dose. By administering the salt, a very excellent treatment effect of cerebral infarction, for example, neuropathy improvement effect, S100β increase suppression effect, etc. can be obtained very safely and with very little clinical manifestation. The present invention was completed by finding out usefulness and conducting more detailed studies based on this finding.

That is, the present invention
[1] Prevention of neurodegenerative disease, neuropathy, or disease requiring nerve regeneration, characterized by administering an effective amount of (2R) -2-propyloctanoic acid or a salt thereof to a mammal parenterally And / or treatment methods;
[2] The method according to [1] above, which is a neurodegenerative disease;
[3] The method according to [1] above, wherein the parenteral dose per administration is about 100 mg to about 2000 mg;
[4] The method according to [2] above, wherein the neurodegenerative disease is stroke;
[5] The method according to [2] above, wherein the neurodegenerative disease is cerebral infarction;
[6] The method of the above-mentioned [1], wherein the parenteral administration is intravenous administration;
[7] The method of the above-mentioned [6], wherein intravenous administration is continuous administration;
[8] The method of the above-mentioned [7], wherein the continuous administration is administration by an infusion bag;
[9] The method according to [1] above, wherein the parenteral dose per day during the dosing period of 1 to 100 days is about 100 mg to about 2000 mg;
[10] The method of the above-mentioned [9], wherein the dosing period is 1 day to 10 days;
[11] The method according to [10] above, wherein the dosing period is 3 days, 4 days, 5 days, 6 days, or 7 days;
[12] The method according to [11] above, wherein the dosing period is 7 days;
[13] The method according to [1] above, wherein the dose per kg body weight of the patient is about 2 mg to about 12 mg;
[14] The method described in [13] above, wherein the dose per kg body weight of the patient is about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg or about 12 mg;
[15] The method according to [14] above, wherein the dose per kg body weight of the patient is about 4 mg or about 8 mg;
[16] The method of the above-mentioned [1], which is a method for suppressing S100β increase;
[17] A method for inhibiting S100β increase, wherein an effective amount of (2R) -2-propyloctanoic acid or a salt thereof is parenterally administered to a mammal;
[18] The method described in [17] above, wherein the parenteral dose per administration is about 100 mg to about 2000 mg.
[19] The method of the above-mentioned [17], wherein the parenteral administration is intravenous administration.
[20] The method according to [17] above, wherein the parenteral dose per day during a dosing period of 1 to 100 days is about 100 mg to about 2000 mg;
[21] The method described in [17] above, wherein the dose per kg body weight of the patient is about 2 mg to about 12 mg;
[22] A therapeutic agent for neurodegenerative diseases, neuropathies, or diseases requiring nerve regeneration for parenteral administration, comprising (2R) -2-propyloctanoic acid or a salt thereof;
[23] Use of (2R) -2-propyloctanoic acid or a salt thereof for the manufacture of a preventive and / or therapeutic agent for neurodegenerative disease, neuropathy, or a disease requiring nerve regeneration, administered parenterally;
[24] A combination of an effective amount of (2R) -2-propyloctanoic acid or a salt thereof and an effective amount of a tissue plasminogen activator, which is administered parenterally to a mammal, Prevention and / or treatment methods;
[25] The parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 4 mg or about 8 mg per kg of the patient's body weight, and the parenteral dose of tissue plasminogen activator is The method according to [24] above, wherein the amount is about 0.6 mg or about 0.9 mg per kg body weight;
[26] The method according to [25] above, wherein the dosing start time is within 3 hours after the onset of cerebral infarction;
[27] A prophylactic and / or therapeutic agent for cerebral infarction for parenteral administration, comprising a combination of (2R) -2-propyloctanoic acid or a salt thereof and tissue plasminogen activator;
[28] Use of a combination of (2R) -2-propyloctanoic acid or a salt thereof and a tissue plasminogen activator for producing a preventive and / or therapeutic agent for cerebral infarction administered parenterally;
[29] The method according to [1], [17] or [24] above, which is a method using (2R) -2-propyloctanoic acid;
[30] The agent according to [22] or [27] above, comprising (2R) -2-propyloctanoic acid;
[31] Use of the above-mentioned [23] or [28], comprising (2R) -2-propyloctanoic acid;
[32] A brain characterized in that about 4 mg or about 8 mg of (2R) -2-propyloctanoic acid per kg of body weight is continuously administered intravenously using an infusion bag once a day during a 7-day dosing period. Infarct treatment method;
[33] A brain characterized by continuous administration of about 4 mg or about 8 mg of (2R) -2-propyloctanoic acid per kg of body weight intravenously using an infusion bag once a day during a 7-day dosing period. Infarct treatment agent;
[34] A brain characterized in that about 4 mg or about 8 mg of (2R) -2-propyloctanoic acid per kg of body weight is continuously administered intravenously using an infusion bag once a day during a 7-day dosing period. Use of (2R) -2-propyloctanoic acid for the manufacture of a therapeutic agent for infarction;
