WO2008078826A1 - 糖尿病性ニューロパチー治療剤 - Google Patents
糖尿病性ニューロパチー治療剤 Download PDFInfo
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- WO2008078826A1 WO2008078826A1 PCT/JP2007/075233 JP2007075233W WO2008078826A1 WO 2008078826 A1 WO2008078826 A1 WO 2008078826A1 JP 2007075233 W JP2007075233 W JP 2007075233W WO 2008078826 A1 WO2008078826 A1 WO 2008078826A1
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- WIPO (PCT)
- Prior art keywords
- diabetic neuropathy
- therapeutic agent
- omg
- tosylate
- acid
- Prior art date
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
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- 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
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- 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
- A61K9/0031—Rectum, anus
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to a therapeutic agent for diabetic neuropathy.
- Diabetes is a metabolic disorder characterized by chronic hyperglycemia that develops due to insulin deficiency, etc., and is classified into type I and type II depending on the cause.
- Type I is caused by destruction of insulin-secreting cells in the knee due to viruses and autoimmunity, and is common among young people.
- Type II develops after middle age due to environmental factors including lifestyle, such as overeating, obesity and lack of exercise, and aging.
- the number of diabetic patients in Japan is said to be about 74 million, of which 90% to 95% are type II diabetes. If these diabetic patients are left untreated and left hyperglycemic for a long time, they not only significantly impair the patient's quality of life, but also develop serious complications related to life prognosis.
- Typical complications are diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy associated with the present invention.
- Diabetic neuropathy is also called diabetic neuropathy, and about 2/3 of diabetic patients are said to have some form of complication.
- a disorder occurs from a part controlled by long nerve fibers (the nerves of the hands and toes), and initially there are numbness and pain in the limbs and an abnormal cooling sensation. It spreads from the tip to the knee, from the hand to the elbow, toward the center of the body.
- This variety of symptoms is caused by the fact that the nerves that are impaired are diverse, such as motor nerves, sensory nerves, and autonomic nerves, and that the functions of each neuron are diverse. It is also a factor that makes diagnosis and treatment difficult.
- An object of the present invention is to provide a therapeutic agent for diabetic neuropathy with few side effects and excellent effect, particularly a drug for treating subjective symptoms such as pain associated with diabetic neuropathy. There is to serve. Disclosure of the invention
- the present invention relates to the following inventions.
- a method for treating diabetic neuropathy wherein an effective amount of a compound of formula (1) is administered to a mammal.
- suplatast tosylate (Sat) represented by formula (1) 1 [2- [4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate (hereinafter referred to as suplatast tosylate) has an excellent IgE antibody production inhibitory action and is known as a therapeutic agent for bronchial asthma, atopic dermatitis, and allergic rhinitis (Japanese Patent Publication No. 3-70698: Patent Document 1).
- the subralast tosilate is a therapeutic agent for dysuria (WO 00/27383: Patent Document 2), an acupuncture drug associated with renal dialysis (Japanese Patent Laid-Open No. 11-315019: Patent) 3), an agent for improving liver function abnormality by C or non-B non-C hepatitis virus (JP 2 0 2-1 1 4 6 7 2 gazette: Patent Document 4), chemical hypersensitivity drug (special No. 2 0 0 4-2 9 2 4 0 7 publication: Patent Document 5), retroperitoneal fibrosis therapeutic agent (Japanese Patent Application Laid-Open No.
- Patent Document 6 for lichen planus Prophylactic agent and Z or therapeutic agent
- Japanese Patent Laid-Open No. 20 0 6-1 9 9 6 4 2: Patent Document 7 preventive and / or therapeutic agent for headache
- Japanese Patent Laid-Open No. 2 0 0 6-1 3 1 5 2 1: Patent Document 8 is also known to be useful as a nephrotic syndrome therapeutic agent
- Japanese Patent Laid-Open No. 2006-067: 58: Patent Document 9 Japanese Patent Laid-Open No.
