Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMBINATION OF SEROTONIN REUPTAKE INHIBITORS AND NOREPINEPHRINE
REUPTAKE INHIBITORS
BACKGROUND OF THE INVENTION
This invention is directed to a pharmaceutical compositions comprising a
serotonin
reuptake inhibitor or pharmaceutically acceptable salts thereof and a
norepinephrine reuptake
inhibitor or pharmaceutically acceptable salts thereof, and to methods of
treatment with such
a composition.
This invention is also directed to a pharmaceutical composition comprising a
serotonin reuptake inhibitor or pharmaceutically acceptable salts thereof and
optionally a
norepinephrine reuptake inhibitor or pharmaceutically acceptable salts
thereof, and to
methods of treatment with such a composition, wherein the serotonin reuptake
inhibitor is
present in an amount sufficient for dopamine reuptake inhibition.
Serotonin plays a role in several psychiatric disorders, including anxiety,
Alzheimer's
disease, depression, nausea and vomiting, eating disorders, and migraine (see
Rasmussen
et al., "Chapter 1. Recent Progress in Serotonin (5HT)~A Receptor Modulators",
in Annual
Reports in Medicinal Chemistry, Section I, 30, pp. 1-9, 1995, Academic Press,
Inc.; Artigas et
al., Trends Neurosci., 19 (9), 1996, pp. 378-383; and Wolf et al., Drug
Development
Research, 40, 1997, pp. 17-34). Serotonin also plays a role in both the
positive and negative
symptoms of schizophrenia, as discussed in Sharma et al., Psychiatric Annals.,
26 (2),
February, 1996, pp. 88-92. Serotonin reuptake inhibitors, have been used to
treat disorders
or conditions such as depression, as described, for example, in WO 94/00047.
The antidepressant effect of norepinephrine reuptake inhibitors has been
described,
for example, in U.S. Patent No. 6,403,645.
The effect of combining selective serotonin reuptake inhibitors (SSRIs) in
depressed
patients with the norepinephrine reuptake inhibitor desipramine has been
described in J.C.
Nelson et aL,Arch. Gen. Psychiatry 39: 1419-1422, 1982; J.C. Nelson et al.,
Arch. Gen.
Psvchiatry_, 48: 303-307, 1991; J.C. Nelson and L.H. Price, Am. J. Psychiatry,
152: 1538
1539, 1995; and M. Fava et al., Am. J. Psychiatry, 152: 1539, 1995. A
combination of
sertraline and of reboxetine has been described in Eur J Pharmacol, 1999,
364(2-3):123-32
and in J. Neural Transm., 2000, 107:1213-1227. A comparison of the stimulus
properties of
reboxetine and certain serotonin reuptake inhibitors has been described in
Pychopharmacoloay 2001, 154:213-218. A combination of citalopram and of
reboxetine has
been described in WO 02/076461.
According to Brunswick et al., Am. J. Psychiatry, 2003, Vol. 160:10, pp. 1836-
1841,
dopamine transporter affinity may be higher than normal in the basal ganglia
of depressed
patients. Racemic reboxetine, a norepinephrine reuptake inhibitor, has been
shown to affect
the dopaminergic system preclinically, increasing dopamine in the prefrontal
cortex. See
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Sacchetti et al., Br. J. Pharmacol. 1999, Vol. 128, pp. 1332-1338; Page et al,
Neuropsychopharmacology, 2002, Vol. 27, pp. 237-247; and Invernizzi et al.,
British J. of
Pharmacology, 2001, Vol. 132, pp. 183-188.
However, citalopram, a serotonin reuptake inhibitor, does not show dopamine
reuptake inhibition. Kugaya et al., Neuropsychopharmacology, 2003, Vol. 28,
pp. 413-420.
Similarly, the serotonin and norepinephrine reuptake inhibitor venlafaxine
does not show
dopamine reuptake inhibition (Marek et al, Society for Neuroscience Meeting,
New Orleans,
November 2003).
None of the previously published studies discloses or suggests a composition
having
a combined action of serotonin reuptake inhibition, norepinephrine reuptake
inhibition, and
dopamine reuptake inhibition in a dual component therapy, or methods of
treatment with such
a composition.
SUMMARY OF THE INVENTION
This invention is directed to a pharmaceutical composition for treating a
disorder or
condition selected from the group consisting of anxiety disorders, phobias,
avoidant
personality disorder, eating disorders, chemical dependencies, Parkinson's
diseases,
obsessive-compulsive disorder, negative symptoms of schizophrenia, cognitive
dysfunction
related to schizophrenia, premenstrual syndrome, stress-induced incontinence,
headache,
neuropathic pain, chronic pain, urinary incontinence, fibromyalgia, depression
comorbid with
fibromyalgia, obesity, migraine, neuropathic pain associated with diabetes,
affective
symptoms of schizophrenia and a combination thereof in a mammal, the
composition
comprising: (i) at least one serotonin reuptake inhibitor or pharmaceutically
acceptable salt
thereof; (ii) at least one norepinephrine reuptake inhibitor or
pharmaceutically acceptable salt
thereof, wherein the at least one norepinephrine reuptake inhibitor is
selected from the group
consisting of
(A) a compound having the formula of Structure II
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-~R~ )n1
~R)n
N R3
R4
Structure II
wherein n and n1 are, independently, 1, 2 or 3; each of the groups R and R~,
which may be
the same or different, is hydrogen; halogen; halo-C~-Cs alkyl; hydroxy; C~-Cs
alkoxy; C~-Cs
alkyl optionally substituted with C~-Cs alkyl or halogen; aryl- C~-Cs alkyl
optionally substituted
with C~-Cs alkyl or halogen; aryl- C~-Cs alkoxy optionally substituted with C~-
Cs alkyl or
halogen; --NO2; -NRSRs wherein R5 and R6 are, independently, hydrogen or C~-Cs
alkyl, or two
adjacent R groups or two adjacent R' groups, taken together, form the --O=CH2--
O-- group;
A is hydrogen or OR2;
RZ is hydrogen; C~-C~~ alkyl optionally substituted with C~-Cs alkyl or
halogen, or aryl-
C~-Cs alkyl;
each of the groups R3 and R4, which may be identical or different, is
hydrogen, C~-Cs
alkyl optionally substituted with C~-Cs alkyl or halogen, CZ-C4 alkenyl, C~-C4
alkynyl, aryl-C~-
C4 alkyl optionally substituted with C~-Cs alkyl or halogen, C3-C~ cycloalkyl
optionally
substituted with C~-Cs alkyl or halogen, or R3 and R4 with the nitrogen atom
to which they are
bound form a pentatomic or hexatomic saturated or unsaturated, optionally
substituted with
C~-Cs alkyl or halogen, heteromonocyclic group optionally containing other
heteroatoms
selected from the group consisting of O,S and N;
or Ra and R4, taken together, form the -CHI-CHI-group;
(B) a compound having the formula of Structure III
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Structure III
wherein D is N or CR9, where R9 is hydrogen, C~-C6 alkyl optionally
substituted with C~-C6
alkyl or halogen, CZ-C4 alkenyl, C2-C4 alkynyl, aryl-C~-C4 alkyl optionally
substituted with C~-
C6 alkyl or halogen, or C3-C~ cycloalkyl optionally substituted with C~-C6
alkyl or halogen; G is
NR'R8, wherein each of R' and R8 is independently hydrogen, C~-C6 alkyl
optionally