[35] S100β increase inhibitor comprising (2R) -2-propyloctanoic acid or a salt thereof;
[36] The agent according to [35] above, comprising (2R) -2-propyloctanoic acid;
[37] Use of (2R) -2-propyloctanoic acid or a salt thereof for producing an S100β increase inhibitor;
[38] Use according to the above [37], comprising (2R) -2-propyloctanoic acid;
[39] The agent described in [22] above, which is a preventive and / or therapeutic agent for neurodegenerative diseases;
[40] The agent according to [22] above, wherein the parenteral dose per administration is about 100 mg to about 2000 mg;
[41] The agent described in [39] above, wherein the neurodegenerative disease is stroke;
[42] The agent described in [39] above, wherein the neurodegenerative disease is cerebral infarction;
[43] The agent according to the above [22], wherein the parenteral administration is intravenous administration;
[44] The agent of the above-mentioned [43], wherein intravenous administration is continuous administration;
[45] The agent according to the above [44], wherein the continuous administration is administration by an infusion bag;
[46] The agent according to [22] above, wherein the parenteral dose per day during a dosing period of 1 to 100 days is about 100 mg to about 2000 mg;
[47] The agent described in [46] above, wherein the dosing period is 1 to 10 days;
[48] The agent according to the above [47], wherein the dosing period is 3 days, 4 days, 5 days, 6 days or 7 days;
[49] The agent according to the above [48], wherein the dosing period is 7 days;
[50] The agent described in [22] above, wherein the dose per kg body weight of the patient is about 2 mg to about 12 mg;
[51] The agent according to [50], wherein the dose per kg body weight of the patient is about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg or about 12 mg;
[52] The agent described in [51] above, wherein the dose per kg body weight of the patient is about 4 mg or about 8 mg;
[53] The agent described in [22] above, which is an S100β increase inhibitor;
[54] The agent of [35], wherein the parenteral dose per administration is about 100 mg to about 2000 mg;
[55] The agent of the above-mentioned [54], wherein the parenteral administration is intravenous administration;
[56] The agent described in [54] above, wherein the parenteral dose per day during a dosing period of 1 to 100 days is about 100 mg to about 2000 mg;
[57] The agent described in [54] above, wherein the dose per kg body weight of the patient is about 2 mg to about 12 mg;
[58] The parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 4 mg or about 8 mg per kg of the patient's body weight, and the parenteral dose of tissue plasminogen activator is The agent according to the above [27], which is about 0.6 mg or about 0.9 mg per kg body weight;
[59] The agent described in [58] above, which is administered within 3 hours after the onset of cerebral infarction;
[60] Use of the above-mentioned [23] for producing a preventive and / or therapeutic agent for a neurodegenerative disease;
[61] The use according to [23] above, wherein the parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 100 mg to about 2000 mg per dose;
[62] The use according to the above [60], wherein the neurodegenerative disease is a stroke;
[63] The use according to the above [60], wherein the neurodegenerative disease is cerebral infarction;
[64] The use according to the above [23], wherein the parenteral administration is intravenous administration;
[65] The use according to the above [64], wherein the intravenous administration is continuous administration;
[66] The use according to the above [65], wherein the continuous administration is administration by an infusion bag;
[67] The above [23], wherein the parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 100 mg to about 2000 mg once a day during a dosing period of 1 to 100 days. Use of;
[68] The use according to the above [67], wherein the dosing period is 1 to 10 days;
[69] The use according to the above [68], wherein the dosing period is 3 days, 4 days, 5 days, 6 days or 7 days;
[70] The use according to the above [69], wherein the dosing period is 7 days;
[71] The use according to [23] above, wherein the parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 2 mg to about 12 mg per kg body weight of the patient;
[72] The use according to the above [71], wherein the dose is about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg or about 12 mg per kg body weight of the patient;
[73] The use according to the above [72], wherein the dose is about 4 mg or about 8 mg per kg body weight of the patient;
[74] The use according to [23] above for use in suppressing S100β increase [75] The parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 100 mg to about 2000 mg per time [37] Use according to the description;
[76] The use according to the above [37], wherein the parenteral administration is intravenous administration;
[77] The aforementioned [37], wherein the parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 100 mg to about 2000 mg once a day during a dosing period of 1 to 100 days. And [78] the use according to [37] above, wherein the parenteral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 2 mg to about 12 mg per kg body weight of the patient;
Etc.

