U.S. patent application number 09/873270 was filed with the patent office on 2002-03-28 for use of riluzole or its salts for the prevention and treatment of adrenoleukodystrophy.
Invention is credited to Aubourg, Patrick, Dib, Michel, Stutzmann, Jean-Marie.
Application Number | 20020037902 09/873270 |
Document ID | / |
Family ID | 27248672 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037902 |
Kind Code |
A1 |
Aubourg, Patrick ; et
al. |
March 28, 2002 |
Use of riluzole or its salts for the prevention and treatment of
adrenoleukodystrophy
Abstract
The present invention relates to the use of riluzole or one of
its pharmaceutically acceptable salts for the prevention and
treatment of adrenoleukodystrophy.
Inventors: |
Aubourg, Patrick;
(Boulogne-Billancourt, FR) ; Dib, Michel; (Paris,
FR) ; Stutzmann, Jean-Marie; (Villecresnes,
FR) |
Correspondence
Address: |
Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
1300 I Street, N.W.
Washington
DC
20005-3315
US
|
Family ID: |
27248672 |
Appl. No.: |
09/873270 |
Filed: |
June 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60216159 |
Jul 3, 2000 |
|
|
|
Current U.S.
Class: |
514/263.34 ;
514/161; 514/263.32; 514/367 |
Current CPC
Class: |
A61K 31/428
20130101 |
Class at
Publication: |
514/263 ;
514/264; 514/367; 514/161 |
International
Class: |
A61K 031/522; A61K
031/428 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 5, 2000 |
FR |
0007162 |
Claims
1. A method of treating adrenoleukodystrophy comprising
administration of a composition comprising at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts.
2. The method of claim 1, wherein said at least one active
ingredient is in an amount ranging from 25 mg to 200 mg.
3. The method of claim 1, wherein said pharmaceutically acceptable
salt is chosen from addition salts with inorganic acids.
4. The method of claim 3, wherein said addition salt is chosen from
hydrochloride, sulfate, nitrate, and phosphate.
5. The method of claim 1, wherein said pharmaceutically acceptable
salt is chosen from addition salts with organic acids.
6. The method of claim 5, wherein said addition salt is chosen from
acetate, propionate, succinate, oxalate, benzoate, fumarate,
maleate, methane-sulfonate, isethionate, theophyllineacetate,
salicylate, phenolphthalinate, and
methylene-bis-.beta.-oxy-naphthoate.
7. The method of claim 1, wherein said administration is chosen
from at least one of oral administration, parenteral
administration, and rectal administration.
8. The method of claim 1, wherein said composition is a solid
composition.
9. The method of claim 8, wherein said solid composition is chosen
from tablets, pills, powders, gelatin capsules, cachets, and
granules.
10. The method of claim 9, wherein said solid composition further
comprises at least one inert diluent chosen from starch, cellulose,
sucrose, lactose and silica.
11. The method of claim 1, wherein said composition is a liquid
composition.
12. The method of claim 11, wherein said liquid composition is
chosen from a pharmaceutically acceptable solution, a
pharmaceutically acceptable suspension, a pharmaceutically
acceptable emulsion, a pharmaceutically acceptable syrup, and a
pharmaceutically acceptable elixir.
13. The method of claim 12, wherein said liquid composition further
comprises at least one inert diluent chosen from water, ethanol,
glycerol, vegetable oil, and paraffin oil.
14. The method of claim 1, wherein said composition is a sterile
composition.
15. The method of claim 14, wherein said sterile composition is
chosen from an aqueous solution, a nonaqueous solution, a
suspension, and an emulsion.
16. The method of claim 1, wherein said sterile composition further
comprises at least one solvent or vehicle chosen from water,
propylene glycol, polyethylene glycol, vegetable oil, and an
injectable organic ester.
17. The method of claim 1, wherein said composition is a rectal
administration composition chosen from a suppository and a rectal
capsule.
18. A method of preventing adrenoleukodystrophy comprising
administration of at least one active ingredient chosen from
riluzole and its pharmaceutically acceptable salts.
