U.S. patent application number 17/162118 was filed with the patent office on 2021-05-27 for pharmaceutical composition for the treatment of autism.
This patent application is currently assigned to Stalicla S.A.. The applicant listed for this patent is Stalicla S.A.. Invention is credited to Lynn DURHAM.
Application Number | 20210154177 17/162118 |
Document ID | / |
Family ID | 1000005380959 |
Filed Date | 2021-05-27 |
United States Patent
Application |
20210154177 |
Kind Code |
A1 |
DURHAM; Lynn |
May 27, 2021 |
PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF AUTISM
Abstract
The present invention relates to a pharmaceutical composition or
a kit comprising, a first substance capable of raising
intracellular cAMP levels, and a second substance capable of
modulating intracellular calcium concentration. Likewise, the
present invention relates to methods of treating patients suffering
from autism spectrum disorder (ASD) phenotype 1 by administering an
effective amount of a substance capable of intracellular cAMP
levels and, optionally, an effective amount of a substance capable
of modulating intracellular calcium concentration.
Inventors: |
DURHAM; Lynn; (Geneva,
CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Stalicla S.A. |
Geneva |
|
CH |
|
|
Assignee: |
Stalicla S.A.
Geneva
CH
|
Family ID: |
1000005380959 |
Appl. No.: |
17/162118 |
Filed: |
January 29, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16182553 |
Nov 6, 2018 |
10940140 |
|
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17162118 |
|
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62582141 |
Nov 6, 2017 |
|
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62663647 |
Apr 27, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/015 20130101;
A61K 45/00 20130101; A61K 31/437 20130101; A61P 25/00 20180101 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 25/00 20060101 A61P025/00; A61K 31/015 20060101
A61K031/015; A61K 45/00 20060101 A61K045/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 6, 2017 |
EP |
17200219.8 |
Apr 27, 2018 |
EP |
18169952.1 |
Claims
1. A pharmaceutical composition comprising (i) a first substance
capable of raising intracellular cAMP levels in human neuronal
cells and (ii) a second substance capable of modulating
intracellular calcium concentration in human neuronal cells,
wherein the first substance is different from the second substance,
wherein the composition does not comprise any additional active
ingredients, wherein the first substance is selected from a PDE4
inhibitor and a substance capable of activating a G protein coupled
adenosine A.sub.2A receptor and the second substance is selected
from a diuretic, an antiarrhythmic agent and a retinoic
acid-related orphan receptor-alpha (RORA) agonist.
2. (canceled)
3. The pharmaceutical composition according to claim 1, wherein the
substance capable of raising intracellular cAMP levels is a PDE4
inhibitor.
4. The pharmaceutical composition according to claim 1, wherein the
PDE inhibitor is selected from the group consisting of
theophylline, caffeine, reuteri, cilostazol, etazolate,
rollumilast, crisaborole, drotaverin, ibudilast, cilomilast,
rolipram, (S)-rolipram, (R)-rolipram, amrinone, milrinone,
enoximone, daxalipram (R-mesopram), lirimilast, cipamfylline,
tofimilast, CI-1044, HT-0712, MK-0873, CI-1018, T-2585, V-11294A,
piclamilast, atizoram, filaminast, IC-485, CDP-840, and
L-826,141.
5. The pharmaceutical composition according to claim 1, wherein the
substance capable of raising intracellular cAMP levels is a
substance capable of activating a G protein coupled adenosine
A.sub.2A receptor.
6. The pharmaceutical composition according to claim 1, wherein the
substance capable of activating a G protein-coupled adenosine
A.sub.2A receptor is selected from the group consisting of
regadenoson, bidenoson, 2-phenilaminoadenosine,
2-amino-4-(4-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridine-
carbonitrile,
4-[2-[(6-amino-9-b-D-ribofuranosyl-9H-purin-2-yl)thio]ethyl]benzenesulfon-
ic acid ammonium salt and 2-hexynyl-5'-N-ethylcarboxamidoadenosine,
CGS-21680 and UK-432,097.
7. The pharmaceutical composition according to claim 1, wherein the
substance capable of modulating intracellular calcium concentration
is a retinoic acid-related orphan receptor-alpha (RORA)
agonist.
8. The pharmaceutical composition according claim 1, wherein the
substance capable of modulating intracellular calcium concentration
is a calcium channel inhibitor of solute carrier family 12 members
1, 2, 4 or 5.
9. The pharmaceutical composition according to claim 8, wherein the
substance capable of modulating intracellular calcium concentration
is selected from the group consisting of dihydropyridines,
phenylakylamines, benzothiazepines, indolazines, aminoglycosides
and 4-substituted derivatives of sulfamoylbenzoic acid.
10. The pharmaceutical composition according to claim 9, wherein
the 4-substituted derivative of sulfamoylbenzoic acid is a
derivative of 4-substituted-3-amino-5-sulfamoylbenzoic acid.
11. The pharmaceutical composition according to claim 10, wherein
the derivative of 4-substituted-3-amino-5-sulfamoylbenzoic acid is
selected from the group consisting of bumetanide, AqB007, AqB011,
PF-2178, BUM13, BUM5, bumepamine and mixtures thereof.
12. The pharmaceutical composition according to claim 1, wherein
the substance capable of modulating intracellular calcium
concentration is selected from the group consisting of nifedipine,
niludipine, nicardipine, nimodipine, NZ-105, amlodipine,
felodipine, isradipine, diperdipine, emopamil, devapamil,
verapamil, diltiazem, flunarizine, fluspirilene, pimozide,
fantofarone, nicergoline, neomycin, gentamycin, kanamycin,
cisapride, clopamide, cyproheptadine, loratadine, domperidone,
fentanyl, alfentanil, sufentanil, flecainide, indoramin,
isonepecotic acids, ketotifen, lobeline, loperamide, mepivacaine,
methylphenidate, minoxidil, nipecotic acid, paroxetine, pempidine,
penfluridol, perhexiline, pipecolics acid, bupivacaine,
cyclohexemide, thalidomide, terfenadine, trihexyphenidyl,
clevidipine, lomerazine, fostedil, anipamil, torasemide,
chlorthalidone, etacrynic acid, furosemide, trichlormethiazide,
hydroflumethiazide, methylclothiazide, bumetanide, ibutilde,
mibefradil, dronedarone, amiodarone, nisoldipine, nitrendipine,
nilvadipine, gabapentine and ambroxol hydrochloride.
13-22. (canceled)
23. The pharmaceutical composition according to claim 1, wherein
the PDE inhibitor is selected from the group consisting of
theophylline, theobromine, aminophylline, prepentofylline,
cilostazol, etazolate, roflumilast, crisaborole, drotaverin,
ibudilast, cilomilast, rolipram, (S)-rolipram, (R)-rolipram,
amrinone, milrinone, enoximone, daxalipram (R-mesopram),
lirimilast, cipamfylline, tofimilast, CI-1044, HT-0712, MK-0873,
CI-1018, T-2585, V-11294A, piclamilast, atizoram, filaminast,
IC-485, CDP-840, and L-826,141.
24. The pharmaceutical composition according to claim 1, wherein
the substance capable of activating a G protein-coupled adenosine
A.sub.2A receptor is not adenosine.