substituted with C~-C6 alkyl or halogen, Ca-CQ alkenyl, Cz-C4 alkynyl, aryl-C~-
C4 alkyl
optionally substituted with C~-C6 alkyl or halogen, or C3-C~ cycloalkyl
optionally substituted
with C~-C6 alkyl or halogen; or R' and R8 taken together with the nitrogen
atom to which they
are bound form a pentatomic or hexatomic, saturated or unsaturated, optionally
substituted
with C~-C6 alkyl or halogen heteromonocyclic group optionally containing one
or more further
additional heteroatoms selected from the group consisting of O,S and N; the
bond between D
and the ring carbon bonded to G is single or double; and J is O or L, where L
is
C
C\M
fVR3R4
where the bond between the ring carbon of L and the carbon of L bonded to M is
single or
double; M is a C~ alkylene chain, where n is between 1 and 3; and each of R'3
and R'4 is
independently hydrogen, C~-C6 alkyl optionally substituted with C~-C6 alkyl or
halogen, CZ-C4
alkenyl, CZ-C4 alkynyl, aryl-C~-C4 alkyl optionally substituted with C~-C6
alkyl or halogen, C3-
C~ cycloalkyl optionally substituted with C~-C6 alkyl or halogen, or R'3 and
R~4 taken together
with the nitrogen atom to which they are bound form a pentatomic or hexatomic,
saturated or
unsaturated, optionally substituted with C~-C6 alkyl or halogen
heteromonocyclic group
optionally containing one or more further additional heteroatoms selected from
the group
consisting of O,S and N; and
(C) a compound having the formula of Structure IV:
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Structure IV
R24
wherein M is a C" alkylene chain, where n is between 1 and 3; and each of R23
and R24 is
independently hydrogen, C~-Cs alkyl optionally substituted with C~-C6 alkyl or
halogen, CZ-C4
alkenyl, C2-C4 alkynyl, aryl-C~-C4 alkyl optionally substituted with C~-Cs
alkyl or halogen, C3-
C~ cycloalkyl optionally substituted with C~-C6 alkyl or halogen, or R23 and
R24taken together
with the nitrogen atom to which they are bound form a pentatomic or hexatomic,
saturated or
unsaturated, optionally substituted with C~-C6 alkyl or halogen
heteromonocyclic group
optionally containing one or more further additional heteroatoms selected from
the group
consisting of O,S and N;
and
(iii) a pharmaceutically acceptable carrier.
This invention is also directed to:
a method for treating a disorder or condition described in the previous
paragraph in a
mammal, the method comprising administering to a mammal in need of such
treatment
components (i) and (ii) described in the previous paragraph;
the use of components (i) and (ii) described in the previous paragraph for
preparing a
medicament for treating a disorder or condition described in the previous
paragraph in a
mammal;
a pharmaceutical composition for treating a disorder or condition that can be
treated
by enhancing serotonergic neurotransmission in a mammal, noradrenergic
neurotransmission
in a mammal, or a combination thereof, the composition comprising components
(i), (ii) and
(iii) described in the previous paragraph;
a method for treating a disorder or condition that can be treated by enhancing
serotonergic neurotransmission in a mammal, noradrenergic neurotransmission in
a mammal,
or a combination thereof, the method comprising administering to a mammal in
need of such
treatment components (i) and (ii) described in the previous paragraph;
a pharmaceutical composition for treating depression in a mammal, the
composition
comprising components (i), (ii) and (iii) described in the previous paragraph;
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a method for treating depression in a mammal, the method comprising
administering
to a mammal in need of such treatment components (i) and (ii) described in the
previous
paragraph; and
the use of components (i) and (ii) described in the previous paragraph for
preparing a
medicament for treating depression in a mammal.
This invention is also directed to a composition for treating a disorder or
condition
described in the previous paragraphs in a mammal, the composition consisting
essentially of
components (i), (ii) and (iii) described in the previous paragraphs.
This invention is also directed to:
a composition comprising (i) at least one serotonin reuptake inhibitor or
pharmaceutically acceptable salt thereof, wherein the at least one serotonin
reuptake inhibitor
is selected from the group consisting of sertraline, fluoxetine and
fluvoxamine; and (ii) at least
one norepinephrine reuptake -inhibitor or pharmaceutically acceptable salt
thereof, wherein
the at least one norepinephrine reuptake inhibitor is selected from the group
consisting of
racemic reboxetine, [S,S]-reboxetine, amoxapine, and maprotiline. The
composition may be
a composition for treating a disorder or condition selected from the group
consisting of
neuropathic pain, chronic pain, urinary incontinence, fibromyalgia, depression
comorbid with
fibromyalgia, obesity, migraine, neuropathic pain associated with diabetes,
affective
symptoms of schizophrenia and a combination thereof in a mammal; and
a composition consisting essentially of (i) at least one serotonin reuptake
inhibitor or
pharmaceutically acceptable salt thereof, wherein the at least one serotonin
reuptake inhibitor
is selected from the group consisting of sertraline, fluoxetine and
fluvoxamine; and (ii)at least
one norepinephrine reuptake inhibitor or pharmaceutically acceptable salt
thereof, wherein
the at least one norepinephrine reuptake inhibitor is selected from the group
consisting of
racemic reboxetine, [S,S]-reboxetine, amoxapine, and maprotiline. The
composition may be
a composition for treating a disorder or condition selected from the group
consisting of
neuropathic pain, chronic pain, urinary incontinence, fibromyalgia, depression
comorbid with
fibromyalgia, obesity, migraine, neuropathic pain associated with diabetes,
affective
symptoms of schizophrenia and a combination thereof in a mammal.
The invention is also directed to:
a method for treating a disorder or condition described in the previous
paragraphs in
a mammal, the method comprising administering to a mammal in need of such
treatment (i) at
least one serotonin reuptake inhibitor or pharmaceutically acceptable salt
thereof, wherein the
at least one serotonin reuptake inhibitor is selected from the group
consisting of sertraline,
fluoxetine and fluvoxamine; and (ii) at least one norepinephrine reuptake
inhibitor or
pharmaceutically acceptable salt thereof, wherein the at least one
norepinephrine reuptake
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inhibitor is selected from the group consisting of racemic reboxetine, [S,S]-
reboxetine,
amoxapine, and maprotiline; and
the use of components (i) and (ii) described in the previous paragraphs for
preparing
a medicament for treating a disorder or condition described in the previous
paragraphs in a
mammal.