19. A method of preparing a medicament useful for the treatment of
adrenoleukodystrophy comprising adding at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts, to the medicament.
20. A method of preparing a medicament useful for the prevention of
adrenoleukodystrophy comprising adding at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts, to the medicament.
21. A method of preparing a medicament useful in the treatment of
adrenoleukodystrophy comprising mixing at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts, with at least one compatible and pharmaceutically acceptable
diluent or adjuvant.
22. A method of preparing a medicament useful in the prevention of
adrenoleukodystrophy comprising mixing at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts, with at least one compatible and pharmaceutically acceptable
diluent or adjuvant.
23. A method of treating adrenoleukodystrophy in a patient,
comprising administering an effective amount of at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts to the patient.
24. A method of preventing adrenoleukodystrophy in a patient,
comprising administering an effective amount of at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts to the patient.
Description
[0001] This application claims priority benefit of French
Application No. FR 00 07162, filed Jun. 5, 2000, and U.S.
Provisional Application No. 60/216,159, filed Jul. 3, 2000; the
contents of which are expressly incorporated by reference
herein.
[0002] The present invention relates to the use of riluzole or one
of its pharmaceutically acceptable salts for the prevention and
treatment of adrenoleukodystrophy.
BACKGROUND OF THE INVENTION
[0003] Riluzole (2-amino-6-trifluoromethoxy-benzothiazole) is
marketed for the treatment of amyotrophic lateral sclerosis
(RILUTEK.RTM.). This compound is also useful as an anticonvulsant,
an anxiolytic, and a hypnotic (EP 50551), in the treatment of
schizophrenia (EP 305276), in the treatment of sleep disorders and
of depression (EP 305277), in the treatment of cerebrovascular
disorders and as an anaesthetic (EP 282971), in the treatment of
spinal, cranial and craniospinal traumas (WO 94/13288), as a radio
restorative (WO 94/15600), in the treatment of Parkinson's disease
(WO 94/15601), in the treatment of neuro-AIDS (WO 94/20103), and in
the treatment of mitochondrial diseases (WO 95/19170).
[0004] X-linked adrenoleukodystrophy (ADL) is the most frequent of
the genetic diseases of myelin, which is characterized by
progressive demyelination of the central nervous system, an adrenal
insufficiency and a moderate accumulation (3 to 5 times) of very
long chain fatty acids (VLCFA) in most tissues, including the brain
and the spinal cord. This accumulation of VLCFA results from a
deficiency in their .beta.-oxidation in the peroxisome.
[0005] The mechanisms which lead in ALD to demyelination and loss
of oligodendrocytes are still not well understood. One of the
possibilities is that the accumulation of VLCFAs leads to a
destabilization of the myelinic membranes or to a dysfunctioning of
the receptors situated at the surface of the oligodendrocytes,
making the receptors more sensitive to signals for programmed cell
death (apoptosis). The death of the oligodendrocytes could also
result from the production of cytokines (in particular TNF-.alpha.
by the activated macrophages, which are present in the cerebral
inflammatory lesions in ALD.
[0006] In a study of the fragmentation of the DNA, by the TUNEL
method and by the expression of caspase-3, 50% of the
oligodendrocytes of ALD patients, brains exhibit signs of cell
death by apoptosis. Further, the intensity of the apoptotic
phenomena is correlated with the intensity of the
demyelination.
[0007] Death of the oligodendrocytes by apoptosis was recently
demonstrated in several other murine models of genetic disease of
myelin: in the twitcher mouse (model of Krabbe's disease), and in
various models such as jimpy mouse, msd mouse, and md rat (models
deficient in proteolipid protein, PLP).
SUMMARY OF THE INVENTION
[0008] It has now been found that at least one active ingredient
chosen from riluzole and its pharmaceutically acceptable salts
reduces oligodendrocyte death from apoptosis induced by kainite.
Thus, in one embodiment, the invention provides a method of
treating adrenoleukodystrophy comprising administration of at least
one active ingredient chosen from riluzole and its pharmaceutically
acceptable salts.
