WO2004032917A1 - ミトコンドリア機能異常に起因する疾患における臨床症状発現の予防・治療用組成物 - Google Patents
ミトコンドリア機能異常に起因する疾患における臨床症状発現の予防・治療用組成物 Download PDFInfo
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- WO2004032917A1 WO2004032917A1 PCT/JP2003/012891 JP0312891W WO2004032917A1 WO 2004032917 A1 WO2004032917 A1 WO 2004032917A1 JP 0312891 W JP0312891 W JP 0312891W WO 2004032917 A1 WO2004032917 A1 WO 2004032917A1
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- mitochondrial dysfunction
- arginine
- acid
- disease caused
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Classifications
-
- 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
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
- composition for prevention and treatment of clinical manifestations
- the present invention relates to a composition for preventing and / or treating clinical symptoms in a disease caused by a mitochondrial dysfunction characterized by containing L-arginine as an active ingredient, which is to be orally administered.
- Mitochondria are one of the organelles of the cell, have mitochondrial DNA with genetic information, and are mainly responsible for energy production. If the mitochondrial DNA mutation causes abnormalities in the mitochondrial electron transport system, the energy production is reduced, causing dysfunction of all cells and tissues throughout the body. In particular, disorders of the central nervous system, skeletal muscle, myocardium, etc., which require high energy, are remarkable. Diseases caused by mitochondrial dysfunction are considered to be the most frequent human hereditary diseases, most of which occur in childhood, and the disease types range from short stature, easy fatigue to death Such cases are diverse. On the other hand, mitochondrial dysfunction may occur with aging.
- Diseases caused by mitochondrial dysfunction include, for example, ME LAS (mi to chondrial myopathy, encephalopathy, lactic acidosis, and stroke-like epi sodes), '' CPEO (chronic progressive external ophthalmoplegia), ME RRF (myoclonus e pilepsy associated with ragged-red fibers ) force s Meri, Tutsi ME LA cs hand highest frequency among mitochondrial diseases, accounting for about 25% of the total mitochondrial diseases.
- Symptoms of each disease include, for example, ME LAS, which has repeated stroke-like seizures, causing consciousness disorders, motor paralysis, aphasia, semi-blindness, etc. The patient becomes bedridden. In severe cases, death can occur in a few years.
- the treatment of clinical manifestations in diseases caused by mitochondrial dysfunction in childhood can be administered continuously for the purpose of exacerbating the disease state and preventing progression, and side effects in terms of patients' QOL (Quality of Life)
- QOL Quality of Life
- the present inventors carried out a pathological examination of ME LAS patients, who develop childhood paroxysmal headache, vomiting, semi-convulsions, etc. among various types of diseases caused by mitochondrial dysfunction.
- Biopsy revealed abnormal accumulation of mitochondria and abnormal staining of the small and medium arterial walls, which revealed the presence of mitochondrial abnormalities in skeletal muscle and other tissues.
- abnormal staining of the wall of the small and medium arteries was observed not only in the small and medium arteries in the muscle but also in the arteries of the central nervous system, indicating that MELAS had vascular disorders.
- the present inventors have suggested that the elimination of active oxygen is not sufficient in abnormal mitochondria.
- mitochondria abnormally accumulated in vascular smooth muscle cells may produce these tissue-damaging free radicals and cause vascular damage, stroke-like attacks in ME LAS patients He hypothesized that it was caused by partial diastolic dysfunction of the small arteries.
- brain tissue damage caused by blood flow blockage selected from various drugs that act on endothelial cells in the cerebral small arteries and have an effect on blood flow improvement, and lactate caused by anaerobic glycolysis metabolism It was considered that a substance having an effect of improving cis was useful for improving clinical symptoms of ME LAS patients.
- arginine has been described as being able to treat brain disorders by increasing the brain's resistance to glutamate in the event of a significant elevation of glutamate in the brain due to temporary or intermittent cerebral ischemia.
- a therapeutic agent containing an amino acid and glucose selected from leucine and isoleucine as active ingredients is being studied.
- arginine acts as a substrate for nitric oxide synthase on the vascular wall and has a vasodilating effect via nitric oxide. Therefore, we examined whether it could be applied to the treatment of clinical manifestations in diseases caused by mitochondrial dysfunction.