The invention is also directed to a composition comprising sertraline or a
pharmaceutically acceptable salt thereof and [S,S]-reboxetine or a
pharmaceutically
acceptable salt thereof.
The invention is also directed to a composition for treating, for example, a
disorder or
condition that can be treated by enhancing serotonergic neurotransmission in a
mammal,
dopaminergic transmission in a mammal, noradrenergic neurotransmission in a
mammal, or a
combination thereof, the composition comprising component (i) and optionally
component (ii)
described in the previous paragraphs, wherein component (i) is present in an
amount
sufficient for dopamine reuptake inhibition. Preferably, component (i) is
sertraline or a
pharmaceutically acceptable salt thereof.
The invention is also directed to a method for treating a disorder or
condition that can
be treated by enhancing serotonergic neurotransmission in a mammal,
dopaminergic
transmission in a mammal, noradrenergic neurotransmission in a mammal, or a
combination
thereof, the method comprising administering to a mammal in need of such
treatment
comprising component (i) and optionally component (ii) described in the
previous paragraphs,
wherein component (i) is present in an amount sufficient for dopamine reuptake
inhibition.
Preferably, component (i) is sertraline or a pharmaceutically acceptable salt
thereof.
The invention is also directed to a composition comprising sertraline or a
pharmaceutically acceptable salt thereof and optionally a norepinephrine
reuptake inhibitor
selected from the group consisting of racemic reboxetine, [S,S]-reboxetine,
amoxapine, and
maprotiline, or pharmaceutically acceptable salts thereof, wherein sertraline
or a
pharmaceutically acceptable salt thereof is present in an amount sufficient
for dopamine
reuptake inhibition.
The invention is also directed to a composition comprising sertraline or a
pharmaceutically acceptable salt thereof and optionally [S,S]-reboxetine or a
pharmaceutically
acceptable salt thereof, wherein sertraline is present in an amount sufficient
for dopamine
reuptake inhibition.
In the method for treating a disorder or condition selected from the group
consisting
of anxiety disorders, phobias, avoidant personality disorder, eating
disorders, chemical
dependencies, Parkinson's diseases, obsessive-compulsive disorder, negative
symptoms of
schizophrenia, premenstrual syndrome, stress-induced incontinence, headache,
neuropathic
pain, chronic pain, urinary incontinence, post-traumatic stress disorder,
chronic stress, acute
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stress, post-traumatic stress disorder, fibromyalgia, depression comorbid with
fibromyalgia,
obesity, the serotonin reuptake inhibitor may be sertraline present in an
amount sufficient for
dopamine reuptake inhibition. Similarly, in the composition for treating a
disorder or condition
as recited in this paragraph, the serotonin reuptake inhibitor may be
sertraline present in an
amount sufficient for dopamine reuptake inhibition. Similarly, in the method
for treating a
disorder or condition selected from the group consisting of neuropathic pain,
chronic pain,
urinary incontinence, post-traumatic stress disorder, chronic stress, acute
stress, post-
traumatic stress disorder, fibromyalgia, depression comorbid with
fibromyalgia, obesity, the
serotonin reuptake inhibitor may be sertraline present in an amount sufficient
for dopamine
reuptake inhibition.
In the method for treating depression, the serotonin reuptake inhibitor may be
sertraline or a pharmaceutically salt thereiof present in an amount sufficient
for dopamine
reuptake inhibition. In one embodiment, the serotonin reuptake inhibitor is
sertraline or a
pharmaceutically acceptable salt thereof, and the norepinephrine reuptake
inhibitor is [S,S]-
reboxetine or a pharmaceutically acceptable salt thereof, wherein sertraline
is present in an
amount sufficient for dopamine reuptake inhibition, wherein the amount of
sertraline is from
about 150 mg to about 200 mg.
Similarly, in the composition for treating depression, the serotonin reuptake
inhibitor
may be sertraline present in an amount sufficient for dopamine reuptake
inhibition. In one
embodiment, the serotonin reuptake inhibitor is sertraline or a
pharmaceutically acceptable
salt thereof, and the norepinephrine reuptake inhibitor is [S,S]-reboxetine or
a
pharmaceutically acceptable salt thereof, wherein sertraline is present in an
amount sufficient
for dopamine reuptake inhibition, wherein the amount of sertraline is from
about 150 mg to
about 200 mg.
In the composition comprising (i) at least one serotonin reuptake inhibitor or
pharmaceutically acceptable salt thereof, wherein the at least one serotonin
reuptake inhibitor
is selected from the group consisting of sertraline, fluoxetine and
fluvoxamine; and (ii) at least
one norepinephrine reuptake inhibitor or pharmaceutically acceptable salt
thereof, wherein
the at least one norepinephrine reuptake inhibitor is selected from the group
consisting of
racemic reboxetine, [S,S]-reboxetine, amoxapine, and maprotiline, the
serotonin reuptake
inhibitor may be sertraline present in an amount sufficient for dopamine
reuptake inhibition.
Similarly, in the composition consisting essentially of (i) at least one
serotonin reuptake
inhibitor or pharmaceutically acceptable salt thereof, wherein the at least
one serotonin
reuptake inhibitor is selected from the group consisting of sertraline,
fluoxetine and
fluvoxamine; and (ii) at least one norepinephrine reuptake inhibitor or
pharmaceutically
acceptable salt thereof, wherein the at least one norepinephrine reuptake
inhibitor is selected
from the group consisting of racemic reboxetine, [S,S]-reboxetine, amoxapine,
and
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maprotiline, the serotonin reuptake inhibitor may be sertraline present in an
amount sufficient
for dopamine reuptake inhibition.
The pharmaceutical compositions and methods of this invention may also be used
for
preventing a relapse in a disorder or condition described in the previous
paragraphs by
administering to a mammal in need of such prevention components (i) and (ii)
of the
composition. The pharmaceutical compositions and methods of this invention may
further be
used for treating a symptom associated with a disorder or condition described
in the previous
paragraphs, wherein the symptom is selected from the group consisting of
cognitive
dysfunctions and somatic complaints.
"Enhancing serotonergic neurotransmission," as used herein, refers to
increasing or
improving the neuronal process whereby the monoamine serotonin is released by
a pre-
synaptic cell upon excitation and crosses the synapse to stimulate or inhibit
the post-synaptic
cell. "Enhancing dopaminergic neurotransmission," as used herein, refers to
increasing or
improving the neuronal process whereby the monoamine dopamine is released by a
pre-
synaptic cell upon excitation and crosses the synapse to stimulate or inhibit.
the post-synaptic
cell. "Enhancing noradrenergic neurotransmission," as used herein, refers to
increasing or
improving the neuronal process whereby the monoamine norepinephrine is
released by a pre-
synaptic cell upon excitation and crosses the synapse to stimulate or inhibit
the post-synaptic
cell.
