EP1223943A2 - Therapeutic use of an inhibitor or an antagonist of an abc protein in bone - Google Patents
Therapeutic use of an inhibitor or an antagonist of an abc protein in boneInfo
- Publication number
- EP1223943A2 EP1223943A2 EP00927525A EP00927525A EP1223943A2 EP 1223943 A2 EP1223943 A2 EP 1223943A2 EP 00927525 A EP00927525 A EP 00927525A EP 00927525 A EP00927525 A EP 00927525A EP 1223943 A2 EP1223943 A2 EP 1223943A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- bone
- disease
- inhibitor
- antagonist
- 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.)
- Withdrawn
Links
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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
-
- 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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the use of a compound and composition
- osteoclast associated ABC protein for use in bone, more particularly an osteoclast associated ABC protein, for use in osteoclast associated ABC protein
- osteoclast associated ABC protein for use in the manufacture of
- Such diseases include,
- osteopenia such as osteoporosis, Paget's disease, bone
- the invention also relates to a method of screening for a compound which
- osteoclast associated ABC protein comprising
- ABC proteins ATP binding cassette proteins
- traffic ATP ases also called traffic ATP ases
- ABC proteins are abundant in prokaryotes where they represent almost 5% of the total genome and show specificity for a diverse range of
- cystic fibrosis cystic fibrosis, multi-drug resistance of tumour cells, non-insulin dependent diabetes
- osteoclast associated ABC protein may be useful in treating conditions arising out of osteoclastic function.
- ABC cassette proteins have been implicated in many cellular
- Osteoclasts are terminally differentiated cells and are hence programmed to
- osteoclast associated ABC transporters associated with ion channels will enhance
- adhesion may be promoted by annexin-mediated binding between phospholipids and
- inhibitors or antagonists of ABC proteins will be useful therapeutic agents in the
- osteopenia which includes osteoporosis, Paget's disease, bone metastases, myeloma
- PTH a known stimulant of bone resorption
- urea, Glibenclamide include:
- the compounds may be administered orally, intravenously, subcutaneously
- inventions can be administered in such oral dosage forms as tablets, capsules (each of
- the dosage regimen utilising the compounds of the present invention is
- the adult dosage may, for oral application, range from 0.001 to 5g daily,
- the preferred daily dose is from 0.000014g to 0.0715g per kg of body weight
- dose can range from 0.00 lg to 5.0g, more preferably from 0.01 to 0.5g. This daily
- dose may be administered in divided doses from 1 to 4 times a day giving unit doses
- the compounds of the present invention can form the active ingredient, and
- active drug component can be combined with an oral, non-toxic, pharmaceutically
- inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose,
- magnesium stearate dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the
- the oral drug components can be any suitable oral drug components.
- binders can also be incorporated in to the mixture.
- Suitable binders include starch, gelatin, natural sugars such as
- glucose or beta-lactose corn sweeteners, natural and synthetic gums such as acacia,
- Lubricants used in these dosage forms include sodium oleate, sodium oleate, sodium
- Disintegrators include, without limitation, starch, methyl cellulose, agar,
- the compounds may be administered by any means that treat and/or prevent
- osteopenia which includes osteoporosis, Paget ' s disease, bone
- the compounds of the present invention may be useful in any combination.
- composition which will act as an inhibitor or antagonist of an ABC protein for use
- PTH parathyroid hormone
- the compounds may be administered concomitantly with PTH.
- the dosage of PTH may vary according to the criterion set out for the
- the adult dosage may, for oral application, range from 1 to 200 International
- Units daily more preferably 50 to 100 International Units.
- the preferred daily dose of PTH is from 0.014 to 2.9 International Units per
- This daily dose may be administered in
- inventions include all animals which may benefit therefrom. Included in such animals
- bone reso ⁇ tion which comprises determining whether the compound acts as an
- osteoclast precursors are obtained from human blood.
- Monoclonal antibodies were raised against cells from human bone.
- osteoclasts and Methods in Molecular Medicine, Human cell culture protocols, ed
- the active factors included parathyroid hormone (PTH), which is known to stimulate bone reso ⁇ tion in this
- Fig 1 shows inhibition of reso ⁇ tion by
- Glibenclamide enhanced inhibition of reso ⁇ tion by Glibenclamide and PTH
- Fig.2 shows inhibition of reso ⁇ tion by Glibenclamide using human
- osteoclasts derived from a giant cell tumor according to the above test
- Fig. 3 shows the dose response as inhibition of reso ⁇ tion by Glibenclamide
- the vehicle is tissue culture medium containing 0.1% dimethyl sulphoxide.
