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WO2003097024A1 - Methodes de prevention et/ou de traitement de troubles neurologiques - Google Patents

Methodes de prevention et/ou de traitement de troubles neurologiques Download PDF

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WO2003097024A1
WO2003097024A1 PCT/EP2003/005186 EP0305186W WO03097024A1 WO 2003097024 A1 WO2003097024 A1 WO 2003097024A1 EP 0305186 W EP0305186 W EP 0305186W WO 03097024 A1 WO03097024 A1 WO 03097024A1
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substrate
udp
glucuronosyltransferase
ugt
glutamate
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PCT/EP2003/005186
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Pascal Neuville
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Faust Pharmaceuticals
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Priority to AU2003236668A priority Critical patent/AU2003236668A1/en
Priority to CA002486302A priority patent/CA2486302A1/fr
Priority to JP2004505023A priority patent/JP2005530778A/ja
Publication of WO2003097024A1 publication Critical patent/WO2003097024A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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    • 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 the use of substrates of an UDP-glucuronosyltransferase (UGT) and salts thereof, for the prevention and /or the treatment of neurological disorders.
  • the present invention relates to the use of substrates of at least an UDP- glucuronosyltransferase (UGT) expressed in brain and salts thereof, for the prevention and /or the treatment of neurological disorders.
  • It further relates to the use of said substrates, and salts thereof, for preventing and/or treating glutamate cytotoxicity, and more specifically of glutamate induced neurological disorders.
  • it concerns the use of said substrates, and salts thereof, for making drugs exerting an inhibitory effect on the release of glutamate.
  • a large number of studies have established that cellular communication using excitatory amino acids can be transformed into a mechanism of cell destruction.
  • Glutamate for example, is the main excitatory neurotransmitter in the nervous system, especially brain and spinal cord, of mammals wherein it is working at a variety of excitatory synapses.
  • the NMDA receptor IRL Oxford, 1989. It is for example strongly suggested that it plays a central role in functions such as learning, pattern recognition, and memory (Bliss T. V. P. Collingridge G. L., Nature 361, 31- 39, 1993) .
  • glutamate is toxic to neurons in vi tro and in vivo and that the function of glutamate receptors, especially glutamate receptors of the N-methyl-D-aspartate ("NMDA") receptor subtype, is crucial in a number of neuronal damages and injuries (Appel S. H. , Trends Neurosci . 16, 3- 5, 1993) .
  • NMDA N-methyl-D-aspartate
  • Many neurological disorders involving epileptic seizures and chronic or acute degenerative processes such as for example Alzheimer's, Huntington' s, Parkinson's diseases, multiple sclerosis (MS) , amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy (SMA) , retinopathy, stroke, depression and traumatic brain injury, involve neuronal cell death caused by over- stimulation of the glutamate receptors.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • retinopathy stroke
  • depression and traumatic brain injury involve neuronal cell death caused by over- stimulation of the glutamate receptors.
  • neuronal injury caused by ischemia after occlusion of cerebral arteries could, at least partially, be mediated by excessive activation of glutamate receptors as in the ischemic brain, extracellular glutamate is elevated rapidly after the onset of ischemia and declines following reperfusion (Davalos et al .
  • NMDA N-methyl-D-aspartate
  • glutamate receptors mostly the N-methyl-D-aspartate (“NMDA”) receptor
  • NMDA N-methyl-D-aspartate
  • Examples of such molecules are anthranilic acid derivatives (see US 5,789,444), Basilen Blue D-3G (Reactive Blue 2) and Cibacron Blue 3GA and 5- adenylylimidodiphosphate (AMPPNP) (see US 6,326,370), NMDA specific antagonists such as ketamine, gluconate (Sakaguchi et al .
  • neuromediator or neurotransmiter
  • Ach acetylcholine
  • BuCh butyrylcholine
  • GABA gamma- minobutyrate
  • serotonin the catecholamines, in particular dopamine or ATP.
  • glucuronidation represents a major metabolic pathway which enhances the detoxification and elimination of many lipophilic drugs, pollutants, xenobiotics and endogenous compounds by converting them in less biologically available, and thus less active, glucuronidated substances exhibiting higher polarity and water-solubility, thus facilitating their transport to excretory organs and subsequent excretion in urine or bile (for a review, see Ritter, 2000, Chemico-Biological Interactions, 129, 171-193) .
  • the reaction is catalyzed by UDP-glucuronosyltransferases (UGTs) .
  • This multigenic family of enzymes transfer the glucuronic acid moiety of UDP-glucuronic acid to structurally unrelated compounds through hydroxyl (alcoholic, phenolic) , carboxyl, sulfuryl, carbonyl and amino (primary, secondary or tertiary) linkages (for review, see Tukey and Strassburg, 2000, Annu. Rev. Pharmacol., Toxicol . , 40, 581-616). Initially, glucuronidation has been considered to represent a metabolic pathway performed mainly in the liver.
