WO2005032537A1 - Method for preventing and/or treating neurodegenerative diseases - Google Patents
Method for preventing and/or treating neurodegenerative diseases Download PDFInfo
- Publication number
- WO2005032537A1 WO2005032537A1 PCT/JP2004/014893 JP2004014893W WO2005032537A1 WO 2005032537 A1 WO2005032537 A1 WO 2005032537A1 JP 2004014893 W JP2004014893 W JP 2004014893W WO 2005032537 A1 WO2005032537 A1 WO 2005032537A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- administration
- salt
- days
- dose
- per
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a medicament comprising (2R) -2-propyloctanoic acid or a salt thereof, which is parenterally administered for the prevention and/or treatment of a neurodegenerative disease, for the prevention and/or treatment of a neuropathy or for the prevention and/or treatment of a disease whose treatment requires neural regeneration.
- a method for preventing and/or treating cerebral infarction which comprises parenterally administering (2R) -2-propyloctanoic acid or a salt thereof at a high dose of exceeding about 100 mg per one administration.
- Cerebral infarction is a disease exemplified as a cause of stroke together with cerebral bleeding and subarachnoid hemorrhage. Cerebral infarction is a neurodegenerative disease in which arteriosclerosis of a brain blood vessel or obstruction of a brain blood vessel caused by thrombi brought therein stops blood flow ahead thereof to cease feeding of nutrients into brain cells and finally causes the death of nerve cells. In addition, even when a patient with cerebral infarction has escaped sudden death, it sometimes leaves serious secondary diseases such as hemiplegia and aphasia caused by functional disorder of nerve cells.
- TTW therapeutic time window
- Examples of the currently and mainly used as cerebral infarction treating agents include thrombolytic agents such as tissue plasminogen activator (t-PA) and urokinase, anticoagulants such as warfarin and heparin, and free radical scavengers such as Radicut (edalabon) (product name: manufactured by Mitsubishi Pharma Corporation) .
- thrombolytic agents such as tissue plasminogen activator (t-PA) and urokinase
- anticoagulants such as warfarin and heparin
- free radical scavengers such as Radicut (edalabon) (product name: manufactured by Mitsubishi Pharma Corporation) .
- Radicut (edalabon) (product name: manufactured by Mitsubishi Pharma Corporation)
- t-PA shows its efficacy only when it is administered within 3 hours after onset of cerebral infarction, namely within TTW, and with respect to anticoagulants, since it takes several days to express the anticoagulation action, the effects could hardly be said to be sufficient
- S-lOO ⁇ a kind of the S-100 protein, is a protein which is present at a high concentration in glial cells and Schwann cells in the central nervous system and peripheral nervous system and also in anterior pituitary cells and Langerhans cells. It is known that S-lOO ⁇ in cerebrospinal fluid or blood is increased by cerebral infarction, subarachnoid hemorrhage, head injury, various neurodegenerative diseases or a nervous complication after a heart-lung bypass operation.
- (2R) -2-propyloctanoic acid which has activity of reducing the intracellular S-lOO ⁇ content, has a potentiality to be used as an agent for the treatment or prevention of various cranial nerve diseases including stroke, through the improvement of the function of abnormally activated astrocyte (e.g., see Tateishi, N. and 8 others, Journal of Cerebral Blood Flow & Metabolism, 22(6), 723-734 (2002) ) .
- pentanoic acid derivatives including (2R) -2-propyloctanoic acid have an action to improve functions of astrocyte, it is known that they are effective for treating stroke and other various diseases.