  The agent for preventing and / or treating a neurodegenerative disease, neuropathy, or disease requiring nerve regeneration for parenteral administration, comprising (2R) -2-propyloctanoic acid or a salt thereof of the present invention is safe. In addition, various symptoms associated with these diseases, particularly neurodegenerative diseases such as cerebral infarction, can be remarkably improved. In addition, cerebral infarction is also useful as a medicine because it shows an effect even in cases where 3 hours or more have elapsed since the onset, which was difficult to treat with conventional therapeutic agents. In addition, by administering a drug containing (2R) -2-propyloctanoic acid or a salt thereof to a patient who has been treated with t-PA in the hospital within 3 hours after the onset, t- Compared to treatment with PA alone, a superior therapeutic effect can also be obtained.

The result of analyzing the clinical data obtained in clinical trial example 1 according to the efficacy evaluation item (Rankin Scale) described in clinical trial example 1 is shown. The result of analyzing clinical data obtained in clinical trial example 1 according to the efficacy evaluation item (Glasgow Outcome Scale) described in clinical trial example 1 is shown. The result of analyzing the clinical data obtained in clinical trial example 2 according to the efficacy evaluation item (serum S100β content) described in clinical trial example 2 is shown.

In the present invention, (2R) -2-propyloctanoic acid has the formula (I)
(Where
Represents the β-configuration. )
It is a compound shown by these. The salt of (2R) -2-propyloctanoic acid is preferably a pharmaceutically acceptable salt. As a pharmaceutically acceptable salt, a non-toxic and water-soluble salt is preferable.

  Suitable salts of (2R) -2-propyloctanoic acid include, for example, salts with inorganic bases, salts with organic bases, salts with basic natural amino acids, and the like. As a salt with an inorganic base, for example, alkali metal salts (for example, sodium salt, potassium salt, lithium salt and the like), ammonium salts (for example, tetramethylammonium salt, tetrabutylammonium salt and the like) and the like are preferable. Examples of the salt with an organic base include alkylamine (eg, methylamine, dimethylamine, trimethylamine, triethylamine, etc.), heterocyclic amine (eg, pyridine, picoline, piperidine, etc.), alkanolamine (eg, ethanolamine, Diethanolamine, triethanolamine, etc.), dicyclohexylamine, N, N′-dibenzylethylenediamine, cyclopentylamine, benzylamine, phenethylamine, tris (hydroxymethyl) methylamine, N-methyl-D-glucamine and the like are preferred. The salt with a basic natural amino acid is not particularly limited as long as it is a salt with a basic amino acid that exists in nature and can be purified. For example, a salt with arginine, lysine, ornithine, histidine, etc. is preferable. . Among these salts, an alkali metal salt or a basic natural amino acid salt is preferable, and a sodium salt is particularly preferable.

  In the present invention, (2R) -2-propyloctanoic acid or a salt thereof is not limited to a substantially pure and single substance, but includes impurities (for example, by-products derived from the production process, solvents, Raw materials, etc., or decomposition products, etc.) may be contained as long as they are acceptable as an active pharmaceutical ingredient. The content of impurities acceptable as an active pharmaceutical ingredient varies depending on the contained impurities, for example, heavy metals are about 20 ppm or less, S-isomers that are optical isomers are about 1.49 mass% or less, and are residual solvents. It is preferable that 2-propanol and heptane are about 5000 ppm or less in total, and water is about 0.2 mass% or less.

  In the present invention, (2R) -2-propyloctanoic acid or a salt thereof is obtained by a method known per se, for example, European Patent No. 0632008, International Publication No. 99/58513, International Publication No. WO 00/49882. Various agents as pharmaceutical compositions for parenteral administration, which are produced according to the methods described in Japanese Patent Nos. 3032447 and 3084345, or by appropriately combining these methods. It can be prepared in the form of ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, suppositories, pessaries, injections, etc. . The pharmaceutical composition may be any dosage form that can be administered parenterally to patients with neurodegenerative diseases, patients with neuropathy, or patients who need nerve regeneration. In view of the above, dosage forms that can be administered intravenously, such as infusion preparations and injections, are preferred. In such dosage forms, those containing (2R) -2-propyloctanoic acid or a salt thereof in an amount of 100 mg or more per dose are preferable. Metal salts generally used for injections (for example, trisodium phosphate, disodium monohydrogen phosphate, sodium carbonate, sodium sulfite, etc.) are used for pharmaceutical compositions such as infusion preparations and injections. ) And pH regulators (eg, sodium hydroxide), stabilizers, surfactants, buffers, solubilizers, antioxidants, antifoaming agents, isotonic agents, emulsifiers, suspensions Additives, preservatives, soothing agents, solubilizers, solubilizers, etc., for example, additives such as those described in Yakuji Nippo 2000 “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association) Furthermore, electrolytes (for example, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sodium dihydrogen phosphate, sodium carbonate, magnesium carbonate, etc.), saccharides (for example, glucose, fructose, sorbitol, Ninitol, dextran, etc.), protein amino acids (eg, glycine, aspartic acid, lysine, etc.), vitamins (eg, vitamin B1, vitamin C, etc.), etc. .

  The drug comprising (2R) -2-propyloctanoic acid or a salt thereof used in the method of the present invention is useful for the prevention and / or treatment of neurodegenerative diseases. Here, the neurodegenerative diseases include all diseases associated with neuronal degeneration and are not limited by the pathogenesis. The nerve cell may be any nerve cell in the living body, for example, a central nerve (for example, cranial nerve, spinal nerve, etc.), a peripheral nerve (for example, autonomic nervous system (for example, sympathetic nerve, parasympathetic nerve, etc.), etc.) Or the like. Preferably, the neurodegenerative disease is, for example, a disease of the central nervous system, such as Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, olive bridge cerebellar atrophy, stroke (eg, cerebral hemorrhage (eg, hypertension Intracerebral hemorrhage, etc.), cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, subarachnoid hemorrhage, etc., neurological dysfunction after brain trauma, demyelinating disease (eg, multiple sclerosis) Etc.), brain tumors (eg astrocytoma etc.), infectious diseases (eg meningitis, brain abscess, Creutzfeld-Jakob disease, AIDS dementia etc.), Parkinson's disease and the like. More preferable examples of the neurodegenerative disease include stroke, and particularly preferable examples include cerebral infarction. In particular, acute cerebral infarction is preferable. Although not to be construed strictly, acute cerebral infarction means cerebral infarction within 2 weeks after onset.

