U.S. patent application number 14/849679 was filed with the patent office on 2016-08-11 for methods of treating prader willi syndrome and conditions associated with low basal metabolic rate or hyperphagia using a katp channel opener.
The applicant listed for this patent is Sedogen LLC. Invention is credited to Sara Cotter.
Application Number | 20160228449 14/849679 |
Document ID | / |
Family ID | 52005960 |
Filed Date | 2016-08-11 |
United States Patent
Application |
20160228449 |
Kind Code |
A1 |
Cotter; Sara |
August 11, 2016 |
METHODS OF TREATING PRADER WILLI SYNDROME AND CONDITIONS ASSOCIATED
WITH LOW BASAL METABOLIC RATE OR HYPERPHAGIA USING A KATP CHANNEL
OPENER
Abstract
This invention relates to treating Prader-Willi Syndrome (PWS)
using a KATP channel opener. The channel opener may be
coadministered with other therapies used to treat PWS, such as
human growth hormone, a wakefulness promoting agent, or a
psychiatric or mood stabilizing drug, thereby allowing the baseline
dosages of these other therapies to be decreased or making these
other therapies unnecessary. The invention also relates to treating
PWS based on the PWS nutritional phase of a patient, to prevent the
patient's PWS nutritional phase from progressing or shift the
patient's PWS nutritional phase back to an earlier phase. The
invention further relates to treating PWS, and conditions
associated with low basal metabolic rate or hyperphagia, with the
KATP channel opener based on a patient's blood ketone levels.
Inventors: |
Cotter; Sara; (Wilmette,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sedogen LLC |
Glenview |
IL |
US |
|
|
Family ID: |
52005960 |
Appl. No.: |
14/849679 |
Filed: |
September 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14298480 |
Jun 6, 2014 |
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14849679 |
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61832779 |
Jun 8, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 31/522 20130101; A61K 38/27 20130101; A61K 38/095 20190101;
A61K 31/549 20130101; A61K 31/549 20130101; A61K 31/145 20130101;
A61K 31/522 20130101; A61K 31/198 20130101; A61K 38/095 20190101;
A61K 38/27 20130101; A61K 31/19 20130101; A61K 31/145 20130101;
A61K 45/06 20130101; A61K 31/19 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/549 20060101
A61K031/549; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method for treating Prader-Willi Syndrome, comprising
administering a K.sub.ATP channel opener and a second therapeutic
agent to a patient in need thereof, wherein the second therapeutic
agent is selected from the group consisting of (a) a human growth
hormone (GH), wherein the dose of human growth hormone is reduced
in comparison to a baseline or adjusted GH dose; (b) a psychiatric
or mood stabilizing drug, wherein the dose of the psychiatric or
mood stabilizing drug is reduced in comparison to a baseline
psychiatric or stabilizing drug dose; and (c) a wakefulness
promoting agent, wherein the dose of the wakefulness promoting
agent is reduced in comparison to a baseline wakefulness promoting
agent dose.
2. The method of claim 1, wherein the baseline or adjusted GH dose
is reduced by at least 10, 20, 50, 80, 90, or 100%.
3. (canceled)
4. The method of claim 1, wherein the baseline psychiatric
medication dose is reduced by at least 10, 20, 50, 80, 90, or
100%.
5. The method of claim 4, wherein the psychiatric or mood
stabilizing drug is selected from the group consisting of a
selective serotonin reuptake inhibitor (SSRI), a norepinephrine
reuptake inhibitor (NRI), a noradrenergic and specific serotonergic
antidepressant (NaSSA), a serotonin-norepinephrine reuptake
inhibitor (SNRI), a serotonin antagonist and reuptake inhibitor
(SARI), a norepinephrine-dopamine reuptake inhibitor, a selective
serotonin reuptake enhancer, a norepinephrine-dopamine
disinhibitor, a tricyclic antidepressant, a tetracyclic
antidepressant, a monoamine oxidase inhibitor (MAOI),
N-acetylcysteine, cysteamine, oxytocin, a mood stabilizer, an
anticonvulsant, a metabotropic glutamate receptor modulator, a
typical antipsychotic, and an atypical antipsychotic.
6. (canceled)
7. The method of claim 1, wherein the baseline wakefulness
promoting agent dose is reduced by at least 10, 20, 50, 80, 90, or
100%.
8. The method of claim 7, wherein the wakefulness promoting agent
is selected from the group consisting of a stimulant, an
amphetamine, a norepinephrine reuptake inhibitor (NRI), a
norepinephrine-dopamine reuptake inhibitor (NDRI), a tricyclic
antidepressant, a serotonin-norepinephrine reuptake inhibitor
(SNRI), an H3-receptor antagonist, an orexin agonist, sodium
oxybate, caffeine, and a eugeroic.
9.-13. (canceled)
14. A method for treating a disease or condition selected from the
group consisting of Prader-Willi Syndrome, a condition associated
with low basal metabolic rate, and a condition associated with
hyperphagia, comprising administering a KATP channel opener to a
patient in need thereof, wherein the patient's blood ketone level
is less than a target level selected from the group consisting of
3.0, 2.5, 2.0, 1.5, 1.0, 0.6, 0.5, 0.4, 0.3, 0.2, and 0.1
mmol/mL.
15. The method of claim 14, further comprising the step of
administering a subsequent dose of the KATP channel opener to the
patient, wherein the subsequent dose is higher than the previous
dose if the patient's blood ketone level is less than or equal to
the target level after administration of the previous dose, and
wherein the subsequent dose is equal to or less than the previous
dose if the patient's blood ketone level is greater than or equal
to the target level after administration of the previous dose.
16. A method for treating an autistic symptom or behavior or an
autism spectrum disorder (ASD) comprising administering a K.sub.ATP
channel opener to a patient with Prader-Willi Syndrome in need
thereof.
17. The method of claim 16, wherein the patient meets the criteria
for an ASD, which is indicated by an elevated score on the
Pervasive Developmental Disorder-Mental Retardation questionnaire,
or by criteria on the Autism Diagnostic Observation Schedule or the
Autism Diagnostic Interview (Revised).
18. The method of claim 16, wherein the autistic symptom or
behavior or ASD is selected from the group consisting of an
impairment in social interaction, language or communication;
restricted, repetitive, or stereotyped behavior; stereotypies; a
pronounced repetitive or compulsive behavior; skin picking; a need
to tell, ask, or say; hoarding; ordering, arranging; symmetry or
exactness; ritualized eating; rereading and rewriting; fearful of
losing things; repeated checking; touching, tapping and rubbing;
excessive washing; rectal picking; repetition of routines; and
pulling hair out.
19. The method of claim 16, wherein the K.sub.ATP channel opener is
diazoxide.
20. The method of claim 19, wherein the dose of the diazoxide is at
least 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0, or 20.0 mg per kg of the
subject's body weight.
21. The method of claim 20, wherein the diazoxide is administered
once or twice per day.
22. The method of claim 19, wherein the dose of the diazoxide is
less than 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0, or 20.0 mg per kg of
the subject's body weight.
23. The method of claim 22, wherein the diazoxide is administered
once or twice per day.
Description
FIELD OF THE INVENTION
[0001] This invention relates to treating Prader-Willi Syndrome
(PWS) and conditions affecting basal metabolic rate using a
K.sub.ATP channel opener. The K.sub.ATP channel opener may be
coadministered with other therapies used to treat PWS, such as
human growth hormone, a wakefulness promoting agent, or a
psychiatric/mood stabilizing medication, which may allow the dose
of these other therapies to be reduced relative to the dose that
would otherwise be given to a patient with PWS in the absence of
the K.sub.ATP channel opener (e.g., baseline dose). The K.sub.ATP
channel opener may also obviate the need for the use of the other
therapies used to treat PWS, such that PWS may be treated without
human growth hormone, a wakefulness promoting agent, or a
psychiatric/mood stabilizing medication. The K.sub.ATP channel
opener dosage may also be administered according to the PWS
nutritional phase of a patient. The K.sub.ATP channel opener may
also be administered to prevent the PWS patient's PWS nutritional
phase from progressing, or to shift the PWS nutritional phase back
to an earlier phase. The K.sub.ATP channel opener dosage for
treating PWS or conditions associated with low basal metabolic rate
or hyperphagia, such as obesity, may be modulated according to a
patient's blood ketone level or diet.