- the present invention relates to [1] a method for preventing and/or treating a neurodegenerative disease, neuropathy or a disease whose treatment requires neural regeneration, which comprises parenteral administration of an effective amount of (2R) -2-propyloctanoic acid or a salt thereof to a mammal; [2] the method according to above [1], wherein the disease to be treated with the method is neurodegenerative disease; [3] the method according to above [1], wherein the amount per dose in the parenteral administration is within a range of about 100 mg to about 2,000 mg; [4] the method according to above [2] , wherein the neurodegenerative disease is stroke; [5] the method according to above [2] , wherein the neurodegenerative disease is cerebral infarction; [6] the method according to above [1], wherein the parenteral administration is intravenous administration; [7] the method according to above [6], wherein the intravenous administration is continuous administration; [8] the method according to above [7], wherein the continuous administration
- 1 kg of body weight of a patient is about 2 mg, about 4 mg, about
- 1 kg of body weight of a patient is about 4 mg or about 8 mg; [16] the method according to above [1] , which is a method for inhibition of S-lOO ⁇ increase; [17] a method for inhibition of S-lOO ⁇ increase, which comprises parenterally administering to a mammal an effective amount of (2R) -2-propyloctanoic acid or a salt thereof; [18] the method according to above [17], wherein the amount per dose in the parenteral administration is within a range of about
- a parenterally administered agent for preventing and/or treating a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration which comprises
- (2R) -2-propyloctanoic acid or a salt thereof [23] use of (2R) -2-propyloctanoic acid or a salt thereof for the manufacture of a parenterally administered agent for preventing and/or treating a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration; [24] a method for preventing and/or treating cerebral infarction, which comprises parenterally administering to a mammal an effective amount of (2R) -2-propyloctanoic acid or a salt thereof in combination with an effective amount of a tissue plasminogen activator; [25] the method according to above [24], wherein the dose of (2R) -2-propyloctanoic acid or a salt thereof per 1 kg of body weight of a patient is about 4 mg or about 8 mg, and the dose of the tissue plasminogen activator per 1 kg of body weight of a patient is about 0.6 mg or about 0.9 mg; [26] the method according to above [25], wherein
- a parenterally administered agent for preventing and/or treating cerebral infarction which comprises (2R) -2-propyloctanoic acid or a salt thereof in combination with a tissue plasminogen activator;
- the parenterally administered agent according to above [39], wherein the neurodegenerative disease to be treated is stroke;
- the parenterally administered agent for preventing and/or treating cerebral infarction method according to above [58] which is administered within 3 hours after onset of the cerebral infarction;
- the (2R) -2-propyloctanoic acid or a salt thereof for the manufacture of an agent according to above [37], wherein the dose per 1 kg of body weight of a patient is within a range of about 2 mg to about 12 mg; and the like.
- the (2R) -2-propyloctanoic acid is a compound represented by a formula (I)
- (2R) -2-propyloctanoic acid a pharmaceutically acceptable salt is preferable.
- pharmaceutically acceptable salt those which have no toxicity and are soluble in water are desirable.
- Examples of the appropriate salt of (2R) -2-propyloctanoic acid include a salt with an inorganic base, a salt with an organic base, a salt with a basic natural amino acid, and the like.
- Examples of the salt with inorganic base include alkali metal salts (e.g., sodium salt, potassium salt, lithium salt) , ammonium salts (e.g., tetramethylammonium salt, tetrabutylammonium salt) and the like.
- alkali metal salts e.g., sodium salt, potassium salt, lithium salt
- ammonium salts e.g., tetramethylammonium salt, tetrabutylammonium salt
- Examples of the salt with organic base include salts with alkyl amine (e.g., methylamine, dimethylamine, trimethylamine, triethylamine) , heterocyclic amine (e.g., pyridine, picoline, piperidine) , alkanolamine (e.g., ethanolamine, diethanolamine, triethanolamine) , dicyclohexylamine, N,N' -dibenzylethylenediamine, cyclopentylamine, benzylamine, phenetylamine, tris (hydroxymethyl) methylamine, N-methyl-D-glucamine and the like.
- alkyl amine e.g., methylamine, dimethylamine, trimethylamine, triethylamine
- heterocyclic amine e.g., pyridine, picoline, piperidine
- alkanolamine e.g., ethanolamine, diethanolamine, triethanolamine
- dicyclohexylamine N,
- the salt with basic natural amino acid is not particularly limited, so long as it is a salt with a basic amino acid which is distributed in the natural sources and can be purified, and its preferred examples include salts with arginine, lysine, ornithine, histidine and the like.
- these salts preferred are an alkali metal salt or a basic natural amino acid salt, and particularly preferred is a sodium salt.
- (2R) -2-propyloctanoic acid or a salt thereof is not limited to a substantially pure single substance, and it may contain impurities (e.g., a byproduct, a solvent, a material originated from the production process, a degraded product) , within such a range that they are acceptable as pharmaceutical materials.
- the amount of impurities acceptable as pharmaceutical materials varies depending on each impurity to be contained, and it is desirable for example that heavy metals are about 20 ppm or less, S-forms as optical isomers are about 1.49% by mass or less, 2-propanol and heptane as residual solvents are about 5, 000 ppm or less in total and the water content is about 0.2% by mass or less.
- (2R) -2-propyloctanoic acid or a salt thereof can be produced in accordance with a known method, for example, a method described in the specification of European Patent No. 0632008, International Publication No. 99/58513, International Publication No. 00/48982, Japanese Patent No.