  The drug containing (2R) -2-propyloctanoic acid or a salt thereof used in the method of the present invention is also useful for the prevention and / or treatment of a disease requiring nerve regeneration. Here, the nerve regeneration includes both “neurogenesis” and “nerve regeneration” which are terms used in the art. Nerve regeneration refers to at least partially reproducing the normal development process in the nerve, and is not influenced by the origin of the cells to be regenerated. Examples of the cells to be regenerated include stem cells (eg, neural stem cells, embryonic stem cells, bone marrow cells), neural progenitor cells, or neural cells. Furthermore, the cells that regenerate nerves may be endogenous cells (eg, neural stem cells, neural progenitor cells, neural cells, mature neural cells, etc.) or exogenous cells (eg, transplanted neural stem cells, transplanted neural progenitor cells). Transplanted nerve cells, transplanted mature nerve cells, etc.). The exogenous cell may be an autologous cell or a cell derived from another family. Furthermore, even cells that are undifferentiated from neural stem cells are all included in nerve regeneration in the present invention as long as they differentiate through neural stem cells. In addition, nerve regeneration includes tissue regeneration or functional regeneration, and includes, for example, the above-described cell engraftment, differentiation, proliferation and / or maturation. Here, maturation means, for example, that a nerve cell grows into a functionally active state such as signal exchange. The regeneration also includes a neurotrophic factor-like action and a neurotrophic factor activity enhancing action. Here, the neurotrophic factor represents a factor that acts as a nutrient for neural stem cells, neural progenitor cells, neurons, mature neurons, and the like. Examples of the neurotrophic factor-like action include axon extension action, neurotransmitter synthesis promoting action, nerve cell differentiation / proliferation action, and action as a nutrient that maintains nerve cell activity. However, it is not limited to these. The neurotrophic factor activity enhancing action means an activity that enhances the action of the neurotrophic factor.

  The drug comprising (2R) -2-propyloctanoic acid or a salt thereof used in the method of the present invention is also useful for the prevention and / or treatment of neuropathy. Here, the neurological disorder includes all disorders of neural function. Examples of neurological disorders include transient blindness (for example, transient cataract), consciousness disorder, contralateral hemiplegia, sensory disorder, homonymous half-blindness, aphasia, alternating hemiplegia, bilateral limb paralysis, Homogeneous half-blindness, dizziness, tinnitus, nystagmus, double vision, coma and the like can be mentioned, and these neurological disorders associated with neurodegenerative diseases are preferable. Neuropathy associated with neurodegenerative diseases, for example, neuropathy in cerebral infarction varies depending on the site of vascular occlusion, and the symptoms differ depending on the level of damage, but the above-mentioned neuropathy is mainly observed. In addition, the presence or absence of neuropathy in cerebral infarction may be determined by various diagnostic tests known in the art for detecting neuropathy. Specific examples of the diagnostic test include, for example, Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS), Rankin Scale (RS), Modified Rankin Scale (modified Rankin) Scale: mRS), disability rating scale (DRS), NIH Stroke Scale (NIHSS), and the like, which can be performed using known methods. Diagnostic tests for detecting these neurological disorders may be performed in appropriate combination with a test method for detecting physical brain abnormalities, for example, a CAT scan or measurement of intracranial pressure. In general, in clinical trials conducted on patients with cerebral infarction, the above-described diagnostic test is conducted as a main evaluation item to evaluate the effectiveness. In addition, secondary evaluation items as desired include, for example, consciousness level, motor function, Barthel Index, general safety, outcome, head CT findings, head MRI findings, blood pressure, pulse rate, body temperature, general clinical examination, etc. A known evaluation item may be evaluated by a known method and used alone or in combination with the main evaluation item for evaluation of effectiveness.

  The drug containing (2R) -2-propyloctanoic acid or a salt thereof used in the method of the present invention has an S100β increase inhibitory action. (2R) -2-propyloctanoic acid or a salt thereof also prevents the above-mentioned disorders and diseases (for example, neurodegenerative diseases, neurological disorders, or diseases that require nerve regeneration, etc.) and / or by suppressing S100β increase. Or it can function as a therapeutic agent. The inhibitory action of (2R) -2-propyloctanoic acid or a salt thereof on S100β increase does not limit the action site to brain tissue. That is, it may be a systemic action or a local action, and the S100β increase inhibitory action may be confirmed systemically or locally. The method for detecting S100β used for confirming the S100β increase inhibitory action is not particularly limited as long as it can detect S100β. As a detection method of S100β, for example, commercially available immunization such as a kit sold by Byc-Sangtec Diagnostica GmbH & Co. (Diezenbach, Germany) or Syn-X Pharma, Inc. (Ontario, Canada). Using a radiation measurement assay kit, a luminescence measurement immunoassay kit, a fluorescence measurement immunoassay kit, a chromogenic measurement immunoassay kit, etc., measurement is performed in a patient's blood or a fraction thereof (for example, serum, etc.) or a biological sample such as cerebrospinal fluid. be able to. Depending on the number of specimens, known methods used for protein detection by those skilled in the art, for example, various biological experimental methods using anti-S100β antibody (eg, Western blotting, immunoprecipitation, flow cytometry, etc.) You may measure using. As the S100β increase inhibitory action by (2R) -2-propyloctanoic acid or a salt thereof, one detected in the blood of a patient or a fraction thereof (for example, serum) is preferable. The inhibitory effect on S100β increase in the patient's blood or a fraction thereof (eg, serum) is not affected by the cause of the increase in S100β or the mechanism of action for suppressing S100β increase. For example, the increase in S100β in the patient's blood or a fraction thereof (eg, serum) may reflect an increase in the local area of the infarct, the surrounding brain tissue, or the entire brain tissue due to a disorder. Alternatively, the level of S100β that is normally present in the cell may reflect that it has flowed out due to tissue or cell damage. Moreover, even if the S100β increase inhibitory action in the patient's blood or a fraction thereof (for example, serum, etc.) is due to the suppression of infarct enlargement, the outflow from the brain tissue to the blood is suppressed. It may be caused by the fact that it has been caused, or it may be caused by suppressing the increase in S100β at the cell level.