25. The pharmaceutical composition according to claim 1, which is
in the form of a tablet or capsule suitable for oral administration
to a human, which consists of said first substance and said second
substance as active ingredients and one or more pharmaceutically
acceptable carriers, excipients and/or diluents.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application claims priority from EP 17200219.8, filed
Nov. 6, 2017, EP 18169952.1, filed Apr. 27, 2018, Provisional
Application 62/582141, filed Nov. 6, 2017, and Provisional
Application 62/663,647, filed Apr. 27, 2018, all of which are
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to a pharmaceutical composition for
treating the core symptoms of autism spectrum disorder (ASD) and/or
associated symptoms including learning disabilities, language
impairment and impairments in executive functioning that can be
associated with the disease in patients with ASD--and preferably in
phenotype 1 patients--a subcategory of patients presenting with
specific differentiating clinical sets of signs and symptoms.
BACKGROUND OF THE INVENTION
[0003] Autism spectrum disorder (ASD) are a group of
neurodevelopmental disorders frequently characterized by
impairments in social interactions, difficulties with language and
communication, and the presence of repetitive, perseverative
behaviors. ASD typically appears during the first three years of
life and manifests in characteristic symptoms or behavioral traits.
A diagnosis of ASD currently includes several conditions that used
to be diagnosed separately: autistic disorder, pervasive
developmental disorder not otherwise specified (PDD-NOS), and
Asperger syndrome. All of these conditions are now encompassed by
the diagnostic criteria for autism spectrum disorder as set forth
in the American Psychiatric Association's Diagnostic &
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
[0004] While ASD is currently defined by symptoms in core areas,
there exists significant heterogeneity in genetics, phenotypes,
clinical presentation, and associated comorbidities The genetic
contribution to the causation/predisposition to autism is
considered to be substantial on the basis of high concordance in
monozygous twins s contribute 83% of the risk for ASD, and
environmental factors thus seem to play a minor 17% though
significant role in the developmental etiology of ASD. However, to
further complicate matters, genetic and epigenetic factors
intertwine with prenatal and lifelong dynamic environmental factors
to influence individual patient pathogenesis. Nevertheless, causal
genetic factors can only be identified in 15 to 20% of patients,
and the vast majority ASD patients are still considered
idiopathic.
[0005] A subgroup of ASD patients, the so called ASD phenotype 1
(see EP 17200185.1), shows an upregulation of pathways involved in
adaptation to stress, apoptosis or cell differentiation, cell
proliferation, cell cycle progression, cell division, and
differentiation. In particular, but not limited to, the P13K, AKT,
mTOR, MAPK, ERK/JNK-P38 pathways have been implicated in autism.
Patients diagnosed with ASD phenotype 1 also exhibit a significant
increase in proinflammatory cytokines (TNF-.alpha., IL-6,
IL-1.beta., IL-17A, IL-22 and GM-CSF), Th1 cytokine (INF-.gamma.)
and (chemokine (IL-8) expression in the brain compared to healthy
control patients, whereas no significant differences between ASD
phenotype 1 patients and normal controls were shown for the Th2
cytokines (IL-4, IL-5) and IL-10. Accordingly, the Th1/Th2 ratio
may be significantly increased in the ASD Phenotype 1 patients.
[0006] Currently, there is no effective treatment for the ASD
Phenotype 1 subgroup of patients. In fact, these patients react
negatively to administration of antioxidant substances, despite the
fact that these have been reported to improve some patients with
autism.
[0007] Fragile X is the most common monogenetic cause of both
intellectual disability and autism spectrum disorder. Patients with
Fragile X syndrome (FXS), caused by loss of function of the fragile
X mental retardation 1 (Fmr1) gene, often exhibit many of the
symptoms commonly associated with ASD, such as developmental
delays, communication impairments and anxiety.
[0008] Despite these studies of neurodevelopmental disorders such
as ASD, ASD Phenotype 1, and Fragile X syndrome, there remains a
need for novel treatments of neurodevelopmental disorders such as
ASD, ASD phenotype 1, and Fragile X Syndrome.
SUMMARY OF THE INVENTION
[0009] The present invention meets this need by providing methods
and pharmaceutical compositions or kits for treating patients
diagnosed with an autism spectrum disorder (ASD), ASD phenotype 1,
or fragile X syndrome.
[0010] In one aspect of the present disclosure, the pharmaceutical
composition comprises [0011] a first substance capable of raising
intracellular cAMP levels, and [0012] a second substance capable of
modulating intracellular calcium concentration.
[0013] In some embodiments, the substance capable of raising
intracellular cAMP levels is a PDE inhibitor. In some embodiments,
the PDE inhibitor is a PDE4 inhibitor or a PDE4-3 dual inhibitor.
In some embodiments, the PDE inhibitor is selected from the group
consisting of theophylline, enprofylline, pentoxifyiline,
dyphylline, caffeine, dipyridamole, roflumilast, crisaborole,
apremilast, cilomilast, tetomilast, rolipram, (S)-rolipram,
(R)-rolipram, amrinone, milrinone, enoximone, daxalipram
(R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast,
tofimilast, CI-1044, HT-0712, MK-0873, arofylline, CI-1018, T-2585,
YM-976, V-11294A, piclamilast, atizoram, filaminast, SCH 351591,
IC-485, D-4418, CDP-840, and L-826,141. In some embodiments, the
substance capable of raising intracellular cAMP levels comprises a
substance capable of activating a G protein-coupled adenosine
A.sub.2A receptor. In some embodiments, the substances capable of
activating a G protein-coupled adenosine A.sub.2A receptor is
selected from the group consisting of regadenoson, bidenoson,
adenosine, 2-phenilaminoadenosine,
2-amino-4-(4-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridine-
carbonitrile,
4-[2-[(6-amino-9-b-D-ribofuranosyl-9H-purin-2-yl)thio]ethyl]benzenesulfon-
ic acid ammonium salt, 2-hexynyl-5'-N-ethylcarboxamidoadenosine,
CGS-21680, and UK-432,097.
[0014] In some embodiments, the substance capable of modulating
intracellular calcium concentration comprises a retinoic
acid-related orphan receptor-alpha (RORA) agonist. In some
embodiments, the substance capable of modulating intracellular
calcium concentration comprises a calcium channel inhibitor or an
inhibitor of the solute carrier family 12 member 1, solute carrier
family 12 member 1, 2, 4 or solute carrier family 12 member 1, 2,
4, 5. In some embodiments, the substance capable of modulating
intracellular calcium concentration is selected from the group
consisting of dihydropyridines, phenylakylamines, benzothiazepines,
indolazines, aminoglycosides, and 4-substituted derivatives of
sulfamoylbenzoic acid. In some embodiments, the 4-substituted
derivative of sulfamoylbenzoic acid is a derivative of
4-substituted-3-amino-5-sulfamoylbenzoic acid.
[0015] In some embodiments, the derivative of
4-substituted-3-amino-5-sulfamoylbenzoic acid is selected from the
group consisting of bumetanide, AqB007, AqB011, PF-2178, BUM13,
BUM5, bumepamine, and mixtures thereof.
[0016] In some embodiments, the substance capable of modulating
intracellular calcium concentration is selected from the group
consisting of nifedipine, niludipine, nicardipine, nimodipine,
NZ-105, amlodipine, felodipine, isradipine, diperdipine, emopamil,
devapamil, verapamil, diltiazem, flunarizine, fluspirilene,
pimozide, fantofarone, nicergoline, neomycin, gentamycin,
kanamycin, cisapride, clopamide, cyproheptadine, loratadine,
domperidone, fentanyl, alfentanil, sufentanil, flecainide,
indoramin, isonepecotic acids, ketotifen, lobeline, loperamide,
mepivacaine, methylphenidate, minoxidil, nipecotic acid,
paroxetine, pempidine, penfluridol, perhexiline, pipecolics acid,
bupivacaine, cyclohexemide, thalidomide, terfenadine,
trihexyphenidyl, clevidipine, lomerazine, fostedil, anipamil,
torasemide, chlorthalidone, etacrynic acid, furosemide,
trichlormethiazide, hydroflumethiazide, methylclothiazide,
bumetanide, ibutilde, mibefradil, dronedarone, amiodarone,
nisoldipine, nitrendipine, nilvadipine, gabapentine, and ambroxol
hydrochloride.