BACKGROUND OF THE INVENTION
[0002] Prader-Willi syndrome (PWS) is a complex neurobehavioral
disorder which is due to the absence of normally active paternally
expressed genes from the chromosome 15q11-q13 region. PWS is an
imprinted condition with 70-75% of the cases due to a de novo
deletion in the paternally inherited chromosome 15 11-q13 region,
20-30% from maternal uniparental disomy 15 (UPD), and the remaining
2-5% from either microdeletions or epimutations of the imprinting
center (i.e., imprinting defects). Clinical features of PWS include
hypotonia and poor feeding in infancy which almost always requires
some type of assisted feeding for a period of time, followed by
hyperphagia as the child ages. Obesity typically begins around 2
years of age if the diet is not restricted. Behavioral problems and
neuroendocrine abnormalities are also characteristic of PWS.
[0003] Given the complexity of PWS, its symptoms are treated with a
number of different medications, including human growth hormone
(GH), psychiatric/mood stabilizing medications, and wakefulness
promoting agents. Many of the aforementioned drugs that are
currently used to treat PWS have undesirable side effects.
Accordingly, there is a need in the art to reduce these side
effects by providing a way to reduce the dosages of the drugs used
to treat PWS, or eliminate the need to use such drugs.
SUMMARY OF THE INVENTION
[0004] Provided herein is a method for treating Prader-Willi
Syndrome, which may comprise administering a K.sub.ATP channel
opener and a human growth hormone (GH) to a patient in need
thereof. The dose of human growth hormone may be reduced in
comparison to a baseline or adjusted GH dose. The baseline or
adjusted GH dose may be reduced by at least 10, 20, 50, 80, 90, or
100%.
[0005] Further provided herein is a method for treating
Prader-Willi Syndrome, which may comprise administering a K.sub.ATP
channel opener and a psychiatric or mood stabilizing drug to a
patient in need thereof. The dose of the psychiatric or mood
stabilizing drug may be reduced in comparison to a baseline
psychiatric or stabilizing drug dose. The baseline psychiatric
medication dose may be reduced by at least 10, 20, 50, 80, 90, or
100%. The psychiatric or mood stabilizing drug may be a selective
serotonin reuptake inhibitor (SSRI), a norepinephrine reuptake
inhibitor (NRI), a noradrenergic and specific serotonergic
antidepressant (NaSSA), a serotonin-norepinephrine reuptake
inhibitor (SNRI), a serotonin antagonist and reuptake inhibitor
(SARI), a norepinephrine-dopamine reuptake inhibitor, a selective
serotonin reuptake enhancer, a norepinephrine-dopamine
disinhibitor, a tricyclic antidepressant, a tetracyclic
antidepressant, a monoamine oxidase inhibitor (MAOI),
N-acetylcysteine, cysteamine, oxytocin, a mood stabilizer, an
anticonvulsant, a metabotropic glutamate receptor modulator, a
typical antipsychotic, or an atypical antipsychotic.
[0006] Also provided herein is a method for treating Prader-Willi
Syndrome, which may comprise administering a K.sub.ATP channel
opener and a wakefulness promoting agent to a patient in need
thereof. The dose of the wakefulness promoting agent may be reduced
in comparison to a baseline wakefulness promoting agent dose. The
baseline wakefulness promoting agent dose may be reduced by at
least 10, 20, 50, 80, 90, or 100%. The wakefulness promoting agent
may be a stimulant, an amphetamine, a norepinephrine reuptake
inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor
(NDRI), a tricyclic antidepressant, a serotonin-norepinephrine
reuptake inhibitor (SNRI), an H3-receptor antagonist, an orexin
agonist, sodium oxybate, caffeine, or a eugeroic.
[0007] Further provided herein is a method for treating
Prader-Willi Syndrome which may comprise administering a K.sub.ATP
channel opener to a patient in need thereof. The patient may be in
PWS nutritional phase 0, 1a, 1b, 2a, 2b, 3, or 4. The patient's PWS
nutritional phase may be prevented from progressing to a later
phase. The patient may be in PWS nutritional phase 1a, 1b, 2a, or
2b, and the patient's PWS nutritional phase may be prevented from
progressing to phase 1b, 2a, 2b, or 3. The patient's PWS
nutritional phase may be shifted back to an earlier PWS nutritional
phase. The patient may be in PWS nutritional phase 3 or 4, and the
patient's PWS nutritional phase may be shifted back to phase 1a,
1b, 2a, or 2b.
[0008] Also provided herein is a method for treating a disease or
condition selected from Prader-Willi Syndrome, a condition
associated with low basal metabolic rate, and a condition
associated with hyperphagia. The method may comprise administering
a K.sub.ATP channel opener to a patient in need thereof, and the
patient's blood ketone level may be less than a target level
selected from 3.0, 2.5, 2.0, 1.5, 1.0, 0.6, 0.5, 0.4, 0.3, 0.2, and
0.1 mmol/mL. The method may further comprise the step of
administering a subsequent dose of the K.sub.ATP channel opener to
the patient. The subsequent dose may be higher than the previous
dose if the patient's blood ketone level is less than or equal to
the target level after administration of the previous dose, and the
subsequent dose may be equal to or less than the previous dose if
the patient's blood ketone level is greater than or equal to the
target level after administration of the previous dose.
[0009] Also provided herein is a method for treating autistic
symptoms or behaviors associated with Prader-Willi Syndrome, which
may comprise administering a K.sub.ATP channel opener to a patient
in need thereof.
DETAILED DESCRIPTION
[0010] The inventor has made the surprising discovery that
administering a K.sub.ATP channel opener (e.g., diazoxide) in
combination with other therapies used to treat Prader-Willi
Syndrome (PWS) allows the dosages of these other therapies to be
reduced relative to the dosages that would ordinarily be
administered in the absence of the K.sub.ATP channel opener, or to
be entirely eliminated from a PWS treatment regimen. For example,
various symptoms of PWS can be treated with human growth hormone,
wakefulness promoting agents (e.g., modafinil), and
psychiatric/mood stabilizing medications. The standard doses of
such therapies are associated with undesirable side effects, such
as insulin resistance in the case of growth hormone.
Coadministering a K.sub.ATP channel opener allows lower doses of
these other PWS therapies to be used, thereby resulting in fewer or
reduced side effects. The inventor has also unexpectedly found that
the efficacy of a K.sub.ATP channel opener is affected by the
nutritional phase of a patient's PWS. Therefore, the K.sub.ATP
channel opener may be administered according to the PWS nutritional
phase of the patient, and may prevent the patient's PWS nutritional
phase from progressing or shift the patient's PWS nutritional phase
back to an earlier phase. Surprisingly, the inventor has also
discovered that PWS and conditions associated with low basal
metabolic rate or hyperphagia can be treated by modulating the dose
of K.sub.ATP channel opener based on a patient's blood ketone level
and/or diet.
1. DEFINITIONS
[0011] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting. As
used in the specification and the appended claims, the singular
forms "a," "an" and "the" include plural referents unless the
context clearly dictates otherwise.
[0012] For recitation of numeric ranges herein, each intervening
number there between with the same degree of precision is
explicitly contemplated. For example, for the range of 6-9, the
numbers 7 and 8 are contemplated in addition to 6 and 9, and for
the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
[0013] "Halo" and "halogen" refer to all halogens, that is, chloro
(Cl), fluoro (F), bromo (Br), or iodo (I).
[0014] "Hydroxyl" and "hydroxy" means the group --OH.
[0015] "Substituted oxy" means the group --OR.sup.aa, where
R.sup.aa can be alkyl, substituted alkyl, acyl, substituted acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, or substituted heterocyclyl.
[0016] "Substituted thiol" means the group --SR.sup.bb, where
R.sup.bb can be alkyl, substituted alkyl, acyl, substituted acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, or substituted heterocyclyl.
[0017] "Alkyl" means an alkane-derived radical containing from 1 to
10, preferably 1 to 6, more preferably 1-4, yet more preferably
1-2, carbon atoms. Alkyl includes straight chain alkyl, branched
alkyl and cycloalkyl, such as methyl, ethyl, propyl, isopropyl,
butyl, t-butyl, and the like. The alkyl group can be attached at
any available point to produce a stable compound. An "alkylene" is
a divalent alkyl.