  In the present invention, (2R) -2-propyloctanoic acid or a salt thereof is administered parenterally to a patient for the prevention and / or treatment of a neurodegenerative disease, neuropathy, or a disease requiring nerve regeneration. In particular, there is no particular limitation as long as it is a method of administering a dose of about 100 mg or more (for example, about 100 mg to about 2000 mg) at a time. Examples of typical dosing period, dosing frequency, dose, and administration method include those exemplified below.

The dosing period may be continuously administered for any number of days in order to obtain a preferable prophylactic and / or therapeutic effect on the above-mentioned diseases. If desired, it may be administered intermittently with an appropriate drug holiday. Specific examples of the dosing period include 1 day to 100 days. The preferred dosing period is, for example, 1 day to 10 days, etc., the more preferred dosing period is, for example, 3, 4, 5, 6, 7 days, etc. The most preferred dosing period is, for example, 7 days.
In order to obtain a preferable preventive and / or therapeutic effect on the above-mentioned diseases, any number of doses may be used. Moreover, you may change according to a patient's condition and other reasons. Specific examples of the number of administrations per day include 1 to 5 times. The preferred number of doses per day is, for example, 1 to 3 times, etc., the more preferred number of doses per day is, for example, 1 to 2 times, etc., and the most preferred number of doses per day is, for example, 1 time etc.

  As described above, the dose is not particularly limited as long as it is about 100 mg or more (for example, about 100 mg to about 2000 mg, etc.), but in order to obtain a preferable preventive and / or therapeutic effect for the above-mentioned diseases, patients It is preferable to be defined by the body weight. When (2R) -2-propyloctanoic acid is administered parenterally, it is preferable to administer, for example, about 2 mg to about 12 mg per kg of the patient's body weight. More specific doses include, for example, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, or about 12 mg per kg of the patient's body weight. More preferred doses include, for example, about 4 mg, about 6 mg, about 8 mg, or about 10 mg per kg patient body weight, and the most preferred dose is, for example, about 4 mg or about about 1 mg per kg patient body weight. 8 mg etc. are mentioned. Moreover, when administering the salt of (2R) -2-propyloctanoic acid parenterally, the dosage shown above is suitable as the amount of (2R) -2-propyloctanoic acid.

  As described above, the administration method is not particularly limited as long as it is a method for parenteral administration. However, in order to obtain a preferable preventive and / or therapeutic effect on the disease, a dosage form that can be administered intravenously, for example, It is preferable to prepare and use for injections and infusion preparations. By making it into a dosage form that can be administered intravenously, it is possible to obtain a rapid onset of effects by (2R) -2-propyloctanoic acid or a salt thereof. Furthermore, (2R) -2-propyloctanoic acid or a salt thereof prepared as such an intravenously administrable dosage form is continuously administered intravenously using, for example, a syringe or an infusion bag, It is also possible to avoid side effects associated with a rapid increase in blood concentration, and to control the blood concentration and the like as desired. The duration of continuous administration is not particularly limited, and may be changed depending on the patient's condition and other reasons. For example, the duration is about 0.5 hours to about 3 hours, preferably about 0.5 hours to about 1 It is preferable to continuously administer for 5 hours, particularly preferably about 1 hour.

  In the present invention, about 100 mg to about 2000 mg of (2R) -2-propyloctanoic acid or a salt thereof is not used for the prevention and / or treatment of a neurodegenerative disease, neuropathy, or a disease requiring nerve regeneration. A preferred method of oral administration includes, for example, from about 2 mg to about 12 mg (2R) -2-propyloctanoic acid or a salt thereof per kg of patient body weight per day during a dosing period of 1 to 100 days. And a method of continuously administering intravenously over about 1 hour using an infusion bag or the like.

