WO2000078296A2 - Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium - Google Patents

Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium Download PDF

Info

Publication number
WO2000078296A2
WO2000078296A2 PCT/EP2000/005303 EP0005303W WO0078296A2 WO 2000078296 A2 WO2000078296 A2 WO 2000078296A2 EP 0005303 W EP0005303 W EP 0005303W WO 0078296 A2 WO0078296 A2 WO 0078296A2
Authority
WO
WIPO (PCT)
Prior art keywords
tocotrienol
treatment
prophylaxis
glutamate
derivatives
Prior art date
Application number
PCT/EP2000/005303
Other languages
English (en)
Other versions
WO2000078296A3 (fr
Inventor
Klaus Krämer
Chandan K. Sen
Savita Khanna
Lester Packer
Original Assignee
Basf Aktiengesellschaft
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Basf Aktiengesellschaft, The Regents Of The University Of California filed Critical Basf Aktiengesellschaft
Publication of WO2000078296A2 publication Critical patent/WO2000078296A2/fr
Publication of WO2000078296A3 publication Critical patent/WO2000078296A3/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

Definitions

  • Tocotrienol and/or tocotrienol derivatives for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders are tocotrienol and/or tocotrienol derivatives for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders
  • the invention relates to a method for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders which comprises administering a therapeuticaUy active amount of at least one compound selected from the group consisting of ⁇ -tocotrienol, ⁇ -tocotrienol , ⁇ -tocotrienol and ⁇ -tocotrienol and their derivatives .
  • Reactive oxygen compounds are, inter alia, co-responsible for the production of brain damage in connection with epilepsy, trauma and reperfusion. Oxidative cell damage is likewise associated with neurodegenerative disorders such as Alzheimer's, Parkinson's or Huntington's disease.
  • amino acid L-glutamate which is excreted by primary afferent neurons and is the most important excitatory transmitter in the brain and the spinal cord.
  • a lack of equilibrium in excitatory transmitters can, under certain circumstances, cause disorders. Excessive glutamate concentrations are highly toxic to neurons. In tissue cultures, many neurons die if they are exposed to a high glutamate concentration, even for only a short time, a process which is designated glutamate excitotoxicity.
  • Glutamate excitotoxicity is predominantly based on an excessive Ca 2+ inflow through NDMA
  • the glutamate toxicity is also presumed to contribute to cell damage after a stroke, to cell death in continuous epileptic attacks and to degenerative disorders, such as Huntington's Chorea.
  • this object is achieved by a method for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders which comprises administering a therapeuticaUy active amount of at least one compound selected from the group consisting of ⁇ -tocotrienol , ⁇ -tocotrienol , ⁇ -tocotrienol and ⁇ -tocotrienol and their derivatives.
  • derivatives are, for example, prodrugs which, in vivo, are metabolized into compounds having the therapeutic effect according to the invention.
  • Typical prodrugs are, inter alia, phosphates or esters, such as tocotrienol acetate or tocotrienol succinate.
  • the compounds used according to the invention can in this case be used as racemates or as enantiomerically pure compounds .
  • Preferred representatives of the abovementioned compounds are ⁇ -tocotrienol and ⁇ -tocotrienol and their esters. Particular preference is given to ⁇ -tocotrienol and ⁇ -tocotrienol and their acetates .
  • the compounds mentioned in the context of the invention can be used for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders, in particular neurodegenerative disorders and neuronal damage.
  • the tocotrienol compounds used according to the invention shall accordingly be used for the treatment and prophylaxis of neurodegenerative disorders which occur after ischemia, reperfusion, trauma (craniocerebral injury trauma) , massive bleeding, subarachnoidal hemorrhages and stroke, and of neurodegenerative disorders such as multiple infarct dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and of epilepsies, in particular generalized epileptic attacks, such as petit mal and tonic-clonic attacks and partially epileptic attacks, such as temporal lope and complex-partial attacks, and in addition for the treatment and prophylaxis of heart damage after cardial ischemias and damage to the kidneys after renal ischemias, for example acute kidney insufficiency, acute kidney failure or damage which occurs during and after kidney transplantation.
  • trauma craniocerebral injury trauma
  • massive bleeding subarachnoidal hemorrhages and stroke
  • neurodegenerative disorders such as multiple infarct dementia, Alzheimer
  • the invention therefore also relates to a method for the treatment or prophylaxis of glutamate- and/or calcium-induced disorders which comprises administering a therapeuticaUy active amount of at least one compound selected from the group consisting of ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol and ⁇ -tocotrienol and their derivatives as inhibitor of c-src kinase.
  • this is a method for the treatment or prophylaxis of tumors and their metastasization.
  • the invention likewise relates to drugs for the treatment or prophylaxis of glutamate-induced disorders, in particular neurodegenerative disorders and neuronal damage, which drugs, in addition to customary carriers and auxiliaries, comprise at least one compound selected from the group consisting of ⁇ -tocotrienol, ⁇ -tocotrienol , ⁇ -tocotrienol and ⁇ -tocotrienol and their derivatives .
  • drugs for the treatment or prophylaxis of Alzheimer's disease, Parkinson's disease and Huntington's disease are particularly preferred.
  • the invention likewise relates to drugs for the treatment or prophylaxis of disorders which are relieved or healed by processes leading to inhibition of inducible c-src kinase activity.
  • drugs for the treatment or prophylaxis of tumors and their metastasization.