[0018] A "substituted alkyl" means an alkyl group independently
substituted with 1 or more, e.g., 1, 2, or 3, groups or
substituents such as halo, hydroxy, optionally substituted alkoxy,
optionally substituted alkylthio, alkylsulfinyl, alkylsulfonyl,
optionally substituted amino, optionally substituted amido,
amidino, urea optionally substituted with alkyl, amino sulfonyl
optionally N-mono- or N,N-di-substituted with alkyl,
alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,
nitro, cyano, thiol, sulfonylamino or the like attached at any
available point to produce a stable compound. In particular,
"fluoro substituted" refers to substitution by 1 or more, e.g., 1,
2, or 3 fluorine atoms. "Optionally fluoro substituted" means that
substitution, if present, is fluoro. The term "optionally
substituted" as used herein means that substitution may, but need
not, be present.
[0019] "Lower alkyl" means an alkyl group having 1-6 carbon
atoms.
[0020] A "substituted lower alkyl" means a lower alkyl which is
substituted with 1 or more, e.g., 1, 2, or 3, groups or
substituents, as defined above, attached at any available point to
produce a stable compound.
[0021] "Cycloalkyl" means saturated or unsaturated, non-aromatic
monocyclic, bicyclic or tricyclic carbon ring systems of 3-8, more
preferably 3-6, ring members per ring, such as cyclopropyl,
cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene"
is a divalent cyclo alkyl.
[0022] "Substituted cycloalkyl" means saturated or unsaturated,
non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems
of 3-8, more preferably 3-6, ring members per ring, such as
cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like
independently substituted with 1 or more, e.g., 1, 2, or 3, groups
or substituents such as halo, hydroxy, optionally substituted
alkoxy, optionally substituted alkylthio, alkylsulfinyl,
alkylsulfonyl, optionally substituted amino, optionally substituted
amido, amidino, urea optionally substituted with alkyl,
aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl,
alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,
nitro, cyano, thiol, sulfonylamino or the like attached at any
available point to produce a stable compound.
[0023] "Aryl" alone or in combination means phenyl or naphthyl
optionally carbocyclic fused with a cycloalkyl of preferably 5-7,
more preferably 5-6, ring members.
[0024] "Substituted aryl" means an aryl group as defined above
independently substituted with 1 or more, e.g., 1, 2, or 3, groups
or substituents such as halo, hydroxy, optionally substituted
alkoxy, optionally substituted alkylthio, alkylsulfinyl,
alkylsulfonyl, optionally substituted amino, optionally substituted
amido, amidino, urea optionally substituted with alkyl,
aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl,
alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,
nitro, cyano, thiol, sulfonylamino or the like attached at any
available point to produce a stable compound.
[0025] "Alkoxy" means the group --OR.sup.cc, where R.sup.cc is
alkyl. "Lower alkoxy" denotes the group --OR.sup.ccc, where
R.sup.ccc is lower alkyl
[0026] "Substituted alkoxy" means the group --OR.sup.dd, where
R.sup.dd is substituted alkyl. "Substituted lower alkoxy" means the
group --OR.sup.ddd, where R.sup.ddd is substituted lower alkyl.
[0027] "Alkylthio" or "thioalkoxy" means the group --S--R.sup.ee,
where R.sup.ee is alkyl.
[0028] "Substituted alkylthio" or "substituted thioalkoxy" means
the group --S--R, where R is substituted alkyl.
[0029] "Sulfinyl" means the group --S(O)--.
[0030] "Sulfonyl" means the group --S(O).sub.2--.
[0031] "Substituted sulfinyl" means the group --S(O)--R.sup.ff,
where R.sup.ff is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,
aralkyl or substituted aralkyl.
[0032] "Substituted sulfonyl" means the group --S(O).sub.2R.sup.gg,
where R.sup.gg is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,
aralkyl or substituted aralkyl.
[0033] "Sulfonylamino" means the group --S(O).sub.2NR.sup.hh--
where R.sup.hh is hydrogen or alkyl.
[0034] "Substituted sulfonylamino" means the group
--S(O).sub.2NR.sup.ii--R.sup.jj, where R.sup.ii is hydrogen or
optionally substituted alkyl, and R.sup.jj is alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,
aralkyl or substituted aralkyl.
[0035] "Amino" or "amine" means the group --NH.sub.2. A "divalent
amine" denotes the group --NH--. A "substituted divalent amine"
denotes the group --NR.sup.kk-- wherein R.sup.kk is alkyl,
substituted alkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, acyl, substituted acyl, sulfonyl or substituted
sulfonyl.
[0036] "Substituted amino" or "substituted amine" means the group
--NR.sup.mmR.sup.nn, wherein R.sup.mm and R.sup.nn are
independently hydrogen, alkyl, substituted alkyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl,
sulfonyl, substituted sulfonyl, or cycloalkyl provided, however,
that at least one of R.sup.mm and R.sup.nn is not hydrogen.
R.sup.mmR.sup.nn in combination with the nitrogen may form an
optionally substituted heterocyclic or heteroaryl ring.
[0037] "Alkylsulfinyl" means the group --S(O)R.sup.oo, wherein
R.sup.oo is optionally substituted alkyl.
[0038] "Alkylsulfonyl" means the group --S(O).sub.2R.sup.pp,
wherein R.sup.pp is optionally substituted alkyl.
[0039] "Alkylsulfonylamino" means the group
--NR.sup.qqS(O).sub.2R.sup.rr, wherein R.sup.rr is optionally
substituted alkyl, and R.sup.qq is hydrogen or alkyl.
[0040] A "primary amino substituent" means the group
--NH.sub.2.
[0041] A "secondary amino substituent" means the group
--NHR.sup.ss, wherein R.sup.ss is alkyl, substituted alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, acyl,
substituted acyl, sulfonyl, substituted sulfonyl, or
cycloalkyl.
[0042] A "tertiary amino substituent" means the group
--NR.sup.ssR.sup.tt, wherein R.sup.ss and R.sup.tt are
independently alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, acyl, substituted acyl,
sulfonyl, substituted sulfonyl, or cycloalkyl.
[0043] "Quaternary ammonium substituent" means the group
--N.sup.+R.sup.ssR.sup.ttR.sup.uu, wherein R.sup.ss, R.sup.tt and
R.sup.uu are independently alkyl, substituted alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, acyl,
substituted acyl, sulfonyl, substituted sulfonyl, or
cycloalkyl.
[0044] "Heteroaryl" means a monocyclic aromatic ring structure
containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8
to 10 atoms, containing one or more, preferably 1-4, more
preferably 1-3, even more preferably 1-2, heteroatoms independently
selected from the group consisting of O, S, and N. Heteroaryl is
also intended to include oxidized S or N, such as sulfinyl,
sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or
nitrogen atom is the point of attachment of the heteroaryl ring
structure such that a stable aromatic ring is retained. Examples of
heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl,
quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl,
indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl,
thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl,
imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, and the like.
"Heteroarylene" means a divalent heteroaryl.
[0045] "Heterocycle" or "heterocyclyl" means a saturated or
unsaturated, non-aromatic carbocyclic group having a single ring or
multiple condensed rings, e.g. a cycloalkyl group having from 5 to
10 atoms in which from 1 to 3 carbon atoms in a ring are replaced
by heteroatoms, such as O, S, N, and are optionally fused with
benzo or heteroaryl of 5-6 ring members and/or are optionally
substituted. Heterocyclyl is intended to include oxidized S or N,
such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
Examples of heterocycle or heterocyclyl groups are morpholino,
tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl,
piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like.
[0046] "Heterocyclylalkyl" means the group --R-Het where Het is a
heterocycle group and R is an alkylene group.
[0047] A "substituted heteroaryl," "substituted heterocyclyl," or
"substituted heterocyclylalkyl" means a heteroaryl, heterocyclyl,
or heterocyclylalkyl, respectively, independently substituted with
1 or more, e.g., 1, 2, or 3, groups or substituents such as
halogen, hydroxy, optionally substituted alkoxy, optionally
substituted alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heteroaryloxy, optionally substituted amino,
optionally substituted amido, amidino, urea optionally substituted
with alkyl, aryl, heteroaryl or heterocyclyl groups, amino sulfonyl
optionally N-mono- or N,N-di-substituted with alkyl, aryl or hetero
aryl groups, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, carboxyl, heterocycle, substituted
heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano,
thiol, sulfonylamino, optionally substituted alkyl, optionally
substituted alkenyl, or optionally substituted alkynyl, attached at
any available point to produce a stable compound.