  The drug containing (2R) -2-propyloctanoic acid or a salt thereof used in the method of the present invention is another drug such as an antiepileptic drug (for example, phenobarbital, mehobarbital, metalbital, primidone). Phenytoin, ethotoin, trimetadione, ethosuximide, acetylphenetride, carbamazepine, acetazolamide, diazepam, sodium valproate, etc.), acetylcholinesterase inhibitor (eg, donevezil hydrochloride, TAK-147, rivastigmine, galantamine, etc.), neurotrophic factor (eg, , ABS-205, etc.), aldose reductase inhibitors, antithrombotic agents (eg, t-PA, heparin, etc.), oral anticoagulants (eg, warfarin, etc.), synthetic antithrombin agents (eg, gabexate mesylate, mesyl) acid Famostat, argatroban, etc.), antiplatelet drugs (eg, aspirin, dipyridamole, ticlopidine hydrochloride, beraprost sodium, cilostazol, ozagrel sodium, etc.), thrombolytic drugs (eg, urokinase, tisokinase, alteplase, etc.), factor Xa inhibitor, factor VIIa Inhibitors, cerebral circulation metabolism improving drugs (for example, idebenone, calcium hopantenate, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, pyrithioxine hydrochloride, γ-aminobutyric acid, bifemelane hydrochloride, lisuride maleate, indeloxy hydrochloride Sazine, nicergoline, propentofylline, etc.), antioxidants (eg, edaravone, etc.), glycerin preparations (eg, glycerol, etc.), β-secretase inhibitors (eg, 6- (4- Biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin, 6- (4-biphenylyl) Methoxy-2- (N, N-dipropylamino) methyltetralin, 2- (N, N-dimethylamino) methyl-6- (4′-methoxybiphenyl-4-yl) methoxytetralin, 6- (4-biphenylyl) ) Methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin, 2- [2- (N, N-dimethylamino) ethyl] -6- (4′-methylbiphenyl-4-yl) methoxytetralin 2- [2- (N, N-dimethylamino) ethyl] -6- (4′-methoxybiphenyl-4-yl) methoxytetralin, 6- (2 ′, 4 ′ Dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- [4- (1,3-benzodioxol-5-yl) phenyl] methoxy-2 -[2- (N, N-dimethylamino) ethyl] tetralin, 6- (3 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin , Optically active forms thereof, salts thereof and hydrates thereof, OM99-2 (WO01 / 00663) and the like, β amyloid protein aggregation inhibitory agents (for example, PTI-00703, ALZHEMED (NC-531), PPI-368 ( No. 11-514333), PPI-558 (No. 2001-500852), SKF-74652 (Biochem. J. et al. 340 (1), 283-289 (1999), etc.), brain function activators (eg, aniracetam, nicergoline, etc.), dopamine receptor agonists (eg, L-dopa, bromocriptine, pergolide, talipexol, pramipexole) , Cabergoline, amantadine, etc.), monoamine oxidase (MAO) inhibitors (eg, safradine, deprenyl, sergiline (selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexyphenidyl, Biperidene, etc.), COMT inhibitors (eg, entacapone, etc.), amyotrophic lateral sclerosis (eg, riluzole, etc.), statin hyperlipidemia (eg, pravastatin sodium, atto Lovastatin, simba Tatin, rosuvastatin, etc.), fibrate hyperlipidemia drug (eg, clofibrate, etc.), apoptosis inhibitor (eg, CPI-1189, IDN-6556, CEP-1347, etc.), neuronal differentiation / regeneration promoter (eg, , Reteprim, xaliproden (SR-57746-A), SB-216763, etc., non-steroidal anti-inflammatory drugs (eg, meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (For example, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (for example, progesterone, estradiol, estradiol benzoate, etc.) may be used in combination. Also, nicotine receptor modulator, γ-secretase inhibitor, β-amyloid vaccine, β-amyloid degrading enzyme, squalene synthetase inhibitor, therapeutic agent for abnormal behavior and epilepsy associated with dementia progression, antihypertensive agent, antidiabetic agent, Even when used together with antidepressants, anxiolytics, disease-modifying antirheumatic drugs, anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), parathyroid hormone (PTH), calcium receptor antagonists, etc. Good. The above concomitant drugs are illustrative and are not limited thereto. Other drugs may be administered in combination of any two or more. In addition, the drugs used in combination include not only those found so far, but also those that will be found in the future based on the above-described mechanism.

  Among the above-mentioned neurodegenerative diseases, neurological disorders or diseases that require nerve regeneration, for example, diseases associated with thrombus generation such as cerebral infarction are treated with (2R) -2-propyloctanoic acid or a salt thereof. Among the above-listed concomitant drugs, it is particularly preferable to use in combination with t-PA when administering the contained drug. By using in combination with t-PA, an excellent therapeutic effect can be obtained as compared with the case where each is used alone. The method of combining a drug containing (2R) -2-propyloctanoic acid or a salt thereof and t-PA is not particularly limited, but preferably, the dosage and the administration method when each drug is used alone. Just follow. The dosage and administration method of a drug containing (2R) -2-propyloctanoic acid or a salt thereof are as described above. The dosage and administration method of t-PA alone is, for example, about 0.6 mg or about 0.9 mg per kg of the patient's body weight parenterally within 6 hours, preferably within 3 hours after the onset of cerebral infarction. In particular, it is preferably administered intravenously. More specifically, 10% of the total dose to be administered is rapidly administered over several minutes (eg, about 1 minute to about 2 minutes), and then the rest is administered over about 1 hour. Therefore, in order to use a combination of a drug containing (2R) -2-propyloctanoic acid or a salt thereof and t-PA, for example, t-PA is treated by the above method within 3 hours after the onset of cerebral infarction. (2R) -2-propyloctanoic acid or a salt thereof is administered at any time, preferably within 2 weeks after the onset of cerebral infarction, more preferably within 72 hours after the onset of cerebral infarction. Administration may be carried out according to the dosing period, dosing frequency, dose, and administration method of a drug containing 2-propyloctanoic acid or a salt thereof. Therefore, t-PA and (2R) -2-propyloctanoic acid or a salt thereof can be administered simultaneously within 3 hours after the onset of cerebral infarction. In the case of simultaneous administration, separate preparations may be used, or a preparation containing both t-PA and (2R) -2-propyloctanoic acid or a salt thereof in one preparation. Of course, these administration methods are examples, and may be appropriately increased or decreased depending on the condition of the patient.