[0017] In some embodiments, the substance capable of raising
intracellular cAMP levels is ibudilast, and the substance capable
of modulating intracellular calcium concentration is bumetamide. In
some embodiments, A method of treating a patient diagnosed with
Fragile X syndrome comprising administering to a patient in need
thereof an effective amount of a pharmaceutical composition
comprising a first substance capable, of raising intracellular cAMP
levels and an effective amount of a second substance capable of
modulating intracellular calcium concentration.
[0018] In accordance with some embodiments, there are provided
methods of treating a patient diagnosed with autism spectrum
disorder (ASD) comprising administering to a patient in need
thereof an effective amount of a pharmaceutical composition
comprising a first substance capable of raising intracellular cAMP
levels, and a second substance capable of modulating intracellular
calcium concentration.
[0019] In another aspect, there are provided kits comprising [0020]
a first substance capable of raising intracellular cAMP levels, and
[0021] a second substance capable of modulating intracellular
calcium concentration.
[0022] In some embodiments of the kit, the substance capable of
raising intracellular cAMP levels is a PDE inhibitor. In some
embodiments of the kit, the PDE inhibitor is a PDE4 inhibitor or a
PDE4-3 dual inhibitor. In some embodiments of the kit, the PDE
inhibitor is selected from the group consisting of caffeine,
theophylline, enprofylline, pentoxifylline, dyphylline,
theobromine, aminophylline, prepentofylline, L-reuteri,
dipyridamole, cilostazol, etazolate, rofiumilast, crisaborole
resembrenone, drotaverin, ibudilast, apremilast, cilomilast,
tetomilast, rolipram, (S)-rolipram, (R)-rolipram, amrinone,
milrinone, enoximone, daxalipram (R-mesopram), lirimilast,
AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044, HT-0712,
MK-0873, arofylline, CI-1018, T-2585, YM-976, V-11294A,
piclamilast, atizoram, filaminast, SCH 351591, IC-485, D-4418,
CDP-840, and L-826,14.
[0023] In some embodiments of the kit, the substance capable of
raising intracellular cAMP levels is a substance capable of
activating a G protein-coupled adenosine A.sub.2A receptor. In some
embodiments of the kit, the substance capable of activating a G
proteincoupled adenosine A.sub.2A receptor is selected from the
group consisting of regadenoson, bidenoson, adenosine,
2-phenilaminoadenosine,
2-amino-4-(4-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridine-
carbonitrile,
4-[2-[(6-amino-9-b-D-ribofuranosyl-9H-purin-2-yl)thio]ethyl]benzenesulfon-
ic acid ammonium salt and 2-hexynyl-5'-N-ethylcarboxamidoadenosine,
CGS-21680 and UK-432,097. In some embodiments of the kit, the
substance capable of modulating intracellular calcium concentration
is a retinoic acid-related orphan receptor-alpha (RORA) agonist
[0024] In some embodiments of the kit, the substance capable of
modulating intracellular calcium concentration is a calcium channel
inhibitor or an inhibitor of the solute carrier family 12 member 1,
an inhibitor of the solute carrier family 12 member 1, 2, 4 or an
inhibitor of the solute carrier family 12 member 1, 2, 4, 5.
[0025] In some embodiments of the kit, the substance capable of
modulating intracellular calcium concentration is selected from the
group consisting of dihydropyridines, phenylakylamines,
benzothiazepines, indolazines, aminoglycosides and a 4-substituted
derivative of sulfamoylbenzoic acid. In some embodiments of the
kit, the 4-substituted derivative of sulfamoylbenzoic acid is
selected from the group consisting of bumetanide, AqB007, AqB011,
PF-2178, BUM13, BUM5, bumepamine and mixtures thereof. In some
embodiments of the kit, the 4-substituted derivative of
sulfamoylbenzoic acid is a derivative of
4-substituted-3-amino-5-sulfamoylbenzoic acid.
[0026] In some embodiments of the kit, the substance that modulates
intracellular calcium concentration is selected from the group
consisting of nifedipine, niludipine, nicardipine, nimodipine,
NZ-105, amlodipine, felodipine, isradipine, diperdipine, emopamil,
devapamil, verapamil, diltiazem, flunarizine, fluspirilene,
pimozide, fantofarone, nicergoline, neomycin, gentamycin,
kanamycin, cisapride, clopamide, cyproheptadine, loratadine,
domperidone, fentanyl, alfentanil, sufentanil, flecainide,
indoramin, isonepecotic acids, ketotifen, lobeline, loperamide,
mepivacaine, methylphenidate, minoxidil, nipecotic acid,
paroxetine, pempidine, penfluridol, perhexiline, pipecolics acid,
bupivacaine, cyclohexemide, thalidomide, terfenadine,
trihexyphenidyl, clevidipine, lomerazine, fostedil, anipamil,
torasemide, chlorthalidone, etacrynic acid, furosemide,
trichlormethiazide, hydroflumethiazide, methylclothiazide,
bumetanide, ibutilde, mibefradil, dronedarone, amiodarone,
nisoldipine, nitrendipine, nilvadipine, gabapentine and ambroxol
hydrochloride.
[0027] In some embodiments of the kit, the substance capable of
raising intracellular cAMP levels comprises ibudilast and the
substance capable of modulating intracellular calcium concentration
comprises bumetamide.
[0028] In some embodiments, the kit disclosed herein is for use in
the treatment of autism spectrum disorder (ASD). In some
embodiments, the kit disclosed herein is for use in the treatment
of Fragile X syndrome
[0029] In another aspect, the methods disclosed herein is for
treating patient exhibits characteristics consistent with being an
ASD phenotype 1 patient. In some embodiments of the method for
treating an ASD phenotype 1 patient, the substance capable of
raising intracellular cAMP levels is a PDE inhibitor. In some
embodiments of the method for treating an ASD phenotype 1 patient,
the PDE inhibitor is a PDE4 inhibitor or a PDE4-3 dual inhibitor.
In some embodiments of the method for treating an ASD phenotype 1
patient wherein the PDE inhibitor is ibudilast. In some embodiments
of the method for treating an ASD phenotype 1 patient, the
pharmaceutical composition is administered to the patient at a
daily total dosage ranging from about 1-150 mg, preferably from
about 10-80 mg, and more preferably from about 15-50 mg, divided
among one, two, or three doses. In some embodiments of the method
for treating an ASD phenotype 1 patient, the pharmaceutical
composition is administered orally once, twice, or thrice daily to
the patient using a dosage form that comprises 1, 5, 10, 15, 20,
25, 30, 35, 40, 45, or 50 mg ibudilast, or a pharmaceutically
acceptable salt thereof.