[0009] The invention also provides a method of preventing
adrenoleukodystrophy comprising administration of at least one
active ingredient chosen from riluzole and its pharmaceutically
acceptable salts.
[0010] In another embodiment, the invention relates to a method of
preparing a medicament useful for the treatment of
adrenoleukodystrophy comprising adding at least one active
ingredient chosen from riluzole and its pharmaceutically acceptable
salts, to the medicament.
[0011] The invention also relates to a method of preparing a
medicament useful for the prevention of adrenoleukodystrophy
comprising adding at least one active ingredient chosen from
riluzole and its pharmaceutically acceptable salts, to the
medicament.
[0012] The invention further relates to a method of preparing a
medicament useful in the treatment of adrenoleukodystrophy
comprising mixing at least one active ingredient chosen from
riluzole and its pharmaceutically acceptable salts, with at least
one compatible and pharmaceutically acceptable diluent and/or
adjuvant.
[0013] The invention further relates to a method of preparing a
medicament useful in the prevention of adrenoleukodystrophy
comprising mixing at least one active ingredient chosen from
riluzole and its pharmaceutically acceptable salts, with at least
one compatible and pharmaceutically acceptable diluent and/or
adjuvant.
[0014] In another embodiment, the invention relates to the method
of treating adrenoleukodystrophy in a patient, comprising
administering an effective amount of at least one active ingredient
chosen from riluzole and its pharmaceutically acceptable salts to
the patient.
[0015] The invention also relates to the method of preventing
adrenoleukodystrophy in a patient, comprising administering an
effective amount of at least one active ingredient chosen from
riluzole and its pharmaceutically acceptable salts to the
patient.
[0016] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention as
claimed. Reference will now be made in detail to exemplary
embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Pharmaceutically acceptable salts of riluzole include, but
are not limited to, addition salts with inorganic acids such as,
for example, hydrochloride, sulfate, nitrate, or phosphate, or with
organic acids such as acetate, propionate, succinate, oxalate,
benzoate, fumarate, maleate, methane-sulfonate, isethionate,
theophyllineacetate, salicylate, phenolphthalinate, or
methylene-bis-.beta.-oxy-naphthoate, and substitution derivatives
of these derivatives.
[0018] The medicaments of the invention may comprise, for example,
at least one riluzole compound, chosen from riluzole in free form,
and riluzole in the form of an addition salt with a
pharmaceutically acceptable acid. The at least one riluzole
compound may be in a pure state or in the form of a composition in
which it is combined with any other pharmaceutically compatible
product, which may be inert or physiologically active. The
medicaments according to the invention may, for example, be used by
at least one of the oral, parenteral and rectal routes.
[0019] Solid compositions for oral administration may be chosen
from, for example, tablets, pills, powders, gelatin capsules,
cachets, and granules. In one embodiment, these compositions
comprise the active ingredient according to the invention mixed
with at least one inert diluent such as, for example, starch,
cellulose, sucrose, lactose, and silica, under an argon stream.
These compositions may also comprise substances other than
diluents, such as, for example at least one of a lubricant, such as
magnesium stearate or talc, a coloring, a coating (sugar-coated
tablets), and a glaze.
[0020] Liquid compositions for oral administration may be chosen
from, for example, pharmaceutically acceptable solutions,
suspensions, emulsions, syrups, and elixirs. The liquid composition
may further comprise inert diluents such as water, ethanol,
glycerol, vegetable oils, and paraffin oil. These compositions may
also comprise substances other than diluents, chosen from, for
example wetting, sweetening, thickening, flavoring, and stabilizing
products.
[0021] Sterile compositions for parenteral administration may be
chosen from, for example, aqueous solutions, nonaqueous solutions,
suspensions, and emulsions. As a solvent or vehicle, water,
propylene glycol, polyethylene glycol, vegetable oils (such as
olive oil), injectable organic esters (such as ethyl oleate), and
other suitable organic solvents may be used. These compositions may
also contain adjuvants, including, for example, wetting agents,
isotonizing agents, emulsifying agents, dispersing agents, and
stabilizing agents.