  • the abovementioned drugs advantageously comprise at least one active compound selected from the group consisting of ⁇ -tocotrienol and ⁇ -tocotrienol and their derivatives. Particular preference is given to the abovementioned drugs which comprise at least one active compound selected from the group consisting of ⁇ -tocotrienol, ⁇ -tocotrienol and their acetates.
  • the active compounds can be present at the customary concentrations.
  • the active compounds are present in an amount of from 0.001 to 1% by weight, preferably from 0.001 to 0.1% by weight .
  • the preparations are administered in single doses.
  • a single dose from 0.01 to 150 mg, preferably from 0.1 to 100 mg, per kg of body weight are administered.
  • the composition can be administered daily in one or more doses depending on the type and severity of the disorders.
  • the drug compositions of the invention comprise, in addition to the active compound, the customary carriers and diluents.
  • technical pharmaceutical aids such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin oil, Vaseline and lanolin.
  • lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable, for example.
  • the drugs can also comprise 6-chromanol compounds and their quinoid oxidation products.
  • 6-chromanol compounds are, inter alia, derivatives of 6-chromanol which contain a saturated Ci 6 isoprene side chain. These include, for example, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol and ⁇ -tocopherol and their derivatives.
  • 6-chromanol compounds and their quinoid oxidation products are the structures I to VIII given below.
  • X N
  • Y halogen, OS (0 2 ) alkyl, OS(0 2 )aryl
  • the amount of these 6-chromanol compounds and their quinoid oxidation products, which may be used in association, is likewise in the range from 0.01 to 150 mg, preferably in the range from 0.1 to 100 mg, per kg of body weight.
  • antioxidants can be present, such as butylated hydroxyanisole and butylated hydroxytoluene , flavor-enhancing additives, stabilizers, e ulsifiers and lubricants .
  • the active compounds can be the following:
  • Vitamins for example ascorbic acid, tocopherol, tocopherol acetate, vitamin A and vitamin A derivatives, vitamin K and vitamin K derivatives or vitamin D and vitamin D derivatives, riboflavin, vitamin B ⁇ 2 , nicotic acid, nicotina ide, pyridoxine hydrochloride , biotin, folic acid, folic acid derivatives such as tetrahydrofolic acid, 5-methyltetrahydrofolic acid,
  • Carotenoids such as ⁇ -carotene, lycopene, lutein or zeaxanthin.
  • Polyunsaturated fatty acids such as linoleic acid, linolenic acid, arachidonic acid, docosahexaenoic acid or eicosapentaenoic acid.
  • vitamin or coenzyme character e.g. lipoic acid, carnitine, choline chloride, choline bitartrate, choline citrate, taurine, creatine, ubiquinones , S-methylmethionine or S-adenosylmethionine .
  • the substances present in the composition in addition to the active compound, as well as the substances used in the manufacture of the pharmaceutical compositions, are toxicologically harmless and compatible with the respective active compound.
  • the drug compositions are manufactured in a conventional manner, for example by mixing the active compound with other conventional carriers and diluents.
  • the drug preparations can be administered in various application methods, for example perorally, parenterally and intravenously by infusion, subcutaneously, intraperitoneally and topically.
  • composition forms such as tablets, emulsions, infusion solutions and injection solutions, pastes, ointments, gels, creams, lotions, powder and sprays, in particular inhalation sprays, are possible .
  • Mouse hippocampal HT4 cells kindly provided by D.E. Koshland Jr., University of California at Berkeley, were grown in Dulbecco's Modified Eagle Medium supplemented with 10% fetal calf serum, penicillin (100 U/ml) and streptomycin (100 mg/ml) at 37°C in a humidified atmosphere containing 95% air and 5% C0 .
  • Confluent cells were trypsinized and subcultivated in culture dishes at a concentration of 68xl0 4 cells/ml (5 ml per plate) . The cells were cultured at standard condition described above. Following 24 h of seeding, the culture medium was replaced with fresh medium supplemented with serum and antibiotic. The cells were then exposed to 10 ⁇ iM glutamate as described previously (Am. J. Physiol., 273, R1771-8, 1997). No change in medium pH was observed in response to addition of glutamate.
  • DCFH-DA dichlorodihydrofluorescein-diacetate
  • Intracellular free Ca 2+ levels were measured using cell-permeant calcium green-1, AM (Molecular probe, Eugene, OR) .
  • Cells were loaded with calcium green-1 and then excited at 488 nm using an argon-ion laser and emission was recorded at 530 nm using a flow-cytometer .
  • HT4 cells were transfected with eukaryotic expression vector containing mouse src (activated or kinase dead) cDNA under the control of a CMV promoter.
  • the kinase activating mutation is a substitution of the phenyl alanine for tyrosine at position 529.
  • the kinase inactivating mutation is a substitution of arginine for lysine at position 297.
  • SuperFect transfection reagent Quiagen, Valencia, CA
  • FIG. 1 is a diagrammatic representation of FIG. 1:
  • FIG. 2 is a diagrammatic representation of FIG. 1
  • FIG. 3 is a diagrammatic representation of FIG. 3
  • Intracellular free calcium level A, low concentration of ⁇ -tocotrienol, but not ⁇ -tocopherol, significantly attenuated glutamate induced elevation of [Ca 2+ ]j . . B, at 250 nM, ⁇ -tocotrienol prevented glutamate-induced elevation of [Ca 2+ ]i even when treated to cells 3 h after glutamate-challenge .
  • FIG. 4 is a diagrammatic representation of FIG. 4
  • Intracellular peroxide levels Treatment of HT4 cells with 10 mM glutamate increased intracellular peroxide level as a function of time (solid bars) . Treatment with 100 nM ⁇ -tocotrienol completely prevented glutamate-induced increase in peroxide level even when tocotrienol was added 5 h after glutamate treatment.
  • FIG. 5 is a diagrammatic representation of FIG. 5
  • Kinase-dead refers to catalytically inactive src kinase; kinase-active refers to constitutively activate src kinase.

