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WO2002066032A1 - Traitement de la schizophrenie - Google Patents

Traitement de la schizophrenie Download PDF

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Publication number
WO2002066032A1
WO2002066032A1 PCT/US2002/005688 US0205688W WO02066032A1 WO 2002066032 A1 WO2002066032 A1 WO 2002066032A1 US 0205688 W US0205688 W US 0205688W WO 02066032 A1 WO02066032 A1 WO 02066032A1
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WO
WIPO (PCT)
Prior art keywords
symptoms
ameliorating
psychosis
schizophrenia
flavonoid
Prior art date
Application number
PCT/US2002/005688
Other languages
English (en)
Inventor
Randy Ziegler
Original Assignee
Randy Ziegler
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 Randy Ziegler filed Critical Randy Ziegler
Priority to BR0204228-2A priority Critical patent/BR0204228A/pt
Priority to EP02723237A priority patent/EP1377286A1/fr
Publication of WO2002066032A1 publication Critical patent/WO2002066032A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • 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
    • 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 
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Schizophrenia is a common, complex, heterogeneous, adult onset, polygenic neuropsychiatric disease. Schizophrenia affects 1 -1 .5% of the population and is a major cause of mortality and morbidity. Although clearly heritable, the disease follows a non-Mendelian pattern of inheritance.
  • One theory posits that schizophrenia is a caused by neuro-degenerative CAG trinucleotide repeats encoding polyglutamine arrays typically longer than 35 repeats in the coding regions, or the untranslated sequences (introns) of genes. These polyglutamine repeats modulate gene or protein structure and function.
  • Pathophysiological models of the disease have localized its expression to the dopaminergic neurons of the mid-brain— the substantia nigra and ventral tegmental area— from these dopaminergic neurons into the nigrostriatal and mesolimbic pathways. These two pathways encompass the very limited region of the central nervous system (CNS) that expresses Dopamine D2 receptors. Imaging and functional studies have previously implicated these two pathways in the pathogenesis of schizophrenia.
  • the human hippocampus and amygdala are two regions also implicated in effect and psychosis. All of these regions show the presence of a novel human cDNA sequence that encodes a neuronal small conductance calcium- activated potassium channel (hSKCa3). This nucleotide has been isolated and sequenced. Small conductance calcium activated potassium (K + ) channels play a critical role in determining the firing pattern of neurons.
  • NMDA-R receptors N-methyl-o-aspartate type glutamate receptor channels.
  • the NMDA-R receptors are the major excitatory receptors in the central nervous system. Hyperactive hSKCa3 channels would therefore be expected to induce NMDA-R receptor hypofunction and might thereby enhance susceptibility to disease.
  • the NMDA-R receptor channels When bound by an agonist, the NMDA-R receptor channels allow calcium and sodium to be transduced by potassium channels in a inward current.
  • voltage-gated calcium channels products of the alpha-1 calcium channel gene
  • calcium activated potassium channels hSKCa3
  • NMDA-R receptors Each channel has the potential to control the activity of the other. Alteration of function in any one of these important proteins might perturb a common physiological process.
  • the hippocampus and the amygdala have demonstrated an abundant expression of hSKCa3. This hSKCa3 is expressed in dopaminergic neurons of the dopaminergic pathways of the nigrostriatal and mesolimbic pathways.
  • the hSKCa3 gene encodes a protein of 731 amino acids and is extremelyly sensitive to cytosolic free calcium.
  • the rise in calcium via NMDA-R and ligand binding of glutamate causes the hSKCa3 gene to send a small conductance of 4-14 pS (pico Siemens) to after-hyperpolarize the membrane and set up Kv (voltage gated potassium channel) to further polarize the membrane with 12-40pS.
  • This also sets the tonic magnesium (Mg 2+ ) block into the NMDA-R channel stopping the Ca 2+ pumping.
  • Increased potassium channel activity would indirectly cause the reduction in activity of the NMDA-R via an extracellular Mg 2+ block. Thereby the pathophysiology of schizophrenia would be exacerbated. Drugs like valproate and lithium stimulate glutamate release and activate NMDA-Rs.
  • a novel therapeutic would be a small regulatory molecule whose function would be to potentiate the ion channel by way of sequestering calcium. This would allow the ion channel to have greater load electrochemically to hyperpolarize and thereby maintain the NMDA-Rs open by delaying onset of the tonic magnesium block. This would maintain the cytosolic free calcium potentiating the hSKCa3 channel itself to fire less often. Keeping the NMDA-R open would allow neural excitability and relief of psychosis. Conversely, hyperactive hSKCa3 channels would be expected to induce NMDA-R receptor hypofunction and thereby enhance disease susceptibility.