[toxicity]
As shown in the examples below, the toxicity of (2R) -2-propyloctanoic acid or a salt thereof is very low. In particular, as long as it is used for mammals, particularly humans, in the dosage and administration of the present invention, It can be judged that it is sufficiently safe.

[Application to pharmaceutical products]
The preventive and / or therapeutic agent for neurodegenerative diseases, neuropathies, or diseases requiring nerve regeneration for parenteral administration, comprising (2R) -2-propyloctanoic acid or a salt thereof of the present invention is a mammal. (For example, humans and non-human animals such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, mice, etc.) and the like can be used. In particular, a preferred preventive and / or therapeutic effect on neurodegenerative diseases, neurological disorders, or diseases requiring nerve regeneration is obtained by parenteral administration to mammals, preferably humans, in the dosage and administration of the present invention. be able to. The usage / dosage of the present invention is suitable for obtaining an effect of improving various symptoms of cerebral infarction patients. The usage of the present invention may be applied at any time after the onset of cerebral infarction. Preferably, it is within 2 weeks, more preferably within 2 to 5 days, particularly preferably within 24 hours, and particularly within 6 hours, which is regarded as TTW of cerebral infarction. The usage of the present invention overcomes the limitation on the administration time of a therapeutic agent such as t-PA, which has been used in conventional cerebral infarction treatment, and the effect obtained by the usage is remarkably excellent.

  Hereinafter, the clinical effects of patients with cerebral infarction using (2R) -2-propyloctanoic acid or a salt thereof using the dosage and administration of the present invention will be described in detail with reference to Examples and Formulation Examples. Is not limited to these. Moreover, you may change in the range which does not deviate from the range of this invention.

Example 1:
As a clinical trial, a randomized trial with 2 doses was performed on patients with acute cerebral infarction (within 72 hours after onset) under the following conditions.
Subjects: 97 patients with acute cerebral infarction.
Dosage and administration: Intravenous continuous administration once a day for 1 hour in each group;
(1) (2R) -2-propyloctanoic acid 0.4 mg / kg / h;
(2) (2R) -2-propyloctanoic acid 4 mg / kg / h.
Administration period: 7 days Number of cases:
(1) (2R) -2-propyloctanoic acid 0.4 mg / kg / h administration group 51 patients;
(2) (2R) -2-propyloctanoic acid 4 mg / kg / h administration group 46 patients.
Evaluation item:
Main endpoint <Efficacy endpoint>
(1) Rankin Scale (RS)
Evaluation method: The patient's symptoms were classified into the grades shown in Table 1 below and scored.
(2) Glasgow Outcome Scale (GOS)
Evaluation method: The patient's symptoms were classified into the grades shown in Table 2 below and scored.
<Safety evaluation items>
Incidence rate and content of adverse events (symptoms, causality, etc.)
Analysis: The therapeutic effect of continuous administration of (2R) -2-propyloctanoic acid was evaluated using the main evaluation items described above.
Results: Results are shown below.
<Effectiveness evaluation items>
In cases where Japan Stroke Scale (JSS: evaluated according to literature (Stroke, 32, 1800-1807, 2001)) is 15 or less (JSS ≦ 15) before administration, RS and GOS 3 months after the start of administration There was a statistically significant difference between the 0.4 mg / kg / h administration group and the 4 mg / kg / h administration group in terms of the proportion of the improvement category. The results are shown in FIG. 1 and FIG.
<Safety evaluation items>
In this study, 7 deaths (3 in the 0.4 mg / kg / h administration group, 4 in the 4 mg / kg / h administration group) and other serious adverse events in the 0.4 mg / kg / h administration group In one case, a causal relationship with the study drug was denied. The incidence of adverse events was 78.9% in the 0.4 mg / kg / h administration group and 74.1% in the 4 mg / kg / h administration group, and no significant difference was observed between the two groups. The incidence of side effects was 43.9% in the 0.4 mg / kg / h administration group and 44.4% in the 4 mg / kg / h administration group, and no significant difference was observed between the two groups. The main content of side effects was an increase in liver function parameters “AST (GOT), ALT (GPT), γ-GTP, Al-p, LDH, total bilirubin”, but none of them was serious. It was.