- Japanese Patent No.3084345 or the like, or by optionally combining these methods, and, as a pharmaceutical composition for parenteral administration use, it can be prepared into various dosage forms such as ointments, gels, creams, fomentations, adhesive preparations, liniments, atomized agents, inhalations, sprays, eye drops, suppositories, pessaries, injections and the like.
- the pharmaceutical composition may be in any dosage forms which can be parenterally administered to a patient of a neurodegenerative disease, a patient of a neuropathy or a patient of a disease whose treatment requires neural regeneration, but when both of its immediate effect and blood concentration control are taken into consideration, dosage forms which can be intravenously administered, such as transfusion preparations, injections and the like, are desirable.
- dosage forms which can be intravenously administered, such as transfusion preparations, injections and the like, are desirable.
- Preferred as such dosage forms are those which contain 100 mg or more of (2R) -2-propyloctanoic acid or a salt thereof per one administration.
- additives described, for example, in Dictionary of Pharmaceutical Additives (edited by Japan Pharmaceutical Additives Association), published by Yakuj i Nipposha in 2000, such as metal salts (e.g., sodium phosphate, disodium hydrogenphosphate, sodium carbonate, sodium sulfite) and pH adjuster (e.g., sodium hydroxide) , as well as a stabilizing agent, a surfactant, a buffer agent, a solubilizing agent, an antioxidant, an antifoaming agent, a tonicity agent, an emulsifying agent, a suspending agent, a preservative, a soothing agent, a resolvent, a solubilization assisting agent and the like, which are generally used in injections, and also from components generally used in transfusions such as electrolytes (e.g.
- saccharides e.g., glucose, fructose, sorbitol, mannitol, dextran
- protein amino acids e.g., glycine, aspartic acid, lysine
- vitamins e.g., vitamin Bl, vitamin C
- the agent comprising (2R) -2-propyloctanoic acid or a salt thereof to be used in the method of the present invention is useful for the treatment of neurodegenerative diseases.
- the neurodegenerative diseases include all diseases which are accompanied by degeneration of nerve cells and are not limited by the cause of diseases .
- the nerve cells may be any type of nerve cells in vivo and, for example, they may be cells of central nerves (e.g., cranial nerves, spinal nerves) or peripheral nerves (e.g., of autonomic nerve system (such as sympathetic nerve and parasympathetic nerve)) and the like.
- the neurodegenerative diseases are desirably diseases of central nerves, and their examples include Alzheimer disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, olivopontocerebellar atrophy, strokes (e.g., cerebral bleeding (such as hypertensive intracerebral hemorrhage) , cerebral infarction (such as cerebral thrombosis and cerebral embolism) , transient ischemic attack, subarachnoid hemorrhage) , neurological dysfunction after brain injury, demyelinating diseases (e.g., multiple sclerosis) , brain tumors (e.g., astrocytoma) , infectious diseases (e.g., meningitis, brain abscess, Creutzfeldt-Jacob disease, AIDS dementia) , Parkinson disease and the like.
- Alzheimer disease amyotrophic lateral sclerosis, progressive supranuclear palsy, olivopontocerebellar atrophy
- strokes e
- neurodegenerative diseases are, for example, stroke and the like, and particularly preferred are, for example, cerebral infarction and the like.
- Acute phase cerebral infarction is most particularly desirable. Though it should not be interpreted strictly, the acute phase cerebral infarction means cerebral infarction within 2 weeks after onset.
- the agent comprising (2R) -2-propyloctanoic acid or a salt thereof, to be used in the method of the present invention is also useful for the treatment of a disease whose treatment requires neural regeneration.
- the neural regeneration includes both of "neural neogenesis” and “neural regeneration” as the terms used in said field.
- the neural regeneration means that the process of normal development in nerve cells is at least partially reproduced, and it is not influenced by the origin of the cells to be regenerated.
- the cells to be regenerated include stem cells (e.g., nervous stem cell, embryonic stem cell, bone marrow cell) , nerve precursor cells, nerve cells and the like.
- the nerve cells to be regenerated may be either endogenous cells (e.g., nerve stem cell, nerve precursor cell, nerve cell, mature nerve cell) or exogenous cells (e.g., grafted nerve stem cell, grafted nerve precursor cell, grafted nerve cell, grafted mature nerve cell) .
- the exogenous cells may be either autogenous cells or heterogeneous cells.
- the neural regeneration includes tissue regeneration or functional regeneration, and, for example, survival, differentiation, proliferation and/or maturation of the above cells are included.
- the term maturation as used herein means, for example, that a nerve cell grows into a proper state to fulfill functions such as exchange of signals.
- the regeneration also includes neurotrophic factor-like action and neurotrophic factor activity-reinforcing action.