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- General Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Use of a compound which will act as an inhibitor or antagonist of the expression or function of an ABC protein, and a method of screening for a compound which will act as an inhibitor or antagonist of the expression or function of an ABC protein.
Description
DESCRIPTION
A COMPOUND FOR USE IN MEDICINE
The present invention relates to the use of a compound and composition
which will act as an inhibitor or antagonist of the expression or function of an ABC
protein in bone, more particularly an osteoclast associated ABC protein, for use in
medicine, and more particularly to the use of a compound and composition which
will act as an inhibitor or antagonist of the expression or function of an ABC protein,
more particularly an osteoclast associated ABC protein for use in the manufacture of
a medicament for use in the treatment of a disease where full or partial inhibition of
bone resorption will result in an improvement in the disease. Such diseases include,
but are not limited to, osteopenia, such as osteoporosis, Paget's disease, bone
metastases, myeloma, periodontal disease and humoral hypercalcaemia of
malignancy.
The invention also relates to a method of screening for a compound which
will act as an inhibitor or antagonist of the expression or function of an ABC protein
in bone, more particularly an osteoclast associated ABC protein, comprising
determining whether the presence of said compound leads to full or partial inhibition
of bone resorption.
ABC proteins (ATP binding cassette proteins), also called traffic ATP ases,
are a super family of transmembrane proteins involved in the movement of substrates
across cell membranes. ABC proteins are abundant in prokaryotes where they
represent almost 5% of the total genome and show specificity for a diverse range of
substrates ranging from peptides and amino acids to ions and sugars. ABC proteins
are characterised by the presence of 2 peptide motifs, Walker A and Walker B motifs.
These motifs are common to many nucleotide binding proteins. However, ABC
proteins are distinguished from these other proteins by the presence of a third C-
signature motif, separating Walker A and B motifs with conserved spacing.
The importance of ABC proteins in mammalian systems is now being
recognised. Several members of the ABC family have been shown to be important
in human disease, their dysfunction results in a variety of disease states including
cystic fibrosis, multi-drug resistance of tumour cells, non-insulin dependent diabetes
and adrenoleukodystrophy. These ABC proteins are known to be involved in the
translocation of ion and hydrophobic drugs across the plasma membrane. Other
human ABC proteins have also been shown to be involved in peptide translocation
(PAB) and phospholipid transfer across the canalicular membrane, as is the case with
the MRP sub family. In addition, human ABC - 1 has recently been implicated as a
regulator of phospholipid equilibrium and non-classical (signal independent)
secretion of IL1- β in macrophages.
The applicant has discovered ABC transporter proteins in bone and osteoclast
rich tissue and identified several novel members of the ABC protein family from
osteoclastoma cDNA libraries and human bones cDNA libraries by immuno-
screening and hybridrisation screening.
The applicant's discovery has indicated that compounds which will either
inhibit or promote expression or function of an ABC protein, more particularly an
osteoclast associated ABC protein, may be useful in treating conditions arising out of osteoclastic function.
This role of ABC proteins, more particularly an osteoclast specific protein has
not previously been identified.
However, in view of the fact that P-glycoprotein has recently been found to
be present in osteoblasts (Calcified Tissue International, 1996 Vol 58 No. 3 PI 86-
191) one can postulate that members of the ABC family of proteins may be involved
in bone formation.
More generally, ABC cassette proteins have been implicated in many cellular
functions. As such an osteoclast associated family of ABC transporters may regulate
many processes within these cells.
The ability of members of the ABC super family to regulate volume-activated
channels via ATP release has been documented in other cell types.
Osteoclasts are terminally differentiated cells and are hence programmed to
die by apoptosis. The ABCl member of the ABC superfamily has been implicated
in the recognition of apoptotic cells by macrophages, a process thought to involve
transmembrane flux of phosphatidylserine.
Inhibition or promotion of some of these putative functions of ABC proteins
expressed in bone and osteoclasts is indicated as having complex effects on, for
example, bone resorption ranging from inhibition, through no effect, to stimulation.