[0030] In another aspect, there are provided methods of treating a
patient diagnosed with autism spectrum disorder (ASD), wherein the
treatment comprises [0031] (i) determining whether the patient
suffers from ASD phenotype 1, and [0032] (ii) administering a
therapeutically effective amount of a pharmaceutical composition
comprising a first substance capable of raising intracellular cAMP
levels, and a second substance capable of modulating intracellular
calcium concentration. to the patient if the patient suffers from
ASD phenotype 1;
[0033] wherein determining whether the patient suffers from ASD
phenotype 1 includes at least one step selected from [0034] a)
subjecting the patient to a challenge test with Nrf2-activator,
[0035] b) verifying for clinical signs of heightened expression of
proliferation-associated pathways, [0036] c) verifying for
upregulation of Nrf2, or [0037] d) verifying for low levels of
protein kinase A; and
[0038] wherein it is determined that the patient suffers from ASD
phenotype 1 if the patient exhibits at least one characteristic
selected from negative behavioral response in the challenge test
with a Nrf2 inducer, clinical signs of heightened expression of
proliferation-associated pathways, upregulation of Nrf2, and low
blood levels of protein kinase A.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present disclosure provides novel methods and
compositions for treating patients diagnosed with autism spectrum
disorder (ASD), in particular subtype ASD phenotype 1, and Fragile
X syndrome. The herein disclosed methods, compositions and kits are
based on the surprising discovery, illustrated in the Example
herein, that the effect of substances capable of increasing
intracellular cyclic adenosine monophosphate (cAMP) on treating
cognitive dysfunctions associated with ASD can be synergistically
and unexpectedly improved by co-treatment with substances capable
of modulating intracellular calcium concentration. Accordingly, in
one aspect, the present invention relates to a pharmaceutical
composition or a kit comprising [0040] a) a first substance capable
of raising intracellular cAMP levels, and [0041] b) a second
substance capable of modulating intracellular calcium
concentration.
[0042] The present disclosure is based on the surprising discovery,
exemplified in the example herein, that ibudilast, a substance
capable of raising intracellular cAMP levels, and bumetamide, a
substance capable of modulating intracellular calcium
concentration, in combination can treat patients diagnosed with ASD
phenotype 1.
I. Definitions
[0043] Technical and scientific terms used herein have the meanings
commonly understood by one of ordinary skill in the art to which
the present invention pertains, unless otherwise defined.
Materials, reagents and the like to which reference is made in the
following description and examples are obtainable from commercial
sources, unless otherwise noted.
[0044] As used herein, the singular forms "a," "an," and "the"
designate both the singular and the plural, unless expressly stated
to designate the singular only.
[0045] The term "about" means that the number comprehended is not
limited to the exact number set forth herein, and is intended to
refer to numbers substantially around the recited number while not
departing from the scope of the invention. As used herein, "about"
will be understood by persons of ordinary skill in the art and will
vary to some extent on the context in which it is used. If there
are uses of the term which are not clear to persons of ordinary
skill in the art given the context in which it is used, "about"
will mean up to plus or minus 10% of the particular term.
[0046] A "kit" is herein defined as combination product provided as
a package and containing several individual parts that show a
complementary effect when applied together. In this aspect, the
effect achieved by a kit and a pharmaceutical composition are
similar. A kit offers the advantage that dosage regimens of the
individual parts may be adjusted to specific requirements and over
time.
[0047] As used herein "subject," "patient," or "individual" refers
to any subject, patient, or individual, and the terms are used
interchangeably herein. When used in conjunction with "in need
thereof," the term "subject," "patient," or "individual" intends
any subject, patient, or individual having or at risk for a
specified symptom or disorder.
[0048] As used herein, the term "administering" includes directly
administering to another, self-administering, and prescribing or
directing the administration of an agent as disclosed herein.
[0049] As used herein, the phrases "effective amount" and
"therapeutically effective amount" mean that active agent dosage or
plasma concentration in a subject, respectively, that provides the
specific pharmacological effect for which the active agent is
administered in a subject in need of such treatment. It is
emphasized that an effective amount of an active agent will not
always he effective in treating the conditions/diseases described
herein, even though such dosage is deemed to be an effective amount
by those of skill in the art.
[0050] As used herein, the term "pharmaceutical composition" refers
to one or more active agents formulated with a pharmaceutically
acceptable carrier, excipient or diluent.
[0051] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in viva without excessive toxicity, irritation,
allergic response, or other problem or complication, commensurate
with a reasonable benefit/risk ratio.
II. Autism Spectrum Disorders
[0052] As used herein, the term "autism spectrum disorder (ASD)" is
understood to cover a family of neurodevelopmental disorders
characterized by deficits in social communication and interaction
and restricted, repetitive patterns of behavior, interests or
activities. In the following, the terms "autism spectrum disorder",
"autism" and "ASD" are used interchangeably.
[0053] Herein, the terms "ASD phenotype 1" and "phenotype 1" are
used interchangeably.
[0054] The term "ASD patient" is intended to cover not only humans
diagnosed as having ASD, but also humans suspected of having
ASD.
[0055] The person skilled in the art is well aware of how a patient
may be diagnosed with ASD. For example, the skilled person may
follow the criteria set up in "American Psychiatric Association;
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Fifth
edition" to give a subject a diagnosis of ASD. Likewise, ASD
patients may have been diagnosed according to standardized
assessments tools including but not limited to CIM-10, ICD-10,
DISCO, ADI-R, ADOS or CHAT.
[0056] In other cases, patients may have a well-established DSM-IV
diagnosis of autistic disorder, Asperger's disorder, or pervasive
developmental disorder not otherwise specified (PDD-NOS).
[0057] Additionally, the present invention may be useful for
subjects fulfilling one or more of the following criteria:
persistent deficits in social communication and social interaction
across multiple contexts as manifested by the following, currently
or by history; restricted, repetitive patterns of behavior,
interests, or activities, as manifested by at least two of the
following, currently or by history; symptoms present in the early
development period (but may not become fully manifest until social
demands exceed limited capacities, or maybe masked by learned
strategies in later life); symptoms cause clinically significant
impairment in social, occupational, or other important areas of
current functioning; these disturbances are not better explained by
intellectual disability (intellectual development disorder) or
global development delay.
[0058] ASD may occur with or without accompanying intellectual
and/or language impairment. It may be associated with a known
medical or genetic condition or an environmental factor or other
neurodevelopmental, mental or behavioral disorders.
[0059] ASD may occur in different severity levels which may be
classified according to impairment in social communication and in
terms of restricted, repetitive behavior. Importantly, the term ASD
phenotype 1 is not associated with a particular severity level of
ASD. The present invention may be applied to patients suffering
from any severity level of ASD.
[0060] Without being bound by a mechanism, it is believed that ASD
patients can be characterized depending on whether or not they show
an upregulation, a downregulation or normal levels of expression of
biomolecular pathways involved in stress response.
[0061] Depending on whether and how the level of expression of
these pathways in the respective individuals are modified,
challenging ASD patients with Nrf2-activators which are known to
upregulate the respective pathways will improve or worsen ASD
symptoms.
[0062] In one aspect, the pharmaceutical composition or kit
according to the present invention is for use in the treatment of
an ASD or of a subgroup of ASD patients called ASD phenotype 1
patients.
[0063] ASD phenotype 1 patients may be identified with the help of
a challenge test as described in non-published EP17200185.1,
incorporated herein by reference in its entirety. Briefly, the
concept of a challenge test is based on administration of an
Nrf2-activator to an ASD patient. In ASD phenotype 1 patients, who
already show an upregulation of the respective pathways, further
activation of Nrf2 will lead to a worsening of core symptoms.
Consequently, ASD phenotype 1 patients may be identified by a
negative behavioral response to a challenge test.
[0064] Likewise, the skilled person can identify ASD phenotype 1
patient according to the clinical signs as defined in EP
17200185.1.
[0065] Another way of identifying ASD phenotype 1 patient is to
check for upregulation of Nrf2. The person skilled in the art is
well aware of how upregulation of the expression of a specific gene
such as Nrf2 may be investigated. For example, it may be
investigated at the mRNA level using quantitative PRC, techniques
such as qPCR or RT-qPCR. Likewise, upregulation of the expression
of a gene may be determined on the protein level using protein
quantification techniques such as Western Blot and quantitative dot
blots. Upregulation is understood to mean an increase of mRNA
levels or protein levels of at least 10% when compared to samples
from healthy subjects.
