Note: Descriptions are shown in the official language in which they were submitted.
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The combination of a serotonin reuptake inhibitor and Amoxapine
The present invention relates to the use of a combination of Amoxapine and a
serotonin
reuptake inhibitor (SRI), or any other compound, which causes an elevation in
the level of
extracellular serotonin, for the treatment of depression and other affective
disorders.
Background
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs)
have become first
1o choice therapeutics in the treatment of depression, certain forms of
anxiety and social
phobias, because they are effective, well tolerated and have a favourable
safety profile
compared to the classic tricyclic antidepressants.
However, clinical studies on depression and anxiety disorders indicate that
non-response to
15 SSRIs is substantial, up to 30%. Another, often neglected, factor in
antidepressant treatment
is compliance, which has a rather profound effect on the patient's motivation
to continue
pharmacotherapy.
First of all, there is the delay in therapeutic effect of SSRIs. Sometimes
symptoms even
2o worsen during the first weeks of treatment. Secondly, sexual dysfunction is
a side effect
common to all SSRIs. Without addressing these problems, real progress in the
pharmacotherapy of depression and anxiety disorders is not likely to happen.
In order to cope with non-response, psychiatrists sometimes make use of
augmentation
25 strategies. Augmentation of antidepressant therapy may be accomplished
through the co-
administration of mood stabilizers such as lithium carbonate or
triiodothyronin or by the use
of electroshock.
In 1993, an augmentation strategy with pindolol was described by Artigas et
al. in Trends
30 Pharrrcacol. Sci. 1993, 14, p 262-263. Artigas' idea is based on
intracerebral microdialysis
experiments in animals. In fact, later neurochemical studies built on the
desensitization
hypothesis by Blier and co-workers stated that the delay in therapeutic effect
of
antidepressants is related to a gradual desensitization of 5-HT autoreceptors
(Blier et al. J.
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2
Clin. Psycipharmacol. 1987, 7 suppl. 6, 245-355). A key point in their
hypothesis is that the
effects of SSRIs on the release-controlling somatodendritic autoreceptors (5-
HT~A) limit the
release of 5-HT in terminal areas and thus the effect of S-HT uptake
inhibition in those regions.
This is supported by microdialysis experiments in rats, showing that the
increase in
extracellular 5-HT elicited by a single dose of an SSRI is augmented by co-
administration of a
5-HT~A autoreceptor antagonist (Invernizzi et al. Brain Res, 1992, 584, p 322-
324 and Hjorth,
S., J. Neurochem, 1993, 60, p 776-779).
The effect of combined administration of a compound that inhibits serotonin
reuptake and a
5-HT, A receptor antagonist has been evaluated in several studies (Innis, R.B.
et al. Eur. J.
Pharmacol. 1987, 143, p. 1095-204 and Gartside, S.E., Br. J. Pharmacol, 1995,
115, p
1064-1070, Blier, P. et al. Trends in Pharmacol. Science 1994, I5, 220). In
these studies it
was found that 5-HT» receptor antagonists would abolish the initial brake on 5-
HT
neurotransmission induced by the serotonin reuptake inhibitors and thus
produce an
immediate boost of 5-HT transmission and a rapid onset of therapeutic action.
Several patent applications have been filed which cover the use of a
combination of a 5-
HT,A antagonist and a serotonin reuptake inhibitor for the treatment of
depression (see e.g.
EP-A2-687 472 and EP-A2-714 663).
Another approach to increase terminal 5-HT would be through blockade of the 5-
HT, B
autoreceptor. Microdialysis experiments in rats have indeed shown that
increase of
hippocampal 5-HT by citalopram is potentiated by GMC 2-29, an experimental 5-
HT1B
receptor antagonist.
Several patent applications covering the combination of an SSRI and a 5-HT~B
antagonist or
partial agonist have also been filed (WO 97/28141, WO 96/03400, EP-A-701819
and WO
99/13877).