  • the inventors have now shown that the UGT activity in vivo, and more specifically in brain, can be turned away and used for defining a new class of compounds for the treatment and/or prevention of acute and chronic neuromediator-related diseases or conditions, particularly neurological diseases.
  • the present invention is a pharmacological alternative to previously described methods implementing compounds, such as competitive and non-competitive glutamate antagonists or agonists, gangliosides and growth factors.
  • the present invention provides a new class of compounds which can be used as pharmacological tools for the modulation of neuromediator cellular release and cytotoxicity, preferably neurotoxicity, and which allows the possible treatment and/or prevention of many neurological disorders involving epileptic seizures and acute and chronic neurodegenerative diseases, as well as neuronal injury caused by ischemia or neuromediator- related diseases or conditions, wherein said disorders are, at least partially, associated with excessive activation of neuromediator receptors and/or with excessive extracellular neuromediator levels.
  • the invention concerns the use of at least one substrate of an UDP-glucuronosyltransferase (UGT) , and salts thereof, for the preparation of a pharmaceutical composition having an inhibitory effect on the extracellular neuromediator release into an individual treated with said- composition.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • said UDP-glucuronosyltransferase (UGT) is expressed in brain.
  • said UDP- glucuronosyltransferase is selected among the group consisting of UDP-glucuronosyltransferase 1A1 (UGT1A1, also termed HUG-Brl or UGT1.1), UDP- glucuronosyltransferase 1A3 (UGT1A3 , also termed lc) , UDP- glucuronosyltransferase 1A4 (UGT1A4, also termed HUG-Br2) , UDP-glucuronosyltransferase 1A6 (UGT1A6) , UDP- glucuronosyltransferase 1A9 (UGT1A9, also termed HLUG P4) , UDP-glucuronosyltransferase 2B4 (UGT2B4, also termed Hlug- 25, Th-1, h-1, or h-20) , UDP-glucuronosyltransferase
  • said UDP-glucuronosyltransferase is expressed in brain and is selected among the group consisting of UDP-glucuronosyltransferase 1A6 (UGT1A6) and UDP-glucuronosyltransferase 2B7 (UGT2B7) .
  • UGT UDP- glucuronosyltransferase
  • UGT refers to enzymes catalyzing the glucuronidation reaction. Said reaction utilizes UDP-glucuronic acid as a cosubstrate for the formation of glucuronides . All of these terms are widely used in the litterature; for a review, please refer to Tukey and Strassburg, 2000, Annu. Rev. Pharmacol. Toxicol., 40, 581-616.
  • the method of choice for analysing the activity of a define UGT is the expression of the corresponding cDNA in a cell line that express minimal levels of the respective protein.
  • cells are transfected by standard transient transfection methods or by stable introduction of the cDNA into the genome following selection of the cells with an appropriate antibiotic. Then the cells are homogenized in a buffer containing Tris-HCl and MgCl 2 and subjected to sonication. Cell homogenates are then tested for their ability to glucuronidate series of substrates. The activity and selectivity of the UGT for a substrate could be compared with known specific substrates if available (Rem el and Burchell, 1993, Biochem. Pharmacol., 46, 559-566). Currently, 15 UGT cDNAs have been identified in human, eight UGT1A proteins encoded by the UGT1A locus and seven proteins encoded by UGT2B genes.
  • UGT- glucuronosyltransferase (UGT) 1A6 refers to one of the UGT proteins encoded by the UGT1A locus.
  • the human UGT1A6 sequence is presented in SEQ ID NO:l (Harding et al . , 1988, Proc. Natl . Acad. Sci. 85, 8381-8385 ).
  • UGT1A6 is also called PNP-UGT, phenol p I 6.2, UGT1*6, UGT1A06 or HLUGP1.
  • UGT1A6 is also called PNP-UGT, phenol p I 6.2, UGT1*6, UGT1A06 or HLUGP1.
  • UGT2B locus refers to one of the UGT proteins encoded by the UGT2B locus .
  • UGT2B7 The human UGT2B7 sequence is presented in SEQ ID NO : 2 (Ritter et al., 1990, J. Biol . Chem. , 265, 7900-7906. UGT2B7 is also named Th-2, h-2, Hlug-6, UGT2*7 or Catechol Estrogen UDPGT .
  • the term "UGT substrate” generally designates both the aglycone substrate (i.e. compound which can be enzymatically converted, or metabolized, by the UGT enzyme as disclosed above) and the glucuronidated substrate (i.e. compound which has been converted by addition of at least one glucuronic acid moiety through active groups) .
  • neuromediator a synonym of “neurotransmitter” , is intended to designate chemicals that transmit information across the junction (synapse) that separates one nerve cell (neuron) from another nerve' cell or a muscle.