[0066] Additionally, an ASD phenotype 1 patient may exhibit one or
more of the following symptoms: increased levels of TH1 and
pro-inflammatory sera cytokines (including but not limited to
TNF-.alpha., IL-1.beta., IL-6, Il-17A and IL-22) and/or of tissue
expressions of mRNAs that encode inflammatory cytokines and/or
excessive challenged T cell secretion of proinflammatory cytokines;
upregulation of pathways involved in adaptation to stress,
apoptosis, cell differentiation, cell proliferation, cell cycle
progression, cell division and differentiation (in particular but
not limited to PI3K, AKT, mTOR/MAPK, ERK/JNK-P38).
[0067] Currently, there remain a need for effective treatment
available for patients diagnosed with autism spectrum disorders
(ASDs), and in particular ASD phenotype 1. The present disclosure
meets this need by providing a novel method of treating ASD and ASD
phenotype 1 in particular by administering substances capable of
raising intracellular cAMP levels and substances capable of
modulating intracellular calcium concentration, which is
unprecedented in the literature.
III. Pharmaceutical Compositions and Methods for Treatment of
Autism.
[0068] The methods and compositions described herein are based on
the surprising discovery that the effect of treating patients
diagnosed with an autism spectrum disorder with substances capable
of raising intracellular cyclic Adenosine Monophosphate (cAMP)
levels can be synergistically and unexpectedly enhanced by
co-treatment with substances capable of modulating intracellular
calcium levels. This combined treatment with substances capable of
raising intracellular cAMP and substances capable of modulating
intracellular calcium levels is unprecedented in literature, and
provides a novel method of treating autism spectrum disorders and
fragile X syndrome.
[0069] a. Substances Capable Raising Intracellular cAMP Levels
[0070] Cyclic Adenosine Monophosphate (cAMP) is synthetized from
adenosine triphosphate (ATP) via the action of adenylyl cyclase
(AC) and is converted to its inactive form 5'-adenosin
monophosphate (5'-AMP) via hydrolysis by phosphodiesterase (PDE).
Accordingly, one class of substances available for increasing cAMP
levels is inhibitors of PDE.
[0071] In one aspect, the substance capable of increasing the
intracellular levels of cAMP is a phosphodiesterase (PDE)
inhibitor. Since phosphodiesterases convert cAMP to its inactive
form, inhibiting phosphdiesterases will increase the levels of
cAMP. One type of cAMP-PDEs is the PDE4 family which comprises four
genes, PDE4A to D. PDE4s differ from other cAMP-PDEs by their
kinetic properties and, particularly, their sensitivity to
inhibition by the prototypical PDE4 inhibitor rolipram.
[0072] Accordingly, the present disclosure provides pharmaceutical
compositions that comprises a substance that is capable of raising
intracellular cAMP levels. The substance may be capable of raising
intracellular cAMP levels directly or indirectly or both. A
substance capable of directly raising intracellular cAMP levels may
directly stabilize cAMP or inhibit degradation of cAMP. A substance
capable of indirectly raising intracellular cAMP levels may
activate molecules which lead to the generation of cAMP or may
inhibit molecules degrading cAMP.
[0073] Inhibition is herein understood to mean blocking or reducing
the activity of the respective molecule. In some embodiments,
activity may be reduced by more than 20%, 30%, 40%, 50%, 60%, 70%,
80% or 90%. In a preferred embodiment, activity is reduced by at
least 50%.
[0074] Activation is herein understood to mean upregulating or
enhancing the activity of the respective molecule. In some
embodiments, activity may be enhanced by more than 20%, 30%, 40%,
50%, 60%, 70%, 80% or 90%. In a preferred embodiment, activity may
be enhanced by at least 50%.
[0075] Substances capable of inhibition of phosphodiesterase may be
any molecule having a c-AMP-specific 3'-5'-cyclic phosphodiesterase
4A/B/C; inhibitory effect, any molecule having a c-AMP 3'-5'-cyclic
phosphodiesterase 4A/B inhibitory effect, any molecule having a
cAMP 3'-5'-cyclic phosphodiesterase 4A inhibitory effect, any
molecule having a cAMP 3'-5'-cyclic phosphodiesterase 4A/B/C/D
inhibitory effect, any molecule having a cAMP 3'-5'-cyclic
phosphodiesterase 4A/B/D inhibitory effect, any molecule having a
cAMP 3'-5'-cyclic phosphodiesterase 4/B/D inhibitory effect, any
molecule having a cAMP 3'-5'-cyclic phosphodiesterase 4D inhibitory
effect, any molecule having a cAMP phosphodiesterase 4B/D
inhibitory effect, any molecule having a cAMP 3'-5'-cyclic
phosphodiesterase 4B inhibitory effect.
[0076] Substances capable of inhibition of PDE include
pyrazopyridines, preferably ibudilast, xanthines and derivatives,
in particular enprofylline, pentoxifylline, dyphylline,
aminophylline, propentofylline, preferably caffeine, theobromine,
theophilline; flavonoids, in particular xanthohumol, leucocyanidol,
delphinidin; flavones, in particular apigenin, luteolin;
biflavones, in particular podocarpusflavone A; sequoiaflavones, in
particular podocarpusflacvone B, 7,7''-dio-methylaminoflavone,
bilobetin; flavanones, in particular dioclein, naringenin,
hesperetin; stilbens, in particular E-(epsilon)-viniferin,
curcumin; alkaloids, in particular chelerythrine, glaucine,
apomorphine; aminopyrimidines and derivatives, in particular
diakylarylamines, preferably dipyridamole; arenecarboxamides in
particular benzamides, preferably roflumilast or piclamilast;
benzoxaboroles, in particular crisaborole; isoindolones, in
particular phthalimides, preferably apremilast; methoxybenzenes, in
particular cilomilast; pyridinecarboxylic acids, in particular
tetomilast; phenylpyrrolidines, in particular pyrrolidin-2-ones,
preferably rolipram, (S)-rolipram, (R)-rolipram, bipyridines,
oligopyridines, in particular amrinone, milrinone,
arylphenylketones, in particular enoximone; oxazolidin-2-ones, in
particular daxalipram (R-mesopram); probiotics, in particular
L-reuteri.
[0077] In a preferred embodiment, the substance capable of
inhibiting PDE is selected from the group consisting of ibudilast,
caffeine, theobromine, theophylline, enprofylline, pentoxifylline,
dyphylline, L-reuteri, dipyridamole, cilostazol, etazolate,
roflumilast, crisaborole resembrenone, drotaverin, apremilast,
cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram,
amrinone, milrinone, enoximone, daxalipram (R-mesopram),
lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast,
Cl-1044
((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi-
]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone,
5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl),
MK-0873
(3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyr-
idin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline,
CI-1018
(N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-jk)(1,4)benzo-
diazepin-3-yl)-4-Pyridinecarboxamide), T-2585
(2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyl}-2-pyridinyl]-4--
(3-pyridinyl)-1(2H)-phthalazinone), YM-976
(4-(3-chlorophenyl)-1,7-diethyl-1H,2H-pyrido[2,3-d]pyrimidin-2-one),
V-11294A
(3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine),
piclamilast, atizoram, filaminast, SCH 351591
(N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-qui-
nolinecarboxamide), IC-485, D-4418
(N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide),
CDP-840
(4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine
hydrochloride), L-826,141
(4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hyd-
roxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770
(2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl-
)acetamide), TDP101.