"Chemical dependency," as used herein, means an abnormal craving or desire
for, or
an addiction to a drug. Such drugs are generally administered to the affected
individual by
any of a variety of means of administration, including oral, parenteral, nasal
or by inhalation.
"Treating a chemical dependency," as used herein, means reducing or
alleviating such
dependency.
A "unit dosage form" as used herein is any form that contains a unit dose of
the
serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, of
the
norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt
thereof, or of the
serotonin reuptake inhibitor or pharmaceutically acceptable salt thereof and
the
norepinephrine reuptake inhibitor or pharmaceutically acceptable salt thereof.
A unit dosage
form may be, for example, a tablet or a capsule. The unit dosage form may also
be in liquid
form, such as a solution or suspension.
A "serotonin reuptake inhibitor" as used herein is a reuptake inhibitor of the
monoamine serotonin. For example, the serotonin reuptake inhibitor may be a
selective
serotonin reuptake inhibitor (SSRI). The serotonin reuptake inhibitor may have
additional
pharmacological properties, for example, antagonism of 5-HT~A or 5-HT~,~
receptors, or
partial inhibition of a norepinephrine transporter (NET). At or above certain
doses, as
described further herein, the serotonin reuptake inhibitor shows dopamine
reuptake inhibition.
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"An amount sufficient for dopamine reuptake inhibition" is intended to refer
to an
amount that is sufficient to displace at least about 15% (3-CIT from the
dopamine transporter
as assessed by SPECT imaging.
Exemplary selective serotonin reuptake inhibitors (SSRI) which may be used in
accordance with this invention include those having structure I shown below:
32
Z
or a pharmaceutically acceptable salt thereof,
wherein R3~ is selected from the group consisting of hydrogen and normal alkyl
of
from 1 to 3 carbon atoms, R3~ is normal alkyl of from 1 to 3 carbon atoms, Z
is
/X
/
/\ Y
X and Y are each selected from the group consisting of hydrogen, fluoro,
chloro,
bromo, trifluoromethyl, alkoxy of from 1 to 3 carbon atoms and cyano, with at
least one of X
and Y being other than hydrogen,
W is selected from the group consisting of hydrogen, fluoro, chloro, bromo,
trifluoromethyl and alkoxy of from 1 to 3 carbon atoms,
and NR3~R32 and Z have a cis relationship.
An exemplary compound of Structure I is sertraline, (1 S-cis)-4-(3,4-
dichlorophenyl)
1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, which may be prepared as
described in U.S.
Pat. No. 4,536,518. SSRI that may be used in accordance with this invention
also include,
but are not limited to: femoxetine, which may be prepared as described in U.S.
Pat. No.
3,912,743; fluoxetine, which may be prepared as described in U.S. Pat. No.
4,314,081;
fluvoxamine, which may be prepared as described in U.S. Pat. No. 4,085,225;
indalpine,
which may be prepared as described in U.S. Pat. No. 4,064,255; indeloxa~ine,
which may be
prepared as described in U.S. Pat. No. 4,109,088; milnacipran, which may be
prepared as
described in U.S. Pat. No. 4,478,836; paroxetine, which may be prepared as
described in
U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sibutramine, which may be
prepared as
Structure 1
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described in U.S. Pat. No. 4,929,629; zimeldine, which rnay be prepared as
described in U.S.
Pat. No. 3,928,369; citalopram; escitalopram; fenfluramine; venlafaxine and
duloxetine.
A "norepinephrine reuptake inhibitor" as used herein is a reuptake inhibitor
of the
monoamine norepinephrine. For example, the norepinephrine reuptake inhibitor
may be a
selective norepinephrine reuptake inhibitor. As another example, the
norepinephrine
reuptake inhibitor may have additional pharmacological properties, for
example, antagonism
of 5-HTZ receptors. As another example, the norepinephrine reuptake inhibitor
may affect the
dopaminergic tranport system, for example, through the intermediacy of NET.
Norepinephrine reuptake inhibition is readily determined by those skilled in
the art according
to standard assays. As an example, norepinephrine reuptake inhibitors which
may be used in
accordance with this invention include compounds having structure II defined
above, or a
pharmaceutically acceptable salt thereof. As another example, norepinephrine
reuptake
inhibitors which may be used in accordance with this invention include
compounds having
structure III defined above, or a pharmaceutically acceptable salt thereof. As
another
example, norepinephrine reuptake inhibitors which may be used in accordance
with this
invention include compounds having structure IV defined above, or a
pharmaceutically
acceptable salt thereof.
In an exemplary embodiment of the invention, the norepinephrine reuptake
inhibitor is
the [S,S]-enantiomer of Structure II, shown as Structure II' below, where A =
QR~ and R, R',
R2, R3, R4, n and n1 are as defined in Structure II:
WR~)n1
~R)n
N R3
R4
Structure II
For example, the norepinephrine reuptake inhibitor of Structure II' may be
[S,S]-
reboxetine, which is described in British patent GB 2,167,407, U.S. Patent
Application No.
20020061910, U.S. Patent No. 6,465,458.
In another exemplary embodiment of the invention, the norepinephrine reuptake
inhibitor of Structure II is atomoxetine or racemic reboxetine.
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In another exemplary embodiment of the invention, the norepinephrine reuptake
inhibitor of Structure III is amoxapine, nortriptyline, or protriptyline.
In another exemplary embodiment of the invention, the norepinephrine reuptake
inhibitor of Structure IV is maprotiline.
In one exemplary embodiment of the composition of the invention, the
composition
comprises a norepinephrine reuptake inhibitor having Structure II', and
sertraline as the
serotonin reuptake inhibitor.
In another exemplary embodiment of the invention, the composition comprises
sertraline as the serotonin reuptake inhibitor and [S,S]-reboxetine as the
norepinephrine
reuptake inhibitor.
In another exemplary embodiment of the invention, the composition consists
essentially of sertraline as the serotonin reuptake inhibitor and [S,S]-
reboxetine as the
norepinephrine reuptake inhibitor.