[0048] "Amido" means the group --C(O)NH.sub.2. "Substituted amido"
means the group --C(O)NR.sup.kR.sup.l, wherein R.sup.k and R.sup.l
are independently hydrogen, lower alkyl, substituted lower alkyl,
aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
provided, however, that at least one of R.sup.k and R.sup.l is not
hydrogen. R.sup.kR.sup.l in combination with the nitrogen may form
an optionally substituted heterocyclic or heteroaryl ring.
[0049] "Amidino" means the group --C(.dbd.NR.sup.m)NR.sup.nR.sup.o,
wherein R.sup.m, R.sup.n, and R.sup.o are independently hydrogen or
optionally substituted lower alkyl.
[0050] "Acyloxy" means the group --OC(O)R.sup.h, where R.sup.h is
hydrogen, alkyl, substituted alkyl, cyclo alkyl, substituted
cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl and the
like.
[0051] "Aryloxy" means the group --OAr, where Ar is an aryl, or
substituted aryl, group. "Heteroaryloxy" means groups --OHet,
wherein Het is an optionally substituted heteroaryl group.
[0052] "Arylsulfonylamino" means the group
--NR.sup.qS(O).sub.2R.sup.s, wherein R.sup.s is optionally
substituted aryl, and R.sup.q is hydrogen or lower alkyl.
"Heteroarylsulfonylamino" means the group
--NR.sup.qS(O).sub.2R.sup.t, wherein R.sup.t is optionally
substituted heteroaryl, and R.sup.q is hydrogen or lower alkyl.
[0053] "Alkylcarbonylamino" means the group --NR.sup.qC(O)R.sup.p,
wherein R.sup.p is optionally substituted alkyl, and R.sup.q is
hydrogen or lower alkyl.
[0054] "Arylcarbonylamino" means the group --NR.sup.qC(O)R.sup.s,
wherein R.sup.s is optionally substituted aryl, and R.sup.q is
hydrogen or lower alkyl.
[0055] "Heteroarylcarbonylamino" means the group
--NR.sup.qC(O)R.sup.t, wherein R.sup.t is optionally substituted
aryl, and R.sup.q is hydrogen or lower alkyl.
[0056] "Treatment" or "treating," when referring to protection of
an animal from a disease, means preventing, suppressing,
repressing, or completely eliminating the disease. Preventing the
disease involves administering a composition of the present
invention to an animal prior to onset of the disease. Suppressing
the disease involves administering a composition of the present
invention to an animal after induction of the disease but before
its clinical appearance. Repressing the disease involves
administering a composition of the present invention to an animal
after clinical appearance of the disease.
2. METHOD OF TREATING PRADER-WILLI SYNDROME WITH A K.sub.ATP
CHANNEL OPENER
[0057] Provided herein are methods of treating PWS by administering
a K.sub.ATP channel opener to a patient. The K.sub.ATP channel
opener may be used to treat obesity, prediabetes, diabetes,
hypertension, depression, elevated cholesterol, other obesity
associated co-morbidities, ischemic and reperfusion injury,
epilepsy, cognitive impairment, schizophrenia, mania, other
psychotic diseases, and the like. The K.sub.ATP channel opener may
(a) inhibit fasting insulin secretion, (b) inhibit stimulated
insulin secretion, (c) elevate energy expenditure, (d) elevate beta
oxidation of fat, or (e) inhibit hyperphagia.
[0058] a. Combined Treatment with Reduced Dosage of Growth
Hormone
[0059] The K.sub.ATP channel opener may be coadministered with a
human growth hormone (GH) to treat PWS. The combination therapy may
be used to improve body composition abnormalities and improve
linear growth of an infant or child with PWS, or to improve body
composition abnormalities in an adult with PWS. The combination
therapy may also be used to improve lean body mass, decrease body
fat, modulate bone mineral density, or normalize adult height. The
therapy may also be used to improve cognition, tone, endurance,
stamina, strength, agility, or motor development, or to positively
affect nitrogen balance or increase energy expenditure.
[0060] The GH dose may be 0.18-0.3 mg/kg/week, and may be
administered as a daily subcutaneous injection. The baseline GH
dose may also be at least 0.01, 0.05, 0.1, 0.15, 0.2, 0.3, 0.4,
0.5, 1.0, 1.5, or 2.0 mg/kg/week. The baseline GH dose may also be
less than 0.01, 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, or
2.0 mg/kg/week. The GH dose may be adjusted based on the weight of
the patient. The dose may also be adjusted based on the patient's
lean mass or on insulin growth factor (IGF-1) levels, such that the
IGF-1 levels do not exceed 3 standard deviations above the upper
limit of normal. The upper limit of normal for IGF-1 levels may be
25-1000 ng/mL, and may be in a range as described in Table 1.
TABLE-US-00001 TABLE 1 IGF-1 Reference Levels Age Male (ng/mL)
Female (ng/mL) Adult 19-30 y 126-382 138-410 31-40 y 106-255
126-291 41-50 y 86-220 88-249 51-60 y 87-225 92-190 61-70 y 75-228
87-178 71-80 y 31-187 25-171 81-88 y 68-157 31-162 Children 1-7 d
.ltoreq.31 .ltoreq.31 8-14 d .ltoreq.43 .ltoreq.43 15 d-1 y 25-265
25-265 1-2 y 45-222 99-254 3-4 y 36-202 36-202 5-6 y 32-259 57-260
7-8 y 65-278 97-352 9-10 y 52-330 49-461 11-12 y 80-723 101-580
13-14 y 142-855 199-658 15-16 y 176-845 236-808 17-18 y 152-668
165-526
[0061] When administered together with the K.sub.ATP channel
opener, the dose of GH may be reduced as compared to the baseline
dose of GH. The reduction may be by at least 10, 20, 50, 80, or 90%
of the baseline or adjusted GH dose. The GH dosage may also be
reduced by decreasing the frequency of GH administration, such that
GH is administered 6, 5, 4, 3, 2, or 1 time(s) per week. The
reduction in GH dose may decrease the side effects or risks of GH,
such as the induction of insulin resistance or diabetes mellitus,
acromegaly, scoliosis, intracranial hypertension, neoplasm or
death. PWS may also be treated by administering the KATP channel
opener in the absence of GH.
[0062] The KATP channel opener may also be used to treat an adult
patient with PWS. The adult may be greater than or equal to 18
years of age. The K.sub.ATP channel opener may normalize IGF-1
levels in the adult. Accordingly the adult may be treated with the
K.sub.ATP channel opener without having to use GH, or by using a
lower dose of GH than the baseline dose.
[0063] (1) Treatment Based on IGF-1 Levels
[0064] IGF-1 levels may be indicative of the levels of GH.
Administering the KATP channel opener may allow a lower dose of GH
to be administered in combination with the KATP channel opener.
This may be due to an increase IGF-1 levels mediated by the channel
opener in patients with PWS. Accordingly, the dosage of the KATP
channel opener may be based on IGF-1 levels, such that the IGF-1
levels do not exceed 3 standard deviations above the upper limit of
normal. The upper limit of normal for IGF-1 levels may be 25-1000
ng/mL, and may be in a range as described in Table 1.
