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WO2001052861A1 - Diagnostic et traitement de troubles mentaux - Google Patents

Diagnostic et traitement de troubles mentaux Download PDF

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Publication number
WO2001052861A1
WO2001052861A1 PCT/GB2000/000159 GB0000159W WO0152861A1 WO 2001052861 A1 WO2001052861 A1 WO 2001052861A1 GB 0000159 W GB0000159 W GB 0000159W WO 0152861 A1 WO0152861 A1 WO 0152861A1
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WO
WIPO (PCT)
Prior art keywords
gdp
fucose
agent
metabolism
hydrolase
Prior art date
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Ceased
Application number
PCT/GB2000/000159
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English (en)
Inventor
Kazuo Miyanaga
Shin Yazawa
Hideyuki Asaoka
Masakazu Adachi
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Japan Immunoresearch Laboratories Co Ltd
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Japan Immunoresearch Laboratories Co Ltd
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 Japan Immunoresearch Laboratories Co Ltd filed Critical Japan Immunoresearch Laboratories Co Ltd
Priority to PCT/GB2000/000159 priority Critical patent/WO2001052861A1/fr
Priority to AU2000230653A priority patent/AU2000230653A1/en
Publication of WO2001052861A1 publication Critical patent/WO2001052861A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase

Definitions

  • the present invention relates to the diagnosis and treatment of schizophrenia.
  • Schizophrenia is a chronic, severe and disabling brain disease that affects approximately 1% of the population. It often affects people from an early age, and there is a strong, though not invariable hereditary factor in its aetiology.
  • the present invention relates to two enzymes involved in the metabolism of fucose, namely ⁇ - (1—»3) -fucosyl transferase and guanidinediphosphate-fucose (GDP-fucose) hydrolase.
  • ⁇ - (1—»3) -fucosyl transferase is GDP-L-fucose : 2 -acetamido-2-deoxy-D-gluco- pyranosyl- (1—»3) - ⁇ -L-fucosyl transferase.
  • the enzyme catalyses the transfer of L-fucose from GDP-L-fucose to glucose or N-acetyl glucosamine .
  • the enzyme has been detected inter alia in human milk, submaxillary glands and stomach, plasma or serum, bone marrow and saliva.
  • ⁇ (l—»2), ⁇ (l—4) and ⁇ (l-6) fucosyl transferases are also known. Initial interest in these enzymes was largely related to their involvement in the synthesis of blood group active substances.
  • GDP-fucose hydrolase hydrolyses GDP fucose to GDP and fucose.
  • the present invention is based on the observations that the activity of ⁇ - (1—3) -fucosyl transferase in serum of human schizophrenia sufferers is lower than that in humans who do not suffer from schizophrenia and that increasing the activity of that enzyme in schizophrenia sufferers may improve their condition. It has also been found that GDP-fucose hydrolase can be inhibited by certain agents and that administration of a GDP-fucose hydrolase inhibitor to schizophrenia sufferers may lead to an improvement of the schizophrenia condition. Our observations suggest that directing GDP-fucose to metabolism via ⁇ - (1—»3) -fucosyl transferase rather than via GDP-fucose hydrolase improves the condition of patients with schizophrenia.
  • the present invention provides a method of treatment of schizophrenia, which comprises administering to a human schizophrenia patient an effective amount of an agent that increases the metabolism of GDP- fucose by ⁇ - (1—3) -fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase .
  • the present invention also provides the use of an agent that increases the metabolism of GDP-fucose by ⁇ - (l-»3) -fucosyl transferase and/or an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase in the manufacture of a medicament for the treatment of schizophrenia .
  • the agent is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt. More preferably the agent is an adenosine phosphate for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof, for example the disodium salt of ATP.
  • adenosine phosphates both increase the metabolism of GDP-fucose by ⁇ - (l->3) -fucosyl transferase and decrease the metabolism of GDP-fucose by GDP-fucose hydrolase by acting as an inhibitor of that enzyme.
  • a different inhibitor of GDP-fucose hydrolase may be used.
  • the metabolism of GDP-fucose by ⁇ - (1—»3) -fucosyl transferase may be increased by decreasing the metabolism of GDP-fucose by any other enzyme that metabolises that compound in vivo .
  • ⁇ -(l-3) fucosyl transferase ( ⁇ - (1—3) FT) was determined in plasma samples from normal human donors i.e. humans not suffering from schizophrenia, and patients with schizophrenia using the assay described in detail in Example 1, measuring transfer of radiolabelled GDP-fucose to N-acetyl-2 ' -O-methyllactosamine, see Madiyalakan et al Analytical Biochemistry 152, 22-28
  • ⁇ - (1— 3) FT was determined in plasma samples of 17 normal donors and 26 schizophrenic patients in the presence of added ATP (0.2 ⁇ mol) as described in detail in Example 2.
  • the activity of - (1— >3 ) FT of normal donors was 10,523 ⁇ 3,323 dpm (mean ⁇ S.D.), while that of schizophrenic patients was 8,512+5,366 dpm (mean ⁇ S.D).
  • ATP-2Na disodium salt of ATP
  • BPRS Brief Psychiatric Rating Scale
  • the invention provides the use in the treatment of schizophrenia of an agent that increases the activity of ⁇ - (1—3 ) -fucosyl transferase and also comprises a method of treatment of schizophrenia comprising administering an effective amount of such an agent to a schizophrenia patient.
  • the agent that increases the activity of ⁇ - (1—3) -fucosyl transferase is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof. More preferably the inhibitor is an adenosine phosphate for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof.
  • the main substrates for ⁇ - (1—»3 ) -fucosyl transferase are GDP-fucose and N-acetylglucosamine or glucose (alternative synthetic substrates have been described, see for example Madiyalakan et al Analytical Biochemistry 152 , 22-28 (1986)).
  • a second fate for GDP-fucose in the body is its hydrolysis by a GDP-fucose hydrolase. It has now been found that it is possible to inhibit the hydrolase enzyme and that such inhibition leads to an amelioration of the symptoms of schizophrenia.
  • the invention provides the use of an inhibitor of GDP-fucose hydrolase in the treatment of schizophrenia and also a method of treatment of schizophrenia comprising administering an effective amount of an inhibitor of GDP-fucose hydrolase to a schizophrenia patient.
  • the inhibitor of GDP-fucose is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof.
  • the inhibitor is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof.
  • the agent is ATP or a salt thereof.
  • the invention provides a method of diagnosing schizophrenia in a human subject which comprises determining in vi tro the activity level of ⁇ - (l-»3) -fucosyl transferase in a sample of a body fluid or tissue of the subject, generally a sample of blood, plasma or serum, and comparing the activity level with that of positive and negative controls to make a diagnosis, a level lower than that of negative controls being indicative of schizophrenia .
  • Positive controls are obtained from patients diagnosed by other methods as having schizophrenia.
  • Negative controls include samples obtained from humans who do not have schizophrenia.
  • the diagnostic method of the invention may also be used predict which subjects are likely to respond to treatment according to the present invention.
  • the diagnostic method may be used to screen subjects for suitability for treatment according to the invention.
  • the subjects may be patients already diagnosed as suffering from schizophrenia, which patients may not be responding to their current treatment or may be requiring a change in treatment for any reason.
  • subjects may be simultaneously diagnosed as schizophrenic and screened for suitability for treatment according to the present invention.
  • Methods for determining the level of ⁇ - (l—»3) -fucosyl transferase are known in the art (see for example that described in Madiyalakan et al Analytical Biochemistry 152, 22-28 (1986)), and methods of assay design are well known.
  • An immunosorbent assay a radioactivity-, luminescence- or fluorescence-based assay may be used.
  • the assay is a radioactivity-based assay.
  • a suitable acceptor for the fucose should be provided, for example, glucose or N-acetylglucosamine . Fucose or an appropriate analogue or derivative thereof should be provided, preferably in labelled form. Radiolabelled fucose may be used.
  • the activity of ⁇ - (1— >3 ) - fucosyl transferase is determined by assessing the transfer of radioactively-labelled GDP-fucose to 2-acetamido-2- deoxy-4-0- (2-0-methyl- ⁇ -D-galactopyranosyl) -D-glucopyranose
  • the present invention further provides a pharmaceutical preparation comprising a therapeutically effective amount of an agent that increases the metabolism of GDP-fucose by ⁇ - (l-3) -fucosyl transferase and/or a therapeutically effective amount of an agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase, for example, an inhibitor therof, in admixture or conjunction with a pharmaceutically suitable carrier therefor.
  • the agent that increases the metabolism of GDP-fucose by ⁇ - (1—3 ) -fucosyl transferase is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt. More preferably the agent is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof. Most preferably the agent is ATP or a salt thereof, for example the disodium salt of ATP.
  • the agent that decreases the metabolism of GDP-fucose by GDP-fucose hydrolase is a nucleotide or a derivative of a nucleotide, especially a phosphorylated derivative, or is a salt thereof, for example, a sodium or potassium salt .
  • the agent is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof.
  • the agent is ATP or
  • the present invention further provides a pharmaceutical preparation comprising a therapeutically effective amount of an agent that increases the activity of ⁇ - (1—3) -fucosyl transferase, in admixture or conjunction with a pharmaceutically suitable carrier therefor.
  • the agent that increases the activity of ⁇ - (1—»3) -fucosyl transferase is a nucleotide or a derivative of nucleotide, especially a phosphorylated derivative, or is a salt thereof.
  • the inhibitor is an adenosine phosphate, for example AMP, ADP or ATP, or is a salt thereof.
  • the agent is ATP or a salt thereof .
  • the medicaments and pharmaceutical preparations of the present invention may be in a form suitable for enteral administration, for example, oral or rectal administration, or for parenteral administration, for example, for percutaneous, permucous or sublingual administration, or for injection or infusion, for example, for intravenous or intramuscular injection or intravenous infusion.
  • a medicament or pharaceutical preparation of the invention may be, for example, in the form of tablets, dragees, sachets, capsules, syrups, drinkable solutions, suspensions or emulsions, or injectable or infusible suspensions or solutions.
  • a medicament or pharaceutical preparation of the invention may be in a controlled release form.
  • the active ingredient may generally be used in an amount of more than 10 mg per day, for example, more than 20 mg per day, for example, in an amount of at least 50 mg per day. Generally, the active ingredient may be used in amount of less than 1000 mg per day, for example, less than 800 mg per day, for example, in an amount of less than 600 mg per day. The amount may be, for example, in the range of from 50 mg per day to 500 or 600 mg per day. Examples of daily doses within that range are 60 mg, 120 mg, 180 mg, 240 mg, 300 mg and 360 mg. The daily dosage may conveniently be given in divided doses, for example two, three, four or five times per day.
  • Figure 2 Graphs showing the inhibition of GDP-fucose hydrolase by 0.2 ⁇ mol adenosine phosphate ester (AMP, ADP and ATP) .
  • AMP adenosine phosphate ester
  • ATP adenosine phosphate ester
  • Figure 3 Graph showing the activity of GDP-fucose hydrolase in the presence of ATP (0.2, 0.5 and 1.0 ⁇ mol) .
  • Figure 4 Graph showing the ⁇ (1—3) -fucosyl transferase activity in plasma samples from schizophrenic patients before and after oral administration of ATP-2Na.
  • Example 1 Comparison of the activity of ⁇ - (1—3) -fucosyl transferase in the plasma of normal and schizophrenic subjects
  • Plasma was prepared from blood of 35 schizophrenic patients and 20 normal donors using a standard protocol.
  • the activity of ⁇ - (1— >3 ) -fucosyl transferase was determined using the following protocol:
  • a reaction mixture was prepared by combining plasma (10 ⁇ l), HEPES-NaOH buffer (pH7.0) (10 ⁇ l of a 4 ⁇ mol / 10 ⁇ l solution), MnCl 2 (10 ⁇ l of a 1 ⁇ mol / 10 ⁇ l solution), sugar acceptor N-acetyl-2 ' -O-methyllactosamine (10 ⁇ l of a 10 n ol / 10 ⁇ l solution) and sugar donor GDP- [ 3 H] fucose (10 ⁇ l of a 78,000 dpm / lO ⁇ l solution).
  • the reaction mixture was left to stand for 16 hours at 37°C.
  • ethanol 100 ⁇ l was added to the reaction mixture.
  • the sample was then centrifuged at 10,000 rpm for 15 minutes.
  • the product was separated from the reaction solution by passing through a Sep-Pak Plas C18 column (Waters Co) and eluting with water.
  • the radioactivity was determined by addition of ACS II scintillation fluid and counting in a liquid scintillation counter (Beckman LS6000TA) .
  • the number of disintegrations per minute represents the activity of ⁇ - (1—3) -fucosyl transferase.
  • the results are shown in Fig 1 (a) .
  • the activity of ⁇ - (l-3) -fucosyl transferase of normal donors was 7,972.92+3,092.8 dpm (disintegrations per minute, mean+S.D.), while that of schizophrenic patients was 1,714.0+1,039.7 dpm (mean+S.D.).
  • the activity of ⁇ - (1—>3) -fucosyl transferase of schizophrenic patients is significantly lower than that of normal persons .
  • Example 2 Comparison of the activity of - (1—»3) -fucosyl transferase in the plasma of normal and schizophrenic subjects in the presence of ATP
  • the protocol of Example 1 was carried out using plasma from 14 normal donors and 26 schizophrenia patients with the addition of ATP (0.2 ⁇ mol) .
  • the results are shown in Fig 1 (b) .
  • the activity of ⁇ - (1—3) -fucosyl transferase of normal donors was 10,523+3,323 dpm (mean+S.D.), while that of schizophrenic patients was 8,512+5,366 dpm (mean+S.D.).
  • ATP adenosine 5' triphosphate
  • the difference of activity ⁇ - (l-3) -fucosyl transferase between normal and schizophrenic patients in the presence of ATP was reduced from 6259 to 2011 dpm, and was no longer statistically significant.
  • the reaction mixture was prepared by mixing together plasma (from patients with schizophrenia) (10 ⁇ l) , HEPES- NaOH Buffer (pH 7.0) (10 ⁇ l of a 4 ⁇ mol / 10 ⁇ l solution), MnCl 2 (10 ⁇ l of a 1 ⁇ mol / 10 ⁇ l solution), GDP- [ 3 H] fucose + GDP-fucose (10 ⁇ l of a 10 ⁇ mol / 10 ⁇ l solution) .
  • adenosine phosphate ester AMP (adenosine monophosphate)
  • ADP (adenosine 5 ' -diphosphate)
  • ATP adenosine 5'- triphosphate
  • the reaction mixture was left to stand for 2 hours at 37°C.
  • ethanol 100 ⁇ l was added to the reaction mixture and the mixture was centrifuged at 10000 rpm.
  • the product in the reaction solution [ 3 H] fucose was separated from the reaction mixture by paper chromatography.
  • the radioactivity was measured by addition of ACS II scintillation fluid and coating in a liquid scintillation counter (Beckman LS6000TA) to determine the activity of hydrolase. The results are shown in Fig 2.
  • hydrolase activity of GDP-fucose in plasma of schizophrenic patients was inhibited by either AMP, ADP or ATP.
  • Example 5 Treatment of Schizophrenic patients with 60 mg / day oral ATP-2Na
  • ATP-2Na ATP disodium salt
  • BPRS Brief Psychiatric Rating Scale
  • Example 6 Treatment of schizophrenic patients with 180 mg per day of ATP-2Na
  • Example 7 Treatment of schizophrenic patients with 360 mg per day of ATP-2Na.

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Abstract

L'invention concerne une méthode de traitement de la schizophrénie, qui consiste à administrer à un patient humain une quantité efficace d'un agent qui augmente le métabolisme du GDP-fucose par α-(1→3)-fucosyl transférase et/ou d'un agent qui réduit le métabolisme du GDP-fucose par GDP-fucose hydrolase. L'invention concerne également l'utilisation de ces agents dans la préparation d'un médicament, ainsi que des méthodes de diagnostic de la schizophrénie.
PCT/GB2000/000159 2000-01-21 2000-01-21 Diagnostic et traitement de troubles mentaux Ceased WO2001052861A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/GB2000/000159 WO2001052861A1 (fr) 2000-01-21 2000-01-21 Diagnostic et traitement de troubles mentaux
AU2000230653A AU2000230653A1 (en) 2000-01-21 2000-01-21 Diagnosis and treatment of mental disorders

Applications Claiming Priority (1)

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PCT/GB2000/000159 WO2001052861A1 (fr) 2000-01-21 2000-01-21 Diagnostic et traitement de troubles mentaux

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6429395A (en) * 1987-07-24 1989-01-31 Taisho Pharmaceutical Co Ltd Adenosine compound
EP0415018A1 (fr) * 1989-08-31 1991-03-06 Eliezer Rapaport Utilisation des nucléotides d'adénine et/ou adénosine et phosphates inorganiques pour l'élévation des concentrations en 5'-triphosphate d'adénosine dans le foie, le sang et le plasma sanguin
US5679649A (en) * 1990-05-10 1997-10-21 Fukunaga; Atsuo F. Use of adenosine compounds for autonomic nervous system attenuation
JPH11196898A (ja) * 1998-01-09 1999-07-27 Nippon Koutai Kenkyusho:Kk 精神分裂病診断薬

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6429395A (en) * 1987-07-24 1989-01-31 Taisho Pharmaceutical Co Ltd Adenosine compound
EP0415018A1 (fr) * 1989-08-31 1991-03-06 Eliezer Rapaport Utilisation des nucléotides d'adénine et/ou adénosine et phosphates inorganiques pour l'élévation des concentrations en 5'-triphosphate d'adénosine dans le foie, le sang et le plasma sanguin
US5679649A (en) * 1990-05-10 1997-10-21 Fukunaga; Atsuo F. Use of adenosine compounds for autonomic nervous system attenuation
JPH11196898A (ja) * 1998-01-09 1999-07-27 Nippon Koutai Kenkyusho:Kk 精神分裂病診断薬

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HAYASHI, MASATOSHI ET AL: "Adenosine derivatives as antipsychotic drugs and brain function-protecting agents", XP002148182, retrieved from STN Database accession no. 111:195333 *
NIETO D: "TREATMENT OF SCHIZOPHRENIA AND OTHER MENTAL DISORDERS BY ADENYLIC-ACID AMP.", SEM. HOP., (1966) 42 (47), 2854-2855., XP002148181 *
PATENT ABSTRACTS OF JAPAN vol. 1999, no. 12 29 October 1999 (1999-10-29) *

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