Landscapes

  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement thérapeutique ou prophylactique de troubles provoqués par le glutamate et/ou le calcium, qui comporte l'administration d'une quantité thérapeutiquement active d'au moins un composé sélectionné dans le groupe constitué par α-tocotriénol, β-tocotriénol, η-tocotriénol et δ-tocotriénol ainsi que leurs dérivés.
PCT/EP2000/005303 1999-06-17 2000-06-08 Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium WO2000078296A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33465999A 1999-06-17 1999-06-17
US09/334,659 1999-06-17

Publications (2)

Publication Number Publication Date
WO2000078296A2 true WO2000078296A2 (fr) 2000-12-28
WO2000078296A3 WO2000078296A3 (fr) 2002-05-30

Family

ID=23308200

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/005303 WO2000078296A2 (fr) 1999-06-17 2000-06-08 Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium

Country Status (1)

Country Link
WO (1) WO2000078296A2 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1230923A1 (fr) * 2001-02-08 2002-08-14 Fuji Chemical Industry Co Ltd Tocotriénols comme Inhibiteurs de la néovascularisation, multiplication cellulaire, formation du lumen et fgf
EP1199076A3 (fr) * 2000-10-06 2003-09-10 Fuji Chemical Industry Co Ltd Médicament contenant du tocotriènol comme agent actif
US7872042B2 (en) * 2004-05-14 2011-01-18 Rubin Berish Y Use of tocotrienols for elevating IKBKAP gene expression and treating Familial Dysautonomia
WO2011025785A1 (fr) 2009-08-26 2011-03-03 Edison Pharmaceuticals, Inc. Procédés de prévention et de traitement d’une ischémie cérébrale
EP2337561A1 (fr) * 2008-10-23 2011-06-29 Davos Life Science Pte. Ltd. Utilisation d une composition de tocotriénol pour la prévention du cancer
US8969420B2 (en) 2008-09-10 2015-03-03 Edison Pharmaceuticals, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US9090576B2 (en) 2008-03-05 2015-07-28 Edison Pharmaceuticals, Inc. 2-substituted-p-quinone derivatives for treatment of oxidative stress diseases
US9169196B2 (en) 2007-11-06 2015-10-27 Edison Pharmaceuticals, Inc. 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US9278085B2 (en) 2006-02-22 2016-03-08 Edison Pharmaceuticals, Inc. Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9296712B2 (en) 2013-03-15 2016-03-29 Edison Pharmaceuticals, Inc. Resorufin derivatives for treatment of oxidative stress disorders
US9370496B2 (en) 2009-04-28 2016-06-21 Edison Pharmaceuticals, Inc. Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones
US9447006B2 (en) 2005-06-01 2016-09-20 Edison Pharmaceuticals, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9670170B2 (en) 2013-03-15 2017-06-06 Bioelectron Technology Corporation Resorufin derivatives for treatment of oxidative stress disorders
US9868711B2 (en) 2013-03-15 2018-01-16 Bioelectron Technology Corporation Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders
US10039722B2 (en) 2008-10-14 2018-08-07 Bioelectron Technology Corporation Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells
US10251847B2 (en) 2014-12-16 2019-04-09 Bioelectron Technology Corporation Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4333794A1 (de) * 1993-10-04 1995-04-06 Carl Heinrich Dr Weischer Neue Acetyl-Salicylsäure-Derivate zur Bekämpfung von Entzündungs- und Schmerzzuständen sowie zur Thromboseprophylaxe und -terapie
WO1999006040A1 (fr) * 1997-08-04 1999-02-11 Berry Christopher J Procede pour traiter les maladies a l'aide d'un tocotrienol, et d'un acide alpha-lipoique ou des derives ou un ester de ces derniers