The combination of a norepinephrine reuptake inhibitor or a pharmaceutically
acceptable salt thereof and a serotonin reuptake inhibitor or pharmaceutically
acceptable salt
thereof is also referred to herein as "the active combination." The term "the
active
combination" may also be used to denote the combination of a norepinephrine
reuptake
inhibitor or a pharmaceutically acceptable salt thereof and a serotonin
reuptake inhibitor or
pharmaceutically acceptable salt thereof wherein the serotonin reuptake
inhibitor or
pharmaceutically acceptable salt also inhibits dopamine reuptake. The active
combination is
a useful psychotherapeutic and may be used in the treatment of the disorders
or conditions
described herein. Examples of the disorders or conditions which may be
treated: by the
methods and compositions of this invention are as follows:
depression, including, for example, depression in cancer patients, depression
in
Parkinson's patients, Postmyocardial Infarction depression, depression in
patients with
human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression,
depression in
infertile women, pediatric depression, major depression, single episode
depression, recurrent
depression, child abuse induced depression, post partum depression, DSM-IV
major
depression, treatment-refractory major depression, severe depression,
psychotic depression,
post-stroke depression, neuropathic pain, manic depressive illness, including
manic
depressive illness with mixed episodes and manic depressive illness with
depressive
episodes, seasonal affective disorder, bipolar depression BP I, bipolar
depression BP II,
melancholy, or major depression with dysthymia; dysthymia; anxiety disorders,
including, for
example, generalized anxiety disorder, panic disorder, PTSD, and social
anxiety disorder;
phobias, including, for example, agoraphobia, social phobia or simple phobias;
eating
disorders, including, for example, anorexia nervosa or bulimia nervosa;
chemical
dependencies, including, for example, addictions to alcohol, cocaine,
amphetamine and other
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psychostimulants, morphine, heroin and other opioid agonists, Phenobarbital
and other
barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive
substances;
Parkinson's diseases, including, for example, dementia in Parkinson's disease,
neuroleptic-
induced parkinsonism or tardive dyskinesias; and headache, including, for
example,
headache associated with vascular disorders.
Disorders or conditions that may be treated by the composition and method of
the
present invention also include withdrawal syndrome; adjustment disorders,
including
depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and
mixed
disturbance of conduct and depressed mood; age-associated learning and mental
disorders,
including Alzheimer's disease; apathy; attention-deficit disorders, or other
cognitive disorders,
due to general medical conditions; attention-deficit hyperactivity disorder
(ADHD); bipolar
disorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder;
cyclothymic
disorder; somatoform disorders such as somatization disorder, conversion
disorder, pain
disorder, hypochondriasis, body dismorphic disorder, undifferentiated
disorder, and
somatoform NOS; incontinence; inhalation disorders; intoxication disorders;
mania;
oppositional defiant disorder; peripheral neuropathy; post-traumatic stress
disorder; late luteal
phase dysphoric disorder; psychotic disorders including schizoaffective
disorders; sleep
disorders, including narcolepsy and enuresis; specific developmental
disorders; SSRI "poop
out" syndrome, or a patient's failure to maintain a satisfactory response to
SSRI therapy after
an initial period of satisfactory response; and tic disorders including
Tourette's disease.
As an example, the mammal in need of the treatment or prevention may be a
human.
As another example, the mammal in need of the treatment or prevention may be a
mammal
other than a human.
A norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor, each
of which
is used in formulating the pharmaceutical composition of this invention, are
each referred to
herein as an "active compound." An active compound which is basic in nature is
capable of
forming a wide variety of different salts with various inorganic and organic
acids. The acid
addition salts are readily prepared by treating the base compounds with a
substantially
equivalent amount of the chosen mineral or organic acid in an aqueous solvent
medium or in
a suitable organic solvent such as methanol or ethanol. Upon careful
evaporation of the
solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid salts
of
the active compounds used in formulating the pharmaceutical compositions of
this invention
that are basic in nature are those which form non-toxic acid addition salts,
i.e., salts
containing pharmacologically acceptable anions. Non-limiting examples of the
salts include
the acetate, benzoate, a-hydroxybutyrate, bisulfate, bisulfite, bromide,
butyne-1,4-dioate,
carpoate, chloride, chlorobenzoate, citrate, dihydrogenphosphate,
dinitrobenzoate, fumarate,
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glycollate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, iodide, lactate,
maleate,
malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate,
methylbenzoate, monohydrogenphosphate, naphthalene-1-sulfonate, naphthalene-2-
sulfonate, oxalate, phenylbutyrate, phenylproionate, phosphate, phthalate,
phylacetate,
propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate,
sebacate, suberate,
succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, acid
phosphate, acid citrate,
bitartrate, succinate, gluconate, saccharate, nitrate, methanesulfonate and
pamoate [i.e., 1,1'-
methylene-bis-(2-hydroxy-3-naphthoate)] salts. For the norepinephrine reuptake
inhibitors,
such as reboxetine and [S,S]-reboxetine, advantageous examples include the
fumarate,
succinate, citrate and tartrate salts.
DETAILED DESCRIPTION OF THE INVENTION
The norepinephrine reuptake inhibitors and serotonin reuptake inhibitors,
which may
also show dopamine reuptake inhibition as described herein, that are used in
formulating the
pharmaceutical compositions of this invention are preferably administered
together in a
pharmaceutical composition. For example, compositions containing the ~erotonin
reuptake
inhibitors and the norepinephrine reuptake inhibitors can be administered as
solutions in a
volume of 1 ml/kg. The vehicle used is varied depending on the solubility of
the serotonin
reuptake inhibitor and of the norepinephrine reuptake inhibitor used.
The norepinephrine reuptake inhibitors and the serotonin reuptake inhibitors,
which
may also show dopamine reuptake inhibition as described herein, that are used
in formulating
the pharmaceutical compositions of this invention may advantageously be used
in conjunction
with other therapeutic agents which do not appreciably block serotonin uptake
Gr affect
monoamine oxidase, such as mirtazapine, mianserin, bupropion, lithium salts,
antiepileptic
drugs such as caramazepine, valproate, lamotrigine, topiramate, gabapentin,
pregabalin, with
atypical antipsychotic drugs such as olanzapine, risperidone, quetiapine,
ziprasidone and
aripiprazole, and/or with antiparkinsonian agents such as dopaminergic
antiparkinsonian
agents such as levodopa, preferably in combination with a peripheral
decarboxylase inhibitor
such as benserazide or carbidopa. As another example, the norepinephrine
reuptake
inhibitor and the serotonin reuptake inhibitor, which may also show dopamine
reuptake
inhibition as described herein, that are used in formulating the
pharmaceutical composition of
this invention may advantageously be used in combination with a 5-HT1 B
antagonist. An
exemplary is elzasonan or a pharmaceutically acceptable salt thereof. For
example,
elzosonan may be present in amounts such as about 0.1 to about 200 mg, for
example about
0.1 mg to about 50 mg, as another example from about 0.1 mg to about 20 mg, as
another
example from about 0.1 mg to about 10 mg, as another example from about 0.1 mg
to about
5 mg. The methods of treatment of the invention likewise may include treatment
of a disorder
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or condition with a norepinephrine reuptake inhibitor, a serotonin reuptake
inhibitor, and a 5-
HT1 B antagonist such as elzasonan.
It is to be understood that the present invention covers the use of a
serotonin
reuptake inhibitor or a pharmaceutically acceptable salt thereof and a
norepinephrine
reuptake inhibitor or pharmaceutically acceptable salt thereof in combination
with one or more
other therapeutic agents.
Activity of the active combinations as antidepressants and related
pharmacological
properties can be determined by methods (1 )-(3) below, which are described in
Koe, B. et al.
Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700
(1983).
Specifically, activity can be determined by studying (1 ) their ability to
affect the efforts of mice
to escape from a swim-tank by the Porsolt mouse "behavior despair" test, (2)
their ability to
potentiate 5-hydroxytryptophan-induced behavioral symptoms in mice in vivo,
and (3) their
ability to block the uptake of serotonin, norepinephrine, dopamine or a
combination thereof by
synaptosomal rat brain cells in vitro. The ability of the active combinations
to counteract
reserpine hypothermia in mice in vivo can be determined according to the
methods described
in U.S. Pat. No. 4,029,731. The activity of the active combinations as
antidepressants and
related pharmacological properties also can be determined by methods (4)-(8)
below.
Specifically, activity can be determined by studying (4) their ability to
reverse the stress-
induced decrease in sucrose intake in rodents described in Papp, M, et al.,
European Journal
of Pharmacoloay, 261, 141-147 (1994), (5) learned helplessness paradigm
described in
Martin P et al., Life Sciences, 48, 2505-2511 (1991 ), (6) reversing the
behavioral deficits of
olfactory bulbectomized rats described in Broekkamp CL et al., Pharmacoloay.
Biochemistry
and Behavior, 13, 643-646 (1980), (7) increasing down-regulation or
desensitization of beta-
adrenergic receptors described in Mishra R. et al., Neuropharmacoloqy, 19, 983-
987 (1980),
and (8) increasing extracellular levels of serotonin, norepinephrine, and/or
dopamine in the
prefrontal cortex of freely-moving rodents by in vivo dialysis described in
Millan MJ et al.,
European Journal of Neuroscience, 12, 1079-1095 (2000).
Activity of the active combinations in the treatment of anxiety may be
determined from
lactate-induced panic-like responses in panic-prone rats as described in
Shekhar, A. and
Keim S.R., J. Neurosci, 1997, 17:9726-9735, and Shekhar, A. and Keim, S.R.,
Neuropharmacol., 2000, 39:1139-1146. Activity of the active combinations in
the treatment of
anxiety may also be determined from anxiety screens such as those that include
various
derivations of conflict models or punishment models in rodents as described by
J.L. Howard
and G.T. Pollard in Psychopharmacoloay of Anxiolytics and Antidepressants,
(ED) SE File
(1991), Pergamon press Inc. (New York), pp. 131-153.
The pharmaceutical compositions described, herein may be prescription
pharmaceutical compositions or over-the-counter pharmaceutical compositions.
As used
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herein, a "prescription pharmaceutical composition" is a composition which is
effective to
deliver an active compound to a human as prescribed by a physician. An "over-
the-counter
pharmaceutical composition" is a composition which is effective to deliver an
active
compound to a human which does not require a prescription from a physician in
order to be
administered to the human.
The pharmaceutical compositions described herein may be formulated in a
conventional manner using one or more pharmaceutically acceptable carriers.
Thus, the
active combinations of this invention may be formulated for oral, buccal,
intranasal, parenteral
(for example, intravenous, intramuscular or subcutaneous), sublingual or
rectal
administration, or may be in the form of a patch, or in a form suitable for
administration by
inhalation or insufflation, and may be administered orally, buccally,
intranasally, parenterally
(for example, intravenously, intramuscularly or subcutaneously) or rectally or
by inhalation or
insufflation.
For oral administration, the pharmaceutical compositions may take the form of,
for
example, tablets or capsules prepared by conventional means with..
pharmaceutically
acceptable excipients such as binding agents, including pregelatinized maize
starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers, including
lactose,
microcrystalline cellulose or calcium phosphate; lubricants, including
magnesium stearate,
talc or silica; disintegrants, including potato starch or sodium starch
glycolate; or wetting
agents, including sodium lauryl sulphate. The tablets may be coated by methods
well known
in the art. Liquid preparations for oral administration may take the form of,
for example,
solutions, syrups or suspensions, or they may be presented as a dry product
for constitution
with water or other suitable vehicle before use. Such liquid preparations may
be prepared by
conventional means with pharmaceutically acceptable additives such as
suspending agents,
including sorbitol syrup, methyl cellulose or hydrogenated edible fats;
emulsifying agents,
including lecithin or acacia, non-aqueous vehicles, including almond oil, oily
esters or ethyl
alcohol; and preservatives, including methyl or propyl p-hydroxybenzoates or
sorbic acid.
For buccal administration, the composition may take the form of tablets or
lozenges
formulated in conventional manner.
The active compounds used in formulating the pharmaceutical composition of
this
invention may be formulated for parenteral administration by injection,
including using
conventional catheterization techniques or infusion. Formulations for
injection may be
presented in unit dosage form, for example, in ampoules or in multi-dose
containers, with an
added preservative.
The compositions containing the active compounds may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles, and may
contain formulating
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active
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ingredient may be in powder form for reconstitution with a suitable vehicle,
for example, sterile
pyrogen-free water, before use.
The active compounds used in formulating the pharmaceutical composition of
this
invention may also be formulated in rectal compositions such as suppositories
or retention
enemas, for example, containing conventional suppository bases such as cocoa
butter or
other glycerides.
For intranasal administration or administration by inhalation, the active
compounds
used in formulating the pharmaceutical compositions of this invention are
conveniently
delivered in the form of a solution or suspension from a pump spray container
that is
squeezed or pumped by the patient or as an aerosol spray presentation from a
pressurized
container or a nebulizer, with the use of a suitable propellant, for example,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
carbon dioxide or
other suitable gas. In the case of a pressurized aerosol, the unit dose may be
determined by
providing a valve to deliver a metered amount. The pressurized container or
nebulizer may
contain a solution or suspension of the active compounds. Capsules and
cartridges, made, for
example, from gelatin, for use in an inhaler or insufflator may be formulated
containing a
powder mix of a compound of this invention and a suitable powder base such as
lactose or
starch.
The norepinephrine reuptake inhibitors and the serotonin reuptake inhibitors
used in
formulating the pharmaceutical compositions of this invention may be
administered alone or
preferably together with pharmaceutically acceptable carriers by any of the
routes previously
indicated, and such administration may be carried out in both single and
multiple c~.oses.
More particularly, the active combination can be administered in a wide
variety of different
dosage forms, i.e., the active combination may be combined with various
pharmaceutically-
acceptable inert carriers in the form of tablets, capsules, lozenges, troches,
hard candies,
powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups,
and the like. Such
carriers include solid diluents or fillers, sterile aqueous media and various
non-toxic organic
solvents, etc. Moreover, oral pharmaceutical formulations containing the
active combination
may be suitably sweetened and/or flavored by means of various agents of the
type commonly
employed for such purpose.
The amounts of a) the serotonin reuptake inhibitor or pharmaceutically
acceptable
salt thereof, and b) the norepinephrine reuptake inhibitor or pharmaceutically
acceptable salt
thereof are preferably amounts such that the combination of a) and b) is
effective in treating
the disorder or condition. The amount of the serotonin reuptake inhibitor or
pharmaceutically
acceptable salt thereof is preferably an amount effective in enhancing
serotonergic
neurotransmission in a mammal. The amount of the norepinephrine reuptake
inhibitor or
pharmaceutically acceptable salt thereof is preferably an amount effective in
enhancing
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noradrenergic neurotransmission in a mammal. In one preferred embodiment, the
amount of
the serotonin reuptake inhibitor is an amount sufficient for dopamine reuptake
inhibition.