Inhibition of osteoclast apoptosis, would lead to a subsequent elevation in the
functional osteoclast pool and enhanced resorption. Similarly, sulphonylurea
sensitivity is conferred on K/ATP channels through the presence of ABC
transporters, inhibition of which blocks potassium ion efflux and consequent calcium
ion influx thereby promoting insulin secretion. It is therefore indicated that blocking
osteoclast associated ABC transporters associated with ion channels will enhance
release of factors that may stimulate resorption, including regulatory factors, protons
and proteases including Cathepsin K. Conversely, the processes of osteoclast fusion
from mononuclear precursors, and those of cellular adhesion, if blocked will lead to
decreased resorption. As suggested earlier, transmembrane phospholipid trafficking
by the ABC 1 transporter provides a mechanism for osteoclast fusion, whilst cellular
adhesion may be promoted by annexin-mediated binding between phospholipids and
extracellular matrix.
The applicant has gone on to convincingly demonstrate that inhibition of
ABC proteins using Glibenclamide, a known inhibitor of known ABC proteins, in
osteoclast containing populations inhibits resorption. These results demonstrate that
inhibitors or antagonists of ABC proteins will be useful therapeutic agents in the
therapy of diseases where inhibition of resorption is desirable. These include
osteopenia, which includes osteoporosis, Paget's disease, bone metastases, myeloma
periodontal disease and humoral hypercalcaemia of malignancy.
Additionally, the applicant has surprisingly found that parathyroid hormone
(PTH), a known stimulant of bone resorption, when present with compounds of the
present invention, enhances the inhibitory effect of the compound.
According to a first aspect of the present invention there is provided a
compound which will act as an inhibitor or antagonist of an ABC protein in bone for
use in the manufacture of a medicament for use in the treatment of a disease where
full or partial inhibition of bone resorption will result in an improvement in the
disease.
Examples of existing compounds which have similar action to the sulphonyl
urea, Glibenclamide, include:
TOLBUT AMIDE,
CHLOROPROPAMIDE,
TOLOZAMIDE,
GLIPIZIDE,
GLIQUIDONE, and
GLICLAZIDE.
The compounds may be administered orally, intravenously, subcutaneously
or by any other traditional route. For oral application, the compounds of the present
invention can be administered in such oral dosage forms as tablets, capsules (each of
which includes sustained release or timed release formulations), pills, powders,
granules, elixirs, tinctures, suspensions, syrups and emulsions.
The dosage regimen utilising the compounds of the present invention is
selected in accordance with a variety of factors including type, species, age, weight,
sex and medical condition of the patient; the severity of the condition to be treated;
the route of administration; and the particular compound employed. An ordinarily
skilled physician or veterinarian can readily determine and prescribe the effective
amount of the compound required to prevent, counter or arrest the progress of the condition
The adult dosage may, for oral application, range from 0.001 to 5g daily,
more preferably 0.0 lg to 0.5g daily.
The preferred daily dose is from 0.000014g to 0.0715g per kg of body weight,
and more preferably from 0.00014g to 0.00715g. Thus for a 70kg adult the daily
dose can range from 0.00 lg to 5.0g, more preferably from 0.01 to 0.5g. This daily
dose may be administered in divided doses from 1 to 4 times a day giving unit doses
for an adult of from 0.00025 to 5.0g.
The compounds of the present invention can form the active ingredient, and
are typically administered in admixture with suitable pharmaceutical diluents,
excipients or carriers suitably selected with respect to the intended form of
administration.
For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic, pharmaceutically
acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose,
magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the
like; for oral administration in liquid form, the oral drug components can be
combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as
ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable
binders, lubricants, disintegrating agents and coloring agents can also be incorporated
in to the mixture. Suitable binders include starch, gelatin, natural sugars such as
glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,
tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes
and the like. Lubricants used in these dosage forms include sodium oleate, sodium
stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and
the like. Disintegrators include, without limitation, starch, methyl cellulose, agar,
bentonite, xanthan gum and the like.
The compounds may be administered by any means that treat and/or prevent
conditions where full or partial inhibition of bone resoφtion is desirable. Such
conditions include osteopenia, which includes osteoporosis, Paget's disease, bone
metastases, myeloma, perodontal disease and humeral hypercalcaemia or malignancy.
Compounds of the present invention may be useful for treating and/or
preventing conditions prevalent in post-menopausal women; in particular those
individuals suffering from osteoporosis.