- neurotrophic factor as used herein means a factor which acts as a nutrient of, for example, nerve stem cell, nerve precursor cell, nerve cell, mature nerve cell and the like. Examples of the neurotrophic factor-like action include axon elongation action, neurotransmitter synthesis accelerating action, action to accelerate differentiation and proliferation of nerve cells and action as a nutrition for maintaining the activity of nerve cells, though not limited thereto.
- neurotrophic factor activity reinforcing action means the activity to reinforce actions of the above neurotrophic factor.
- the agent to be used in the method of the present invention comprising (2R) -2-propyloctanoic acid or a salt thereof is also useful in treating neuropathy.
- neuropathy as used herein includes all neurological dysfunctions.
- neuropathy examples include transient blindness (e.g., transient amaurosis) , disturbance of consciousness, hemiplegia, sensory disturbance, homonymous hemianopsia, aphasia, alternate hemiplegia, two-side quadriplegia, vertigo, ear noises, nystagmus, double vision, coma and the like, and preferred are these neuropathies accompanied by neurodegenerative diseases.
- transient blindness e.g., transient amaurosis
- the presence or absence of neuropathy in cerebral infarction may be judged by various diagnosing tests known in this technical field for the detection of neuropathy.
- Illustrative examples of said diagnosing tests include Glasgow Outcome Scale (GOS) , Glasgow Coma Scale (GCS) , Rankin Scale (RS) , modified
- mRS Disability Rating Scale
- DRS Disability Rating Scale
- NIH Stroke Scale NIH SS
- these neuropathy-detecting diagnosing tests may be carried out by optionally combining with a physical testing method for detecting abnormality in the brain, such as CAT-scan, intracranial pressure measurement or the like.
- CAT-scan spinal Rating Scale
- intracranial pressure measurement or the like.
- the effectiveness is evaluated by carrying out the above diagnosing tests as the main evaluation item.
- evaluation items such as level of consciousness, motor function, Barthel Index, general safety, outcome, head CT findings, head MRI findings, blood pressure, pulse, body temperature and general clinical tests may be evaluated as secondary evaluation items by conventionally known methods and used in the evaluation of effectiveness, alone or in combination with the main evaluation item.
- the agent comprising (2R) -2-propyloctanoic acid or a salt thereof to be used in the method of the present invention has an inhibitory activity against S-100 ⁇ increase.
- the (2R) -2-propyloctanoic acid or a salt thereof can also function as a therapeutic agent of the above disorders and diseases (e.g., a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration) .
- the inhibitory action against S-100 ⁇ increase of (2R) -2-propyloctanoic acid or a salt thereof does not limit its acting region to the brain tissues. That is, it may be either a systemic action or a local action, or the S-100 ⁇ increase inhibiting action may be observed systemically or topically.
- the S-100 ⁇ detection method for use in the verification of the S-100 ⁇ increase inhibiting action is not particularly limited, so long as it is a method which can detect S-100 ⁇ .
- the S-100 ⁇ detection method it can be measured in biological samples, such as a blood sample of a patient or a fraction thereof (e.g., serum) and cerebrospinal fluid, by using a commercially available kit released, for example, from Byc-Sangtec Diagnostica GmbH & Co. (Diezenbach, Germany) or Syn-X Pharma, Inc. (Ontario, Canada), such as a radioimmunoassay kit, a luminescence immunoassay kit, a fluorescence immunoassay kit or a colorimetric immunoassay kit.
- the inhibitory action against S-lOO ⁇ increase by (2R) -2-propyloctanoic acid or a salt thereof the activity detected in a blood sample of a patient or a fraction thereof (e.g. , serum) is preferred.
- the inhibitory action against S-lOO ⁇ increase in a blood sample of a patient or a fraction thereof e.g.
- serum is not influenced by the cause of the increase of S-lOO ⁇ or the action mechanism of S-lOO ⁇ increase inhibition.
- increase in the S-lOO ⁇ in a blood sample of a patient or a fraction thereof may reflect its increase caused by a damage on topical infarction foci or its peripheral brain tissue or on the whole brain tissue, or may reflect that the S-lOO ⁇ at a level generally existing in the cells is released due to disorders in tissues or cells.
- the inhibitory action against S-100 ⁇ increase in a blood sample of a patient or a fraction thereof may be caused either by the inhibition of expansion of infarction foci, by the inhibition of S-100 ⁇ outflow from a brain tissue into blood, or by the inhibition of increase in S-100 ⁇ at a cellular level.
- this method is not particularly limited, so long as it is a method which parenterally administers it in an amount of about 100 mg or more (e.g., from about 100 mg to about 2,000 mg) per dose, but the followings can be exemplified as illustrative administration period, administration frequency, dose and administration method for obtaining desirable therapeutic effects on the above diseases.
- the agent may be administered continuously for an optional number of days .
- the agent may be administered at an optional frequency. In addition, it may be changed depending on the condition of each patient and other reasons.
- the illustrative administration frequency per day from 1 to 5 times per day can be exemplified.
- Preferred administration frequency per day is, for example, from 1 to 3 times, more preferred administration frequency per day is, for example,
- the dosage amount is not particularly limited, so long as it is about 100 mg or more (e.g., from about 100 mg to about 2,000 mg) per one dose as described in the foregoing, but in order to obtain desirable therapeutic effects on the above diseases, it is preferable to determine the amount depending on the body weight of each patient.
- the parenteral administration of (2R) -2-propyloctanoic acid it is desirable to administer for example from about 2 mg to about 12 mg per 1 kg of body weight of each patient.
- the more specific example of the amount about
- the administration method is not particularly limited, so long as it is a parenteral administration method as described in the foregoing, but in order to obtain desirable therapeutic effects on the above diseases, it is desirable to use the agent by preparing it into dosage forms which can be intravenously administered, such as injections and infusions.
- Administration of (2R) -2-propyloctanoic acid or a salt thereof in a dosage form which can be intravenously administered enables quick expression of the effect.
- preparation of (2R) -2-propyloctanoic acid or a salt thereof into such dosage forms which can be intravenously administered can avoid side effects accompanying sudden increase in its blood level and, if necessary, can even control of the blood level and the like, for example by carrying out its continuous intravenous administration using a syringe, infusion bag or the like .
- the period of continuous administration is not particularly limited and may be changed depending on the condition of each patient or other reasons, but it is desirable to carry out the continuous administration, for example, over an about 0.5 to about 3 hour period of time, preferably about 0.5 to about 1.5 hours, particularly preferably about 1 hour.
- a desirable method for parenterally administering from about 100 mg to about 2,000 mg per dose of (2R) -2-propyloctanoic acid or a salt thereof for the treatment of a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration its examples include a method in which (2R) -2-propyloctanoic acid or a salt thereof is continuously administered into a vein spending about 1 hour once a day using an infusion bag or the like, at a dose of about 2 mg to about 12 mg per 1 kg of body weight of each patient during a drug administration period of 1 day to 100 days.
- the agent to be used in the method of the present invention which comprises (2R) -2-propyloctanoic acid or a salt thereof may be jointly used with other agents such as antiepileptic agents (e.g., phenobarbital, mephobarbital, metharbital, primidone, phenytoin, ethotoin, trimethadione, ethosuximide, acetyl pheneturide, carbamazepine, acetazolamide, diazepam, sodium valproate) , acetylcholine esterase inhibitors (e.g., donepezil hydrochloride, TAK-147, rivastigmine, galantamin) , neurotrophic factors (e.g., ABS-205) , aldose reductase inhibitors, anti-thrombus agents (e.g., t-PA, heparin) , oral anticoagulant (e.g., warfarin), synthetic anti-throm
- brain function activators e.g., aniracetam, nicergoline
- dopamine receptor agonists e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine
- MAO monoamine oxidase
- anticholinergic agents e.g., trihexyphenidyl, biperidene
- COMT inhibitors e.g., entakapon
- amyotrophic lateral sclerosis treating agents e.g., riluzole, neurotrophic factors
- statin-based hyperlipemia treating agents e.g., pravastatin sodium, atrov
- a nicotine receptor modulating agent e.g., a ⁇ -secretase inhibitor, a ⁇ -amyloid vaccine, a ⁇ -amyloid hydrolase, a squalene synthase inhibitor, an agent for treating abnormal behavior, wandering and the like accompanied by the advance of dementia, an anti-hypertensive agent, a diabetes treating agent, an antidepressant, an anti-anxiety agent, a disease-modifying anti-rheumatic drug, an anti-cytokine agent (e.g., TNF inhibitor, MAP kinase inhibitor) , parathyroid hormone (PTH) , a calcium receptor antagonist and the like.
- a nicotine receptor modulating agent e.g., a ⁇ -secretase inhibitor, a ⁇ -amyloid vaccine, a ⁇ -amyloid hydrolase, a squalene synthase inhibitor, an agent for treating abnormal behavior, wandering and the like accompanied by the advance of dementia, an anti-hyperten
- agents may be administered by an optional combination of two or more.