Affinity for the sertraline transporter (SERT) and for DAT transporter is
determined by the
amount of the ~3-CIT ligand that is displaced. The extent of dopamine reuptake
inhibition,
measured by transporter displacement using ~i-CIT in combination with
extracellular
dopamine increase, is greater than the extent of placebo.
The pharmaceutical compositions of the inventions achieve occupancy of the
serotonin transporter and of the norepinephrine transporter by combining a
serotonin
reuptake inhibitor or pharmaceutically acceptable salt thereof with a
norepinephrine reuptake
inhibitor or pharmaceutically acceptable salt thereof. In one exemplary
embodiment of the
invention, the serotonin reuptake inhibitor or pharmaceutically acceptable
salt thereof may be
present in an amount sufficient to displace at least about 45% ~i-CIT from the
serotonin
transporter as assessed by SPECT imaging. The norepinephrine reuptake
inhibitor or
pharmaceutically acceptable salt thereof may be present in an amount such that
the
norepinephrine transporter has at least 50% occupancy, as an example at least
75%
occupancy, as another example between 75% and 90% occupancy, as another
example at
least 90% occupancy, as another example between 90% and 100% occupancy,
including
100% occupancy. In an exemplary embodiment, at least 75% occupancy of the
norepinephrine transporter is maintained until the administration of a
successive unit dose or
unit dosage form of the composition of the invention. As used herein,
"occupancy of the
norepinephrine transporter" is intended to refer to occupancy of all
norepinephrine
transporters. Similarly, for example, "at least 75% occupancy" of the
norepiri~ephrine
transporter is intended to mean that all norepinephrine transporters have an
occupancy of at
least 75%. Similarly, as another example, "at least 90% occupancy" of the
norepinephrine
transporter is intended to mean that all norepinephrine transporters have an
occupancy of at
least 90%. Similarly, as used herein, "an amount sufficient to displace at
least about 45% a-
CIT from the serotonin transporter" is an amount sufficient to displace at
least about 45% (3-
CIT from all serotonin transporters.
In another embodiment of the invention, the serotonin reuptake inihibitor is
present in
an amount sufficient for dopamine reuptake inhibition. An amount sufficient
for dopamine
reuptake inhibition is an amount sufficient to displace at least about 15% ~i-
CIT from the
dopamine transporter, wherein "an amount sufficient to displace at least about
15% ~i-CIT
from the dopamine transporter" is intended to mean an amount sufficient to
displace at least
about 15% (i-CIT from all dopamine transporters. For example, the amount
sufficient for
dopamine reuptake inhibition may be an amount sufficient to displace about
15%, 16%, 17%,
18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%,
33%,
34%, 35%, 36%, 37%, 38%, 39%, and 40% ~i-CIT from the dopamine transporter.
When
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sertraline is used as the serotonin reuptake inihibitor, the amount sufficient
to displace at least
about 15% R-CIT from the dopamine transporter is about 150 mg.
Binding data are shown in Tables 1 -3 herein. During periods 1, 2, and 3,
there were
statistically significant differences among the treatment groups for each
brain site shown in
the tables (p <_ 0.040). For midbrain and diencephalon, the mean (~23 I] a -
CIT binding for
sertraline 25 mg and sertraline 50 mg were significantly less than for
placebo. For striatum,
the mean ~~23 I] (3 _CIT binding for sertraline 25 mg and sertraline 50 mg
were significantly
greater than for placebo. There were no statistically significant period or
carryover effects (p
>_ 0.052). The comparisons of the treatments during successive randomization
periods 1, 2,
and 3 are summarized in Table 1 below.
Table 1: Summary of Analysis of [1a3 I] (3 -CIT Binding for Periods 1, 2, and
3
90%
Confidence
Treatment Means (LS means) Limits
Site Test Reference Test Reference Difference ' Lower Upper
Midbrain Sertraline Placebo 0.91 1.49 -0.58 -1.03 -0.13
25 mg
Sertraline Placebo 0.60 1.49 -0.89 -1.34 -0.45
50 mg
Diencephalon Sertraline Placebo 1.91 3.42 -1.51 -2.23 -0.80
25 mg
Sertraline Placebo 1.58 3.42 -1.84 -2.56 -1.13
50 mg
Striatum Sertraline Placebo 10.06 9.44 0.62 0.26 0.98
25 mg
Sertraline Placebo 9.83 9.44 0.39 0.03 0.75
50 mg
For the comparison of periods 1, 2, 3, and 4, there were statistically
significant
differences among the treatment groups for each site (p _< 0.007). For
midbrain and
diencephalon, the mean ['23 I] ~3 -CIT binding for sertraline 25 mg,
sertraline 50 mg, and
sertraline 150 mg were significantly less than for placebo. For striatum, the
mean
123 I~ ~ -CIT binding for sertraline 150 mg was significantly less than for
placebo. The Least
I.Square Means for sertraline 25 mg and sertraline 50 mg were greater than the
mean for
placebo but these differences were not statistically significant. The
comparisons of the
treatments during successive randomization periods 1, 2, 3, and 4 are
summarized in Table 2
below.
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Table 2: Summary of Analysis of [~23 I]
(3 -CIT Binding for Periods 1, 2, 3, and
4
90%
Confidence
Treatment Means (LS means) Limits
Site Test Reference Test Reference Difference Lower
Upper
Midbrain Sertraline Placebo 0.93 1.45 -0.52 -0.84 -0.20
25 mg
Sertraline Placebo 0.63 1.45 -0.82 -1.14 -0.50
50 mg
Sertraline Placebo 0.77 1.45 -0.68 -0.99 -0.36
150 mg
Diencephalon Sertraline Placebo 1.88 3.23 -1.35 -1.97 -0.72
25 mg
Sertraline Placebo 1.80 3.23 -1.43 -2.05 -0.80
50 mg
Sertraline Placebo 1.62 3.23 -1.60 -2.23 -0.98
150 mg
Striatum Sertraline Placebo 10.04 9.32 0.72 -0.16 1.60
25 mg
Sertraline Placebo 9.97 9.32 0.64 -0.23 1.52
50 mg
Sertraline Placebo 8.17 9.32 -1.15 -2.03 0.28
150 mg
Table 3 shows the mean binding and mean isplacement for
percent d [~2~1] [i-CIT in
the midbrain, diencephalon, and striatum collected with the
based on images Prism-XP
camera. These data show that sertraline dopamine transporter.