  • neuromediators are acetylcholine (Ach) , butyrylcholine (BuCh) , gamma-aminobutyrate (GABA) , serotonin, norepinephrine, epinephrine, endorphins, or the catecholamines, in particular dopamine or adenosine triphosphate .
  • said neuromediator is the glutamate.
  • the UGT substrate of the invention is selected among the group consisting of planar and small phenols, polycyclic aromatic hydrocarbons, and compounds which are structurally related. More specifically, said UGT substrate contains at least one moiety selected in the group consisting in hydroxyl (alcoholic, phenolic, etc..) , carboxyl , sulfuryl, carbonyl and amino (primary, secondary or tertiary) moieties.
  • said substrate is a compound which can be converted by at least the UDP- glucuronosyltransferase 1A6 (UGT1A6) and is selected in the group consisting of 1-Naphthol, 2-Naphthol , 4- nitrophenol , methylsalicylate, ketoprofen , naproxen, 5- OH tryptamine/serotonin, carprofen/rimadyl , acetaminophen/paracetamol ,benzidine, 4- methylumbelliferone (4-MU) , silymarin (Venketaramanan et al .
  • UDP- glucuronosyltransferase 1A6 UDP- glucuronosyltransferase 1A6
  • silymarin is a mixture of toxifolin, silichristin, silidianin, silybin A et B, isosilybin A et B) [see Figure 1A and IB] .
  • said substrate is a compound which- can be converted by at least the UDP- glucuronosyltransferase 2B7 (UGT2B7) and is selected in the group consisting of transretinoic acid, ASA , AZT , benoxaprofen , benzidine, (benzo (a) pyrene mbs) , buprenorphine, carprofen, chloramphenicol, clofibric acid , flavenoids quercetin, kaempfenol, cyclosporin, DMXAA, diclofenac, dihydrocodeine DHC, dihydromorphone , mefenamic acid, fenemate NSAID, mycophenolic acid MCPA mofetil, fenoprofen, hydromorphone, ibuprofen, ketoprofen, linoleic acid , lorazepam, losartan, menthol, morphine 3 and morphine 3 and
  • said substrate is selected in the group consisting of ketoprofen , naproxen, 5 -OH tryptamine/serotonin, carprofen/rimadyl and benzidine.
  • the UGT substrates of the invention are further substituted with, one to four, identical or different, heteroatoms and/or hetero groups.
  • the addition salts of the substrates of the invention comprise conventional salt formed from inorganic or organic " acids " or ⁇ bases, such as ' hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ethylenediamine ; formic, benzoic, maleic, tartaric, citric, oxalic, aspartic acid, and alkane-sulfonic acids is even mentioned.
  • UGT substrates used according to the invention are commercially available in many commercial catalogues for example in Merck, "Produits chimiques et repercussion” 2002 and Acros Organics “Fine Chemicals” 2002-2003 : 1-Naphtol : 822289 (Merck)
  • Naproxen Apranax (FR, Roche) or Naprosyn (US, Roche)
  • Ketoprofen Toprec (FR, Aventis) or Orudis (US, Wyeth) .
  • UGT substrates of the invention are suitable for treating and/or preventing diseases, conditions and attacks related to deleterious effects of glutamate released, and preferably neurological ones.
  • said diseases, conditions and attacks are related to deleterious effects of neurotransmitter released in excess, and more particularly to deleterious effects of glutamate released in excess .
  • the present invention further relates to a method for treating and/or preventing neuromediator-evoked cytotoxicity in a patient in need thereof comprising administering to said patient a composition containing a therapeutically effective amount of at least one substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • said UGT substrate is a compound which can be converted by at least one UDP-glucuronosyltransferase (UGT) , and preferably by at least one UDP- glucuronosyltransferase (UGT) expressed in brain.
  • the present invention relates to a method for treating and/or preventing glutamate-evoked cytotoxicity in a patient in need thereof comprising administering to said patient a composition containing a therapeutically effective amount of at least one substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • said UGT substrate is a compound which can be converted by at least one UDP-glucuronosyltransferase (UGT) , and preferably by at least one UDP- glucuronosyltransferase (UGT) expressed in brain.
  • said UGT substrate is selected among the group consisting of planar and small phenols, polycyclic aromatic hydrocarbons, and compounds which are structurally related. More specifically, said UGT substrate contains at least one moiety selected in the group consisting in hydroxyl (alcoholic, phenolic, etc.), carboxyl, sulfuryl, carbonyl and amino (primary, secondary or tertiary) moieties.