WO2000015201A2 (fr) * 1998-09-10 2000-03-23 Forbes Medi-Tech Inc. COMPOSITIONS COMPRENANT UN OU PLUSIEURS PHYTOSTEROLS, PHYTOSTANOLS, OU LEURS MELANGES, UN OU PLUSIEURS TOCOTRIENOLS, $G(ab, $G(b), $G(d) OU $G(g), OU LEURS DERIVES, UTILISATION DE CES COMPOSITIONS POUR TRAITER OU PREVENIR L'AFFECTION CARDIO-VASCULAIRE, SES ATTEINTES SOUS-JACENTES ET D'AUTRES ETATS PATHOLOGIQUES
WO2000057876A1 (fr) * 1999-03-26 2000-10-05 Lipogenics, Inc. Preparations antioxydantes et procedes d'utilisation de telles preparations
WO2001013901A2 (fr) * 1999-08-20 2001-03-01 Ferrosan A/S Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08217681A (ja) * 1995-02-13 1996-08-27 Lion Corp 老人性痴呆症予防治療剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4333794A1 (de) * 1993-10-04 1995-04-06 Carl Heinrich Dr Weischer Neue Acetyl-Salicylsäure-Derivate zur Bekämpfung von Entzündungs- und Schmerzzuständen sowie zur Thromboseprophylaxe und -terapie
WO1999006040A1 (fr) * 1997-08-04 1999-02-11 Berry Christopher J Procede pour traiter les maladies a l'aide d'un tocotrienol, et d'un acide alpha-lipoique ou des derives ou un ester de ces derniers
WO2000015201A2 (fr) * 1998-09-10 2000-03-23 Forbes Medi-Tech Inc. COMPOSITIONS COMPRENANT UN OU PLUSIEURS PHYTOSTEROLS, PHYTOSTANOLS, OU LEURS MELANGES, UN OU PLUSIEURS TOCOTRIENOLS, $G(ab, $G(b), $G(d) OU $G(g), OU LEURS DERIVES, UTILISATION DE CES COMPOSITIONS POUR TRAITER OU PREVENIR L'AFFECTION CARDIO-VASCULAIRE, SES ATTEINTES SOUS-JACENTES ET D'AUTRES ETATS PATHOLOGIQUES
WO2000057876A1 (fr) * 1999-03-26 2000-10-05 Lipogenics, Inc. Preparations antioxydantes et procedes d'utilisation de telles preparations
WO2001013901A2 (fr) * 1999-08-20 2001-03-01 Ferrosan A/S Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
C.K.SEN ET AL.: "INTRACELLULAR EVENTS IN GLUTAMATE INDUCED DEATH OF HT4 NEURONAL CELLS" FREE RADICAL BIOLOGY & MEDICINE (6TH ANNUAL MEETING OF THE OXYGEN SOCIETY), vol. 27, no. Suppl. 1, 18 - 22 November 1999, page S66 XP000997357 *
C.K.SEN ET AL.: "Molecular Basis of Vitamin E Action, TOCOTRIENOL POTENTLY INHIBITS GLUTAMATE-INDUCED pp60c-Src KINASE ACTIVATION AND DEATH OF HT4 NEURONAL CELLS" J.BIOL.CHEM., vol. 275, no. 17, 28 April 2000 (2000-04-28), pages 13049-13055, XP000990628 *
C.K.SEN ET AL.: "Vitamin E Alpha-Tocotrienol Potently Inhibits lutamate Induced pp60c-Src Kinase Activation and Death of HT4 Neuronal Cells" FASEB J., vol. 14, no. 4, 15 March 2000 (2000-03-15), page A554 XP000997352 *
CHEMICAL ABSTRACTS, vol. 125, no. 22, 25 November 1996 (1996-11-25) Columbus, Ohio, US; abstract no. 284890n, H.ADACHI ET AL.: "Extraction of forskohlin from Coleus forskohlii roots and compositions containing forskolin and tocotrienol for Alzheimer's disease" XP002184649 & JP 08 217681 A (LION CORP) 27 August 1996 *
J.P.KAMAT ET AL.: "Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria" NEUROSCIENCE LETTERS, vol. 195, 1995, pages 179-182, XP001041658 *
L.PACKER ET AL.: "Molecular Aspects of alpha-Tocotrienol Antioxidant Action and Cell Signalling" J.NUTR., vol. 131, no. 2, February 2001 (2001-02), pages 369S-373S, XP001041648 *
L.PACKER: "Molecular aspects of alphaTocotrienol antioxidant action and cell signalling" FASEB J., vol. 14, no. 4, 15 March 2000 (2000-03-15), page a245 XP000997412 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1199076A3 (fr) * 2000-10-06 2003-09-10 Fuji Chemical Industry Co Ltd Médicament contenant du tocotriènol comme agent actif
EP1230923A1 (fr) * 2001-02-08 2002-08-14 Fuji Chemical Industry Co Ltd Tocotriénols comme Inhibiteurs de la néovascularisation, multiplication cellulaire, formation du lumen et fgf
US6608103B2 (en) 2001-02-08 2003-08-19 Fuji Chemical Industry Co., Ltd. Inhibitor for neovasculation, cell multiplication, lumen formation and FGF
US7872042B2 (en) * 2004-05-14 2011-01-18 Rubin Berish Y Use of tocotrienols for elevating IKBKAP gene expression and treating Familial Dysautonomia