Furthermore, the compounds of the present invention may be useful for
treating and/or preventing conditions prevalent in Caucasian elderly men (e.g.
individuals over 50 years of age); in particular, those individuals suffering from
Paget's disease.
In addition, the compounds of the present invention may be useful in
preventing accelerated bone loss in individuals who are genetically disposed to suffer
from disease where loss of bone occurs.
According to another aspect of the present invention there is provided a
composition which will act as an inhibitor or antagonist of an ABC protein for use
in the manufacture of a medicament for use in the treatment of a disease where full
or partial inhibition of bone resoφtion will result in an improvement in the disease
comprising a compound as described hereinabove and parathyroid hormone (PTH).
The compounds may be administered concomitantly with PTH.
Alternatively, PTH may be administered separately. The mode of administration
may be the same or different as that for the compounds of the present invention.
The dosage of PTH may vary according to the criterion set out for the
compounds of the present invention, as hereinabove described.
The adult dosage may, for oral application, range from 1 to 200 International
Units daily, more preferably 50 to 100 International Units.
The preferred daily dose of PTH, is from 0.014 to 2.9 International Units per
kg of body weight and more preferably from 0.7 to 1.4 International Units. Thus for
a 70 kg adult, the daily dose can range from 1 to 200 International Units, more
preferably 50-100 International Units. This daily dose may be administered in
divided doses from 1 to 4 times a day giving unit doses for an adult of from 12.5 to
200 International Units.
Animals which may be treated according to the methods of the present
invention include all animals which may benefit therefrom. Included in such animals
are humans and horses, although the invention is not intended to be so limited.
This discovery also allows candidate compounds to be screened.
According to a further aspect of the present invention there is provided a
method of screening for a compound which will lead to full or partial inhibition of
bone resoφtion, which comprises determining whether the compound acts as an
inhibitor or antagonist of the expression or function of an ABC protein in bone.
According to a further aspect of the present invention there is provided a
method of screening for a compound which will act as an inhibitor or antagonist of
the expression or function of an ABC protein in bone comprising determining
whether the presence of said compound leads to full or partial inhibition of bone
resoφtion.
The method may comprise the use of osteoclasts and/or osteoclast precursors.
Osteoclasts may be obtained from any suitable source. Preferably, human bone,
human bone marrow, human blood or any suitable tissues from experimental animals.
More preferably, osteoclast precursors are obtained from human blood.
According to a further aspect of the present invention there is provided a
method of treatment of a disease where full or partial inhibition of bone resoφtion
will result in an improvement in the disease comprising administering a compound
which will act as an inhibitor or antagonist of an ABC protein in bone.
The invention will be further described, by way of example only, with
reference to the following test data.
Identification of novel ABC transporters from human giant cell tumour
Monoclonal antibodies were raised against cells from human bone. One
antibody was shown to strongly stain the osteoclast. In order to identify the antigen
a human bone cDNA expression library constructed in lambda gtl l was
immunoscreened. Two clones were identified of size 300bp and 435bp. A second
separate immunoscreen identified the 435bp clone which was then sequenced and
identified as a partial length cDNA clone encoding a novel ATP binding cassette
(ABC) protein. Subsequently this clone was used to hybridization screen an
osteoclastoma cDNA library in lambda gtl l and 19 clones were identified and
purified. The longest sequenced was 1.5kb and found to be a highly homologous, but
distinct from the 435bp clone and encoded a second novel ABC transporter. Further
sequencing of the additional clones suggests that there may be additional family
members. Comparative sequence analysis and phylogenetic analysis demonstrates
that these ABC's comprise a novel sub family of transporters which have not
previously been described. This novel sub family of ABC transporters would appear
to have restricted tissue expression.
Inhibition of resoφtion bv Glibenclamide.
In order to determine whether ABC proteins were involved in bone resoφtion
the applicant conducted in vitro bone resoφtion assays (as per C.A. Walsh et al,
Journal of Bone and Mineral Research, volume 6, number 7, 1991 with avian
osteoclasts, and Methods in Molecular Medicine, Human cell culture protocols, ed
G.E. Jones, Humana Press, pages 263- 275 with human osteoclasts) to look at the
effect of a well characterised ABC protein inhibitor, Glibenclamide, using avian and
human osteoclasts. Active factors known to have an effect on bone resoφtion and
/or Glibenclamide were also introduced into the assays. The active factors included
parathyroid hormone (PTH), which is known to stimulate bone resoφtion in this
system, and ATP since it has been suggested that Glibenclamide inhibits ATP release
from cells (E.M. Schwiebert et al, Cell, Vol 81, 1063-1073, 1995).