  • said substrate is a compound which can be converted by the UDP- glucuronosyltransferase 1A6 (UGT1A6) and is selected in the group consisting of 1-Naphthol, 2-Naphthol , 4- nitrophenol , methylsalicylate, ketoprofen , naproxen, 5- OH tryptamine/serotonin, carprofen/rimadyl , acetaminophen/paracetamol , benzidine, 4- methylumbelliferone (4-MU) , silymarin (Venketaramanan et al., 2000, Drug Metab Dispos., 28,1270-3 ; Silymarin is a mixture of toxifolin, silichristin, silidianin, silybin A et B, isosilybin A et B) [see Figure 1] .
  • UDP- glucuronosyltransferase 1A6 UDP- glucuronosyltrans
  • said substrate is a compound which can be converted by the UDP- glucuronosyltransferase 2B7 (UGT2B7) and is selected in the group consisting of transretinoic acid, ASA , AZT , benoxaprofen, benzidine, (benzo (a) pyrene bs) , buprenorphine, carprofen, chloramphenicol, clofibric acid , flavenoids quercetin, kaempfenol, cyclosporin, DMXAA, diclofenac, dihydrocodeine DHC, dihydromorphone, mefenamic acid, fenemate NSAID, mycophenolic acid MCPA mofetil, fenoprofen, hydromorphone, ibuprofen, ketoprofen, linoleic acid , lorazepam, losartan, menthol, morphine 3 and morphine 6, nalbu
  • said substrate is selected in the group consisting of ketoprofen, naproxen, 5-OH tryptamine/serotonin, carprofen/rimadyl and benzidine .
  • neuromediator-evoked cytotoxicity or neurotransmitter-evoked cytotoxicity within the present invention is intended to designate cell toxicity associated with excessive activations of the concerned neuromediator receptors . These terms are well known by the one skilled in -the art. More specifically, the "glutamate- evoked cytotoxicity" concerns all affected cells expressing glutamate receptors. According to preferred embodiments, these cells are susceptible to be affected by neuromediators are nervous cells (i.e. neuro-cells) , preferably neurons. These affected nervous cells are, for example, present in brain, spinal cord, retina, at the neuro-muscular junction, etc ... "Cytotoxicity" means that the cell functions and/or properties are affected, leading to cell malfunctioning, and finally to cell death.
  • the method of the invention is intended for treating and/or preventing neuromediator-evoked neurotoxicity, and even more preferably for treating and/or preventing neurodegeneration (i.e. degeneration of nervous cells).
  • the method of the invention is intended for treating and/or preventing glutamate-evoked neurotoxicity, and even more preferably for treating and/or preventing neurodegeneration (i.e. degeneration of nervous cells).
  • the present invention further relates to a method for modulating the release of at least one neuromediator in a patient comprising administering to said patient a composition containing a therapeutically effective amount of at least one substrate of an UDP- glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above.
  • said UGT substrate is a compound which can be converted by at least one UDP- glucuronosyltransferase (UGT) , and preferably by at least one UDP-glucuronosyltransferase (UGT) expressed in brain.
  • the present invention further relates to a method for modulating the release of glutamate in a patient comprising administering to said patient a composition containing a therapeutically effective amount of at least one substrate of an UDP-glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above.
  • said UGT substrate is a compound which can be converted by at least one UDP-glucuronosyltransferase (UGT) , and preferably by at least one UDP-glucuronosyltransferase
  • treatment of, the patient with the substrates of the invention leads to a negative modulation, preferably to the inhibition, of the neuromediator release by the producing cells, and thus to a decreased neuromediator level in the treated patient compared to the same neuromediator level observed before said treatment.
  • the present invention further relates to a method for treating and/or preventing disease and/or condition associated with the excessive release of at least one neuromediator in a patient comprising administration to said patient of a composition containing a therapeutically effective amount of at least one substrate of an UDP- glucuronosyltransferase (UGT) arid a pharmaceutically acceptable carrier, wherein said substrate is as detailed above.
  • said UGT substrate is a compound which can be converted by at least one UDP- glucuronosyltransferase (UGT) , and preferably by at least one UDP-glucuronosyltransferase (UGT) expressed in brain.
  • the present invention further relates to a method for treating and/or preventing disease and/or condition associated with the excessive release of glutamate in a patient comprising administration to said patient of a composition containing a therapeutically effective amount of at least one substrate of an UDP- glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above.
  • said UGT substrate is a compound which can be converted by at least one UDP- glucuronosyltransferase (UGT) , and preferably by at least one UDP-glucuronosyltransferase (UGT) expressed in brain.
  • the terms "treating and/or preventing” refer to a process that is intended to produce a beneficial change in the condition of a mammal, e.g., a human, often referred to as a patient.
  • a beneficial change can, for example, include one or more of: restoration of function, reduction of symptoms, limitation or retardation of progression of a disease, disorder, or condition or prevention, limitation or retardation of deterioration of a patient ' s condition, disease or disorder.
  • Such therapy can involve, for example, nutritional modifications, administration of radiation, administration of a drug, behavioural modifications, and combinations of these, among others.