- compounds so far discovered but also those which will be found in the future are included in the agents to be jointly used.
- an agent comprising (2R) -2-propyloctanoic acid or a salt thereof is preferably administered in combination with t-PA among other drugs exemplified as above.
- t-PA t-PA
- the method of administrating a combination of the agent comprising (2R) -2-propyloctanoic acid or a salt thereof with t-PA is not limited in particular, but preferably, they are administered in combination according to a dosage and an administration method employed when each of the agents is used alone.
- the independent dosage and administration method of the agent comprising (2R) -2-propyloctanoic acid or a salt thereof are described above.
- the independent dosage and administration method of t-PA include a method in which about 0.6 mg or about 0.9 mg of t-PA per 1 kg of body weight of the patient is parenterally, preferably intravenously, administered within 6 hours, preferably 3 hours, after onset of cerebral infarction.
- t-PA is administered within 3 hours after onset of cerebral infarction according to the above method, and the agent comprising (2R) -2-propyloctanoic acid or a salt thereof is administered at any time, preferably within 2 weeks after onset of cerebral infarction, and more preferably within 72 hours after onset of cerebral infarction, in accordance with the above administration period, administration frequency, dosage and administration method of (2R) -2-pro ⁇ yloctanoic acid.
- t-PA and (2R) -2-propyloctanoic acid or a salt thereof can be administered at the same time within 3 hours after onset of cerebral infarction.
- separate formulations may be used, or a single formulation which contains t-PA and (2R) -2-propyloctanoic acid or a salt thereof in it may be used.
- these injection methods are illustrations, and the dose may be increased and decreased depending on the condition of the patient appropriately.
- (2R) -2-propyloctanoic acid or a salt thereof has markedly low toxicity and can be judged sufficiently safe so far as it is used in mammals, particularly humans, by the method and dosage of the present invention.
- the agent of the present invention for parenteral administration for preventing and/or treating a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration, comprising (2R) -2-propyloctanoic acid or a salt thereof, is safe and can markedly improve these diseases, particularly various symptoms accompanying neurodegenerative diseases such as cerebral infarction.
- the compound is markedly useful as a medicament, because it shows the effect in the case of cerebral infarction 3 hours or more after the onset of the disease, which is difficult to treat by the conventional therapeutic agents.
- (2R) -2-propyloctanoic acid or a salt thereof can be used in mammals (e.g., human and non-human animals such as monkey, sheep, cattle, horse, dog, cat, rabbit, rat and mouse) and the like.
- mammals e.g., human and non-human animals such as monkey, sheep, cattle, horse, dog, cat, rabbit, rat and mouse
- desirable therapeutic effects upon neurodegenerative diseases, neuropathies or diseases whose treatment require neural regeneration can be obtained by parenterally administering it to mammals, particularly human, by the administration method and dosage of the present invention.
- the method and dose of the present invention are suitable for obtaining improving effects of various symptoms of cerebral infarction patients.
- the administration may be started at any time after onset of cerebral infarction.
- the method of the present invention overcame the limitation on the administration period of therapeutic agents such as t-PA used in the conventional cerebral infarction treatment, so that the effects obtained by said method are markedly excellent.
- Fig. 1 shows a result of the analysis of clinical data obtained in Clinical Test Example 1 in accordance with the efficacy evaluation item (Rankin Scale) described in Clinical Test Example 1.
- Fig. 2 shows a result of the analysis of clinical data obtained in Clinical Test Example 1 in accordance with the efficacy evaluation item (Glasgow Outcome Scale) described in Clinical Test Example 1.
- Fig. 3 shows a result of the analysis of clinical data obtained in Clinical Test Example 2 in accordance with the efficacy evaluation item (serum S-lOO ⁇ content) described in Clinical Test Example 2.
- Example 1 As a clinical test, a randomization test was carried out on patients with cerebral infarction at the acute phase (within
- Object 97 patients in the acute phase cerebral infarction.
- Administration method and dosage 1 hour of continuous intravenous administration once a day 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
- Rankin Scale (RS) Evaluation method Symptoms of patients were scored by classifying them into the following grades of Table 1. Table 1 No disorders All daily activities are possible. Activities which were formerly possible are Very slight partially limited. Slight Active walking is possible, but slight assistance is necessary for personal activities . Slight assistance is necessary for walking and Moderate personal activities. Moderately Assistance is necessary for walking and severe personal activities. Life on a bed, assistance and observation are Severe always required.