  • Enzyme active site modeling and X-ray crystallography have shown that flavones with specific hydroxylation patterns can cause calcium sequestration in signal transduction pathways.
  • Receptors r3 and r4 of the thyroid hormone family are inhibited by ligand binding of hydroxlylated flavones, thereby deactivating the oxygen transport hormone and therefore oxygen transport.
  • the polyglutamine arrays (CAG repeats) can produce a increased affinity in the hSKCa3 gene channel due to the increased accumulated potential. These additional arrays can be combated by increased Ca 2+ loading in the signal transduction pathways.
  • Application of ligand specific flavonoids would draw calcium to the S5 and S6 pore or p region to keep the NMDA-R channel open.
  • the hSKCa3 gene product would need to modulate less frequently due to calcium cytosolic loading. This potentiation would cause less frequent after-hyperpolarization leading to less tonic blocking of the NMDA-R by Mg 2+ , thereby increasing calcium flow for further hypofuction.
  • the present invention involves the use of flavonoids to treat psychoses such as schizophrenia.
  • flavonoids act as the ideal modulators of hSKCa3 ion channels.
  • common flavonoids such as quercetin, luteolin and myricetin
  • the symptoms of the disease are dramatically ameliorated.
  • Many of the effective flavonoids are common in a number of fruits and vegetable. However, normal dietary intake does not appear to provide sufficient flavonoids for therapeutic action.
  • Flavonoids are ubiquitous chemicals found in many vascular plants. Flavonoids are a well-studied group of chemicals and the standard system of numbering and nomenclature are used in the following discussion. A variety of different structural groups are found in differing configurations on the three rings of a flavonoid. Additionally, organic chemists can add many new and non-naturally occurring structural groups to create novel flavonoids. Key structural components in the flavonoid molecule which impart functionality to effectively treat schizophrenia are sites for the complexing of Ca 2+ created by hydroxyl groups and other electron donating atoms or groups including but not limited to methoxy, ethoxy, amino, amido, hydroxyethyl, halogens, sulfuryl and sulfhydryl, and phosphoryl groups.
  • flavones quercetin luteolin, myricetin, hesperetin, apigenin, baicalein, naringenin, and the many glycosides and methyl ethers thereof including but not limited to rutin, diosmin, hesperidin, myricitrin, etc.
  • flavones quercetin luteolin, myricetin, hesperetin, apigenin, baicalein, naringenin, and the many glycosides and methyl ethers thereof including but not limited to rutin, diosmin, hesperidin, myricitrin, etc.
  • Subject number one was 21 -22-year-old paranoid schizophrenic male. He exerted classic symptoms of schizophrenia: he would not come out of his room; he would not converse with his family or parents; and he reported hearing voices coming out of the pipes in his bedroom. He had gained approximately 35 + pounds while receiving classic neuroleptics, and anti-psychotic drugs to treat his symptoms. His speech was slow, and he would not look directly at the interviewer. His thought process seemed unfocused and scattered. His gait was "stuttered" showing small baby steps. His weight was approximately 230 pounds, and he had dark circles under his eyes.
  • quercetin 3, 5, 7, 3', 4'-pentahydroxyflavone
  • Subject number two was a 44-year-old female and had been diagnosed with Lupus about five years before the time of treatment. Lupus is often associated with dementia. Probably in relation to that disease, M.F.'s emotional status began to decline severely. Her husband took her to psychiatric and marriage counseling and became discouraged to the point of contemplating divorce. He felt that his wife was lost to him and "gone” emotionally. After thirty days of treatment with the mixed quercetin and myricetin (1 500 mg/day), she regained composure, and her husband stated that she had returned to him. The irrational behavior and psychosis's abated and counseling was terminated.
  • Subject number three was a 42-year-old Caucasian female.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L"invention concerne une méthode pour traiter les symptômes d"une psychose, et plus particulièrement pour traiter la schizophrénie. Ce traitement consiste en une administration orale répétée d"un flavonoïde. La quercetine est efficace, tout comme un certain nombre d"autres flavonoïdes contenant des flavones telles que la lutéoline. Les flavonoïdes agissent en réduisant l"activité des canaux ioniques hSKCa3.
PCT/US2002/005688 2001-02-20 2002-02-20 Traitement de la schizophrenie WO2002066032A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR0204228-2A BR0204228A (pt) 2001-02-20 2002-02-20 Métodos para melhorar os sintomas de uma psicose e de esquizofrenia e para triar moléculas de teste, e, composto orgânico
EP02723237A EP1377286A1 (fr) 2001-02-20 2002-02-20 Traitement de la schizophrenie

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27008701P 2001-02-20 2001-02-20
US60/270,087 2001-02-20

Publications (1)

Publication Number Publication Date
WO2002066032A1 true WO2002066032A1 (fr) 2002-08-29

Family

ID=23029855

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/005688 WO2002066032A1 (fr) 2001-02-20 2002-02-20 Traitement de la schizophrenie

Country Status (3)

Country Link
EP (1) EP1377286A1 (fr)
BR (1) BR0204228A (fr)
WO (1) WO2002066032A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1721613A1 (fr) * 2005-05-13 2006-11-15 Mewicon med. wiss. Beratung GmbH Hesperidine pour le traitement de l'épilepsie, la migraine, la dépression et l'abus de drogues
WO2006079021A3 (fr) * 2005-01-20 2007-03-22 Sirtris Pharmaceuticals Inc Methodes et compositions destinees au traitement des bouffees vasomotrices et de la prise de poids d'origine medicamenteuse
JP2007538078A (ja) * 2004-05-18 2007-12-27 ブライト フューチャー ファーマシューティカル ラボラトリーズ 睡眠障害のためのミリシトリン化合物
WO2008000142A1 (fr) * 2006-06-23 2008-01-03 Cell Star Bio-Technologies Co., Limited Agoniste du transporteur de la dopamine et ses utilisations
WO2009121155A3 (fr) * 2008-04-01 2009-11-26 Aché Laboratórios Farmacêuticos S/A Utilisation d'une ou de plusieurs benzopyranones, composition pharmaceutique et procédé de prévention ou de traitement de maladies, de dysfonctionnements et de perturbations associés à la monoamone oxydase
US20110201565A1 (en) * 2008-10-30 2011-08-18 University Of South Florida Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism
US20120029066A1 (en) * 2010-07-30 2012-02-02 Taipei Medical University Use of flavones for treating psychiatric disorders with sensorimotor gating deficits

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0085579A2 (fr) * 1982-02-03 1983-08-10 Efamol Limited Compositions pharmaceutiques topiques
EP0558753A1 (fr) * 1991-08-09 1993-09-08 TSUMURA & CO. Inhibiteur de beta-glucuronidase
WO1999021005A2 (fr) * 1997-10-23 1999-04-29 Pharmaprint, Inc. Millepertuis de qualite pharmaceutique
US6030621A (en) * 1998-03-19 2000-02-29 De Long; Xie Ginkgo biloba composition, method to prepare the same and uses thereof
US6083526A (en) * 1997-05-22 2000-07-04 Gorbach; Sherwood L. Use of isoflavonoids in the treatment or prevention of postpartum depression
WO2002015901A1 (fr) * 2000-08-22 2002-02-28 Neuronex Co., Ltd. Myricetine utile comme inhibiteur de la serotonine n-acetyltransferase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0085579A2 (fr) * 1982-02-03 1983-08-10 Efamol Limited Compositions pharmaceutiques topiques
EP0558753A1 (fr) * 1991-08-09 1993-09-08 TSUMURA & CO. Inhibiteur de beta-glucuronidase
US6083526A (en) * 1997-05-22 2000-07-04 Gorbach; Sherwood L. Use of isoflavonoids in the treatment or prevention of postpartum depression
WO1999021005A2 (fr) * 1997-10-23 1999-04-29 Pharmaprint, Inc. Millepertuis de qualite pharmaceutique
US6030621A (en) * 1998-03-19 2000-02-29 De Long; Xie Ginkgo biloba composition, method to prepare the same and uses thereof
WO2002015901A1 (fr) * 2000-08-22 2002-02-28 Neuronex Co., Ltd. Myricetine utile comme inhibiteur de la serotonine n-acetyltransferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAHADIK S P ET AL: "Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia.", PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY. ENGLAND APR 2001, vol. 25, no. 3, April 2001 (2001-04-01), pages 463 - 470, XP002204382, ISSN: 0278-5846 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007538078A (ja) * 2004-05-18 2007-12-27 ブライト フューチャー ファーマシューティカル ラボラトリーズ 睡眠障害のためのミリシトリン化合物
WO2006079021A3 (fr) * 2005-01-20 2007-03-22 Sirtris Pharmaceuticals Inc Methodes et compositions destinees au traitement des bouffees vasomotrices et de la prise de poids d'origine medicamenteuse
EP1721613A1 (fr) * 2005-05-13 2006-11-15 Mewicon med. wiss. Beratung GmbH Hesperidine pour le traitement de l'épilepsie, la migraine, la dépression et l'abus de drogues
WO2008000142A1 (fr) * 2006-06-23 2008-01-03 Cell Star Bio-Technologies Co., Limited Agoniste du transporteur de la dopamine et ses utilisations
WO2009121155A3 (fr) * 2008-04-01 2009-11-26 Aché Laboratórios Farmacêuticos S/A Utilisation d'une ou de plusieurs benzopyranones, composition pharmaceutique et procédé de prévention ou de traitement de maladies, de dysfonctionnements et de perturbations associés à la monoamone oxydase
US20110201565A1 (en) * 2008-10-30 2011-08-18 University Of South Florida Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism
US20120029066A1 (en) * 2010-07-30 2012-02-02 Taipei Medical University Use of flavones for treating psychiatric disorders with sensorimotor gating deficits

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Publication number Publication date
BR0204228A (pt) 2004-06-22
EP1377286A1 (fr) 2004-01-07

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