US11021424B2 (en) 2005-06-01 2021-06-01 Ptc Therapeutics, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9447006B2 (en) 2005-06-01 2016-09-20 Edison Pharmaceuticals, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9932286B2 (en) 2006-02-22 2018-04-03 Bioelectron Technology Corporation Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9278085B2 (en) 2006-02-22 2016-03-08 Edison Pharmaceuticals, Inc. Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US10968166B2 (en) 2007-11-06 2021-04-06 Ptc Therapeutics, Inc. 4-(P-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US9169196B2 (en) 2007-11-06 2015-10-27 Edison Pharmaceuticals, Inc. 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US10167251B2 (en) 2007-11-06 2019-01-01 Bioelectron Technology Corporation 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US11840497B2 (en) 2007-11-06 2023-12-12 Ptc Therapeutics, Inc. 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US9546132B2 (en) 2007-11-06 2017-01-17 Edison Pharmaceuticals, Inc. 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
US9090576B2 (en) 2008-03-05 2015-07-28 Edison Pharmaceuticals, Inc. 2-substituted-p-quinone derivatives for treatment of oxidative stress diseases
US8969420B2 (en) 2008-09-10 2015-03-03 Edison Pharmaceuticals, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US9399612B2 (en) 2008-09-10 2016-07-26 Edison Pharmaceuticals, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US10736857B2 (en) 2008-09-10 2020-08-11 Ptc Therapeutics, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US10105325B2 (en) 2008-09-10 2018-10-23 Bioelectron Technology Corporation Treatment of pervasive developmental disorders with redox-active therapeutics
US10039722B2 (en) 2008-10-14 2018-08-07 Bioelectron Technology Corporation Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells
EP2337561A1 (fr) * 2008-10-23 2011-06-29 Davos Life Science Pte. Ltd. Utilisation d une composition de tocotriénol pour la prévention du cancer
EP2337561A4 (fr) * 2008-10-23 2012-04-04 Davos Life Science Pte Ltd Utilisation d une composition de tocotriénol pour la prévention du cancer
AU2009307099B2 (en) * 2008-10-23 2013-02-14 Davos Life Science Pte. Ltd. Use of tocotrienol composition for the prevention of cancer
US10195161B2 (en) 2009-04-28 2019-02-05 Bioelectron Technology Corporation Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones
US9370496B2 (en) 2009-04-28 2016-06-21 Edison Pharmaceuticals, Inc. Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones
WO2011025785A1 (fr) 2009-08-26 2011-03-03 Edison Pharmaceuticals, Inc. Procédés de prévention et de traitement d’une ischémie cérébrale
US9670170B2 (en) 2013-03-15 2017-06-06 Bioelectron Technology Corporation Resorufin derivatives for treatment of oxidative stress disorders
US9296712B2 (en) 2013-03-15 2016-03-29 Edison Pharmaceuticals, Inc. Resorufin derivatives for treatment of oxidative stress disorders
US9868711B2 (en) 2013-03-15 2018-01-16 Bioelectron Technology Corporation Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders
US10751302B2 (en) 2014-12-16 2020-08-25 Ptc Therapeutics, Inc. Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10251847B2 (en) 2014-12-16 2019-04-09 Bioelectron Technology Corporation Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US11304914B2 (en) 2014-12-16 2022-04-19 Ptc Therapeutics, Inc. Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US11938101B2 (en) 2014-12-16 2024-03-26 Ptc Therapeutics, Inc. Polymorphic forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10981855B2 (en) 2015-12-17 2021-04-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US11680034B2 (en) 2015-12-17 2023-06-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders

Also Published As

Publication number Publication date
WO2000078296A3 (fr) 2002-05-30

Similar Documents

Publication Publication Date Title
WO2000078296A2 (fr) Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium
US6011067A (en) Antioxidant composition for the treatment of psoriasis and related diseases
Chow et al. Vitamin E regulates mitochondrial hydrogen peroxide generation
US6630507B1 (en) Cannabinoids as antioxidants and neuroprotectants
ES2685947T3 (es) Agentes antienvejecimiento
US20110003774A1 (en) Compounds having anti-proliferative properties
WO2002056823A2 (fr) Therapie par oxydoreduction pour des tumeurs
WO2018154145A3 (fr) Composés pour le traitement de la peau
KR100310499B1 (ko) 메티오날 또는 말론디알데히드의 세포 내 비율에 영향을 치는 인자를 함유하는 세포소멸 조절 조성물
US20030007961A1 (en) Orthomolecular vitamin E derivatives
MXPA05004526A (es) Derivados isoflavonoides aminados y usos de los mismos.
KR20070108382A (ko) 항암성 화합물
KR20000075919A (ko) 이소프레노이드와 스타틴의 배합물로 종양 성장을 억제하는 방법
Fu et al. Ultraviolet radiation and reactive oxygen generation as inducers of keratinocyte apoptosis: protective role of tea polyphenols
JPS63225321A (ja) 緑内障治療用医薬組成物
US20040265345A1 (en) Treatment of skin damage using acetyl carnitine and lipoic acid
EP1443897B1 (fr) Composition a base de carotenoides et methode destinee a proteger la peau
US6350776B1 (en) Method of treating proliferative disease with lycopene and alpha-tocopherol
US20080171032A1 (en) Dietary supplement composition and method of use for the treatment and prevention of oxidative stress
EP2170331B1 (fr) Combinaison synergique de proanthocyanidines, de gamma-tocotriénol et de niacine
Ates‐Alagoz et al. Antioxidant properties of novel benzimidazole retinoids
Iuchi Anemia caused by oxidative stress
Packer New horizons in vitamin E research—the vitamin E cycle, biochemistry, and clinical applications
González et al. Mitochondria, energy and cancer: the relationship with ascorbic acid
US20020012642A1 (en) Method of skin care and/or treatment using lipoic acid

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): JP RO SI US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): JP RO SI US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP