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WO1999024830A1 - Procede pour diagnostiquer la maladie d'alzheimer - Google Patents

Procede pour diagnostiquer la maladie d'alzheimer Download PDF

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Publication number
WO1999024830A1
WO1999024830A1 PCT/US1998/023198 US9823198W WO9924830A1 WO 1999024830 A1 WO1999024830 A1 WO 1999024830A1 US 9823198 W US9823198 W US 9823198W WO 9924830 A1 WO9924830 A1 WO 9924830A1
Authority
WO
WIPO (PCT)
Prior art keywords
efflux
channel
disease
platelets
absence
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1998/023198
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English (en)
Inventor
Jeffrey K. Aronson
Asita H. De Silva
David G. Grahame-Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
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 Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to JP2000519782A priority Critical patent/JP2001523002A/ja
Priority to EP98957464A priority patent/EP1031034A4/fr
Priority to CA002308371A priority patent/CA2308371A1/fr
Priority to AU13716/99A priority patent/AU750582B2/en
Publication of WO1999024830A1 publication Critical patent/WO1999024830A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer
    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means

Definitions

  • Alzheimer's disease is a progressive neurodegenerative disorder which causes irreversible damage to brain cells leading to dementia and ultimately death. It is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain. Currently, it is primarily diagnosed by exclusion of other known causes of dementia. Diagnosis at an early stage prior to irreversible changes is practically non-existent. In order for a therapeutic intervention to be significantly effective, it will have to be administered very early on prior to irreversible changes .
  • Mahaut-Smith 8a discloses that blood platelets contain a 30pS conductance charybdotoxin-sensitive channel.
  • a 113 pS K + channel sensitive to tetraethylammonium has been described as being absent or not functional in cultured fibroblasts from patients with AD 9 , and this defect was mimicked in normal fibroblasts by the addition of amyloid beta-protein (A ⁇ ) 10 , which is also plentiful in platelets 11 ' 12 .
  • a ⁇ amyloid beta-protein
  • tetraethylammonium is not a selective inhibitor of K + channels, and so the pharmacological identity of the abnormal channel in cultured fibroblasts is not clear.
  • December 3, 1996) discloses a method for the diagnosis of Alzheimer's disease using human cells such as fibroblasts, buccal mucosal cells, neurons, and blood cells such as erythrocytes , lymphocytes and lymphoblastoid cells, wherein the absence of a functional 133 pS potassium channel in the test cells indicates the presence of Alzheimer's disease.
  • Tetraethylammonium is employed as a potassium channel blocker to aid in detecting the presence of the functioning 113 pS potassium channel.
  • a method for diagnosing Alzheimer's disease which includes the steps of (a) obtaining a sample of platelets from a human subject, and (b) detecting the presence or absence in such platelets of functioning calcium- dependent potassium (Kc a ) channels, the absence of such functioning Kc a channel indicating a positive diagnosis for Alzheimer's disease.
  • a potassium channel blocker which has the ability to block the functioning Kc a channel, and may, for example, include apamin, charybdotoxin, or a combination thereof, depending upon the specific functioning calcium- dependent potassium channel involved.
  • a method for diagnosing Alzheimer's disease which includes the step of detecting the presence or absence of one or more functioning small-conductance calcium-dependent potassium (SKc a ) channels in blood platelets of a human subject, the absence of a functioning SK_ a channel in such platelets indicating a positive diagnosis for Alzheimer's disease.
  • SKc a small-conductance calcium-dependent potassium
  • SKc channel blocker which has the ability to block the functioning SKca channel, and may, for example, include apamin, charybdotoxin, or a combination thereof, depending upon the specific SKc a channel involved.
  • Detection of the presence or absence of the functional Kc a channel, SKc a channel and/or K Ch channel may be determined by conventional techniques for measuring electrical currents in cells such as the patch clamp technique disclosed by Sakmann, B. et al 28 .
  • the presence or absence of the functional potassium channel may also be detected by (1) loading blood platelets with 86 Rb + , (2) stimulating 86 Rb + efflux (from the platelets via K_ a channels) with thrombin or ionomycin, (3) subjecting the thrombin- or ionomycin-stimulated 86 Rb + efflux to the action of an appropriate potassium channel blocker, such as apamin, charybdotoxin or a combination thereof, depending upon the particular functional Kc a channel involved, and (4) determining if the Kc a channel blocker significantly inhibits the thrombin- or ionomycin-stimulated 86 Rb + efflux to cause significant reductions in the 86 Rb + efflux, a lack of
  • the potassium channel blocker employed will preferably be apamin or a combination of apamin and charybdotoxin (weight ratio apamin: charybdotoxin from about 4:1 to about 1:1, preferably from about 3:1 to about 1.5:1) .
  • the potassium channel blocker employed will be charybdotoxin or a combination of charybdotoxin and apamin (weight ratio charybdotoxin: apamin from about 4:1 to about 1:1, preferably from about 3:1 to about 1.5:1).
  • Figures la and lb are graphs showing the effects of apamin and charybdotoxin on thrombin-stimulated 86 Rb + efflux in Control subjects ( Figure la) and in patients with Alzheimer's disease ( Figure lb) ;
  • Figures 2a and 2b are graphs showing the effect of -dendrotoxin on thrombin-stimulated 86 Rb + efflux in
  • Figures 3a and 3b are graphs showing the effect of apamin and charybdotoxin on ionomycin-stimulated 86 Rb + efflux in Control subjects ( Figure 3a) and in patients with Alzheimer's disease ( Figure 3b).
  • Subjects recruited as part of OPTIMA were 14 patients with dementia of the Alzheimer type and 14 non-demented age- and sex-matched controls (details in Table 1) ; each experiment was performed on 11 or 12 of these individuals.
  • Platelet perfusion-1 7 - Blood was drawn by venepuncture and anticoagulated with acid-citratedextrose (ACD) . Platelets were prepared by centrifugation within an hour of venesection and incubated with 86 Rb + for 2 h. The platelet suspension (2.5 x 10 7 platelets per ml) was then injected into perfusion chambers, where the cells settled and became immobilized on inert filters (Millipore) .
  • Figures 3a and 3b show effect of apamin and charybdotoxin on ionomycin-stimulated 86 Rb + efflux.
  • Control sub iects Ionomycin 1 ⁇ M (5-filled circles) increased 86 Rb + efflux over the non- stimulated efflux (1-open circles) .
  • Apamin 100 nM (4-open squares) and charybdotoxin 300 nM (3-open triangles) inhibited the stimulated 86 Rb + efflux (P ⁇ 0.0001).
  • SK Ca and Kc h channels may not be present at all in AD. However, if that is so, then 86 Rb + efflux must be occurring through other K + channels, since the thrombin-stimulated and ionomycin-stimulated effluxes were quantitatively normal.
  • normal human platelets do not contain large-conductance calcium- dependent (BKc a ) channels 21 , and iberiotoxin, a selective inhibitor of BKc channels, had no effect on ionomycin- stimulated effluxes in platelets from any individual (Table 2) , while the only other type of K + channel found in platelets, K v channels 20 ' 21 , responded normally to ⁇ - dendrotoxin.
  • K_ a channel abnormalities provide a marker for patients with AD.
  • Table 1 Patient data. The data are given as mean (sd) . There were no significant differences between the groups .

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

On décrit un procédé qui permet de diagnostiquer la maladie d'Alzheimer au moyen de plaquettes de sang humain dans lesquelles la présence ou l'absence de canaux potassium fonctionnels dépendant du calcium est déterminée par l'emploi d'inhibiteurs de canal potassium, tels que l'apamine ou la charybdotoxine, l'absence de canaux potassium fonctionnels dépendant du calcium indiquant un diagnostic positif de la maladie d'Alzheimer.
PCT/US1998/023198 1997-11-10 1998-11-02 Procede pour diagnostiquer la maladie d'alzheimer Ceased WO1999024830A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000519782A JP2001523002A (ja) 1997-11-10 1998-11-02 アルツハイマー病の診断方法
EP98957464A EP1031034A4 (fr) 1997-11-10 1998-11-02 Procede pour diagnostiquer la maladie d'alzheimer
CA002308371A CA2308371A1 (fr) 1997-11-10 1998-11-02 Procede pour diagnostiquer la maladie d'alzheimer
AU13716/99A AU750582B2 (en) 1997-11-10 1998-11-02 Method for diagnosing Alzheimer's disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6477997P 1997-11-10 1997-11-10
US60/064,779 1997-11-10

Publications (1)

Publication Number Publication Date
WO1999024830A1 true WO1999024830A1 (fr) 1999-05-20

Family

ID=22058224

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/023198 Ceased WO1999024830A1 (fr) 1997-11-10 1998-11-02 Procede pour diagnostiquer la maladie d'alzheimer

Country Status (5)

Country Link
EP (1) EP1031034A4 (fr)
JP (1) JP2001523002A (fr)
AU (1) AU750582B2 (fr)
CA (1) CA2308371A1 (fr)
WO (1) WO1999024830A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077686A3 (fr) * 2000-04-05 2002-08-29 Neurologic Inc Coefficient de reponse cellulaire au calcium pour le diagnostic et le pronostic de la maladie d'alzheimer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401652A (en) * 1992-07-30 1995-03-28 American Cyanamid Company Nucleic acid sequence encoding apamin receptor protein
US5427931A (en) * 1990-04-24 1995-06-27 Then Regents Of The University Of California Monoclonal antibody produced against native βamyloid precursor protein
US5580748A (en) * 1993-05-03 1996-12-03 The United States Of America As Represented By The Department Of Health And Human Services Diagnostic tests for alzheimers disease
US5670525A (en) * 1994-08-29 1997-09-23 Bayer Aktiengesellschaft Substituted 4-phenyl-6-amino-nicotinic acid compounds useful in the treatment of CNS disorders
US5778893A (en) * 1991-04-01 1998-07-14 President And Fellows Of Harvard College Method of diagnosing and monitoring a treatment for Alzheimer's disease

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5427931A (en) * 1990-04-24 1995-06-27 Then Regents Of The University Of California Monoclonal antibody produced against native βamyloid precursor protein
US5778893A (en) * 1991-04-01 1998-07-14 President And Fellows Of Harvard College Method of diagnosing and monitoring a treatment for Alzheimer's disease
US5401652A (en) * 1992-07-30 1995-03-28 American Cyanamid Company Nucleic acid sequence encoding apamin receptor protein
US5607843A (en) * 1992-07-30 1997-03-04 The American Cyanamid Company Nucleic acid sequence encoding apamin binding protein
US5652111A (en) * 1992-07-30 1997-07-29 American Cyanamid Company Binding assay utilizing a nucleic acid encoding apamin binding protein
US5580748A (en) * 1993-05-03 1996-12-03 The United States Of America As Represented By The Department Of Health And Human Services Diagnostic tests for alzheimers disease
US5670525A (en) * 1994-08-29 1997-09-23 Bayer Aktiengesellschaft Substituted 4-phenyl-6-amino-nicotinic acid compounds useful in the treatment of CNS disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1031034A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077686A3 (fr) * 2000-04-05 2002-08-29 Neurologic Inc Coefficient de reponse cellulaire au calcium pour le diagnostic et le pronostic de la maladie d'alzheimer

Also Published As

Publication number Publication date
AU750582B2 (en) 2002-07-25
EP1031034A1 (fr) 2000-08-30
EP1031034A4 (fr) 2004-11-17
CA2308371A1 (fr) 1999-05-20
JP2001523002A (ja) 2001-11-20
AU1371699A (en) 1999-05-31

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