[0022] The sterilization may be carried out in several ways,
including, but not limited to, aseptisizing filtration,
incorporating sterilizing agents into the composition, irradiation
and heating. Sterile compositions can also be prepared in the form
of sterile solid compositions which may be dissolved at the time of
use in sterile water or in any other injectable sterile medium.
[0023] The compositions for rectal administration may be, for
example, suppositories or rectal capsules which may comprise, in
addition to the at least one active ingredient, at least one
excipient such as cocoa butter, semisynthetic glycerides, or
polyethylene glycols.
[0024] The dose(s) of the active ingredient depends on the desired
effect, on the duration of the treatment, and on the route of
administration used. In one embodiment, the dose ranges from 50 mg
and 400 mg per day by the oral route for an adult, with unit doses
ranging from 25 mg to 200 mg of active substance.
[0025] In general, the doctor will determine the appropriate dosage
according to the age, weight and all the other factors specific to
the subject to be treated.
[0026] The invention will be illustrated by, but is not intended to
be limited to, the following example.
EXAMPLE 1
[0027] The protocol used was the following:
[0028] Cultures Enriched with Oligodendrocytes
[0029] Oligodendrocytes were obtained from primary glial cultures
of spinal cords according to the slightly modified method described
by Saneto et al. (Neurochemistry, a Practical Approach, IRL Press,
oxford-Washington, D.C., p 27-63 (1987)). Spinal cords from 1-day
old Wistar rats were dissected under sterile conditions and
separated from the meninges. Five to ten spinal cords were
transferred into PBS (phosphate-buffered saline: NaCl 137 mM, KCl
2.68 mM, Na.sub.2HPO.sub.4 6.45 mM, KH.sub.2PO.sub.4 1.47 mM) to
which 0.25% of trypsin was added. The enzymatic treatment was
stopped by addition of Dubelco's modified Eagle's medium (DMEM) to
which 10% of fetal bovine serum was added (FBS). Another
dissolution step was carried out by means of a 1 ml pipette, and
the cell suspension was filtered. The cells were collected by
centrifugation and plated at a density of 1.5-2.times.10.sup.6
cells/25 cm.sup.2 of culture medium in Dubelco's modified Eagle's
medium (DMEM) to which 10% of fetal bovine serum was added. After 3
days in vitro, the cultures were fed daily. When a visible
monolayer was obtained, the cultures were stirred for 2 hours at
37.degree. C. at 250 rpm, the culture medium was removed, and the
flasks were again stirred for 22 hours. The cell-containing medium
was incubated at 37.degree. C. in petri dishes for 1 hour in order
for the microglia to become attached to the plastic. The
oligodendrocytes were collected by centrifugation, plated at a
density of 1.6.times.10.sup.6/cm.sup.2 and maintained in DMEM
containing 10% FBS for 1 or 2 days. The medium was then replaced
with L15 medium to which sodium bicarbonate (22 mM), conalbumin
(0.1 mg/ml), putrescine (0.1 mM), insulin (5 .mu.g/ml), sodium
selenite (31 nM), glucose (20 mM), progesterone (21 nM), penicillin
(100 IU/ml), streptomycin (100 .mu.g/ml), and horse serum (2%) were
added. The oligodendrocytes rapidly differentiated within 24 to 48
hours into a mature and immature phenotype. These cultures showed a
purity of about 95%, as determined by immunoreactivity to
galactocerebroside-C (Gal-C) and to glial fibrillary acidic protein
(GFAP).
[0030] Kainate in solution in PBS at various concentrations (0.01
mM to 1 mM), riluzole in solution in NaCl at 0.9% and HCl at 0.001
N, at various concentrations (0.01 mM to 10 mM) or solvent were
then added to these cultures. After 48 hours, measured from the
start of treatment, the living oligodendrocytes were counted.
[0031] Counting of the Cells
[0032] The cells immunoreactive for Gal-C and exhibiting branched
processes longer than the diameters of 2 cells were considered
overall as immature or mature oligodendrocytes. The number of Gal-C
(+) oligo-dendrocytes were divided for 2 separate counts of the
labeled cells in at least 12 fields of 0.63 mm.sup.2 under a 400X
microscope. The values were expressed as the number of cells per
cm.sup.2 or as the percentage of the control.