- Patent Document 1 Japanese Patent Publication No. 3-7 6 9 8
- Patent Document 2 WO 0 0/2 7 3 8 3
- Patent Document 3 Japanese Patent Application Laid-Open No. 11-11 3 1 5 0 1 9
- Patent Document 4 Japanese Patent Laid-Open No. 2 0 0 2 1 1 1 4 6 7 2
- Patent Document 5 Japanese Patent Laid-Open No. 2 0 0 4 1 2 9 2 4 0 7
- Patent Document 6 Japanese Patent Laid-Open No. 2 0 0 5 No. 0 9 7 2 2 0
- Patent Document 7 Japanese Patent Laid-Open No. 2 0 0 6 1 9 9 6 4 2
- Patent Document 8 Japanese Patent Laid-Open No. 2 0 0 6 1 1 3 1 5 2 1
- Patent Document 9 Japanese Patent Application Laid-Open No. 2 0 0 6 1 0 7 6 9 5 8
- An active ingredient of the present invention, subralast tosilate, is a known compound, for example, described in Japanese Patent Publication No. 3-7 0 6 9 8 It can manufacture by the method of.
- treatment means prevention and treatment of a disease, and maintenance therapy for alleviating symptoms associated with the disease and preventing recurrence.
- Diabetic neuropathy that can be treated with the therapeutic agent of the present invention is not particularly limited as long as it is a neurological disorder associated with diabetes, and even if it is a polyneuropathy (sensory neuropathy and motor neuropathy), It may be an autonomic disorder.
- the present treatment Symptoms of diabetic neuropathy that can be treated with drugs include symptoms of polyneuropathy, such as pain, numbness, loss of sensation, sensory abnormalities (numbness, burning sensation, cold sensation, etc.)
- Symptoms of autonomic neuropathy include gastrointestinal disorders (constipation / diarrhea), abnormal sweating, orthostatic hypotension, bladder disorders, impotence and the like.
- the drugs that can be used in combination with subtilase tosylate include aldo-reductase inhibitors, antiarrhythmic agents, vitamins, nonsteroidal anti-inflammatory agents, antidepressants, antipsychotics, antispasmodics, etc. Is mentioned.
- the combined use with one or more of these drugs not only further improves the therapeutic effect of the therapeutic agent of the present invention on the pain associated with diabetic neuropathy, but also when compared to the use of a single drug that can be used in combination. Therefore, it is preferable from the viewpoint of reducing side effects.
- aldose reductase inhibitor examples include epallaceat or a pharmaceutically acceptable salt thereof.
- antiarrhythmic agent examples include mexitylene or a pharmaceutically acceptable salt thereof.
- Vitamins include vitamin A, vitamin D, vitamin B, (B1, B2, B6, B12), niacin, folic acid, pantothenic acid, vitamin C, vitamin E, piotin, vitamin K More specifically, retinoyl, ⁇ -calcidol, calcitriol, evening calcitol, calcibotriol, maxacalci 1 ⁇ l, falecalcitol, calcitriol, thiamine, cocarboxylase, full sultiamine, prosultiamine, octothiamine , Thiamine disulfide, bisbenchamine, bis-butiamine, benfotiamine, cetothiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, nicotinic acid, nicotinamide, cyanocobalamin, cobamide, mecobarami Folic acid, calcium pantothenate, panthenol, panthet
- Non-steroidal anti-inflammatory agents include: sodium salicylate, acetyl salicylic acid, salicylamide, flufenamic acid, mefenamic acid, tolfenamic acid, diclofenac, sulindac, fenbufen, anfenac, indomethacin, pro gourmet yushin, acemeyushin, nabumetone , Etodolac, Mofuzolac, Ibupu Mouth Fen, Ketoprofen, Flurbiprofen, Oxaprozin, Fuenobufen, Tiaprofenic acid, Naproxen, Planoprofen, Loxoprofen, Aluminoprofen, Zaltoprofen, Bucolome, Piroxicam, Ampiroxicam, Tenoxicam Epyrizole, thiaramide, emimorphan, or pharmaceutically acceptable salts thereof.
- Anti-depressants include nortriptyline, amoxapine, maprotiline, imipramine, amitriptyline, trimipratin, clomipramine, oral febramine, dosrepin, trazozone, fluvoxamine, paroxetine, milnacipran, mianserin, cetipidoline, sulpiridone, Salts that are acceptable.
- Antipsychotics include fluphenazine, chlorpromazine, or pharmaceutically acceptable salts thereof.
- Anticonvulsants include phenytoin, ethotoin, phenobarbital, primidone, valproic acid, carbamazepine, trimethadione, ethosuximide, acetylene etolide, sultiam, diazepam, clonazepam, clobazam, zonisamide, zonisamide And acceptable salts.
- Examples of the pharmaceutically acceptable salt in the present invention include, for example, hydrochloride, sulfate, tartrate, hydrobromide, nitrate, phosphate, and other inorganic acid salts, propionic acid, dipropionic acid, valeric acid, Butyric acid, pivalic acid, acetate, benzoate, mesylic acid, trifluoroacetate, Tartrate, Succinic acid, Palmitic acid, Chenate, Malate, Maleate, Fumarate, Methanesulfonate, Benzenesulfonate, Toluenesulfonate, Nicotinate Organic acid salt, Potassium Examples thereof include inorganic salts such as salts, sodium salts, calcium salts, and aluminum salts. Some compounds may form hydrates, which are also within the scope of the present invention.
- the therapeutic agent for diabetic neuropathy of the present invention can be administered to humans in various forms.
- Such forms may be, for example, oral preparations, injections, rectal suppositories, and external preparations (ointments, patches, eye drops, etc.), and these preparations are produced by conventional methods well known to those skilled in the art. it can.
- oral preparations as solid preparations, after adding excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, etc., to subrastosyl tosylate as usual, It can be further processed into tablets, coated tablets, granules, powders, capsules, dry syrups and the like.
- oral liquid preparations can be processed into conventional liquid preparations, syrup preparations, etc. by using conventional methods such as flavoring agents, buffering agents, stabilizers, flavoring agents, etc., to subtilized tosylate.
- pH adjusters As injections, pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, etc. are added to subrastosyl tosylate and processed in the usual manner, then subcutaneous injections and intramuscular injections. And intravenous injections.
- a suppository can be prepared by adding an excipient and, if necessary, a surfactant or the like to subrato tosylate, and then treating it by a conventional method.
- ointments such as pastes, creams, and gels are formulated with stabilizers, wetting agents, preservatives, etc., as necessary, in a base containing subratast tosylate, and processed by conventional methods. It can be formulated.
- the base include white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, and bentonite.
- Preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like. Can be mentioned.
- a patch as an external preparation can be produced by applying the above-mentioned ointment, cream, gel, paste or the like on a normal support by a conventional method.
- a woven fabric, non-woven fabric, or a film of soft vinyl chloride, polyethylene, polyurethane, or a foam sheet is preferable.
- the amount of subralast tosilate to be incorporated in the above-mentioned various preparations can be appropriately determined depending on the symptoms of the patient to whom this is to be administered, or depending on the dosage form, etc. 1000 mg, about 0.1 to 500 mg for injections, and about 5 to 100 Omg for suppositories and external preparations are desirable.
- Subratus tosylate may vary depending on the patient's symptoms, weight, age, sex, and other conditions, but is preferably about 5-100 Omg.
- Figure 1 is a graph showing the results of von Frey tes t's analgesia test over time.
- composition having the above blending ratio was processed according to a conventional method to prepare tablets containing 5 Omg of suplatast tosylate per tablet.
- a composition comprising the above blending ratio was processed according to a conventional method to prepare granules containing 30 Omg of suplatast tosylate per packet.
- a composition comprising the above blending ratio was processed according to a conventional method to prepare a capsule containing 10 Omg of supra-tosylate per capsule.
- a composition comprising the above blending ratio is processed according to a conventional method, and 1 ampule (2m
- a composition having the above blending ratio was processed according to a conventional method to prepare a dry syrup containing 5 mg Ospray Tosylate per capsule.
- a composition having the above blending ratio was processed according to a conventional method to prepare a syrup containing 5 Omg of suplatast tosylate in 2 ml.
- a composition comprising the above blending ratio was processed according to a conventional method to prepare a suppository containing 30 Omg of suplatast tosylate per one.
- Example 1 A composition comprising the above blending ratio was processed according to a conventional method to prepare a suppository containing 30 Omg of suplatast tosylate per one.
- a male rat weighing 160 g or more was administered intravenously with streptozotocin (STZ, Sigma— Aldrich Co.) 50 mgZkg at a dose of 2 mL / kg to create an STZ-induced diabetes model.
- STZ streptozotocin
- mice with a blood glucose level of 200 mg / dL or more were used as a diabetes model.
- the blood glucose level was measured using blood (2 L) collected from the tail vein, a measuring chip (Gultest Sensor, Inc., Clay Co., Ltd.) and Daltest PRO R (GT-1661, Arcley Co., Ltd.). ) And measured.
- the oral administration group and intraperitoneal administration group were compared with the STZ control group, respectively.
- the STZ control group was compared with the normal control group to determine the establishment of a diabetic new mouthful model.
- the therapeutic agent of the present invention exhibits an excellent effect in the treatment of pain associated with diabetic neuropathy, particularly diabetic neuropathy, and is very useful with few side effects.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2007339153A AU2007339153B2 (en) | 2006-12-26 | 2007-12-20 | Therapeutic agent for diabetic neuropathy |
US12/448,590 US8247458B2 (en) | 2006-12-26 | 2007-12-20 | Therapeutic agent for diabetic neuropathy |
KR1020097015577A KR101103157B1 (ko) | 2006-12-26 | 2007-12-20 | 당뇨병성 뉴로퍼시 치료제 |
AT07860442T ATE526014T1 (de) | 2006-12-26 | 2007-12-20 | Therapeutisches mittel gegen diabetische neuropathie |
CN2007800469402A CN101563075B (zh) | 2006-12-26 | 2007-12-20 | 糖尿病性神经病治疗剂 |
EP07860442A EP2103305B1 (en) | 2006-12-26 | 2007-12-20 | Therapeutic agent for diabetic neuropathy |
CA2674066A CA2674066C (en) | 2006-12-26 | 2007-12-20 | Therapeutic agent for diabetic neuropathy |
JP2008551162A JP5023074B2 (ja) | 2006-12-26 | 2007-12-20 | 糖尿病性ニューロパチー治療剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006-349987 | 2006-12-26 | ||
JP2006349987 | 2006-12-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008078826A1 true WO2008078826A1 (ja) | 2008-07-03 |
Family
ID=39562616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/075233 WO2008078826A1 (ja) | 2006-12-26 | 2007-12-20 | 糖尿病性ニューロパチー治療剤 |
Country Status (9)
Country | Link |
---|---|
US (1) | US8247458B2 (ja) |
EP (1) | EP2103305B1 (ja) |
JP (1) | JP5023074B2 (ja) |
KR (1) | KR101103157B1 (ja) |
CN (1) | CN101563075B (ja) |
AT (1) | ATE526014T1 (ja) |
AU (1) | AU2007339153B2 (ja) |
CA (1) | CA2674066C (ja) |
WO (1) | WO2008078826A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014172846A (ja) * | 2013-03-07 | 2014-09-22 | Kyushu Univ | がん化学療法剤に起因する末梢神経障害予防剤及び/又は治療剤 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112423742B (zh) * | 2018-06-27 | 2024-03-19 | 阿尔杰农制药股份有限公司 | 使用阿克他利预防或治疗肾纤维化或肾脏疾病 |
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-
2007
- 2007-12-20 AU AU2007339153A patent/AU2007339153B2/en not_active Ceased
- 2007-12-20 EP EP07860442A patent/EP2103305B1/en not_active Not-in-force
- 2007-12-20 AT AT07860442T patent/ATE526014T1/de not_active IP Right Cessation
- 2007-12-20 CN CN2007800469402A patent/CN101563075B/zh not_active Expired - Fee Related
- 2007-12-20 CA CA2674066A patent/CA2674066C/en not_active Expired - Fee Related
- 2007-12-20 KR KR1020097015577A patent/KR101103157B1/ko not_active IP Right Cessation
- 2007-12-20 WO PCT/JP2007/075233 patent/WO2008078826A1/ja active Application Filing
- 2007-12-20 JP JP2008551162A patent/JP5023074B2/ja not_active Expired - Fee Related
- 2007-12-20 US US12/448,590 patent/US8247458B2/en not_active Expired - Fee Related
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Cited By (1)
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JP2014172846A (ja) * | 2013-03-07 | 2014-09-22 | Kyushu Univ | がん化学療法剤に起因する末梢神経障害予防剤及び/又は治療剤 |
Also Published As
Publication number | Publication date |
---|---|
EP2103305A4 (en) | 2010-08-18 |
EP2103305A1 (en) | 2009-09-23 |
CN101563075A (zh) | 2009-10-21 |
CA2674066A1 (en) | 2008-07-03 |
EP2103305B1 (en) | 2011-09-28 |
AU2007339153A1 (en) | 2008-07-03 |
KR20090096640A (ko) | 2009-09-11 |
AU2007339153B2 (en) | 2010-11-25 |
US20100041764A1 (en) | 2010-02-18 |
CN101563075B (zh) | 2011-09-28 |
CA2674066C (en) | 2012-01-24 |
KR101103157B1 (ko) | 2012-01-04 |
JP5023074B2 (ja) | 2012-09-12 |
JPWO2008078826A1 (ja) | 2010-04-30 |
US8247458B2 (en) | 2012-08-21 |
ATE526014T1 (de) | 2011-10-15 |
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