Example 2:
As a clinical trial, a double-blind study using the (2R) -2-propyloctanoic acid administration group (6 doses) and the placebo administration group under the following conditions in patients with acute cerebral infarction (within 24 hours after onset) Carried out.
Subjects: 92 patients with acute cerebral infarction.
Dosage and administration: Intravenous continuous administration once a day for 1 hour in each group;
(1) (2R) -2-propyloctanoic acid 2 mg / kg / h;
(2) (2R) -2-propyloctanoic acid 4 mg / kg / h;
(3) (2R) -2-propyloctanoic acid 6 mg / kg / h;
(4) (2R) -2-propyloctanoic acid 8 mg / kg / h;
(5) (2R) -2-propyloctanoic acid 10 mg / kg / h;
(6) (2R) -2-propyloctanoic acid 12 mg / kg / h;
(7) Placebo.
Administration period: 7 days Number of cases:
(1) (2R) -2-propyloctanoic acid 2 mg / kg / h administration group 9 patients;
(2) (2R) -2-propyloctanoic acid 4 mg / kg / h administration group 8 patients;
(3) (2R) -2-propyloctanoic acid 6 mg / kg / h administration group 8 patients;
(4) (2R) -2-propyloctanoic acid 8 mg / kg / h administration group 8 patients;
(5) (2R) -2-propyloctanoic acid 10 mg / kg / h administration group 8 patients;
(6) (2R) -2-propyloctanoic acid 12 mg / kg / h administration group 8 patients;
(7) Placebo administration group 43 patients.
Evaluation item:
Main endpoint <Efficacy endpoint>
(1) modified Rankin Scale (mRS)
Evaluation method: The patient's symptoms were classified into the grades shown in Table 3 below and scored.
(2) Serum S100β content evaluation method: The blood of a patient was collected and evaluated according to the following method.
(2-1) Blood collection Blood for S100β measurement is 7 hours before administration (Pre-infusion) from day 1 to day 7 and 3 hours after administration on day 1, day 3, day 7. Thereafter, it was collected 12 hours later and 24 hours later (Post-infusion). In addition, the blood 24 hours after the administration on the first day and the third day was the same blood as that before the administration on the second day and the fourth day, respectively.
A blood sample (3 mL) was taken from each patient by catheter or venipuncture. Samples were allowed to clot for 30 minutes and centrifuged at 3500 rpm for 12-15 minutes. Serum was collected and dispensed into two containers of approximately 0.5 mL each. Serum samples were labeled and stored at −20 ° C. until analysis of S100β.
(2-2) S100β assay SMART S100 ELISA Kit (Syn-X Pharma, Inc. (Ontario, Canada)) having a measurement range of 0.02-1.6 ng / mL was used for the measurement of S100β.
<Safety evaluation items>
Adverse events, laboratory test value analysis: The therapeutic effects of intravenous administration of (2R) -2-propyloctanoic acid were evaluated using the main evaluation items described above.
Results: Results are shown below.
<Effectiveness evaluation items>
As a result of evaluating the modified Rankin Scale (mRS) 40 days after the start of administration, the ratio of scores of 2 or less corresponding to the category of favorable improvement was as follows: placebo administration group and (2R) -2-propyloctanoic acid 8 mg / kg / There was a statistically significant difference between the h administration groups (placebo administration group: 32.5%, (2R) -2-propyloctanoic acid 8 mg / kg / h administration group: 87.5%).
In addition, as a result of evaluating the serum S100β content during the administration period, the (2R) -2-propyloctanoic acid administration group tended to suppress the increase in serum S100β after the onset of cerebral infarction compared with the placebo administration group. It was. In particular, the tendency was remarkable after 3 days from the start of administration. The results are shown in FIG.
<Safety evaluation items>
Serious adverse events were observed in 10 cases in the (2R) -2-propyloctanoic acid administration group and 12 cases in the placebo administration group, but a causal relationship with the study drug was denied in both cases. The incidence of adverse events was 98% in the (2R) -2-propyloctanoic acid administration group and 100% in the placebo administration group, and there was no difference between the two groups. The incidence of adverse events (side effects) for which a causal relationship with the study drug could not be ruled out was 42.9% in the (2R) -2-propyloctanoic acid administration group and 39.5% in the placebo administration group. Was not recognized. In addition, no side effect of increasing the frequency of expression depending on the dose was observed.

Formulation example:
Preparation Example 1 of (2R) -2-propyloctanoic acid-containing injection
・ (2R) -2-propyloctanoic acid 2.0 kg
・ Trisodium phosphate ・ 12 hydrate 3.54kg
Each of the above components was added to water for injection, and the volume was made 40 L using water for injection. After preparing a uniform solution, filter with a sterile filter (Durapore 0.22 μm membrane), fill 2 mL each into a plastic ampule, and sterilize with high pressure steam (123 ° C., 15 minutes) to contain 100 mg of active ingredient in one ampule. I got 20,000 ampoules.

  The agent for preventing and / or treating a neurodegenerative disease, neuropathy, or disease requiring nerve regeneration for parenteral administration, comprising (2R) -2-propyloctanoic acid or a salt thereof of the present invention is safe. In addition, various symptoms associated with these diseases, particularly neurodegenerative diseases such as cerebral infarction, can be remarkably improved. In addition, cerebral infarction is also useful as a medicine because it shows an effect even in cases where 3 hours or more have elapsed since the onset, which was difficult to treat with conventional therapeutic agents.

Claims (1)

  (2R) -2-propyloctanoic acid or a salt thereof containing (2R) -2-propyloctanoic acid or a salt thereof in an amount of more than 100 mg at a dose of about 2 mg / kg / h to about 12 mg / kg / h Is a preventive and / or therapeutic agent for cerebral infarction, which is characterized by being administered intravenously once a day.