The results are shown in Figs. 1 to 3. Fig 1 shows inhibition of resoφtion by
Glibenclamide, enhanced inhibition of resoφtion by Glibenclamide and PTH, and
inhibition of resoφtion by Glibenclamide in the presence of ATP. using avian
osteoclasts in vitro according to the above test;
Fig.2 shows inhibition of resoφtion by Glibenclamide using human
osteoclasts derived from a giant cell tumor according to the above test;
Fig. 3 shows the dose response as inhibition of resoφtion by Glibenclamide
using human osteoclasts according to the above test.
The vehicle is tissue culture medium containing 0.1% dimethyl sulphoxide.
In summary, Glibenclamide at concentrations of 100 micromolar inhibited
resoφtion by settled suspensions of avian bone cells (Fig.1). Inhibition of resoφtion
was enhanced by PTH in the presence of Glibenclamide (Fig. l). In addition,
exogenous ATP does not overcome resoφtion inhibition by Glibenclamide (Fig.l).
These findings were supported using a suspension of giant cells obtained from
a human osteoclastoma or giant cell tumour (Fig.2). Glibenclamide at concentrations
lower than 50 micromolar did not inhibit resoφtion, however, at concentrations of
50 and 100 micromolar resoφtion was depressed (Fig.3). This was confirmed using
a different giant cell population. This data demonstrates that inhibiting ABC
proteins inhibits bone resoφtion.
More details of the procedure followed are given below.
Avian osteoclasts were isolated from the femora and tibiae of pre -hatch chicks
and seeded on to sterile devitalised dentine wafer. Cells were allowed to settle for
24 hours after which time the wafers were washed to remove non-adherent cells.
Fresh medium containing active factors (PTH, ATP and/or Glibenclamide) were
added for 72 hours. At the end of this period the wafers were fixed.
Dentine wafers were then washed in PBS at 37°C, fixed in 4% glutaraldehyde
in 0.2% sodium cacodylate, and stained for 5 mins in 1% (w/v) toluidine blue in
0.5% disodium tetraborate. Resoφtion lacunae present on stained devitalised bone
wafers were identified using an Olympus BH2 microscope fitted for incident light
microscopy with metallurgic objectives. The plan area of resoφtion was determined
by point counting using a 10X objective and drawing tube and expressed as a
percentage of the total plan area of the bone wafers.
Human osteoclasts were dislodged from human giant cell tumour (GCT) by
agitation in αMEM. Sterile devitalised dentine wafers were placed in a culture dish
and the GCT suspension dripped over them using a sterile 10ml syringe. The culture
was then incubated at 37 °C in a humidified atmosphere of 95% air and 5% CO2 for
20 min. Wafers were then removed and washed in PBS to dislodge any non-
adherent cells. Wafers were then transferred to 24 well plates, each containing 900 μl
of αMEM supplemented with 10% foetal calf serum and incubated at 37°C in a
humidified atmosphere of 95% air and 5% CO2 for 24 hours. Cells were treated by
adding lOOμl of lOx concentration of inhibitor and incubated at 37°C for a further
72 hours as described above. Dentine wafers were then washed, fixed, stained and
viewed as detailed in the avian osteoclast procedure.
Claims
1. A compound which will act as an inhibitor or antagonist of an ABC protein in bone for use in the manufacture of a medicament for use in the treatment
of a disease where full or partial inhibition of bone resoφtion will result in an
improvement in the disease.
2. A compound as claimed in claim 1 selected from the group consisting of
glibenclamide, tolbutamide, chloφropamide, tolozamide, glipizide, gliquidone and
gliclazide.
3. A compound as claimed in claim 1 or 2, wherein the compound is in a
form for oral or intravenous administration.
4. A compound as claimed in claim 1, 2 or 3 which is in a unit dosage form.
5. A compound as claimed in claim 4 wherein the compound is present in unit
dosage form in an amount of from 0.00 lg to 5g.
6. A compound as claimed in claim 4 wherein the compound is present in
unit dosage form in an amount of 0.01 g to 0.5g daily.