3o Summary of the invention
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3
It has now surprisingly been found that Amoxapine or pharmaceutically
acceptable salts
thereof may be used to augment and provide faster onset of the therapeutic
effect of
serotonin reuptake inhibitors.
In one aspect the invention relates to use of Amoxapine or a pharmaceutically
acceptable
salt thereof for the preparation of a pharmaceutical composition to be used in
combination
with a serotonin reuptake inhibitor or any other compound, which causes an
elevation in the
level of extracellular serotonin.
to In another aspect the invention relates to use of Amoxapine or a
pharmaceutically
acceptable salt thereof for the preparation of a pharmaceutical composition
useful for
augmenting and/or providing faster onset of the therapeutic effect of a
serotonin reuptake
inhibitor or any other compound, which causes an elevation in the level of
extracellular
serotonin.
In a further aspect the invention relates to a pharmaceutical composition or
kit comprising
Amoxapine or a pharmaceutically acceptable salt thereof and a compound, which
is a
serotonin reuptake inhibitor, or any other compound which causes an elevation
in the level
of extracellular serotonin, and optionally pharmaceutically acceptable
carriers or diluents.
In a further aspect the invention relates to a method for the treatment of
diseases or
disorders responsive to a serotonin reuptake inhibitor or any other compound
which causes
an elevation in the level of extracellular serotonin, comprising administering
Amoxapine or
a pharmaceutically acceptable salt thereof and a serotonin reuptake inhibitor,
or a compound
which causes an elevation in the level of extracellular serotonin, to an
individual in need
thereof.
In a further aspect the invention relates to use of Amoxapine or a
pharmaceutically
acceptable salt thereof and a compound, which is a serotonin reuptake
inhibitor, or any other
3o compound which causes an elevation in the level of extracellular serotonin,
for the
preparation of a pharmaceutical composition for the treatment of diseases or
disorders
responsive to the therapeutic effect of a serotonin reuptake inhibitor or any
other compound
causing an elevation in the level of extracellular serotonin.
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In a further aspect the invention relates to the use of Amoxapine or a
pharmaceutically
acceptable salt thereof and a compound, which is a serotonin reuptake
inhibitor, or any other
compound which causes an elevation in the level of extracellular serotonin,
for the
preparation of a kit for the treatment of diseases or disorders responsive to
the therapeutic
effect of a serotonin reuptake inhibitor or any other compound causing an
elevation in the
level of extracellular serotonin.
In a further aspect the invention relates to a method for augmenting and/or
providing faster
to onset of the therapeutic effect of a serotonin reuptake inhibitor, or any
other compound
which causes an elevation in the level of extracellular serotonin, comprising
administering
Amoxapine or a pharmaceutically acceptable salt thereof to an individual to be
treated with
or undergoing treatment with the serotonin reuptake inhibitor, or any other
compound which
causes an elevation in the level of extracellular serotonin.
In an embodiment the serotonin reuptake inhibitor or the compound which causes
an
elevation in the level of extracellular serotonin is used in the treatment of
depression,
anxiety disorders and other affective disorders, eating disorders such as
bulimia, anorexia
and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders,
impulse
2o control disorders, attention deficit hyperactivity disorder and drug abuse,
in particular
depression.
In a further embodiment the serotonin reuptake inhibitor or the compound which
causes an
elevation in the level of extracellular serotonin is used in the treatment of
anxiety disorders
including general anxiety disorder, panic anxiety, obsessive compulsive
disorder, acute
stress disorder, post trauma stress disorder or social anxiety disorder.
In a further embodiment, the serotonin reuptake inhibitor or the compound
which causes an
elevation in the level of extracellular serotonin is used in the treatment of
psychoses,
3o including schizophrenia and schizoaffective disorders.
In a further embodiment the serotonin reuptake inhibitor is selected from
citalopram,
escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine,
dapoxetine,
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nefazodone, imipramin, femoxetine and clomipramine or a pharmaceutically
acceptable salt
of any of these compounds. Just to clarify, each of the serotonin reuptake
inhibitors
specified above is intended to be an individual embodiment. Accordingly, each
of them and
the use thereof may be claimed individually.
In a further preferred embodiement, the serotonin reuptake inhibitor is
escitalopram.
In a further preferred embodiment, the serotonin reuptake inhibitor is
citalopram.
1o
In a further embodiment the serotonin reuptake inhibitor is a selective
serotonin reuptake
inhibitor (SSRI).
In a further embodiment the pharmaceutical composition or kit prepared is
adapted for
15 simultaneous administration of the active ingredients. In an embodiment the
active
ingredients are contained in the same unit dosage form.
In a further embodiment the pharmaceutical composition or kit prepared is
adapted for
sequential administration of the active ingredients. In an embodiment the
active ingredients
2o are contained in discrete unit dosage forms.
Description of the invention
The present invention relates to the use of Amoxapine or a pharmaceutically
acceptable salt
thereof for the preparation of a pharmaceutical composition to be used in
combination with
25 a serotonin reuptake inhibitor or any other compound, which causes an
elevation in the level
of extracellular serotonin.
In particular, the present invention relates to the use of Amoxapine or a
pharmaceutically
acceptable salt thereof for the preparation of a pharmaceutical composition
useful for
3o augmenting and/or providing faster onset of the therapeutic effect of a
serotonin reuptake
inhibitor or any other compound, which causes an elevation in the level of
extracellular
serotonm.
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More particularly, the present invention relates to the use as above, of
Amoxapine, or a
pharmaceutically acceptable salt thereof, for the treatment of depression,
anxiety disorders
and other affective disorders, such as generalized anxiety disorder, panic
anxiety, obsessive
compulsive disorder, acute stress disorder, post traumatic stress disorder and
social anxiety
disorder eating disorders such as bulimia, anorexia and obesity, phobias,
dysthymia,
premenstrual syndrome, cognitive disorders, impulse control disorders,
attention deficit
hyperactivity disorder, psychosis including schizophrenia and schizoaffective
disorders and
drug abuse, in particular depression, in combination with a serotonin reuptake
inhibitor or
any other compound, which causes an elevation in the level of extracellular
serotonin.
to
The anxiety disorders mentioned above include general anxiety disorder, panic
anxiety,
obsessive compulsive disorder, acute stress disorder, post trauma stress
disorder or social
anxiety disorder.
15 As used herein, the term augmenting covers improving the therapeutic effect
and/or
potentiating the therapeutic effect of an SRI or a compound which causes an
elevation in the
level of extracellular 5-HT.
In a further embodiment, the invention relates to the use of Amoxapine or a
2o pharmaceutically acceptable salt thereof and a compound, which is a
serotonin reuptake
inhibitor, or a compound, which causes an elevation in the level of
extracellular serotonin,
for the preparation of a pharmaceutical composition for the treatment of
diseases or
disorders responsive to the therapeutic effect of a serotonin reuptake
inhibitor, or any other
compound, which causes an elevation in the level of extracellular serotonin.
In a further embodiment, the invention relates to the use of Amoxapine or a
pharmaceutically acceptable salt thereof and a compound, which is a serotonin
reuptake
inhibitor, or a compound, which causes an elevation in the level of
extracellular serotonin,
for the preparation of a kit-of parts (kit) for the treatment of diseases or
disorders responsive
3o to the therapeutic effect of a serotonin reuptake inhibitor, or any other
compound, which
causes an elevation in the level of extracellular serotonin.
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The diseases responsive to a serotonin reuptake inhibitor include depression,
anxiety
disorders and other affective disorders, eating disorders such as bulimia,
anorexia and
obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders,
impulse control
disorders, attention deficit hyperactivity disorder, psychosis, including
schizophrenia and
schizoaffective disorders, psychosis, including schizophrenia and
schizoaffective disorders
and drug abuse, in particular depression.
The term anxiety disorders is as defined above.
1o In one embodiment, the present invention relates to the use of Amoxapine or
a
pharmaceutically acceptable salt thereof for the preparation of a
pharmaceutical
composition as above, which is adapted for simultaneous administration of the
active
ingredients. In particular, such pharmaceutical compositions may contain the
active
ingredients within the same unit dosage form, e.g. in the same tablet or
capsule. Such unit
15 dosage forms may contain the active ingredients as a homogenous mixture or
in separate
compartments of the unit dosage form.
In another embodiment, the present invention relates to the use of Amoxapine
or a
pharmaceutically acceptable salt thereof for the preparation of a
pharmaceutical
2o composition or kit as above, which is adapted for sequential administration
of the active
ingredients. In particular, such pharmaceutical compositions may contain the
active
ingredients in discrete unit dosage forms, e.g. discrete tablets or capsules
containing either
of the active ingredients. These discrete unit dosage forms may be contained
in the same
container or package, e.g. a blister pack.
As used herein the term kit means a pharmaceutical composition containing each
of the
active ingredients, but in discrete unit dosage forms.
The invention also relates to a pharmaceutical composition or kit comprising
Amoxapine or
a pharmaceutically acceptable salt thereof and a compound, which is a
serotonin reuptake
inhibitor, or any other compound, which causes an elevation in extracellular S-
HT and
optionally pharmaceutically acceptable carriers or diluents.
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The pharmaceutical composition or kit of the invention may be adapted for
simultaneous
administration of the active ingredients or for sequential administration of
the active
ingredients, as described above.
Finally, the present invention relates to a method for the treatment of
diseases or disorders
responsive to a serotonin reuptake inhibitor or any other compound, which
causes an
elevation in the level of extracellular serotonin, comprising administering
Amoxapine or a
pharmaceutically acceptable salt thereof and a serotonin reuptake inhibitor,
or a compound,
which causes an elevation in the level of extracellular serotonin, to an
individual in need
1o thereof.
In particular, the present invention relates to a method for augmenting and/or
providing
faster onset of the therapeutic effect of a serotonin reuptake inhibitor or
any other
compound, which causes an elevation in the level extracellular serotonin,
comprising
administering Amoxapine or a pharmaceutically acceptable salt thereof to an
individual to
be treated with or undergoing treatment with the serotonin reuptake inhibitor
or any other
compound, which causes an elevation in the level of extracellular serotonin.
The individuals, which may benefit from treatment with a combination as above,
may suffer
from depression, anxiety disorders and other affective disorders, psychosis,
eating disorders
2o such as bulimia, anorexia and obesity, phobias, premenstrual syndrome,
dysthymia,
cognitive disorders, impulse control disorders, attention deficit
hyperactivity disorder,
psychosis, and drug abuse, in particular depression.
As mentioned above, anxiety disorder includes general anxiety disorder, panic
anxiety,
obsessive compulsive disorder, acute stress disorder, post trauma stress
disorder or social
anxiety disorder.
Psychosis includes but is not limited to schizophrenia and schizoaffective
disorders.
3o Amoxapine and the serotonin reuptake inhibitor may be administered
simultaneously as
described above.
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Alternatively, the active ingredients may be administered sequentially, e.g.
in two discrete
unit dosage forms as described above.
It has now, surprisingly, been found that co-administration of Amoxapine and a
serotonin
reuptake inhibitor produces a significant increased response in an animal
model predictive
of antidepressant effect, the 5-HT microdialysis model, compared to the
administration of
the serotonin reuptake inhibitor alone. Administration of Amoxapine alone
causes no
significant effect in the experiments.
1 o As mentioned above, serotonin reuptake inhibitors show delayed onset of
action. Even in
responders to SSRIs, several weeks of treatment are necessary to achieve a
relief in symptoms.
Amoxapine may provide fast onset of therapeutic effect of serotonin reuptake
inhibitors.
The use of a combination of Amoxapine and a serotonin reuptake inhibitor may
greatly
15 reduce the amount of serotonin reuptake inhibitor necessary to treat
depression and other
affective disorders and may thus reduce the side effects caused by the
serotonin reuptake
inhibitor. In particular, the combination of a reduced amount of SRI and
Amoxapine may
reduce the risk of SSRI-induced sexual dysfunction and sleep disturbances.
20 Co-administration of Amoxapine and a serotonin reuptake inhibitor may also
be useful for the
treatment of refractory depression, i.e. depression, which cannot be treated
appropriately by
administration of a serotonin reuptake inhibitor alone. Typically, Amoxapine
may be used as
add-on therapy for the augmentation of the response to SRIs in patients where
at least 40-60%
reduction in symptoms has not been achieved during the first 6 weeks of
treatment with an
25 SRI.
Many antidepressants with serotonin reuptake inhibiting effect have been
described in the
literature. Any pharmacologically active compound which primarily or partly
exerts its
therapeutic effect via inhibition of serotonin reuptake in the CNS, may
benefit from
3o augmentation with Amoxapine.
The following list contains a number of serotonin reuptake inhibitors, which
may benefit
from augmentation with Amoxapine: citalopram, escitalopram, fluoxetine, R-
fluoxetine,
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sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine,
nefazodone,
imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinil, nefopam,
befuraline, fezolamine, femoxetine, clomipramine, cianoimipramine, litoxetine,
cericlamine,
seproxetine, WY 27587, WY 27866, imeldine, ifoxetine, tiflucarbine, viqualine,
5 milnacipran, bazinaprine, YM 922, S 33005, F 98214-TA, OPC 14523,
alaproclate,
cyanodothepine, trimipramine, quinupramine, dothiepin, Amoxapine,
nitroxazepine, McN
5652, McN 5707, Ol 77, Org 6582, Org 6997, Org 6906, amitriptyline,
amitriptyline N-
oxide, nortriptyline, CL 255.663, pirlindole, indatraline, LY 113.821, LY
214.281, CGP
6085 A, RU 25.591, napamezole, diclofensine, trazodone, EMD 68.843, BMY
42.569, NS
l0 2389, sercloremine, nitroquipazine, ademethionine, sibutramine and
clovoxamine. The
compounds mentioned above may be used in the form of the base or a
pharmaceutically
acceptable acid addition salt thereof. Each of the serotonin reuptake
inhibitors specified
above is intended to be an individual embodiment. Accordingly, each of them
and the use
thereof may be claimed individually.
Typically, compounds such as citalopram, escitalopram, fluoxetine, R-
fluoxetine, sertraline,
paroxetine, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine,
dapoxetine,
vilazodone, nefazodone, imipramine, imipramine N-oxide, desipramine,
pirandamine,
dazepinil, nefopam, befuraline, fezolamine, femoxetine, clomipramine,
cianoimipramine,
litoxetine, cericlamine, seproxetine, imeldine, ifoxetine, indeloxazine,
tiflucarbine,
viqualine, milnacipran, bazinaprine, alaproclate, cyanodothepine,
trimipramine,
quinupramine, dothiepin, Amoxapine, nitroxazepine, roxindole, amitriptyline,
amitriptyline
N-oxide, nortriptyline, pirlindole, indatraline, napamezole, diclofensine,
trazodone,
sercloremine, nitroquipazine, ademethionine, sibutramine,
desmethylsubitramine,
didesmethylsubitramine, clovoxamine vilazodone,
N-[( 1-[(6-Fluoro-2-naphthalenyl)methyl]- 4-piperidinyl]amino]carbonyl]-3-
pyridine
carboxamide (WY 27587),
[trans-6-(2-chlorophenyl)-1,2,3,5,6,1Ob-hexahydropyrrolo- (2,1-a)isoquinoline]
(McN
5707),
(dl-4-exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6 alpha(10 alpha)-dime
hydrochloride)(Org 6997),
(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-
8-amine
hydrochloride (Org 6906),
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-[2-[4-(6-fluoro-1 H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl]ethyl]-3-
isopropyl-6-
(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide
(LY393558), [4-
(5,6-dimethyl-2-benzofuranyl)-piperidine] (CGP 6085),
dimethyl-[S-(4-nitro-phenoxy)-6,7,8,9-tetrahydro-SH-benzocyclohepten-7-yl]-
amine (RU
25.591),
~"
''~o (A 80426),
to
0 0
" ~ ~ N H=
"~
(EMD 86006),
(533005),
(OPC 14523),
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Hod ~°
(McN 5652),
,,",~y~
0
H
GIH
(YM 35992),
G~ (Org 6582),
are suitable as SRIs. The Impounds mentioned above may be used in the form of
the base or
a pharmaceutically acceptable acid addition salt thereof. Each of the
serotonin reuptake
1o inhibitors specified above is intended to be an individual embodiment.
Accordingly, each of
them and the use thereof may be claimed individually.
Other therapeutic compounds which may benefit from augmentation with Amoxapine
include compounds, which causes an elevation in the extracellular level of 5-
HT in the
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synaptic cleft, although they are not serotonin reuptake inhibitors. One such
compound is
tianeptine.
The above list of serotonin reuptake inhibitors and other compounds, which
causes an
increase in the extracellular level of serotonin, may not be construed as
limiting.
In an embodiment the SRIs is selected from citalopram, escitalopram,
fluoxetine, sertraline,
paroxetine, fluvoxamine, venlafaxine, dapoxetine, nefazodone, imipramin,
femoxetine and
clomipramine. Just to clarify, each of these SRIs constitute individual
embodiments, and
to may be the subject of individual claims.
The term selective serotonin reuptake inhibitor (SSRI) means an inhibitor of
the monoamine
transporters which has stronger inhibitory effect at the serotonin transporter
than the
dopamine and the noradrenaline transporters.
Selective serotonin reuptake inhibitors (SSRIs) are among the most preferred
serotonin
reuptake inhibitors used according to the present invention. Thus in a further
embodiment
the SRI is selected from SSRIs, such as citalopram, escitalopram, fluoxetine,
fluvoxamine,
sertraline or paroxetine.
The active ingredients according to the invention, i.e. Amoxapine and the SRI
or a
compound causing an increase in extracellular serotonin levels, may be used in
the free base
form or in the form of a pharmaceutically acceptable acid addition salt
thereof, the latter
being obtainable by reaction of the base form with an appropriate acid.
Citalopram is preferably used in the form of the hydrobromide or as the base,
escitalopram
in the form of the oxalate, fluoxetine, sertraline and paroxetine in the form
of the
hydrochloride and fluvoxamine in the form of the maleate.
3o As mentioned above, the combination of Amoxapine with a serotonin reuptake
inhibitor
unexpectedly shows a synergistic effect on the central nervous system (CNS).
As a
consequence, combination therapy using Amoxapine and lower doses of the
serotonin
reuptake inhibitor than normally used in monotherapy, may be effective, and
side-effects
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associated with the larger amounts of serotonin reuptake inhibitor used in
monotherapy may
be reduced or prevented altogether.
Additionally, combination therapy with Amoxapine using a normal dose of
serotonin
reuptake inhibitor has the advantage that an effective CNS effect may be
obtained in the
often large number of patients who do not respond to conventional monotherapy
with
SSRIs.
The amount of Amoxapine used in combination therapy may range from about 0.001
to
1o about 1 g/day, such as from about 0.001 to about 0.1 mg/day, about 0.1 to
about 1 mg/day,
about 1 mg/day to about 10 mg/day, about 10 mg/day to about 100 mg/day and
from about
100 mg/day to about 1 g/day.
Serotonin reuptake inhibitors, including the SSRIs specifically mentioned
hereinabove,
15 differ both in molecular weight and in activity. As a consequence, the
amount of serotonin
reuptake inhibitor used in combination therapy depends on the nature of said
serotonin
reuptake inhibitor. In one embodiment of the invention, the serotonin reuptake
inhibitor or
the compound causing an increase in the level of extracellular 5-HT, is
administered at
lower doses than required when the compound is used alone. In another
embodiment, the
2o serotonin reuptake inhibitor or the compound causing an increase in the
level of
extracellular 5-HT, is administered in normal doses.
To prepare the pharmaceutical compositions of this invention, an appropriate
amount of the
active ingredient(s), in salt form or base form, is combined in an intimate
admixture with a
25 pharmaceutically acceptable carrier, which can take a wide variety of forms
depending on
the form of preparation desired for administration. These pharmaceutical
compositions are
desirably in unitary dosage form suitable for administration orally, rectally,
percutaneously
or by parenteral injection. For example, in preparing the compositions in oral
dosage form,
any of the usual pharmaceutical media may be employed, such as, for example,
water,
3o glycols, oils, alcohols and the like in the case of oral liquid
preparations such as
suspensions, syrups, elixirs and solutions; or solid Garners such as starches,
sugars, kaolin,
lubricants, binders, disintegrating agents and the like in the case of
powders, pills, capsules
and tablets. Because of their ease in administration, tablets and capsules
represent the most
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advantageous oral dosage unit form, in which case solid pharmaceutical Garners
are
obviously employed.
It is especially advantageous to formulate the aforementioned pharmaceutical
compositions
5 in dosage unit form for ease of administration and uniformity of dosage. As
used in the
specification and claims, unit dosage form refers to physically discrete units
suitable as
unitary dosages, each unit containing a predetermined quantity of active
ingredients)
calculated to produce the desired therapeutic effect, in association with the
required
pharmaceutical carrier. Examples of such dosage unit forms are tablets
(including scored or
1o coated tablets), capsules, pills, powder packets, wafers, injectable
solutions or suspensions,
teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Amoxapine may be administered before, during or after the administration of
the serotonin
reuptake inhibitor provided that the time between the administration of
Amoxapine and the
15 administration of the serotonin reuptake inhibitor is such that ingredients
are allowed to act
synergistically on the CNS. When simultaneous administration of Amoxapine and
a
serotonin reuptake inhibitor is envisaged, a composition containing both a
serotonin
reuptake inhibitor and Amoxapine may be particularly convenient.
Alternatively,
Amoxapine and the serotonin reuptake inhibitor may be administered separately
in the form
of suitable compositions. The compositions may be prepared as described
hereinabove.
The present invention also comprises products containing Amoxapine and a
serotonin
reuptake inhibitor as a combination preparation for simultaneous, separate or
sequential use
in psychiatric drug therapy. Such products may comprise, for example, a kit
comprising
discrete unit dosage forms containing Amoxapine and discrete unit dosage forms
containing
a serotonin reuptake inhibitor, all contained in the same container or pack,
e.g. a blister
pack.
The above mentioned preparations for simultaneous or sequential administration
may
3o instead of a serotonin reuptake inhibitor contain another compound causing
an elevation in
the level of extracellular 5-HT.
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Experimental part
Animals
Male albino rats of a Wistar-derived strain (285-320 g; Harlan, Zeist, The
Netherlands) were
used for the experiments. Upon surgery, rats were housed individually in
plastic cages (35 x
35 x 40 cm), and had free access to food and water. Animals were kept on a 12
h light
schedule (light on 7:00 a.m.). The experiments are concordant with the
declarations of
Helsinki and were approved by the animal care committee of the faculty of
mathematics and
natural science of the University of Groningen .
Drugs
The following drugs were used: escitalopram oxalate and amoxapine(Lundbeck
A/S,
Copenhagen, Denmark)
Surgery
Microdialysis of brain serotonin levels was performed using home made I-shaped
probes,
made of polyacrylonitrile / sodium methyl sulfonate copolymer dialysis fiber
(i.d. 220 Vim,
o.d. 0.31 Vim, AN 69, Hospal, Italy). Preceding surgery rats were
anaesthetised using
isoflurane (OZ/NZO; 300/300m1/min). Lidocaine-HCI, 10 % (m/v) was used for
local
anaesthesia. Rats were placed in a stereotaxic frame (Kopf, USA), and probes
were inserted
2o into Ventral Hippcampus (V. Hippo, L +4.8 mm, IA: +3.7 mm, V: -8.0 mm)
(Paxinos and
Watson, 1982). After insertion, probes were secured with dental cement.
Microdialysis experiments
Rats were allowed to recover for at least 24 h. Probes were perfused with
artificial
cerebrospinal fluid containing 147 mM NaCI, 3.0 mM KCI, 1.2 mM CaCl2, and 1.2
mM
MgCl2, at a flow-rate of 1.5 p.l / min (Harvard apparatus, South Natick, Ma.,
USA). 1 S
minute microdialysis samples were collected in HPLC vials containing 7.5 pl
0.02 M acetic
acid for serotonin analysis.
Serotonin analysis:
Twenty-pl microdialysate samples were injected via an autoinjector (CMA/200
refrigerated
microsampler, CMA, Sweden) onto a 100 x 2.0 mm C18 Hypersil 3 p,m column
(Bester,
Amstelveen, the Netherlands) and separated with a mobile phase consisting of 5
g/L di-
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ammoniumsulfate, 500 mg/L EDTA, 50 mg/L heptane sulphonic acid, 4 % methanol
v/v,
and 30 pl/L of triethylamine, pH 4.65 at a flow of 0.4 ml/min (Shimadzu LC-10
AD). 5-
HT was detected amperometrically at a glassy carbon electrode at 500 mV vs
Ag/AgCI
(Antec Leyden, Leiden, The Netherlands). The detection limit was 0.5 fmol 5-HT
per 20 pl
sample (signal to noise ratio 3).
Data presentation and statistics
Four consecutive microdialysis samples with less then 20 % variation were
taken as control
and set at 100 %. Data are presented as per entages of control level (mean +
S.E.M.) in time.
1o Statistical analysis was c performed using Sigmastat for Windows (SPSS,
Jandel
Corporation). Treatments were compared versus controls using two way analysis
of
variance (ANOVA) for repeated measurements, followed by Student Newman Keuls
test.
Drug effects were evaluated using one way ANOVA for repeated measures on
ranks. Level
of significance level was set at p<0.05.
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Results
Co-administration of escitalopram with amoxapine on S-HT levels in ventral
hippocampus
Administration of both doses of amoxapine (1 and 10 ~mol/kg s.c.) did not
induce any
significant effects on hippocampal 5-HT levels (XZ»=16.6 P=0.08, XZ,o=9.63,
P=0.47).
Co-administration of escitalopram (1.5 ~mollkg s.c.) with 1 ~.mol/kg s.c. of
amoxapine did
not induce an augmented effect of escitaloprarn on S-HT levels (Treatment
F(1,13)= 0.464,
P=0.50). Co-administration of 10 ~mol/kg s.c. of amoxapine with 1.5 ~mollkg
escitalopram
1o significantly augmented the increase in 5-HT levels (Treatment F(1,8)=
7.35, P=0.0265,
Treatment versus time F(1,106)= 6.34, P<0.0001). Posthoc analysis revealed
significant
differences at t=75 and 90 minutes (see Fig. 1).