- Example 2 As a clinical test, a double blind test was carried out using patients with cerebral infarction at the acute phase (within 24 hours after onset of the disease) under the following conditions by (2R) -2-propyloctanoic acid administration groups (6 varied doses) and a placebo administration group.
- Object 92 patients in the acute phase cerebral infarction.
- Administration method and dosage 1 hour of continuous intravenous administration once a day in each group; (1) (2R) -2-propyloctanoic acid: 2 mg/kg/h;
- (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-pro ⁇ yloctanoic acid: 10 mg/kg/h;
- the blood samples for use in the S-100 ⁇ measurement were collected before the administration on the 1st to 7th days (pre-infusion) and after 3 hours, 7 hours, 12 hours and 24 hours of the administration on the 1st, 3rd and 7th days (post-infusion) .
- the same blood samples collected after 24 hours of administration on the 1st and 3rd days were respectively used as the blood samples before administration on the 2nd and 4th days.
- a blood sample (3 ml) was collected from each patient using a catheter or by venipuncture. Each sample was coagulated for 30 minutes and then centrifuged at 3,500 rpm for 12 to 15 minutes. Serum was recovered and dispensed in about 0.5 ml portions into two containers. The serum samples were labeled and stored at -20°C until the S-100 ⁇ assay.
- ⁇ Efficacy evaluation item> As a result of evaluating modified Rankin Scale (mRS) 40 days after the commencement of administration, a statistically significant difference was found between the placebo administration group and the 8 mg/kg/h (2R) -2-propyloctanoic acid administration group (placebo administration group: 32.5%, 8 mg/kg/h (2R) -2-propyloctanoic acid administration group: 87.5%), in terms of the ratio occupied by a score of 2 or less which corresponds to the category of good improvement.
- mRS modified Rankin Scale
- the parenteral administration therapeutic agent of the present invention for a neurodegenerative disease, a neuropathy or a disease whose treatment requires neural regeneration, comprising (2R) -2- ⁇ ropyloctanoic acid or a salt thereof, is safe and can markedly improve these diseases, particularly various symptoms accompanied by neurodegenerative diseases such as cerebral infarction.
- the compound is markedly useful as a medicament, because it shows the effect in the case of cerebral infarction in 3 hours or more after the onset of the disease, which is difficult to treat by the conventional therapeutic agents.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04773691A EP1667672A4 (en) | 2003-10-03 | 2004-10-01 | Method for preventing and/or treating neurodegenerative diseases |
US10/574,489 US7928143B2 (en) | 2003-10-03 | 2004-10-01 | Method for preventing and/or treating neurodegenerative diseases |
JP2006531234A JP5485497B2 (en) | 2003-10-03 | 2004-10-01 | Method for preventing and / or treating neurodegenerative diseases |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US50795203P | 2003-10-03 | 2003-10-03 | |
US60/507,952 | 2003-10-03 | ||
JP2004174577 | 2004-06-11 | ||
JP2004-174577 | 2004-06-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005032537A1 true WO2005032537A1 (en) | 2005-04-14 |
Family
ID=34425431
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/014893 WO2005032537A1 (en) | 2003-10-03 | 2004-10-01 | Method for preventing and/or treating neurodegenerative diseases |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1667672A4 (en) |
JP (2) | JP5485497B2 (en) |
WO (1) | WO2005032537A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007072902A1 (en) | 2005-12-22 | 2007-06-28 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for acute cerebral infarct |
EP1859795A1 (en) * | 2005-03-15 | 2007-11-28 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for ophthalmic disease |
EP1938814A1 (en) * | 2005-10-18 | 2008-07-02 | Ono Pharmaceutical Co., Ltd. | Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis |
US8975298B2 (en) * | 2005-06-27 | 2015-03-10 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for pain |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0632008A1 (en) * | 1993-06-01 | 1995-01-04 | Ono Pharmaceutical Co., Ltd. | Pentanoic acid derivatives |
EP1174131A1 (en) * | 2000-07-18 | 2002-01-23 | Ono Pharmaceutical Co., Ltd. | Agent for treating parkinson's disease comprising astrocyte function-improving agent as active ingredient |
WO2003007992A1 (en) * | 2001-07-18 | 2003-01-30 | Ono Pharmaceutical Co., Ltd. | Remedies for brain ischemic diseases |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4706950B2 (en) * | 2000-07-18 | 2011-06-22 | 小野薬品工業株式会社 | Parkinson's disease therapeutic agent containing an astrocyte function improving agent as an active ingredient |