  • disease and/or condition associated with the excessive release of at least one neuromediator is intended to designate large number of acute and chronic neuromediator-related diseases or conditions, particularly neurological diseases. It designates more specifically epileptic seizures and acute and chronic neurodegenerative diseases, as well as neuronal injury caused by ischemia or neuromediator- related diseases or conditions, wherein said disorders are, at least partially, associated with excessive activation of neuromediator receptors and/or with excessive extracellular neuromediator levels.
  • Examples are involving chronic or acute degenerative disorders, such as for example Alzheimer's, Huntington ' s, Parkinson's diseases, multiple sclerosis (MS) , amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy (SMA) , retinopathy, stroke, clinical depression and traumatic brain injury, involve neuronal cell death caused by over- stimulation of the neuromediator receptors, and more specially of the glutamate receptors.
  • neuronal injury caused by ischemia or drug-induced neurotoxicity for example neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons
  • Other indications are the neuromediator-related conditions such as for example pain, hormonal balance, blood pressure, thermoregulation, respiration, learning, pattern recognition or memory, or any disorder subsequent to hypoxia or hypoglycaemia, especially when these indications are glutamate-related conditions.
  • compositions and methods were related to the aglycone form of said substrates.
  • the invention further relates to the use of at least one glucuronidated substrate of an UDP-glucuronosyltransferase
  • the substrate of an UDP- glucuronosyltransferase is understood as being glucuronidated before its administration to the patient in need thereof .
  • Said glucuronidation can be obtained by modifying the aglycone substrate either by chemical or enzymatic way.
  • Chemical glucuronidation can be obtained by using standard chemical method well known by those in the art consisting for example in adding a glucuronide group to the aglycone substrate intended to be used (Lacy and Sainsbury, 1995, Tetrahedron lett .
  • the glucuronidated substrate can be obtained by enzymatic glucuronidation using at least one UDP-glucuronosyltransferase (UGT) able to glucuronidate said aglycone substrate.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • said UDP- glucuronosyltransferase is naturally expressed in brain, e.g. UDP-glucuronosyltransferase (UGT) 1A6 or UDP- glucuronosyltransferase (UGT) 2B7.
  • said glucuronidated UGT substrate is selected among the group consisting of planar and small glucuronidated phenols, polycyclic aromatic glucuronidated hydrocarbons, and compounds which are structurally related. More specifically, said glucuronidated substrate contains at least one moiety selected in the group consisting in hydroxyl (alcoholic, phenolic, etc.), carboxyl, sulfuryl, carbonyl and amino
  • said glucuronidated substrate is selected in the group consisting of 1-Naphthol, 2-Naphthol , 4-nitrophenol , methylsalicylate, ketoprofen , naproxen, 5-OH tryptamine/serotonin, carprofen/rimadyl , acetaminophen/paracetamol, benzidine, 4-methylumbelliferone (4-MU) , silymarin (Venketaramanan et al .
  • Silymarin is a mixture of toxifolin, silichristin, silidianin, silybin A et B, isosilybin A et B) and is further glucuronidated.
  • said glucuronidated substrate is selected in the group consisting of transretinoic acid, ASA , AZT , benoxaprofen, benzidine, (benzo (a) pyrene mbs) , buprenorphine, carprofen, chloramphenicol, clofibric acid, flavenoids quercetin, kaempfenol, cyclosporin, DMXAA, diclofenac, dihydrocodeine DHC, dihydromorphone , mefenamic acid, fenemate NSAID, mycophenolic acid MCPA mofetil, fenoprofen, hydromorphone , ibuprofen, ketoprofen, linoleic acid, lorazepam, losartan, menthol, morphine 3 and morphine 6, nalbufene, nalmefene, naltrindole, nalorphine, na
  • the addition salts of the glucuronidated substrates of the invention comprise conventional salt formed from inorganic or organic acids or bases, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ethylenediamine ; formic, benzoic, maleic, tartaric, citric, oxalic, aspartic acid, and alkane-sulfonic acids is even mentioned.
  • inorganic or organic acids or bases such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ethylenediamine ; formic, benzoic, maleic, tartaric, citric, oxalic, aspartic acid, and alkane-sulfonic acids is even mentioned.
  • the present invention further relates to a method for treating and/or preventing neuromediator-evoked cytotoxicity in a patient in need thereof comprising administering to said patient a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • the present invention further relates to a method for treating and/or preventing glutamate-evoked cytotoxicity in a patient in need thereof comprising administering to said patient a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP-glucuronosyltransferase (UGT) as defined above and a pharmaceutically acceptable carrier.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • said "neuromediator-evoked cytotoxicity" is a neuromediator- evoked neurotoxicity, and even more preferably a neurodegeneration (i.e. degeneration of nervous cells) .
  • said "glutamate-evoked cytotoxicity" is a glutamate-evoked neurotoxicity, and even more preferably a neurodegeneration (i.e. degeneration of nervous cells) .
  • the present invention further relates to a method for modulating the release of at least one neuromediator in a patient comprising administering to said patient a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP- glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above .
  • the present invention further relates to a method for modulating the release of glutamate in a patient comprising administering to said patient a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP- glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above .
  • the present invention further relates to a method for treating and/or preventing disease and/or condition associated with the excessive release of at least one neuromediator in a patient comprising administration to said patient of a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP-glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • the present invention further relates to a method for treating and/or preventing disease and/or condition associated with the excessive release of glutamate in a patient comprising administration to said patient of a composition containing a therapeutically effective amount of at least one glucuronidated substrate of an UDP- glucuronosyltransferase (UGT) and a pharmaceutically acceptable carrier, wherein said substrate is as detailed above .
  • UDP- glucuronosyltransferase UDP- glucuronosyltransferase
  • the UGT substrates (including aglycone or glucuronidated form) described in the present invention are administered as a composition containing at least one active compound and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier can be utilized.
  • the carrier material can be an organic or inorganic inert carrier material suitable for the selected route of administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene-glycols, petroleum jelly and the like.
  • the pharmaceutical composition may contain other pharmaceutically active agents.
  • Additional additives such as flavoring agents, preservatives, stabilizers, emulsifying agents, salts for varying the osmotic pressure, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding.
  • Any conventional form such as tablets, capsules, pills, powders, granules, and the like may be used.
  • they are in the form of tablets, sugar coated tablets, hard gelatin capsules, capsules, granules, for oral administration, or solutions or suspensions for administration via an injectable channel.
  • the methods of the invention may be carried out by administering the composition containing substrates (including aglycone or glucuronidated form) of the invention by any route whereby drugs are conventionally administered.
  • routes include systemic and local routes. Examples are intravenous, intramuscular, subcutaneous, intracranial, intraventricular, inhalation (Gradinaru et al . , 1999 supra), intraperitoneal , as well as oral routes.
  • the method of the invention is carried out via oral or intravenous routes of administration.
  • the substrates described herein are useful in pharmaceutically acceptable oral modes.
  • a preferred oral dosage form comprises tablets, capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • the oral dosages contemplated in accordance with the present invention will vary in accordance with the needs of the individual patient as determined by the prescribing physician.
  • the preferred oral dosage form is capsules or tablets containing from 50 to 500 mg of a substrate of the invention.
  • Typical preparations for intravenous administration would be sterile aqueous solutions including water/buffered solutions .
  • Intraveneous vehicles include fluid, nutrient and electrolyte replenishers .
  • compositions for bolus i.v. administration may contain up to 10 mg/ml (10,000 mg/liter) of substrate described herein.
  • Compositions for i.v. administration preferably contain from about 50 mg/liter to about 500 mg/liter of at least one substrate described herein.
  • substrate of the invention (including aglycone or glucuronidated form) is generally given to adults daily, preferably orally or intravenously, in an amount of from about 5 mg/kg to about 30 mg/kg daily, in single or divided doses, preferably from about 13 mg/kg to about 17 mg/kg daily, with the precise dosage being varied depending upon the needs of the patient.
  • the doses will be adapted according to the patient and the pathology to be treated and are for example 1 mg-100 mg/day. In general, this therapy is carried out for a period of about three months.
  • the method of the invention may be carried out prophylactically for an indefinite time in those patients who are have a high risk of suffering an acute neurotoxic event, such as a stroke.
  • the patient For the treatment of an acute neurotoxic event, the patient should be treated in accordance with the method of the invention as soon as possible after the diagnosis of the acute neurotoxic event, preferably within twelve hours, and most preferably within six hours, of the onset of the neurotoxic event.
  • the drug When the drug is administered orally, it is generally administered at regular intervals.
  • These drugs are notably administered orally or via an injectable channel.
  • the UGT substrates (including aglycone or glucuronidated form) described in the present invention are modified with specific groups facilitating the passage of said UGT substrate throughout the blood-brain barrier (BBB) .
  • BBB blood-brain barrier
  • One strategy is lipidization, which involves the addition of lipid-like groups through modification of the hydrophilic part of the substrate structure. The resulting lipid- soluble substrates are transported through the BBB by accessing pores that transiently form within the lipid bilayer.
  • Another strategy is the addition of hydrophobic groups to enhance BBB transfer by passive diffusion. For examples, addition of methyl groups or acetylation of amine groups increase lipophilicity and brain penetration.
  • a further approach is to modify the substrate so that the compound has a structure that mimics a nutrient, thus gi-ving__j ⁇ ------ access ---. to--- one o-f- ._th.e_ s-peci-aIdzed —c ax er mediated transport systems within the BBB such as amino acid, hexose, vitamin and neuropeptide carriers.
  • An alternative approach is the coupling of the substrates, via chemical linkers, to small synthetic peptide-vectors that cross the cellular membranes efficiently such as Pegelin or Penetratin (for general shutdown, see Temsamani et al . , 2000, Pharm. Sci . Technol . Today, 3, 155-162).
  • the substrate or preparation of the invention (including aglycone or glucuronidated form) is administered to the patient in need in combination with a second compound or formulation aimed at facilitating the transfer throughout the BBB.
  • the substrate or preparation of the invention is combined with a hypertonic solution, a biologically active agents such as bradykinin and angiotensin peptides, a vasoactive substance such as histamine, leukotrienes which have the ability of disrupting BBB transiently.
  • “combination” or “combined with” means that the substrate or preparation of the invention and the second compound or formulation aimed at facilitating the transfer throughout the BBB can be used simultaneously or consecutively or so as to be staggered over time.
  • Simultaneously refers to a coadministration.
  • these two essential components can be mixed to form a composition prior to being administered, or can be administered at the same time to the patient in need. It is also possible to administer them consecutively, that is to say one after the other, irrespective of which component is administered first.
  • the routes and sites of administration of the two components can be different.
  • the time interval between the administration and the routes and sites of administration can be defined by the skilled person. It is possible to recommend an interval of from 10 min to 72 h, advantageously of from 30 min to 48 h, preferably of from 1 to 24 h and, very preferably, of from 1 to 6 h.
  • Pharmacogenomic analysis see for example Ciotti et al . , 1997, Pahrmacogenetics, 7, 485-495) have shown that polymorphisms in the UGT genes can result in affected enzyme activity and in lowering or increasing the patient reactivity towards UGT substrates.
  • the treatment and/or prevention methods of the present invention further comprise a preliminary step consisting in establishing if the patient to be treated is presenting a genetic polymorphism resulting in less or improved UGT activity. More specifically, said preliminary step consists in determining by nucleotide sequence analysis of the patient genomic DNA if the UGT1A6 gene of said patient to be treated comprises at least one of the mutation A541-G541
  • Cortices from foetal Wistar rats were dissected and maintained in PBS without calcium and magnesium. They were then treated in PBS containing 0.25% Trypsin for 15 min at 37°C and placed in a complete medium containing Horse Serum for inhibiting trypsin activity. The cortices were then dissociated in complete medium (Neurobasal, 2% Horse Serum, 2mM Glutamine, B27 supplement (IX) , lOO ⁇ g/ml Gentamicyn, lO ⁇ M ⁇ Mercaptoethanol) .
  • Cells were seeded at 10 5 cells per well in a 96 well plate previously coated with Poly-Ornithine at 9 ⁇ g/ml .
  • the cultures were maintained at 37°C in a humidified incubator with 5% C0 2 .
  • 5 ⁇ M Cytosine Arabinofuranoside was added to the cell cultures in order to inhibit glial cell proliferation.
  • the primary cultures of neurons were available for further experiments .
  • Neuron cell death was estimated by measuring the release of the cytosolic enzyme, lactate dehydrogenase (LDH) , into the medium of cell cultures. The LDH release quantification was performed using the colorimetric CytoTox96 * nonradioactive assay (Promega) . Briefly, lOO ⁇ L of cell culture medium were removed and centrifuged for 4 min at 1500 rpm in order to remove cellular debris. 50 ⁇ L were then added to 50 ⁇ L of assay buffer and placed in the dark for 30min at room temperature. The reaction was stopped with 50 ⁇ L of stop solution and the absorbance at 490nm was measured. The percentage of cell death was calculated by comparison with the control. Assessment of glutamate release .
  • LDH lactate dehydrogenase
  • Glutamate released by neurons in culture was evaluated in aliquots of the supernatants by means of a chemiluminescent enzymatic assay (Israel et al . , Neurochem Int. 1993 Jan;22 (1) : 53-8) .
  • Diazepam (Sigma) and the glucuronide derivative of Diazepam, named Temazepam (Alltech) , a substrate of the UDP-glucuronosyltransferase 2B7 (UGT2B7) , were used to illustrate the preventing and/or treating effects of UGT2B7 substrates on glutamate-induced neurological disorders .
  • Diazepam and Temazepam were used to protect primary cultures of neurons, isolated from the rat brain cortex, from neurotoxin-induced cell death.
  • the neurons were treated in vi tro with 3- nitropropionic acid (3-NP, Sigma) at 400 ⁇ M, a toxin which induces epileptic seizures in animal models, in absence or presence of Diazepam and Temazepam at 0.1, 1 and 5 ⁇ M.