at 150 mg binds to the
Table 3 - Mean Binding and Mean Percent nt of [231] [i-CIT
Displaceme for Midbrain,
Diencephalon, and Striatum Based on images Prism-XP camera
collected with the
No. of subjects =6
Sertraline
Baseline Placebo 25 mg 50 mg 150 mg
Midbrain
Mean SD 1.65 0.39 1.45 0.38 0.93 0.63 0.77
0.64 0.36 0.31
Mean Percent -- -- -46.06 -61.17 -53.69
Dispacement SD 26.72 24.78 10.89
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No. of subjects =6
Sertraline
Baseline Placebo 25 mg 50 mg 150 mg
Diencephalon
Mean SD 3.28 0.96 3.23 1.2 1.88 1.4 1.8 1.62
0.45 0.71
Mean Percent -- -- -46.29 -44.12 -49.41
Dispacement SD 23.97 9.23 16.02
Striatum
Mean SD 9.79 3.48 9.32 3.48 10.04 9.97 8.17
3.85 3.3 2.66
Mean Percent -- -- 2.4 6.81 2.66 -15.27
7.4
Dispacement SD 14.5
Baseline = Value on Day 0. The displacement percentages are based on the
baseline values
An exemplary daily dose of a serotonin reuptake inhibitor in a pharmaceutical
composition of this invention for oral, parenteral, rectal or buccal
administration to the average
adult human for the treatment of the conditions referred to above is from
about 1 mg to 300
mg of serotonin reuptake inhibitor per unit dose administered 1 to 3 times per
day, such as
25mg to about 300mg of sertraline, preferably from about 50mg to about 200mg
of sertraline
per unit dose which could be administered, for example, 1 to 3 times per day,
or such as
about 5 mg to about 80 mg of fluoxetine per unit dose, preferably from about
10 mg to about
40 mg of fluoxetine per unit dose which could be administered, for example, 1
to 3 times per
day, or such as about 50 mg to about 300 mg of fluvoxamine per unit dose,
preferably 100 mg
to 200 mg of fluvoxamine per unit dose, which could be administered, for
example, 1 to 3
times per day, or such as about 5 mg to about 30 mg of escitalopram,
preferably about 10 mg
to about 20 mg of escitalopram, which could be administered, for example, 1 to
3 times per
day, or such as about 10 mg to about 60 mg of citalopram, preferably about 20
mg to about
40 mg of citalopram, which could be administered, for example, 1 to 3 times
per day, or such
as about 10 to about 50 mg of paroxetine, preferably about 10 mg to about 40
mg of
paroxetine, which could be administered, for example, 1 to 3 times per day.
An exemplary daily dose of a serotonin reuptake inihibitor in a pharmaceutical
composition of this invention for oral, parenteral, rectal or buccal
administration to the average
adult human for the treatment of the conditions referred to above, wherein the
dose is
sufficient for dopamine reuptake inhibition, is 150 mg or more of the
serotonin reuptake
inhibitor per unit dose per day. If sertraline is used as the serotonin
reuptake inhibitor,
amounts of about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260,
270, 280, 290,
300, 310, 320, 330, 340, and 350 mg per unit dose per day are exemplary
amounts that are
sufficient for dopamine reuptake inhibition. As additional examples, the
amount of sertraline
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sufficient for dopamine reuptake inhibition may range from about 150 mg to
about 350 mg;
about 150 mg to about 200 mg; from about 170 mg to about 340 mg; from about
190 mg to
about 330 mg; from about 200 mg to about 310 mg; from about 210 mg to about
300 mg;
from about 220 mg to about 290 mg; from about 230 mg to about 280 mg; from
about 240 mg
to about 270 mg; from about 240 mg to about 250 mg; from about 250 mg to about
260 mg;
from about 260 mg to about 270 mg; from about 270 mg to about 280 mg; from
about 280 mg
to about 290 mg; and from about 290 mg to about 300 mg.
An exemplary daily dose of the norepinephrine reuptake inhibitor in a
pharmaceutical
composition of this invention for oral, parenteral, rectal or buccal
administration to the average
adult human for the treatment of the conditions referred to above is from
about 1 to 300 mg of
norepinephrine reuptake inhibitor per unit dose, such as about 1 mg to about
30 mg of racemic
reboxetine, preferably from about 4 mg to about 16 mg of racemic reboxetine
per unit dose
which could be administered, for example 1 to 3 times per day. Another
exemplary daily dose
of the norepinephrine reuptake inhibitor is from about 1 mg to about 15 mg of
[S,S]-
reboxetine, preferably from about 2 mg to about 8 mg of [S,S]-reboxetine per
unit dose which
could be administered, for example 1 to 3 times per day. Another exemplary
daily dose of the
norepinephrine reuptake inhibitor is from about 150 mg to about 300 mg of
amoxapine per
unit dose, preferably between 200 mg and 275 mg of amoxapine per unit dose,
which could
be administered, for example 1 to 3 times per day. Another exemplary daily
dose of the
norepinephrine reuptake inhibitor is from about 25 mg to about 200 mg of
maprotiline per unit
dose, preferably between 50 mg and 150 mg of maprotiline per unit dose, which
could be
administered, for example 1 to 3 times per day.
An exemplary dose ratio by weight of a serotonin reuptake inhibitor to a
norepinephrine reuptake inhibitor combination formulation for oral, parenteral
or buccal
administration to the average adult human for the treatment of the conditions
referred to
above is from about 0.00005 to about 20,000, preferably from about 0.25 to
about 2,000.
In an exemplary embodiment of the invention, a serotonin reuptake inhibitor is
present in a composition of the invention in an amount ranging from about 0.5%
to about 90%
by weight of the total composition, preferably from about 5% to about 80% by
weight of the
total composition; and a norepinenephrin reuptake inhibitor is present in the
composition of
the invention in an amount ranging from about 0.5% to about 90% by weight of
the total
composition, preferably from about 5% to about 80% by weight of the total
composition. The
ratio by weight of the amount of the serotonin reuptake inhibitor to the
amount of the
norepinephrine reuptake inhibitor preferably ranges from 20:1 to 1:20, more
preferably from
10:1 to 1:10.
Aerosol combination formulations for treatment of the conditions referred to
above in
a mammal, such as an average adult human are preferably arranged so that each
metered
CA 02542339 2006-04-11
WO 2005/023265 PCT/IB2004/002864
-23-
dose or "puff' of aerosol contains from about 100~g to about 30,OOOpg of the
norepinephrine
reuptake inhibitor, preferably from about 250pg to about 1,OOOpg of
norepinephrine reuptake
inhibitor, and from about 1,OOOpg to about 30,OOOpg of a serotonin reuptake
inhibitor,
preferably from about 5,OOOpg to about 20,OOONg. Administration may be once or
several
times daily, for example 1, 3, 4 or 8 times, giving for example, 1, 2 or 3
doses each time.
It should be understood that the present invention is not limited to the
embodiments
described herein. Numerous modifications can be made by one skilled in the art
having the
benefits of the teachings given here. Such modifications should be taken as
being
encompassed within the scope of the present invention as set forth in the
appended claims.