[0065] b. Combined Treatment with Reduced Dosage of Psychiatric or
Mood Stabilizing Drugs
[0066] The K.sub.ATP channel opener may be coadministered with a
psychiatric or mood stabilizing drug, such as a psychotropic
medication, to treat PWS by treating a PWS behavioral symptom. The
PWS behavioral symptom may be obsessions, compulsions, addiction,
autism or autistic tendencies, anxiety, depression, mood swings,
skin picking or psychotic behavior. The psychotropic medication may
be a selective serotonin reuptake inhibitor (SSRI), norepinephrine
reuptake inhibitor (NRI), noradrenergic and specific serotonergic
antidepressant (NaSSA), serotonin-norepinephrine reuptake inhibitor
(SNRI), serotonin antagonist and reuptake inhibitor (SARI),
norepinephrine-dopamine reuptake inhibitor, selective serotonin
reuptake enhancer, norepinephrine-dopamine disinhibitor, tricyclic
antidepressant, tetracyclic antidepressant, monoamine oxidase
inhibitor (MAOI), N-acetylcysteine, cysteamine, oxytocin, mood
stabilizer, anticonvulsant, metabotropic glutamate receptor
modulator, typical antipsychotic, or atypical antipsychotic. The
SSRI may be citalopram, dapoxetine, escitalopram, fluoxetine,
fluvoxamine, paroxetine, or sertraline. The NRI may be atomoxetine,
bupropion, reboxetine, edivoxetine, tapentadol or viloxazine. The
NaSSA may be mianserin or mirtazapine. The SNRI may be
desvenlafaxine, duloxetine, milnacipran, or venlafaxine. The SARI
may be etoperidone, nefazodone, or trazdone. The
norepinephrine-dopamine reuptake inhibitor may be bupropion. The
selective serotonin reuptake enhancer may be tianeptine or
amineptine. The norepinephrine-dopamine disinhibitor may be
agomelatine. The tricyclic antidepressant may be amitriptyline,
amitriptylinoxide, clomipramine, butriptyline, clomipramine,
demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin,
doxepin, imipramine, imipraminoxide, lofepramine, imipraminozide,
lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline,
noxiptiline, pipofezine, propizepine, protriptyline, quinupramine,
amineptine, iprindole, opipramol, tianeptine, or trimipramine. The
tetracyclic antidepressant may be amoxapine, maprotiline, mazindol,
mianserin, mirtazapine, or setiptiline. The MAOI may be
isocarboxazid, phenelzine, selgiline, tranylcypromine, moclobemide,
or pirlindole. The mood stabilizer may be lithium or an
anticonvulsant such as valproic acid, divalproex sodium, sodium
valproate, lamotrigine, oxcarbazepine, topiramate, riluzole,
gabapentin, pregabalin, carbamazepine, vigabatrin, progabide,
tiagabine, zonisamide, or phenytoin. The metabotropic glutamate
receptor modulator may be fenobam, mavoglurant, GRN-529, STX107,
STX110, RO4917523, dipraglurant, ADX-71149/JNJ-40411813, RO4491533,
or RO4995819. The typical antipsychotic may be haloperidol,
droperidol, chlorpromazine, fluphenazine, perphenazine,
prochlorperazine, thioridazine, trifluorperazine, mesoridazine,
periciazine, promazine, triflupromazine, levomepromazine,
promethazine, pimozide, cyamemazine, chlorprothixene, clopenthixol,
flupenthixol, thiothixene, or zuclopenthixol. The atypical
antipsychotic may be amisulpride, aripiprazole, asenapine,
blonanserin, carpipramine, clocapramine, clotiapine, clozapine,
iloperidone, lurasidone, mosapramine, olanzapine, paliperidone,
perospirone, quetiapine, remoxipride, risperidone, sertindole,
sulpiride, ziprasidone, zotepine, bitopertin (RG1678), cariprazine
(RGH-188), LY2140023, pimavanserin (ACP-103), vabicaserin
(SCA-136), or zicronapine (Lu 31-130). The baseline psychiatric
drug dose may be at least 1, 5, 10, 15, 20, 30, 40, 50, 100, 200,
300, 400, 500, 1000, or 2000 mg. The dose may also be less than 1,
5, 10, 15, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000
mg. The psychiatric drug may be administered once, twice, three
times, four times, five times, seven times, eight times, nine
times, ten times, eleven times, or twelve times daily. The
psychiatric drug may also be administered once every 1, 2, 3, 4, or
5 weeks.
[0067] When administered together with the KATP channel opener, the
dose of the psychiatric medication may be by at least 10, 20, 50,
80, or 90% of the baseline psychiatric medication dose. The
frequency of administering the psychiatric medication dosage may
also be decreased if the psychiatric medication is coadministered
with the KATP channel opener. The decrease may be by once, twice,
three times, four times, five times, seven times, eight times, nine
times, ten times, eleven times, or twelve times daily; or once
twice, three times, four times, or five times per month. PWS may
also be treated by administering the K.sub.ATP channel opener in
the absence of the psychiatric medication.
[0068] c. Combined Treatment with Reduced Dosage of Wakefulness
Promoting Agents
[0069] The K.sub.ATP channel opener may be coadministered with a
wakefulness promoting agent to treat PWS. The PWS symptom being
treated may be excessive daytime sleepiness, sleep apnea,
narcolepsy (with or without cataplexy), cataplexy, hypnagogic
hallucinations, hypnopompic hallucinations, or sleep paralysis. The
wakefulness promoting agent may be a stimulant such as an
amphetamine, a norepinephrine reuptake inhibitor (NRI),
norepinephrine-dopamine reuptake inhibitor (NDRI), a tricyclic
antidepressant, a serotonin-norepinephrine reuptake inhibitor
(SNRI), an H3-receptor antagonist, an orexin agonist, sodium
oxybate, caffeine, or a eugeroic (e.g., modanafil, adrafinil,
armodafinil). The amphetamine may be dextroamphetamine,
methamphetamine, mixed amphetamine salts (ADDERALL.RTM.), or
lisdexamfetamine. The NRI may be atomoxetine, bupropion,
reboxetine, edivoxetine, tapentadol or viloxazine. The NDRI may be
dexmethylphenidate, fencamine, fencamfamine, or methylphenidate.
The tricyclic antidepressant may be amitriptyline,
amitriptylinoxide, clomipramine, butriptyline, clomipramine,
demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin,
doxepin, imipramine, imipraminoxide, lofepramine, imipraminozide,
lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline,
noxiptiline, pipofezine, propizepine, protriptyline, quinupramine,
amineptine, iprindole, opipramol, tianeptine, or trimipramine. The
SNRI may be desvenlafaxine, duloxetine, milnacipran, or
venlafaxine. The baseline wakefulness promoting agent dose may be
at least 1, 5, 10, 15, 20, 30, 40, 50, 100, 200, 300, 400, 500,
1000, or 2000 mg. The dose may also be less than 1, 5, 10, 15, 20,
30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000 mg. The
wakefulness promoting agent may be administered once, twice, three
times, four times, five times, seven times, eight times, nine
times, ten times, eleven times, or twelve times daily. The
wakefulness promoting agent may also be administered once every 1,
2, 3, 4, or 5 weeks.
[0070] When administered together with the KATP channel opener, the
dose of the wakefulness promoting agent may be reduced as compared
to the baseline dose of the wakefulness promoting agent. The
reduction may be by at least 10, 20, 50, 80, or 90% of the
wakefulness promoting agent dose. The frequency of administering
the wakefulness promoting agent dosage may also be decreased if the
wakefulness promoting agent is coadministered with the K.sub.ATP
channel opener. The decrease may be by once, twice, three times,
four times, five times, seven times, eight times, nine times, ten
times, eleven times, or twelve times daily; or once twice, three
times, four times, or five times per month. PWS may also be treated
by administering the K.sub.ATP channel opener in the absence of the
wakefulness promoting agent.
[0071] d. Treatment Based on Nutritional Phase
[0072] The K.sub.ATP channel opener may be administered based on
the PWS nutritional phase of the patient. The nutritional phase may
be as described in Table 2.
TABLE-US-00002 TABLE 2 PWS Nutritional Phase Phase Clinical
Characteristics Phase 0: Decreased fetal movements Full-term birth
weight and BMI are about 15-20% less than the and lower birth
weight siblings Typically normal gestational age 85% have decreased
fetal movements Phase 1a: Hypotonia with difficulty Weak,
uncoordinated suck. Usually cannot breastfeed feeding (0-9 months)
Needs assistance with feeding either through feeding tubes
(nasal/oral gastric tube or gastrostomy tube) or orally with
special, widened nipples. Many would die without assisted feeding
Oral feeds are very slow Severely decreased appetite. Shows little
or no evidence of being hungry Does not cry for food or get excited
at feeding time If feeding just occurred when baby "acted hungry"
then would have severe "failure-to-thrive" Weak cry Phase 1b: No
difficulty feeding and No longer needs assisted feeding growing
appropriately on growth curve Growing steadily along growth curve
with normal feeding (9-25 months) Normal appetite Phase 2a: Weight
increasing without Infant starts crossing growth curve centile
lines an increase in appetite or excessive No increase in appetite
calories (2.1-4.5 years) Appetite appropriate for age Will become
obese if given the recommended daily allowance (RDA) for calories
or if eating a "typical" toddler diet of 70% carbohydrates
Typically needs to be restricted to 60-80% of RDA to prevent
obesity Phase 2b: Weight increasing with an Increased interest in
food. Frequently asking "food related" increase in appetite (4.5-8
years) questions Preoccupied with food. Very concerned about the
next meal/snack (e.g., "Did you remember to pack my lunch?")