- the present inventors have found that periodic vomiting and was admitted on one side cramping and short stature, Mi Tokondori ⁇ t RNA (L eu) 3 2 4 3 1 7 -year-old woman two others which mutations were found in G, L-arginine monohydrochloride was infused intravenously intravenously, and it was found that this was useful as a treatment for the acute phase of stroke-like attacks with ME LAS.
- ME LAS patients to receive treatment by intravenous injection during the acute phase of a stroke-like attack, they must go to the hospital for intravenous injection immediately after the attack, and a simple treatment method is Can not be.
- a flashing scotoma refers to an abnormal visual field that is a precursor to a stroke-like seizure. Suddenly, a part of the visual field can be seen as waving light, usually lasting 5 to 30 minutes. Furthermore, administration of large amounts of L-arginine monohydrochloride into blood vessels may cause side effects such as lowering of blood pressure and acidosis.
- treatment for the onset of clinical symptoms in childhood-onset diseases caused by mitochondrial dysfunction can be continuously administered for the purpose of exacerbating the condition and preventing the progression of patients.
- the present inventors have been studying the administration route of L-arginine and its dosage. Surprisingly, by administering a low dose of L-arginine orally as a maintenance treatment, not only acute seizures, It has been found that the frequency and extent of the precursor symptoms are also significantly reduced. In other words, instead of administering a high dose rapidly (intravenous infusion of 0.5 g Z kg over 30 minutes) like the previously reported intravenous injection of L-arginine, it is not It was found for the first time that the administration significantly reduced not only the symptoms of seizures including flashing scotoma but also the frequency of acute seizures, and the degree of acute seizures. Based on these findings, the present invention was completed.
- the present invention provides (1) a composition for oral administration containing L-arginine as an active ingredient, which is characterized in that it is a prophylactic and / or therapeutic agent for the development of clinical symptoms in a disease caused by a mitochondrial dysfunction, characterized in that: (2) The clinical manifestation of a disease caused by mitochondrial dysfunction according to the above (1), wherein the composition should be orally administered in an amount of 1 to 30 g per day as an adult in terms of L-arginine. (3) The disease caused by mitochondrial dysfunction is MELAS stroke-like seizure or a precursor symptom of stroke-like seizure.
- the present invention relates to a composition for preventing and / or treating the appearance of clinical symptoms in a disease caused by dysfunction.
- L-arginine to be incorporated in the composition of the present invention may be in the form of not only free L-arginine but also a pharmaceutically acceptable salt thereof.
- L-arginine includes free L-arginine and its pharmaceutically acceptable salts (L-anoreginin in a broad sense).
- salts include acid addition salts and base salts.
- Pharmaceutically acceptable acid addition salts of L-argien include, for example, inorganic acid salts with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, etc., and acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, Organic acid salts with fumaric acid, monomethyl sulfate and the like can be mentioned.
- Examples of pharmaceutically acceptable base salts of L-arginine include, for example, salts of inorganic bases with sodium, potassium, calcium, ammonia, etc., and ethylenediamine, propylenediamine, ethanolamine, and monoalkylethanol.
- composition of the present invention also includes a dosage form comprising only free L-arginine or Z and a pharmaceutically acceptable salt (composition in a broad sense).
- L-arginine to be incorporated as an active ingredient in the composition for oral administration of the present invention is free L-arginine and its monohydrochloride from the viewpoint of easy administration to elderly people and children and prevention of side effects during long-term administration. It is preferable to use either or both of the salt forms.
- L-arginine monohydrochloride which has a low taste, but on the other hand, taking into account acidosis derived from hydrochloride, It is more preferred to mix the unmodified L-argyun and L-argyune monohydrochloride in equimolar amounts.
- the daily dose for an adult is 1 to 50 g, preferably 1 to 30 g in terms of free L-argyun.
- composition for oral administration of the present invention may further contain an adjuvant for enhancing mitochondrial function.
- adjuvants include sugars, citrate cycle (also called TCA cycle, tricarboxylic acid cycle, and Krebs cycle) intermediates, precursors of citrate cycle intermediates or salts thereof, vitamins, amino acids, minerals, antioxidants And metabolic improvers.
- sugars examples include monosaccharides, disaccharides, and polysaccharides, and more specifically, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, starch, and the like.
- cunic acid cycle intermediate examples include cunic acid, acutic acid, isocunic acid, ⁇ -ketoglutaric acid, succinic acid, fumaric acid, malic acid, and oxalic acetic acid.
- the amino acids are not particularly limited as long as they are commonly used for infusion.
- L-aspartic acid examples include cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, glycine and the like.
- These amino acids can be used alone or in combination (combination) of a plurality of types, but a combination of a plurality of types is preferable.
- L-tryptophan, L-methione, L-lysine, L-lysine It is preferable to use a combination of eight essential amino acids, phenylalanine, L-mouth isine, L-isoleucine, L-parin and L-threonine, and more preferably to use a combination of eight essential amino acids and non-essential amino acids. is there. Further, from the viewpoint of storage stability and stability, it is particularly preferable to add a branched-chain amino acid of L-valine, L-lf soleucine and L-leucine as an adjuvant.
- minerals there is no particular limitation as long as they are generally used in this field, for example, as an infusion component. Specifically, mention may be made of calcium, sodium, potassium, magnesium, chlorine and phosphorus in the form of inorganic and organic salts. For each of the inorganic and organic salts, the same active ingredients that can be used in infusions and enteral nutrition already on the market can be used. Also, trace elements can be added as minerals. Fine elements are metallic elements that are trace but essential for living organisms. The addition of a trace element is particularly preferable as an auxiliary agent for increasing the activity of the enzyme in mitochondria.
- nitric oxide releasing agent an agent capable of continuously releasing nitric oxide under physiological conditions
- a compound having a toro group called a nitric acid drug orally falls into the category of drugs capable of continuously releasing the above-mentioned nitric oxide.
- Nitric acid agents include sodium nitroprusside, nitroglycerin, glyceryl trinitrate, isosorbide mononitrate, and isosorbite dinitrate
- composition for oral administration of the present invention is prepared in an appropriate dosage form, for example, powder, fine granules, granules, tablets, capsules, oral liquids and the like.
- L-arginine '(free form or pharmaceutically acceptable salt thereof) can be used as it is or mixed with appropriate pharmaceutically and pharmaceutically acceptable additives for each dosage form. It can be prepared by a conventional method, for example, by granulating or dissolving in an appropriate solvent to emulsify or suspend, and further mixing with an appropriate base.
- binders eg, starch paste solution, gelatin solution, hydroxypropyl cellulose, hydroxypro Pillmethylcellulose, polybutylpyrrolidone, etc.
- disintegrants eg, starch, gelatin powder, carboxymethylcellulose, carboxymethylcellulose potassium salt, etc.
- lubricants eg, magnesium stearate, talc, etc.
- coating agents eg, , Hydroxypropylcellulose, hydroxypropylmethylcellulose, acetyl cellulose, sucrose, titanium oxide, etc.
- other additives such as a coloring agent and a flavoring agent are added as needed.
- additives include preservatives (eg, benzoic acid, para-oxybenzoic acid ester, sodium dehydroacetate, etc.), suspending agents or emulsifiers (eg, arabia gum, tragacanth, sodium carboxymethylcellulose, methylcellulose base) , Egg yolk lecithin, surfactants, etc.), sweeteners (eg, trehalose, citric acid, etc.), and other additives such as colorants, stabilizers, etc., if necessary.
- the solvents used for these are mainly although it is purified water, ethanol, glycerin, propylene glycol and the like can also be used.
- Suitable bases include, for example, polyethylene dalicol and the like.
- L-Argyun (free form or a pharmaceutically acceptable salt thereof) is preferably an enteric preparation because it has an irritating effect on the stomach wall.
- the enteric substance is a substance which does not substantially dissolve in water having a pH of 4 or less, but dissolves in a solution having a pH of 4.5 or more, especially pH 5.5 to 7.5.
- enteric preparations such as cellulose derivatives, dibasic acid esters of cellulose or polybutyl compounds, acrylic acid-based copolymers and maleic acid-based copolymers should be used.
- enteric preparations such as cellulose derivatives, dibasic acid esters of cellulose or polybutyl compounds, acrylic acid-based copolymers and maleic acid-based copolymers should be used.
- Examples of the cellulose derivative include carboxymethylethyl cellulose.
- dibasic acid ester of cellulose or polybutyle conjugate examples include, for example, cellulose acetate phthalate, cenorellose acetate acetate succinate, cellulose acetate 'maleate, hydroxypropyl methylcellulose • phthalate, hydroxylate.
- cellulose acetate phthalate cenorellose acetate acetate succinate
- cellulose acetate 'maleate hydroxypropyl methylcellulose • phthalate
- hydroxylate hydroxylate
- Propylmethylcellulose 'acetate succinate polyvinyl acetate phthalate
- polybutyl propionate' phthalate polyvinyl butylate phthalate and the like.
- Atalylic acid-based copolymer examples include methyl acrylate / methacrylic acid copolymer, ethyl acrylate / methacrylic acid copolymer, and methyl methacrylate / methacrylic acid copolymer.
- maleic acid copolymer examples include butyl acetate / maleic anhydride copolymer and styrene / maleic acid copolymer.
- the enteric substance can be suitably used even if it is commercially available.
- Droxypropyl methylcellulose As phthalate, “HP-50” or “HP-55” (both manufactured by Shin-Etsu Chemical Co., Ltd.) and the like can be used. Further, as the methyl methacrylate / methacrylic acid copolymer, “Eudragit L” or “Eudragit S” (both manufactured by Laem Pharma Co., Ltd.) can be used.
- L-argyun (free or a pharmaceutically acceptable salt thereof), which is an active ingredient of the composition for oral administration of the present invention, causes a Maillard reaction with, for example, podosugar-sucrose, and is colored and decomposed with time. It is preferable to use starch, trehalose or the like which does not cause a Maillard reaction as an additive. More preferably, trehalose is used as an additive to form the enteric preparation described above.
- Such free form of L-arginine or a pharmaceutically acceptable salt thereof can be used, for example, in arginine hydrochloride injection "Argyun Injection Morishita” for use in pituitary function tests as a pharmaceutical, and urea cycle disorder drug “Argi U Granules” and “Argi U Injection” (both made of Ajinomoto Buarmane Earth) are commercially available, and data on toxicity can be found in many publications. There is no.
- the composition of the present invention for preventing or manifesting clinical symptoms in diseases caused by mitochondrial dysfunction which is to be orally administered, and for the treatment of Z or treatment, is characterized in that the active ingredient L-arginine is a monoacid derivative in the blood vessel wall. It can be a substrate for nitrogen synthase, and is effective for treating clinical manifestations in diseases caused by mitochondrial dysfunction due to nitric oxide-mediated vasodilatory effects. It can improve its overall precursor symptoms.
- the composition for oral administration of the present invention can be safely and conveniently administered.Maintenance therapy at home is necessary in order to prevent recurrent seizure symptoms, especially in early-onset patients who come to the hospital with a stroke-like seizure.
- the prophylactic and / or therapeutic composition of the present invention is extremely useful as a maintenance therapy.
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- Biomedical Technology (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/530,056 US20060052455A1 (en) | 2002-10-01 | 2003-10-08 | Composition for preventing treating the xepression of clinical symptom in disease caused by mitochondrial dysfunction |
EP03754031A EP1550442A4 (en) | 2002-10-11 | 2003-10-08 | COMPOSITION FOR PREVENTION / TREATMENT OF THE IMPACT OF CLINICAL SYMPTOMS IN DISEASES EMBODIED BY MITOCHONDRIENE DYSFUNCTION |
AU2003272945A AU2003272945A1 (en) | 2002-10-11 | 2003-10-08 | Composition for preventing/treating the expression of clinical symptom in disease caused by mitochondrial dysfunction |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002299575 | 2002-10-11 | ||
JP2002-299575 | 2002-10-11 | ||
JP2002378176A JP2004182705A (ja) | 2002-10-11 | 2002-12-26 | ミトコンドリア機能異常に起因する疾患における臨床症状発現の予防・治療用組成物 |
JP2002-378176 | 2002-12-26 |
Publications (1)
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WO2004032917A1 true WO2004032917A1 (ja) | 2004-04-22 |
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PCT/JP2003/012891 WO2004032917A1 (ja) | 2002-10-01 | 2003-10-08 | ミトコンドリア機能異常に起因する疾患における臨床症状発現の予防・治療用組成物 |
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US (1) | US20060052455A1 (ja) |
EP (1) | EP1550442A4 (ja) |
JP (1) | JP2004182705A (ja) |
AU (1) | AU2003272945A1 (ja) |
WO (1) | WO2004032917A1 (ja) |
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US20070042078A1 (en) * | 2005-08-22 | 2007-02-22 | Cadbury Adams Usa Llc | Biodegradable chewing gum |
US8287928B2 (en) | 2005-08-22 | 2012-10-16 | Kraft Foods Global Brands Llc | Degradable chewing gum |
US8268371B2 (en) * | 2005-08-22 | 2012-09-18 | Kraft Foods Global Brands Llc | Degradable chewing gum |
US8282971B2 (en) * | 2005-08-22 | 2012-10-09 | Kraft Foods Global Brands Llc | Degradable chewing gum |
US8263143B2 (en) | 2005-08-22 | 2012-09-11 | Kraft Foods Global Brands Llc | Degradable chewing gum |
US20070042079A1 (en) * | 2005-08-22 | 2007-02-22 | Cadbury Adams Usa Llc | Environmentally-friendly chewing gum having reduced stickiness |
EP2036552B1 (en) | 2006-07-05 | 2018-08-08 | Kao Corporation | Senescence inhibitor |
EP2243476A1 (en) * | 2009-04-17 | 2010-10-27 | Centre National de la Recherche Scientifique | Compounds for the treatment of mitochondrial diseases |
AU2012340563B2 (en) | 2011-11-21 | 2017-01-19 | The Institute For Ethnomedicine | L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders |
KR20170110083A (ko) | 2014-12-23 | 2017-10-10 | 인털렉츄얼 프라퍼티 어쏘시에이츠, 엘엘씨 | 경피 투여를 위한 방법 및 제형 |
JOP20190146A1 (ar) | 2016-12-19 | 2019-06-18 | Axcella Health Inc | تركيبات حمض أميني وطرق لمعالجة أمراض الكبد |
CU20200012A7 (es) | 2017-08-14 | 2021-02-04 | Axcella Health Inc | Composiciones de aminoácidos para el tratamiento de enfermedad hepática |
JP2021527670A (ja) | 2018-06-20 | 2021-10-14 | アクセラ・ヘルス・インコーポレイテッドAxcella Health Inc. | 筋肉中の脂肪浸潤の治療のための組成物及び方法 |
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WO1995019170A1 (fr) * | 1994-01-12 | 1995-07-20 | Rhone-Poulenc Rorer S.A. | Application du riluzole dans le traitement des maladies mitochondriales |
WO2000050043A1 (en) * | 1999-02-23 | 2000-08-31 | The Regents Of The University Of California | Methods of treatment of mitochondrial disorders |
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US5385940A (en) * | 1992-11-05 | 1995-01-31 | The General Hospital Corporation | Treatment of stroke with nitric-oxide releasing compounds |
US5891459A (en) * | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US5543430A (en) * | 1994-10-05 | 1996-08-06 | Kaesemeyer; W. H. | Method and formulation of stimulating nitric oxide synthesis |
DE19705233A1 (de) * | 1997-02-12 | 1998-08-13 | Froelich Juergen C | Verfahren zur Herstellung einer Formulierung enthaltend Arginin |
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2002
- 2002-12-26 JP JP2002378176A patent/JP2004182705A/ja active Pending
-
2003
- 2003-10-08 WO PCT/JP2003/012891 patent/WO2004032917A1/ja not_active Application Discontinuation
- 2003-10-08 US US10/530,056 patent/US20060052455A1/en not_active Abandoned
- 2003-10-08 EP EP03754031A patent/EP1550442A4/en not_active Withdrawn
- 2003-10-08 AU AU2003272945A patent/AU2003272945A1/en not_active Abandoned
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WO1995019170A1 (fr) * | 1994-01-12 | 1995-07-20 | Rhone-Poulenc Rorer S.A. | Application du riluzole dans le traitement des maladies mitochondriales |
WO2000050043A1 (en) * | 1999-02-23 | 2000-08-31 | The Regents Of The University Of California | Methods of treatment of mitochondrial disorders |
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BASIVIREDDY J. ET AL.: "Indomethacin-induced mitochondrial dysfunction and oxiative stress in villus enterocytes", BIOCHEMICAL PHARMACOLOGY, vol. 64, no. 2, 2002, pages 339 - 349, XP002977481 * |
DATABASE CAPLUS [online] SREEPRIYA M. ET AL.: "Protective effects of L-arginine on experimental myocardial injury induced", XP002977480, accession no. STN Database accession no. 2000:86589 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1550442A1 (en) | 2005-07-06 |
JP2004182705A (ja) | 2004-07-02 |
AU2003272945A1 (en) | 2004-05-04 |
EP1550442A4 (en) | 2006-03-29 |
US20060052455A1 (en) | 2006-03-09 |
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