  • 3-NP 3- nitropropionic acid
  • Temazepam a toxin which induces epileptic seizures in animal models, in absence or presence of Diazepam and Temazepam at 0.1, 1 and 5 ⁇ M.
  • Figure 2 show that Diazepam protects neurons from 3-NP at all tested doses but that Temazepam significantly reinforces said cell protection by about 50% at 1 and 5 ⁇ M.
  • 1-Naphthol was used to protect primary cultures of neurons, isolated from the rat brain cortex, from neurotoxin-induced cell death.
  • the neurons were treated in vi tro with 5 ⁇ M of Ionomycin (Sigma) , a calcium ionophore, in presence of lO ⁇ M of 1-Naphthol, in absence or in presence of 5 or lO ⁇ M of 3-methylcholanthrene (3-MC, Aldrich) , an UGT inducer which allows the in si tu glucuronidation of 1-Naphthol.
  • the glutamate released by neurons was followed by an enzymatic assay coupled to a chemiluminescent reaction.
  • primary cultures of neurons isolated from the rat brain cortex were treated by 1-Naphthol at lO ⁇ M with or without 3-MC at 1 or 5 ⁇ M.
  • the results ( Figure 5) indicate that 1-Naphthol reduces glutamate release and that glucuronidation of 1-Naphthol by 3-MC reinforces, dose dependently, the decrease of glutamate.
  • Figure 1 Illustrates the chemical structures of designed compounds cited throughout the specification.
  • FIG. 1 Effect of Diazepam and Temazepam on neuron cell death. Neuron cell death in culture was arbitrarily set at 0. The cells were treated with the vehicle (lane 1) and with 3-NP at 400 ⁇ M alone (lane 2) or simultaneously with one of the three tested concentrations of Diazepam
  • Figure 3 Effect of Diazepam and Temazepam on neuron cell death.
  • Neuron cell death in culture was arbitrarily set at 0.
  • the cells were treated with the vehicle (lane 1) and with kainic acid at lOO ⁇ M alone (lane 2) or simultaneously with one of the three tested concentrations of Diazepam (lanes 3-5) and Temazepam (lanes 6-8) .
  • Results indicate that Temazepam at l ⁇ M (lane 7) and 5 ⁇ M (lane 8) but not at 0.
  • l ⁇ M (lane 6) improves the neuroprotective effect of Diazepam observed at all concentrations (lanes 3-5) .
  • FIG. 4 Effect of 1-Naphthol and 1-Naphthol glucuronide on neuron cell death. Neuron cell death in culture was arbitrarily set at 0. The cells were treated with the vehicle (lane 1) and with Ionomycin at 5 ⁇ M alone
  • Figure 5 Effect of 1-Naphthol and 1-Naphthol glucuronide on glutamate released by neurons in culture.
  • Glutamate release was evaluated by means of a chemiluminescent enzymatic assay. The basal levels of glutamate release were quantified in the non-treated cells

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Abstract

L'invention concerne l'utilisation de substrats d'une UDP-glucuronosyltransférase (UGT) et de sels de ceux-ci pour la prévention et/ou le traitement de troubles neurologiques. Dans un mode de réalisation préféré, l'invention concerne l'utilisation de substrats d'au moins une UDP-glucuronosyltransférase (UGT) exprimée dans le cerveau et de sels de ceux-ci, pour la prévention et/ou le traitement de troubles neurologiques. L'invention concerne également l'utilisation de ces substrats et de sels de ceux-ci pour prévenir et/ou traiter la cytotoxicité due au glutamate, et plus spécifiquement des troubles neurologiques induits par le glutamate. En outre, l'invention concerne l'utilisation de ces substrats et de sels de ceux-ci pour fabriquer des médicaments exerçant un effet d'inhibition sur la libération de glutamate.
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US8404686B2 (en) 2004-12-24 2013-03-26 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis
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US8609630B2 (en) 2005-09-07 2013-12-17 Bebaas, Inc. Vitamin B12 compositions
JP2009508940A (ja) * 2005-09-23 2009-03-05 エスケー ホルディングス カンパニー リミテッド フェニル酪酸ナトリウムを使用する、薬物依存症又はアルコール依存症或いは躁うつ病の予防又は治療のための医薬組成物
US8551950B2 (en) 2006-03-20 2013-10-08 Spinifex Pharmaceuticals Pty Ltd Method of treatment or prophylaxis of inflammatory pain
US9227968B2 (en) 2006-03-20 2016-01-05 Novartis Ag Method of treatment or prophylaxis of inflammatory pain
EP3033416A4 (fr) * 2013-08-12 2017-02-08 Benaroya Research Institute at Virginia Mason Traitement par 4-méthylumbelliférone pour l'immunomodulation
US10285976B2 (en) 2013-08-12 2019-05-14 The Board Of Trustees Of The Leland Stanford Junior University 4-methylumbelliferone treatment for immune modulation

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