Increased appetite Will eat more food than a typical child if
allowed Will eat food within their line of sight if unattended Will
become obese if allowed to eat what they want Can be fairly easily
redirected about food Can feel full Will stop eating voluntarily
Phase 3: Hyperphagic, rarely feels full Constantly thinking about
food (8 years to adulthood) While eating one meal they are already
thinking about the next meal Will awaken from sleep early thinking
about food Will continue eating if portion size is not limited
Rarely (truly) feels full Will steal food or money to pay for food
Can eat food from garbage and other unsavory/inedible sources
(e.g., dog food, frozen food, crayons, etc.) Typically are not
truthful about what they have eaten (i.e. amount and types of food)
Will gain considerable amount of weight over a short period of time
if not supervised (e.g., some individuals are known to have gained
up to 20 pounds in one weekend) Food typically needs to be locked
up. Frequently the child will ask the parent to lock the food if
the parent has forgotten Will break into neighbors' houses for food
Temper tantrums and "meltdowns" frequently related to food Needs to
be placed on a diet that is approximately 50-70% of the RDA to
maintain a healthy weight Phase 4: Appetite is no longer Appetite
may still be increased or may be normal or less than normal
insatiable (adulthood) Previously in phase 3, but now a noticeable
improvement in their appetite control Can feel full Appetite can
fluctuate in this phase, but the key component is noticeable
improvement in control of appetite compared to when they were
younger Not as preoccupied with food Absence of major temper
tantrums and "meltdowns" related to food Onset in adulthood. Could
be as early as 20s or as late as 40-50s
[0073] The dose of the K.sub.ATP channel opener may also be
adjusted according to the PWS nutritional phase of the patient.
[0074] The K.sub.ATP channel opener may also be administered to
prevent the progression of a patient's PWS nutritional phase to a
later phase. The K.sub.ATP channel opener may be administered to a
PWS patient in PWS nutritional phase 1a or 1b, and may prevent the
patient's PWS nutritional phase from progressing to phase 2a or 2b.
In addition, the K.sub.ATP channel opener may be administered to a
PWS patient in PWS nutritional phase 2a or 2b, and may prevent the
PWS patient's nutritional phase from progressing to phase 3 or
4.
[0075] The K.sub.ATP channel opener may also be administered to
shift a PWS patient's PWS nutritional phase back to an earlier
phase. The K.sub.ATP channel opener may be administered to a PWS
patient in PWS nutritional phase 3 or 4, and may shift the
patient's PWS nutritional phase back to phase 1a, 1b, 2a, or 2b.
The K.sub.ATP channel opener may also be administered to a PWS
patient in PWS nutritional phase 2a or 2b, and may shift the
patient's PWS nutritional phase back to phase 1a or 1b.
[0076] The K.sub.ATP channel opener dose administered to shift a
patient's PWS nutritional phase or prevent a patient's PWS
nutritional phase from advancing may be higher for a later PWS
nutritional phase than the dose administered for an earlier PWS
nutritional phase. The dose for the later PWS nutritional phase may
be 10, 20, 40, 50, 60 or 80% higher, or may be 2, 3, 4, 5, 6, 7, 8,
9, or 10 times higher.
[0077] e. Treating Autism Symptoms Associated with PWS
[0078] The KATP channel opener may be used to treat an
autism-related symptom or an autism spectrum disorder (ASD)
associated with PWS. The patient may have an elevated score on the
Pervasive Developmental Disorder-Mental Retardation questionnaire
that is indicative of an ASD. The patient may meet the criteria for
an ASD on the Autism Diagnostic Observation Schedule or the Autism
Diagnostic Interview, Revised. The patient may have a symptom such
as an impairment in social interaction, language or communication;
restricted, repetitive, or stereotyped behavior; stereotypies; a
pronounced repetitive or compulsive behavior; skin picking; a need
to tell, ask, or say; hoarding; ordering, arranging; symmetry or
exactness; ritualized eating; rereading and rewriting; fearful of
losing things; repeated checking; touching, tapping and rubbing;
excessive washing; rectal picking; repetition of routines; or
pulling hair out.
3. METHOD OF TREATING PRADER-WILLI SYNDROME AND CONDITIONS
ASSOCIATED WITH LOW BASAL METABOLIC RATE OR HYPERPHAGIA BASED ON
BLOOD KETONE LEVELS
[0079] Provided herein is a method of treating PWS or conditions
associated with low basal metabolic rate or hyperphagia by
administering the K.sub.ATP channel to a patient. The condition may
be obesity. The K.sub.ATP channel opener may be administered
according to a PWS patient's blood ketone level. The patient's
blood ketone level may be less than or equal to a target level of
3.0, 2.5, 2.0, 1.5, 1.0, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mmol/L.
The patient's target level may also be 0.6-1.5 mmol/L, 1.6-3.0
mmol/L, less than or equal to 1.4, 1.5 or 1.6 mmol/L, or greater
than or equal to 1.5 mmol/L or 3.0 mmol/L. The dose of the
K.sub.ATP channel opener may be increased for the patient in
comparison to the patient's previous dose until the patient's blood
ketone level is at least at the target level. The dose of the
K.sub.ATP channel opener being administered to the patient may be
maintained if the patient's blood ketone level is at the target
level. The dose of the K.sub.ATP administered to the patient may be
decreased in comparison to the patient's previous dose until the
patient's blood ketone level is less than or equal to the target
level. The dose of the K.sub.ATP channel opener may also be
decreased in the event that the patient experiences an undesirable
side effect, such as hyperglycemia.
4. K.sub.ATP CHANNEL OPENER
[0080] The K.sub.ATP channel opener may have the structure of one
of Formula I-VIII.
##STR00001##
[0081] In Formula I,
[0082] R1 may be hydrogen, lower alkyl, substituted lower alkyl,
cycloalkyl, or substituted cycloalkyl, provided however that when
R1 is a substituted lower alkyl or a substituted cycloalkyl, then
the substituent may not include an amino group;
[0083] R2a may be hydrogen;
[0084] X may be a 1, 2 or 3 atom chain, in which each atom is
independently halogen, hydroxyl, lower alkyl, substituted lower
alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, or
substituted lower alkoxy, provided however that when an atom of the
chain is substituted with substituted lower alkyl, substituted
lower alkoxy or substituted cycloalkyl, then the substituent may
not include an amino group; and
[0085] ring B may be saturated, monounsaturated, polyunsaturated or
aromatic.
[0086] In Formula I, X may also be C(Ra)C(Rb), and Ra and Rb may be
independently hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy,
substituted lower alkoxy, sulfonyl, or the like. Ra and Rb may also
be independently selected from hydroxyl, substituted oxy,
substituted thiol, alkylthio, substituted alkylthio, sulfinyl,
sulfonyl, substituted sulfinyl, substituted sulfonylalkylsulfinyl,
alkylsulfonyl, and the like. Ring B may not include any
heteroatoms.
[0087] Salts of the channel openers defined by Formula I may be
prepared from the following: (a) metal hydroxides, preferably
alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic
hydroxides, preferably organic compounds which include at least one
tertiary amine or at least one quaternary ammonium ion (e.g.,
diethylamine ethanol, triethylamine, hydroxyethylpyrrolidine,
choline and hexamethylhexamethylenediammonium, and the like).
##STR00002##
[0088] In Formula II,
[0089] R1 may be hydrogen, lower alkyl, substituted lower alkyl,
cycloalkyl, or substituted cycloalkyl, provided however that when
R1 is a substituted lower alkyl or a substituted cycloalkyl, then
the substituent may not include an amino group;
[0090] R2b may be hydrogen;
[0091] X may be a 1, 2 or 3 atom chain, in which each atom is
independently carbon, sulfur or nitrogen, and each atom may be
optionally substituted with halogen, hydroxyl, lower alkyl,
substituted lower alkyl, lower alkoxy, cycloalkyl, substituted
cycloalkyl, or substituted lower alkoxy, provided however that when
an atom of the chain is substituted with substituted lower alkyl,
substituted cycloalkyl or substituted lower alkoxy, then the
substituent may not include an amino group; and
[0092] ring B may be saturated, monounsaturated, polyunsaturated or
aromatic.
[0093] In Formula II, X may also be C(Ra)C(Rb), in which Ra and Rb
are independently hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy,
substituted lower alkoxy, sulfonyl, or the like. Ra and Rb may also
be independently hydroxyl, substituted oxy, substituted thiol,
alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted
sulfinyl, substituted sulfonyl, alkylsulfinyl, alkylsulfonyl, nitro
or the like. Ring B may not include any heteroatoms.
[0094] Salts of the channel openers defined by Formula II may be
prepared from the following: (a) metal hydroxides, preferably
alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic
hydroxides, preferably organic compounds which include at least one
tertiary amine or at least one quaternary ammonium ion (e.g.,
diethylamine ethanol, triethylamine, hydroxyethylpyrrolidine,
choline and hexamethylhexamethylenediammonium, and the like).
##STR00003##
[0095] In Formula III,
[0096] R1 may be hydrogen, lower alkyl, substituted lower alkyl, or
cycloalkyl, provided however that when R1 is a substituted lower
alkyl, then the substituent may not include an amino group;
[0097] R2a may be hydrogen;
[0098] R3 may be hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl or substituted cycloalkyl, provided however that
when R3 is a substituted lower alkyl, then the substituent may not
include an amino group; and
[0099] R4 may be hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl or substituted cycloalkyl, provided however that
when R4 is a substituted lower alkyl, then the substituent may not
include an amino group
[0100] In Formula III, R1 may also be a lower alkyl, (ethyl or
methyl); R2a may be hydrogen; and R3 and R4 may each independently
be halogen.
[0101] In Formula III, R1 may also be methyl; R2a may be hydrogen;
R3 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,
cycloalkyl, or substituted cycloalkyl; and R4 may be chlorine.
[0102] Salts of the channel openers defined by Formula III may be
prepared from the following: (a) metal hydroxides, preferably
alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic
hydroxides, preferably organic compounds which include at least one
tertiary amine or at least one quaternary ammonium ion (e.g.,
diethylamine ethanol, triethylamine, hydroxyethylpyrrolidine,
choline and hexamethylhexamethylenediammonium, and the like).
##STR00004##
[0103] In Formula IV,
[0104] R1 may be hydrogen, lower alkyl, substituted lower alkyl, or
cycloalkyl, provided however that when R1 is a substituted lower
alkyl, then the substituent may not include an amino group;
[0105] R2b may be hydrogen;
[0106] R3 may be hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl or substituted cycloalkyl, provided however that
when R3 is a substituted lower alkyl, then the substituent may not
include an amino group; and
[0107] R4 may be hydrogen, halogen, lower alkyl, substituted lower
alkyl, cycloalkyl or substituted cycloalkyl, provided however that
when R4 is a substituted lower alkyl, then the substituent may not
include an amino group.
[0108] In Formula IV, R1 may also be a lower alkyl, (ethyl or
methyl); R2b may be hydrogen; and R3 and R4 may each independently
be halogen.
[0109] In Formula IV, R1 may also be methyl; R2b may be hydrogen;
R3 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,
cycloalkyl, or substituted cycloalkyl; and R4 may be chlorine.
[0110] Salts of the channel openers defined by Formula IV may be
prepared from the following: (a) metal hydroxides, preferably
alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic
hydroxides, preferably organic compounds which include at least one
tertiary amine or at least one quaternary ammonium ion (e.g.,
diethylamine ethanol, triethylamine, hydroxyethylpyrrolidine,
choline and hexamethylhexamethylenediammonium, and the like).
##STR00005##
[0111] In Formula V,
[0112] R1 may be optionally substituted amino, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heteroarylalkyl;
[0113] R2a may be hydrogen, and lower alkyl;
[0114] X may be a 1, 2 or 3 atom chain, in which each atom is
independently carbon, sulfur or nitrogen, and each atom may be
optionally substituted with halogen, hydroxyl, optionally
substituted lower alkyl, optionally substituted lower alkoxy,
optionally substituted cycloalkyl, or optionally substituted
amino;
[0115] ring B may be saturated, monounsaturated, polyunsaturated or
aromatic; and
[0116] at least one of R1 or a substituent of X may include an
amino group.
[0117] In Formula V, X may be C(Ra)C(Rb), in which Ra and Rb may be
independently hydrogen, halogen, optionally substituted lower
alkyl, optionally substituted cycloalkyl, optionally substituted
lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, or the
like. R1 may also include at least one substituent containing an
amino group. Ra and Rb may be independently hydroxyl, substituted
oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl,
sulfonyl, substituted sulfinyl, substituted sulfonyl, substituted
sulfonylamino, substituted amino, substituted amine, alkylsulfinyl,
alkylsulfonyl, alkylsulfonylamino, or the like. Ring B may not
include any heteroatoms.
##STR00006##
[0118] In Formula VI,
[0119] R1 may be optionally substituted amino, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heteroarylalkyl;
[0120] R2b may be hydrogen or lower alkyl;
[0121] X may be a 1, 2 or 3 atom chain, in which each atom is
independently carbon, sulfur or nitrogen, and each atom may be
optionally substituted with halogen, hydroxyl, optionally
substituted lower alkyl, optionally substituted lower alkoxy,
optionally substituted cycloalkyl, or optionally substituted
amino;
[0122] ring B may be saturated, monounsaturated, polyunsaturated or
aromatic; and
[0123] at least one of R1 or a substituent of X may include an
amino group.
[0124] In Formula VI, X may also be C(Ra)C(Rb), in which Ra and Rb
may be independently hydrogen, halogen, lower alkyl, substituted
lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy,
substituted lower alkoxy, amino, sulfonylamino, amino sulfonyl,
sulfonyl, or the like. Ra and Rb may be independently hydroxyl,
substituted oxy, substituted thiol, alkylthio, substituted
alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted
sulfonyl, substituted sulfonylamino, substituted amino, substituted
amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, or the
like. R1 may include at least one substituent containing an amino
group. Ring B may not include any heteroatoms.
##STR00007##
[0125] In Formula VII,
[0126] R1 may be optionally substituted amino, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heteroarylalkyl;
[0127] R2a may be hydrogen, lower alkyl, or substituted lower
alkyl;
[0128] R3 may be hydrogen, halogen, optionally substituted lower
alkyl, optionally substituted amino, optionally substituted
cycloalkyl or optionally substituted aryl;
[0129] R4 may be hydrogen, halogen, optionally substituted lower
alkyl, optionally substituted amino, optionally substituted
cycloalkyl or optionally substituted aryl; and
[0130] at least one of R1, R3 and R4 may include a substituent
containing an amino group.
[0131] Preferably, R1 includes a substituent containing an amino
group. In particular embodiments of Formula VII; R1 includes an
amino substituent, R2a is hydrogen; and R3 and R4 are each
independently halogen.
[0132] In Formula VII, R2a may be hydrogen; R3 may be hydrogen,
halogen, lower alkyl, substituted lower alkyl, amino, substituted
amino, cycloalkyl, or substituted cycloalkyl; and R4 may be
chlorine.
##STR00008##
[0133] In Formula VIII,
[0134] R1 may be optionally substituted amino, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heteroarylalkyl;
[0135] R2b may be hydrogen, lower alkyl, or substituted lower
alkyl;
[0136] R3 may be hydrogen, halogen, optionally substituted lower
alkyl, optionally substituted amino, optionally substituted
cycloalkyl or optionally substituted aryl;
[0137] R4 may be hydrogen, halogen, optionally substituted lower
alkyl, optionally substituted amino, optionally substituted
cycloalkyl or optionally substituted aryl; and
[0138] at least one of R1, R3 and R4 may include a substituent
containing an amino group.
[0139] R1 may include a substituent containing an amino group. R2b
may be hydrogen; and R3 and R4 may each independently be
halogen.
[0140] In Formula VIII, R2b may also be hydrogen; R3 may be
hydrogen, halogen, lower alkyl, optionally substituted lower alkyl,
optionally substituted amino, or optionally substituted cycloalkyl;
and R4 may be chlorine.
[0141] The KATP channel opener may also have the formula
7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide (shown
below with its tautomer) with the empirical formula C8H7ClN2O2S and
a molecular weight of 230.7.
##STR00009##
[0142] The KATP channel opener may also be a salt of one of the
compounds described by Formulae I-VIII and may have at least one,
of the following properties: (1) opening SURx/Kir6.y potassium
channels, in which x=1, 2A or 2B and y=1 or 2; (2) binding to the
SURx subunit of KATP channels; and (3) inhibiting glucose induced
release of insulin following administration of the compound in
vivo.
[0143] The KATP channel opener may also be a structural variant or
bioequivalent of a compound defined by Formulae I-VIII, such as a
derivative, salt, prodrug or isomer thereof. The salt of KATP
channel opener may have a cation that is a cation of an alkali
metal or an organic compound which includes a tertiary amine or a
quaternary ammonium ion. If the salt includes an anion of diazoxide
and a sodium cation, then the salt may not be in a form suitable
for intravenous use. If the anion is diazoxide in a solution
suitable for intravenous use, then the cation may not be sodium. In
solutions suitable for intravenous use, if the cation is sodium,
then the anion may not be an anion of diazoxide. If the salt
includes an anion of diazoxide and a sodium cation, then the salt
may not be in liquid form. The KATP channel opener may be a salt of
a compound of one of Formulae I-VIII in which the cation is sodium,
potassium, choline or hexamethyl hexamethylene diammonium. The KATP
channel opener may also be BPDZ 62, BPDZ 73, NN414, or BPDZ 154.
For salts of compounds of Formula V-VIII, at least one substituent
of the compound of Formulae V-VIII may include an amino group. The
compound of Formula V-VIII may form an anion of a salt and a
monovalent or divalent metal may form the cation. The cation may
include a tertiary amino or quaternary ammonium group.
[0144] a. Dosage
[0145] The dose of the K.sub.ATP channel opener may be at least 1,
5, 10, 15, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000
mg. The dose may also be less than 1, 5, 10, 15, 20, 30, 40, 50,
100, 200, 300, 400, 500, 1000, or 2000 mg. The dose may further be
determined based on the weight of the subject for which it is to be
administered, such that the formulation may contain a single
administration dose of at least 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0,
or 20.0 mg per kg of the subject's body weight. The formulation may
also contain a single administration dose of less than 0.1, 0.5,
1.0, 2.0, 3.0, 5.0, 10.0, or 20.0 mg per kg of the subject's body
weight.
[0146] The efficacy of the K.sub.ATP channel opener may be enhanced
or reduced by the composition of the patient's diet. Diets high in
carbohydrates (e.g., >40% of calories from carbohydrates) may
require higher doses of diazoxide to achieve optimal results. In
contrast, a patient consuming a higher protein content diet (e.g.
>15% of calories from protein) or higher fat content (e.g.,
>30% of calories from fat) may require lower doses of diazoxide
to achieve optimal results. The variability in patients' diets and
the impact of dietary composition on the drug's efficacy also lends
itself to using a biomarker like blood ketone levels to monitor or
titrate the patient's dose of diazoxide.
[0147] b. Compositions
[0148] This invention also relates to a method of treatment
comprising administering a composition comprising a K.sub.ATP
channel opener, which may be a therapeutically effective amount.
The composition may be a pharmaceutical composition, which may be
produced using methods well known in the art.
[0149] c. Administration
[0150] Administration of the composition using the method described
herein may be orally, parenterally, sublingually, transdermally,
rectally, transmucosally, topically, via inhalation, via buccal
administration, or combinations thereof. Parenteral administration
includes, but is not limited to, intravenous, intraarterial,
intraperitoneal, subcutaneous, intramuscular, intrathecal, and
intraarticular. The compositions may be administered to a human
patient, cat, dog, large animal, or an avian. The composition may
be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per
day.
[0151] d. Formulation
[0152] The compositions provided herein may be in the form of
capsules, sprinkle formulation, tablets or lozenges formulated in a
conventional manner. For example, tablets and capsules for oral
administration may contain conventional excipients including, but
not limited to, binding agents, fillers, lubricants, disintegrants
and wetting agents. Binding agents include, but are not limited to,
syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch
and polyvinylpyrrolidone. Fillers include, but are not limited to,
lactose, sugar, microcrystalline cellulose, maizestarch, calcium
phosphate, and sorbitol. Lubricants include, but are not limited
to, magnesium stearate, stearic acid, talc, polyethylene glycol,
and silica. Disintegrants include, but are not limited to, potato
starch and sodium starch glycollate. Wetting agents include, but
are not limited to, sodium lauryl sulfate. Tablets may be coated
according to methods well known in the art.
[0153] Compositions provided herein may also be liquid formulations
including, but not limited to, aqueous or oily suspensions,
solutions, emulsions, syrups, and elixirs. The compositions may
also be formulated as a dry product for constitution with water or
other suitable vehicle before use. Such liquid preparations may
contain additives including, but not limited to, suspending agents,
emulsifying agents, nonaqueous vehicles and preservatives.
Suspending agents include, but are not limited to, sorbitol syrup,
methyl cellulose, glucose/sugar syrup, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate
gel, and hydrogenated edible fats. Emulsifying agents include, but
are not limited to, lecithin, sorbitan monooleate, and acacia.
Nonaqueous vehicles include, but are not limited to, edible oils,
almond oil, fractionated coconut oil, oily esters, propylene
glycol, and ethyl alcohol. Preservatives include, but are not
limited to, methyl or propyl p-hydroxybenzoate and sorbic acid.
[0154] Compositions provided herein may also be formulated as
suppositories, which may contain suppository bases including, but
not limited to, cocoa butter or glycerides. Compositions provided
herein may also be formulated for inhalation, which may be in a
form including, but not limited to, a solution, suspension, or
emulsion that may be administered as a dry powder or in the form of
an aerosol using a propellant, such as dichlorodifluoromethane or
trichlorofluoromethane. Compositions provided herein may also be
formulated as transdermal formulations comprising aqueous or
nonaqueous vehicles including, but not limited to, creams,
ointments, lotions, pastes, medicated plaster, patch, or
membrane.
[0155] Compositions provided herein may also be formulated for
parenteral administration including, but not limited to, by
injection or continuous infusion. Formulations for injection may be
in the form of suspensions, solutions, or emulsions in oily or
aqueous vehicles, and may contain formulation agents including, but
not limited to, suspending, stabilizing, and dispersing agents. The
composition may also be provided in a powder form for
reconstitution with a suitable vehicle including, but not limited
to, sterile, pyrogen-free water.
[0156] Compositions provided herein may also be formulated as a
depot preparation, which may be administered by implantation or by
intramuscular injection. The compositions may be formulated with
suitable polymeric or hydrophobic materials (as an emulsion in an
acceptable oil, for example), ion exchange resins, or as sparingly
soluble derivatives (as a sparingly soluble salt, for example).
[0157] The present invention has multiple aspects, illustrated by
the following non-limiting examples.
EXAMPLE 1
Treating PWS
[0158] This example shows how a K.sub.ATP channel opener addresses
abnormalities observed in patients with PWS. In particular, the
channel opener diazoxide may hyperpolarize hypothalamic neurons in
a manner similar to leptin.
[0159] Diazoxide has now been prescribed at low doses for two
infants with PWS, both of which had experienced hypoglycemic
episodes. One infant in PWS nutritional phase 1a transitioning to
phase 1b was started at 0.5 mg/kg BID of diazoxide at eight months
of age, increasing to 1 mg/kg BID. No changes in blood pressure or
heart rate were observed, and no signs of edema were present.
Within two weeks of starting diazoxide, the infant's strong
narcoleptic response to solid foods had been virtually eliminated.
Subjectively, her energy level and stamina also improved, and her
therapists documented her significant progress. The infant's
baseline IGF-1 levels were 152 ng/mL while on 0.8 mg QD of
Genotropin. Around three weeks after starting diazoxide levels, the
IGF-1 levels had risen to 185 ng/ml, and the Genotropin was reduced
to 0.6 mg QD with no decline in energy level. Two and half weeks
later, despite the decline in growth hormone dosage, the patient's
IGF-1 levels had continued to rise to 210 ng/ml. A significant
increase in smiling over this period was noted. This child has not
progressed to PWS nutritional phase 2a for a period of 56 weeks,
perhaps as a result of the administration of diazoxide.
[0160] The second infant in PWS nutritional phase 1a was treated
with 1 mg/kg BID of diazoxide. This infant also had experienced
excessive fatigue while feeding and was reliant on a g-tube prior
to initiating the medication. Following initiation of diazoxide,
the infant was feeding exclusively by mouth, transitioning to
nutritional phase 1b. It was further reported that the infant was
more aware of his environment and was making more eye contact. His
IGF-1 levels also rose while on a stable dose of growth hormone,
with similar improvements in energy and stamina noted.
[0161] With respect to safety, no side effects have been reported
for a period of 56 weeks. Both infants' blood sugar levels were
monitored and were in the normal range. Minimal or no excess lanugo
hair growth had been noted. Taken together, these cases are
supportive of the utility of diazoxide in the treatment of PWS.
* * * * *