[0078] More preferred, the substance capable of inhibiting PDE is
ibudilast.
[0079] Ibudilast is an anti-inflammatory and neuroprotective oral
agent, metabolized mainly by the liver. Following administration of
a single dose of 10 mg ibudilast to healthy adults, about 60% of
the dose was excreted as metabolites in urine in 72 hours. The
clinical efficacy of this product has been proven for bronchial
asthma indication and cerebrovascular disorders. Ibudilast is
currently under clinical trial in the U.S. for progressive multiple
sclerosis and other conditions such as amyotrophic lateral
sclerosis and substances dependence (codes: AV-411 or MN-166).
[0080] Substances that are capable of indirectly raising
intracellular cAMP levels include substances capable of stimulating
a G protein-coupled adenosine A.sub.a2 receptor which activates
adenylate cyclase, substances capable of activation of adenylate
cyclase, substances that are capable of inhibiting glycogen
synthetase kinase-3-beta (GSK-3-beta), as well as substances
capable of inhibition of phosphodiesterase.
[0081] More specifically, a substance capable of activation of G
protein-couple adenosine A.sub.a2 receptor may be a purine
nucleoside, in particular regadenoson, bidenoson, adenosine,
2-phenilaminoadenosine,
2-amino-4-(4-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridine-
carbonitrile,
4-[2-[(6-amino-9-b-D-ribofuranosyl-9H-purin-2-yl)thio]ethyl]benzenesulfon-
ic acid ammonium salt, 2-hexynyl-5'-N-ethylcarboxamidoadenosine,
CGS-21680 or UK-432,097.
[0082] Substances capable of inhibiting glycogen synthetase
kinase-3-beta (GSK-3-beta) may be lithium salts.
[0083] b. Substances Capable of Modulating Intracellular Calcium
Levels
[0084] The pharmaceutical composition according to the present
invention may optionally comprise a substance capable of modulating
intracellular calcium levels.
[0085] Herein, the term "modulating" may refer to a global decrease
of cytosolic intracellular calcium, a localized increase of
intracellular calcium in specific organelles, such as the
mitochondria or endoplasmic reticulum, which in turns lead to a
decrease of the cytosolic calcium concentration, or a modulation of
the dynamics of intracellular calcium, such as a modulation of
intracellular calcium vague, intracellular calcium oscillations,
and/or intracellular calcium sparks.
[0086] The substance capable of modulating intracellular calcium
levels may modulate intracellular calcium levels by mechanisms
including either inhibition of intracellular calcium channels such
as ryanodine receptor (RyR) or inositol-1,4,5-triphosphate-receptor
(IP3R), or direct or indirect modulation of calcium-ATPase pumps,
including Sarcoendoplasmic reticulum Ca2+ transport-ATPase (SERCA)
and Plasma Membrane Ca2+ ATPase (PMCA), ionic exchangers, such as
Na+/Ca2+ exchangers, Na+/H+ exchangers, Na+/K+ exchangers, NKKC or
calcium channels.
[0087] The substance capable of modulating intracellular calcium
levels may be any molecule having an inhibitory effect on solute
carrier family 12 member 1, on solute carrier family 12 member
1,2,4 or on solute carrier family 12 member 1, 2, 4, 5.
[0088] Likewise, the substance capable of modulating intracellular
calcium levels may be a molecule having an inhibitory effect on
voltage-dependent calcium channels, preferably on voltage-dependent
L-type, N-type or T-type calcium channels. In a preferred
embodiment, the substance capable of modulating intracellular
calcium levels may be a molecule having an inhibitory effect on
voltage dependent L-type calcium channel subunits beta-1/-4,
subunit beta-2 or subunits alpha-1/delta-2. The substance capable
of modulating intracellular calcium levels may he a substance that
inhibits the NKCC co-transporter.
[0089] In one embodiment, the substance capable of modulating
intracellular calcium levels can be a diuretic. In another
embodiment, the substance capable of modulating intracellular
calcium levels can be an antiarrythmic agent. The skilled person is
well aware of which drug or pharmaceuticals fall under the terms
"diurectic" and "antiarrythmic agent".
[0090] In a preferred embodiment, the substance capable of
modulating intracellular calcium levels may be selected from
pyridinesulfonamides, in particular torasemide; isoindolines, in
particular chlorthalidone; chlorophenoxyacetates, in particular
etacrynic acid; aminobenzenesulfonamides, in particular furosemide
and bumetanide; 4-substituted-3-amino-5-sulfamoylbenzoic acid
derivatives, in particular but not limited to bumetanide, AqB007,
AqB011, bumepamine; 1,2,4-benzothiadiazine-1,1-dioxides, in
particular trichlormethiazide, hydroflumethiazide and
methylclothiazide; dimethoxybenzenes, in particular ibutilde or
veraparnil; tetralins, in particular mibefradil;
aryl-phenylketones, in particular dronedarone and amiodarone;
1,4-dihydropyridine and derivatives, in particular amlodipine,
felodipine, diperdipine, nifedipine nimodipine, nisoldipine,
nitrendipine, clevidipine, nicardipine and nilvadipine;
benzoxadiazoles, preferably dihydropyridinecarboxylic acids and
derivatives, in particular isradipine; diphenylmethylpiperazine and
derivatives in particular flunarizine; heteroarylpiperidine in
particular pimozide, domperidone; piperidines in particular
cyproheptadine, fentanyl, alfentanil, sufentanil, flecainide,
loperamide, methylphenidate, paroxetine, pempidine, perhexiline;
benzocycloheptapyridine in particular loratadine; organic
heterotetracyclic compound in particular nicergoline;
aminoglycoside in particular, neomycin, gentamycin, kanamycin;
piperidinecarboxamide in particular mepivacaine, bupivacaine;
triptamines in particular indoramin; sulfonamides in particular
clopamide; aminobenzamides in particular cisapride; aminopyrimidine
in particular minoxidil; piperidine alkaloid in particular
lobeline; piperidine antibiotic in particular cycloheximide
non-proteinogenic amino acids such as gamma amino acids and
derivatives, in particular gabapentin; piperidinemonocarboxylic
acid in particular nipecotic acid, pipecolics acid; diarylmethane
in particular penfluridol; benzothiazepine derivatives in
particular diltiazem; phthalamides in particular thalidomide;
diarylmethane in particular terfenadine, lomerazine, aromatic amine
in particular ambroxol hydrochloride.
[0091] In another preferred embodiment, the substance capable of
modulating intracellular calcium levels is selected from the group
consisting of nifedipine, niludipine, nicardipine, nimodipine,
NZ-105, amlodipine, felodipine, isradipine, diperdipine, emopamil,
devapamil, verapamil, diltiazem, flunarizine, fluspirilene,
pimozide, cantofarone, nicergoline, neomycin, gentamycin,
kanamycin, cisapride, clopamide, cyproheptadine, loratadine,
domperidone, fentanyl, alfentanil, sufentanil, flecainide,
indoramin, isonepecotic acids, ketotifen, lobeline, loperamide,
mepivacaine, methylphenidate, minoxidil, nipecotic acid,
paroxetine, pempidine, penfluridol, perhexiline, pipecolics acid,
bupivacaine, cyclohexemide, thalidomide, terfenadine,
trihexyphenidyl, clevidipine, lomerazine, fostedil, anipamil,
torasemide, chlorthalidone, etacrynic acid, furosemide,
trichlormethiazide, hydroflumethiazide, methylclothiazide,
bumetanide, ibutilde, mibefradil, dronedarone, amiodarone,
nisoldipine, nitrendipine, nilvadipine, gabapentine, ambroxol
hydrochloride.