-
2004
- 2004-10-01 WO PCT/JP2004/014893 patent/WO2005032537A1/en active Application Filing
- 2004-10-01 JP JP2006531234A patent/JP5485497B2/en not_active Expired - Fee Related
- 2004-10-01 EP EP04773691A patent/EP1667672A4/en not_active Withdrawn
-
2011
- 2011-11-25 JP JP2011256936A patent/JP2012046543A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0632008A1 (en) * | 1993-06-01 | 1995-01-04 | Ono Pharmaceutical Co., Ltd. | Pentanoic acid derivatives |
EP1174131A1 (en) * | 2000-07-18 | 2002-01-23 | Ono Pharmaceutical Co., Ltd. | Agent for treating parkinson's disease comprising astrocyte function-improving agent as active ingredient |
WO2003007992A1 (en) * | 2001-07-18 | 2003-01-30 | Ono Pharmaceutical Co., Ltd. | Remedies for brain ischemic diseases |
Non-Patent Citations (1)
Title |
---|
See also references of EP1667672A4 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1859795A1 (en) * | 2005-03-15 | 2007-11-28 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for ophthalmic disease |
EP1859795A4 (en) * | 2005-03-15 | 2008-06-04 | Ono Pharmaceutical Co | Therapeutic agent for ophthalmic disease |
EP2072047A1 (en) * | 2005-03-15 | 2009-06-24 | Ono Pharmaceutical CO., LTD. | Therapeutic agent for opthalmic disease |
EP2266559A1 (en) * | 2005-03-15 | 2010-12-29 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for ophthalmic disease |
US8975298B2 (en) * | 2005-06-27 | 2015-03-10 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for pain |
EP1938814A1 (en) * | 2005-10-18 | 2008-07-02 | Ono Pharmaceutical Co., Ltd. | Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis |
EP1938814A4 (en) * | 2005-10-18 | 2009-06-03 | Ono Pharmaceutical Co | Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis |
WO2007072902A1 (en) | 2005-12-22 | 2007-06-28 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for acute cerebral infarct |
Also Published As
Publication number | Publication date |
---|---|
JP2007507490A (en) | 2007-03-29 |
JP5485497B2 (en) | 2014-05-07 |
EP1667672A4 (en) | 2010-02-10 |
JP2012046543A (en) | 2012-03-08 |
EP1667672A1 (en) | 2006-06-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6715871B2 (en) | Compositions and methods of use of phorbol esters for the treatment of stroke | |
US20080057115A1 (en) | Capsule Stable Against Mastication | |
US8203016B2 (en) | Anthranilic acid amides and derivatives thereof as cosmetic and pharmaceutical agents | |
Steinke et al. | A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm | |
US20070154498A1 (en) | Intravenous essential fatty acid emulsion | |
GB2421909A (en) | Pharmaceutical compositions comprising EPA and methods of use | |
JP2006143708A (en) | Medicine for treating neurodegenerative disease | |
JP2024010082A (en) | Compositions and methods of use of β-hydroxy-β-methylbutyrate (HMB) to modulate autophagy and lipophagy | |
TWI287447B (en) | Use of 13-HODE as a regulator of vascular biocompatibility and an inhibitor of cell hyperplasia | |
JP2012046543A (en) | Prevention and/or treating method of neurodegenerative diseases | |
RU2388467C2 (en) | Medical agent containing (2r)-2-propyloctane acid as active component | |
Fenske et al. | The response of focal ischemic cerebral edema to dexamethasone | |
US7928143B2 (en) | Method for preventing and/or treating neurodegenerative diseases | |
JP2010280627A (en) | Platelet aggregation inhibitor | |
EP1685832A1 (en) | Nerve regeneration promoters | |
US20220339143A1 (en) | Tak-925 for use in treating narcolepsy | |
Yanai et al. | Concentrations of sulfur‐containing free amino acids in lumbar cerebrospinal fluid from patients with consciousness disturbances | |
JP6977979B2 (en) | Nerve injury treatment or preventive medicine | |
Dhillon et al. | Amphetamine administration improves neurochemical outcome of lateral fluid percussion brain injury in the rat | |
JPH0977666A (en) | Smooth muscle relaxant | |
JPH03141263A (en) | Use of prophenytoin for treating spasm | |
RU2640931C1 (en) | Rectal suppositories for prostate treatment containing lysyl-glutamyl-aspartyl-proline tetrapeptide | |
EP0055996B1 (en) | Antithrombotic treatment | |
CA1185529A (en) | Antithrombotic treatment | |
BRAMSEN | Serum and aqueous humour concentration of tranexamic acid after peroral administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006531234 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004773691 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004773691 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007043116 Country of ref document: US Ref document number: 10574489 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 10574489 Country of ref document: US |