[0033] The statistical analyses were carried out using the
Student's test (t-test).
[0034] The results obtained were as follows:
[0035] The cultures of oligodendrocytes were exposed to
concentrations of 0.1 to 1 mM kainate for 48 hours.
1 Number of oligodendrocytes % relative to the control .+-.
standard deviation Solvent alone 100 .+-. 17.4 Kainate 0.01 mM
108.2 .+-. 25.2 0.1 mM 76.3 .+-. 27.9 0.5 mM 25.3 .+-. 9.3 1 mM
22.9 .+-. 7.1
[0036] These results showed that kainate at doses of from about 0.1
mM to about 1 mM strongly induced death of the oligodendrocytes
through apoptosis.
[0037] Test 2
[0038] Investigation of the toxic effect of riluzole alone on
cultures of oligodendrocytes
[0039] The cultures of oligodendrocytes were exposed to
concentrations of 0.01 mM to 10 mM riluzole for 48 hours.
2 Number of oligodendrocytes % relative to the control .+-.
standard deviation Solvent 100 .+-. 8.2 Riluzole 0.01 mM 99.6 .+-.
15.7 0.1 mM 94.3 .+-. 17.3 1 mM 107.1 .+-. 9.5 10 mM 86.9 .+-.
16
[0040] These results demonstrated that riluzole at the doses of
0.01 mM to 10 mM had no toxic effect on the survival of the
oligodendrocytes, and that at the dose of about 10 mM, a slightly
toxic effect was observed.
[0041] Test 3
[0042] Protective effect of riluzole on oligocytes death induced by
kainate
[0043] The oligodendrocyte cultures were exposed to kainate at a
dose of 1 mM and to riluzole at doses of from about 0.01 mM to
about 10 mM.
3 Number of oligodendrocytes % relative to the control .+-.
standard deviation Kainate 1000 22.9 .+-. 7.1 Kainate 1 mM +
riluzole 0.01 mM 48.7 .+-. 7 Kainate 1 mM + riluzole 0.1 mM 65.2
.+-. 9.2 Kainate 1 mM + riluzole 1 mM 69.4 .+-. 12 Kainate 1 mM +
riluzole 10 mM 56.3 .+-. 6.9
[0044] These results demonstrated that riluzole reduced
oligodendrocyte death from apoptosis induced by kainate, even at
the dose where a slight toxic effect of riluzole alone was
observed. Thus, riluzole may be used in the prevention and
treatment of adrenoleukodystrophy.
EXAMPLE 2
[0045] The following examples illustrate medicaments according to
the invention:
Example A
[0046] Tablets containing a 50 mg dose of at least one active
ingredient having the following composition are prepared according
to standard techniques:
4 Riluzole 50 mg Mannitol 64 mg Microcrystalline cellulose 50 mg
Polyvidone excipient 12 mg Sodium carboxymethylstarch 16 mg Talc 4
mg Magnesium stearate 2 mg Anhydrous colloidal silica 2 mg Mixture
of methylhydroxypropylcellulose, 245 mg polyethylene glycol 6000,
titanium dioxide (72-3.5-24.5) gs 1 finished film-coated tablet
weighing
Example B
[0047] Gelatin capsules containing a 50 mg dose of at least one
active ingredient having the following composition are prepared
according to standard techniques:
5 Riluzole 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica 1
mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesium stearate 1
mg
Example C
[0048] An injectable solution containing 10 mg of active product
having the following composition is prepared:
6 Riluzole 10 mg Benzoic acid 80 mg Benzyl alcohol 0.06 cm.sup.3
Sodium benzoate 80 mg Ethanol at 95% 0.4 cm.sup.3 Sodium hydroxide
24 mg Propylene glycol 1.6 cm.sup.3 Water qs 4 cm.sup.3
[0049] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compositions and
methods of the present invention without departing from the spirit
or scope of the invention. Thus, it is intended that the present
description cover the modifications and variations of this
invention provided that they come within the scope of the appended
claims and their equivalents.
* * * * *