[0092] In yet another aspect, the pharmaceutical composition
according to the present invention may optionally comprise a
retinoic acid-related orphan receptor-alpha (RORA) agonist, RORA is
a ligand dependent orphan nuclear hormone receptor that, in
combination with co-regulator proteins, serves as a transcriptional
regulator. RORA agonists may be phenylnaphthalenes, in particular
adaptalene; sesquiterpenoids, in particular all-trans acitretin;
diterpenoids, in particular alitretinoin or isotretinoin;
thiochromanes, in particular tazarotene, retinoid esters, in
particular etretinate; retinobenzoic acids, in particular
tamibarotene, all-trans-retinoic acid or tretinoin. In a preferred
embodiment, the RORA agonist may be selected from the group
consisting of adapalene, all-trans retinoic acid, tretinoin,
vitamin A, all-trans acitretin, alitretinoin, tazarotene,
etretinate, isotretinoin, tamibarotene, LGD-1550, AM580 and Ch
55.
[0093] In sharp contrast, administering the pharmaceutical
compositions according to the present invention, the effect of a
substance capable of modulating intracellular calcium concentration
such as bumetanide sets in within several days.
[0094] It is also envisaged by the present invention that the
pharmaceutical composition according to the present invention
additionally comprises pharmaceutically acceptable carriers or
excipients such as lubricants, disintegrants, antiadherents,
binders, preservatives, sorbents or vehicles.
[0095] In another aspect, the pharmaceutical composition according
to the present invention may additionally comprise an agent that
inhibits cell proliferation. In another aspect, the present
invention relates to a pharmaceutical composition for use in the
treatment of ASD phenotype 1, the pharmaceutical composition
comprising a substance capable of raising intracellular cAMP
levels.
[0096] In one embodiment, the substance capable of raising
intracellular cAMP levels is preferably a PDE inhibitor. In a
particularly preferred embodiment, the PDE inhibitor is ibudilast.
Ibudilast may be administered to the patient at a daily total
dosage ranging from about 1-150 mg, preferably from about 5-80 mg,
and more preferably from about 15-50 mg, divided among one, two, or
three doses. It may be administered orally once, twice, or thrice
daily to the patient using a dosage form that comprises 1, 5, 10,
15, 20, 25, 30, 35, 40, 45, or 50 mg ibudilast or a
pharmaceutically acceptable salt thereof.
[0097] In yet another aspect, the substance capable of modulating
Ca2+ is a NKKC1 inhibitor. The substance capable of modulating
intracellular calcium levels may be a substance that inhibits the
NKCC co-transporter. NKCC co-transporters have been shown to
promote rise in intracellular calcium either alone or in
combination with other ions exchangers, such as Na/Ca exchanger,
Na+/H+ exchanger, and/or Na+/K+ exchanger.
[0098] In a particularly preferred embodiment, the NKKC1 inhibitor
is bumetanide. Bumetanide may be administered to the patient at a
daily total dosage ranging from about 0.5 to 10 mg, preferably from
1 to 6 mg, and more preferably from 2 mg to 4 mg, divided into one,
two, or three doses, it may be administered orally once, twice, or
thrice daily to the patient using a dosage form that comprises 0.5,
1, 2 mg bumetanide, or a pharmaceutically acceptable salt thereof.
Administration of a single dose may enhance patient compliance,
while administration of several smaller doses ensures constant
serum levels.
[0099] In yet another aspect, the pharmaceutical composition or kit
according to the present invention may additionally comprise an
agent that inhibits cell proliferation, such as compounds targeting
PI3K, AKT, mTOR, MAPK, ERK/JNK-P38 known to modulate cellular
proliferation.
[0100] In yet another aspect, the present invention relates to a
pharmaceutical composition for use in the treatment of ASD in a
patient, comprising a substance capable of raising intracellular
cAMP levels, and a substance capable of modulating intracellular
calcium levels, wherein the treatment comprises: [0101] (i)
determining whether the patient suffers from ASD phenotype 1, and
[0102] (ii) administering a therapeutically effective amount of the
pharmaceutical composition to the patient if the patient suffers
from ASD phenotype 1;
[0103] wherein determining whether the patient suffers from ASD
phenotype 1 includes at least one selected from: [0104] a)
subjecting the patient to a challenge test with Nrf2-activator,
[0105] b) verifying for clinical signs of heightened expression of
proliferation associated pathways, [0106] c) verifying for
upregulation of Nrf2, or [0107] d) verifying for low blood levels
of protein kinase A; and
[0108] wherein it is determined that the patient suffers from ASD
phenotype 1 if he shows at least one of the following: negative
behavioral response in a challenge test with a Nrf2 activator such
as sulforaphane; clinical signs of heightened expression of
proliferation-associated pathways; upregulation of Nrf2 or low
levels of protein kinase A.
[0109] In another aspect, the pharmaceutical composition according
to the invention may be used for the treatment of Fragile X.
[0110] In another aspect, a method is disclosed for treating a
patient diagnosed with Fragile X Syndrome comprising administering
to a patient in need thereof an effective amount of ibudilast or a
pharmaceutically acceptable salt thereof.
[0111] In another aspect, a method is disclosed for treating a
patient diagnosed with autism spectrum disorder (ASD) comprising
administering to a patient in need thereof an effective amount of
ibudilast or a pharmaceutically acceptable salt thereof.
[0112] In another aspect, a method is disclosed in which the
patient exhibits characteristics consistent with being an ASD
subtype 1 patient.
[0113] In another aspect, a method is disclosed in which ibudilast
or a pharmaceutically acceptable salt is administered to the
patient at a daily total dosage ranging from about 1-150 mg,
preferably from about 10-80 mg, and more preferably from about
15-50 mg, divided among one, two, or three doses.
[0114] In another aspect, a method is disclosed in which ibudilast
or a pharmaceutically acceptable salt thereof is administered
orally once, twice, or thrice daily to the patient using a dosage
form that comprises 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg
ibudilast or a pharmaceutically acceptable salt thereof.
IV. Pharmaceutical Composition Carriers and Dosage Forms
[0115] In some embodiments, a pharmaceutical composition disclosed
herein comprises one or more pharmaceutically acceptable carriers,
such as an aqueous carrier, buffer, and/or diluent.
[0116] In some embodiments, a pharmaceutical composition disclosed
herein further comprises a simple polyol compound, such as
glycerin. Other examples of polyol compounds include sugar
alcohols. In some embodiments, a pharmaceutical composition
disclosed herein comprises an aqueous carrier and glycerin at about
a 2:1 ratio.
[0117] The pharmaceutical composition may conveniently be presented
in unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy. An exemplary oral dosage form is a
tablet or capsule. An exemplary intranasal dosage form is a liquid
or powder nasal spray. A nasal spray is designed to deliver drug to
the upper nasal cavity, and can be a liquid or powder formu-lation,
and in a dosage form such as an aerosol, liquid spray, or
powder.
[0118] The pharmaceutical composition herein may be combined or
coordinately administered with a suitable carrier or vehicle
depending on the route of administration. As used herein, the term
"carrier" means a pharmaceutically acceptable solid or liquid
filler, diluent or encapsulating material. A water-containing
liquid carrier can comprise pharmaceutically acceptable additives
such as acidifying agents, alkalizing agents, antimicrobial
preservatives, antioxidants, buffering agents, chelating agents,
complexing agents, solubilizing agents, humectants, solvents,
suspending and/or viscosity-increasing agents, tonicity agents,
wetting agents or other biocompatible materials. A tabulation of
ingredients listed by the above categories can be found in the U.S.
Pharmacopeia National Formulary, 1857-1859, and (1990).
[0119] Some examples of the materials which can serve as
pharmaceutically acceptable carriers are sugars, such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cello-lose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa but-ter
and suppository waxes; oils such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
glycols, such as propylene glycol; polyols such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters such as ethyl
oleate and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen free water;
isotonic saline; Ringer's solution, ethyl alcohol and phosphate
buffer solutions, as well as other nontoxic compatible substances
used in pharmaceutical formulations.
[0120] Wetting agents, emulsifiers and lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions, according to the desires of the formulator. Examples
of pharmaceutically acceptable antioxidants include water soluble
antioxidants such as ascorbic acid, cysteine hydrochloride, sodium
bisulfite, sodium metabisulfite, sodium sulfite and the like;
oil-soluble antioxidants such as ascorbyl palmitate, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,
propyl gallate, alpha-tocopherol and the like; and metalchelating
agents such as citric acid, ethylenediamine tetraacetic acid
(EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
[0121] Pharmaceutical compositions according to the invention may
also comprise one or more binding agents, filling agents,
lubricating agents, suspending agents, sweeteners, flavoring
agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents, and other excipients. Such excipients are
known in the art. Examples of filling agents include lactose
monohydrate, lactose anhydrous, and various starches; examples of
binding agents include various celluloses and cross-linked
polyvinylpyrrolidone, microcrystalline cellulose, such as
Avicel.RTM. PH101 and Avicel.RTM. PH102, microcrystalline
cellulose, and silicified microcrystalline cellulose (ProSolv
SMCC.TM.). Suitable lubricants, including agents that act on the
flowability of the powder to be compressed, may include colloidal
silicon dioxide, such as Aerosil.RTM. 200, talc, stearic acid,
magnesium stearate, calcium stearate, and silica gel. Examples of
sweeteners may include any natural or artificial sweetener, such as
sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and
acesulfame. Ex-amples of flavoring agents are Magnasweet.RTM.
(trademark of MAFCO), bubble gum flavor, and fruit flavors, and the
like. Examples of preservatives include potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or qua-ternary compounds such as benzalkonium chloride.
[0122] Any pharmaceutical used for therapeutic administration can
be sterile. Sterility is readily accom-plished by for example
filtration through sterile filtration membranes (e.g., 0.2 micron
membranes). Any pharmaceutically acceptable sterility method can be
used in the compositions of the invention.
[0123] The pharmaceutical composition comprising a first substance
capable of increasing cAMP levels, and optionally, a second
substance capable of increasing intracellular calcium levels, or
derivatives or salts thereof, will be formulated and dosed in a
fashion consistent with good medical practice, taking into account
the clinical condition of the individual patient, the method of
administration, the scheduling of administration, and other factors
known to practitioners.
EXAMPLE
[0124] A pharmaceutical composition comprising ibudilast and
bumetanide was administered to patients with a diagnosis of autism
spectrum disorder as defined in the DSM-5, or PDD-NOS or Asperger
syndrome as defined in the DSM-IV.
[0125] Eligibility criteria: male sex, age 5-50, no current chronic
illness, no history of active seizures within 1 year, normal liver,
renal and thyroid function. Concomitant medications were permitted
if doses were stable for at least 60 days prior to the initiation
of the challenge test. Patients with no syndromic or identified
genetic etiology.
[0126] Individuals with idiopathic ASD were classified as Phenotype
1 if they showed: [0127] at least 1 mandatory characteristic:
[0128] enlarged head size versus control population characterized
by at least one standard deviations above the mean head
circumference at 24 months and/or formal macrocephaly (HC>97% of
the general population) [0129] and/or [0130] cyclical aggravation
of core or ancillary autism symptoms potentiated by periods of
infectious events, deciduous tooth loss, post-traumatic injury,
endogenous and exogenous temperature variation [0131] and [0132] at
least 2, and most preferably at least 3 of the following 20
characteristics: [0133] accelerated hair and nail growth versus
control population, [0134] increased tendency to present with
lighter colors of skin and eyes as compared to individuals of the
same ethnicity, [0135] substantially longer eyelashes than control
subjects of the same ethnicity, [0136] at least 5 non-contiguous
areas of hypopigmented skin, particularly presenting on the back of
the patient, [0137] signs of edema during periods of infectious
events, deciduous tooth loss, post-traumatic injury, or endogenous
and exogenous factors modifying body temperature; more
specifically, facial edema located in the periorbital and forehead
areas, [0138] increased blood levels of gamma-glutamyl
transpeptidase (GGT) as compared to typically developing
individuals of the same age and ethnicity, [0139] congenital
genitourinary malformations and/or functional impairment to
initiate urinating, [0140] hypoplasia of the patella, [0141]
frequent episodes of diarrhea specifically before the age of 5
years, [0142] frequent episodes of tinnitus, [0143] thinning of the
corpus callosum, [0144] positive family history for hematological
malignancies in particular but not limited to myeloma and acute
promyelocytic leukemia, [0145] positive family history for
rheumatoid arthritis, that is at least two affected first-degree
relatives in two consecutive generations, [0146] adverse events in
response to acetyl-salicylic acid or its derivatives, [0147] iris
coloboma, either monolateral or bilateral, [0148] sleep
hyperhidrosis particularly in newborns, toddlers and young children
(notably increased night sweating during infancy and childhood
often reported by relatives to requires bed linen changes), [0149]
increased Th1/Th2 ratio (i.e. elevated levels of Interleukin 1
beta, Interleukin 6, TNF-alpha, Interferon gamma), [0150]
congenital accessory or duplicated spleen, [0151] congenital
absence of the cisterna chili, [0152] reported history of mother
suffering from viral or bacterial infection during pregnancy and/or
biologically confirmed Maternal immune activation during
pregnancy.
[0153] First Intervention
[0154] Description: Four of the patients characterized as above
were administered ibudilast. The four subjects had varying levels
of functioning ranging from mild to severe, and varying different
levels of verbal and intellectual abilities. IQ values ranged from
61 to 86. All were males.
TABLE-US-00001 TABLE 1 Patient status prior to intervention ADI
baseline score Patient 1 Patient 2 Patient 3 Patient 4 ADI-r SI 28
20 14 27 ADI-r C 24 19 18 17 ADI-r RI 7 5 7 7
Four patients were treated with ibudilast at a daily total dosage
of 0.6 mg/kg, TID.
TABLE-US-00002 TABLE 2 Patient status after treatment for four
weeks of treatment with ibudilast. ADI baseline score Patient 1
Patient 2 Patient 3 Patient 4 ADI-r SI 21 16 12 22 ADI-r C 20 15 14
14 ADI-r RI 6 5 5 7
[0155] After between two and four months of mono-treatment with
ibudilast, loss of treatment efficacy was reported in all four
patients with gradual return to pre-treatment baseline scores.
[0156] A new treatment regimen was introduced, this time ibudilast
at a daily total dosage of 0.6 mg/kg, TID, was administered in
conjunction with bumetanide at a daily total dosage of 0.08 mg/kg,
BD (with a maximum upper daily dose of 2 mg/kg/day).
[0157] Following a mean length of administration of 8 days of
bi-therapy treatment effect on reduction of ADI-r scores reflected
restoration of initial monotherapy efficacy.
TABLE-US-00003 TABLE 3 Patient status after treatment for 8 days
with ibudilast + bumetanide ADI baseline score Patient 1 Patient 2
Patient 3 Patient 4 ADI-r SI 20 15 11 22 ADI-r C 20 13 14 14 ADI-r
RI 7 5 6 5
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