7. A compound as claimed in claim 4 wherein the compound is present in unit
dosage form in an amount of from 0.000014g to 0.0715g per kg of body weight
daily.
8. A compound as claimed in claim 4 wherein the compound is present in
unit dosage form in an amount of 0.00014g to 0.00715g per kg of body weight daily.
9. A compound as claimed in any of claims 1 to 8 for use in the manufacture of a medicament for use in the treatment of osteoporosis.
10. A composition which will act as an inhibitor or antagonist of an ABC
protein in bone for use in the manufacture of a medicament for use in the treatment
of a disease where full or partial bone resoφtion will result in an improvement in the
disease comprising a compound as claimed in any preceding claim and parathyroid
hormone.
1 1. A composition as claimed in claim 10 wherein parathyroid hormone is
in a form for oral, subcutaneously or intravenous administration.
12. A composition as claimed in claim 10 or 1 1 which is in a unit dosage
form.
13. A composition as claimed in claim 12 wherein parathyroid hormone is
present in unit dosage form of from 1 - 200 International Units.
14. A composition as claimed in claim 12 wherein parathyroid hormone is
present in unit dosage form of from 50 - 100 International Units.
15. A composition as claimed in claim 12 wherein parathyroid hormone is
present in unit dosage form of from 0.014 to 2.9 International Units per kg of body
weight.
16. A composition as claimed in claim 12 wherein parathyroid hormone is
present in unit dosage form in an amount from 0.7 to 1.4 International Units per kg
of body weight.
17. A method of screening for a compound which will act as an inhibitor or
antagonist of the expression or function of an ABC protein in bone comprising determining whether the presence of said compound leads to full or partial inhibition of bone resoφtion.
18. A method of screening for a compound which will lead to full or partial
inhibition of bone resoφtion, which comprises determining whether the compound
acts as an inhibitor or antagonist of the expression or function of an ABC protein in
bone.
19. A method of treatment of a disease where full or partial inhibition of bone
resorption will result in an improvement in the disease comprising administering a
compound which will act as an inhibitor or antagonist of an ABC protein in bone.
20. A method of treatment of a disease where full or partial inhibition of bone
resoφtion will result in an improvement in the disease comprising administering a
composition comprising a compound, which will act as an inhibitor or antagonist of
an ABC protein in bone, and parathyroid hormone.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9910693.2A GB9910693D0 (en) | 1999-05-07 | 1999-05-07 | A compound for use in medicine |
GB9910693 | 1999-05-07 | ||
PCT/GB2000/001736 WO2000067736A2 (en) | 1999-05-07 | 2000-05-05 | Therapeutic use of an inhibitor or an antagonist of an abc protein in bone |
Publications (1)
Publication Number | Publication Date |
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EP1223943A2 true EP1223943A2 (en) | 2002-07-24 |
Family
ID=10853073
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP00927525A Withdrawn EP1223943A2 (en) | 1999-05-07 | 2000-05-05 | Therapeutic use of an inhibitor or an antagonist of an abc protein in bone |
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EP (1) | EP1223943A2 (en) |
JP (1) | JP2003501350A (en) |
AU (1) | AU4592000A (en) |
GB (1) | GB9910693D0 (en) |
WO (1) | WO2000067736A2 (en) |
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TW438587B (en) * | 1995-06-20 | 2001-06-07 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
JP4290225B2 (en) * | 1997-02-27 | 2009-07-01 | ベイラー・カレッジ・オブ・メディスン | Nucleic acid sequence of ATP binding cassette transporter |
-
1999
- 1999-05-07 GB GBGB9910693.2A patent/GB9910693D0/en not_active Ceased
-
2000
- 2000-05-05 JP JP2000616763A patent/JP2003501350A/en active Pending
- 2000-05-05 EP EP00927525A patent/EP1223943A2/en not_active Withdrawn
- 2000-05-05 WO PCT/GB2000/001736 patent/WO2000067736A2/en not_active Application Discontinuation
- 2000-05-05 AU AU45920/00A patent/AU4592000A/en not_active Abandoned
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WO2000067736A2 (en) | 2000-11-16 |
GB9910693D0 (en) | 1999-07-07 |
WO2000067736A3 (en) | 2002-05-10 |
AU4592000A (en) | 2000-11-21 |
JP2003501350A (en) | 2003-01-14 |
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