U.S. patent application number 09/811235 was filed with the patent office on 2002-01-31 for antidepressant effect of norepinephrine uptake 2 inhibitors and combined medications including them.
Invention is credited to Mooney, John J., Schildkraut, Joseph J..
Application Number | 20020013312 09/811235 |
Document ID | / |
Family ID | 26885534 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013312 |
Kind Code |
A1 |
Schildkraut, Joseph J. ; et
al. |
January 31, 2002 |
Antidepressant effect of norepinephrine uptake 2 inhibitors and
combined medications including them
Abstract
Norepinephrine uptake 2 inhibitors (or their precursors) are
administered to enhance the effect of norepinephrine reuptake
inhibitors and other antidepressants. The uptake 2 inhibitor may be
combined in a single medication with a norepinephrine reuptake
inhibitor, such as imipramine, desipramine, or reboxetine, in order
to inhibit both uptake mechanisms. The norepinephrine uptake 2
inhibitors may also be combined with MAO inhibitors or with
selective serotonin reuptake inhibitors. Alternatively, the
norepinephrine uptake 2 inhibitors may be useful antidepressants in
their own right, without the need for co-administration of other
antidepressants. One class of norepinephrine uptake 2 inhibitors is
normetanephrine (the O-methylated metabolite of norepinephrine) and
normetanephrine precursors [such as
3-(4-hydroxy-3-methoxyphenyl)-serine (4H-3MePS ), particularly
L-threo-3-(4-H-3MePS)]that are transported to the brain where they
are converted into normethanephrine, thereby enhancing the effect
of other antidepressants. For example, the invention enhances the
antidepressant effect of norepinephrine reuptake inhibitors.
Inventors: |
Schildkraut, Joseph J.;
(Chestnut Hill, MA) ; Mooney, John J.; (Belmont,
MA) |
Correspondence
Address: |
JOHN W. FREEMAN, ESQ.
Fish & Richardson P.C.
225 Franklin Street
Boston
MA
02110-2804
US
|
Family ID: |
26885534 |
Appl. No.: |
09/811235 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60189828 |
Mar 16, 2000 |
|
|
|
Current U.S.
Class: |
514/220 ;
514/567 |
Current CPC
Class: |
A61K 31/4178 20130101;
A61K 45/06 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/5513
20130101; A61K 31/4178 20130101; A61K 31/5513 20130101; A61K 31/198
20130101 |
Class at
Publication: |
514/220 ;
514/567 |
International
Class: |
A61K 031/5513; A61K
031/198 |
Claims
What is claimed is:
1. A method of treating depression by administering to a patient in
need of such treatment an antidepressant amount of a norepinephrine
uptake 2 inhibitor (or a precursor thereof) in combination with a
second antidepressant.
2. The method of claim 1 in which the norepinephrine uptake 2
inhibitor is normetanephrine or a normetanephrine precursor.
3. The method of claim 2, in which the normetanephrine precursor is
4-hydroxy-3-methoxyphenylserine (4H-3MePS ), particularly
L-threo-3-(4-H-3MePS).
4. The method of claim 1, in which the second antidepressant is a
norepinephrine reuptake inhibitor.
5. The method of claim 4, in which the norepinephrine reuptake
inhibitor is imipramine, desipramine or reboxetine.
6. The method of claim 4, in which the norepinephrine reuptake
inhibitor is nortriptyline, maprotiline, protriptyline,
trimipramine or venlafaxine.
7. The method of claim 4, in which the norepinephrine reuptake
inhibitor is amitriptyline, amoxapine, doxepin, nefazodone, or
lamotrigine.
8. The method of claim 1, in which the norepinephrine uptake 2
inhibitor and the second antidepressant are formulated in a single
medicament.
9. The method of claim 1 in which the norepinephrine uptake 2
inhibitor is co-administered with a selective serotonin reuptake
inhibitor.
10. The method of claim 1 in which the norepinephrine uptake 2
inhibitor is co-administered with a monoamine oxidase
inhibitor.
11. The method of claim 2 or claim 3 further comprising
administration of a peripheral decarboxylase inhibitor.
12. The method of claim 11 in which the peripheral decarboxylase
inhibitor is carbidopa.
13. A medicament comprising, in combination,
depression-counteracting amounts, of: a) a norepinephrine uptake 2
inhibitor (or a precursor thereof); and b) a second antidepressant
compound.
14. The medicament of claim 13 in which the norepinephrine uptake 2
inhibitor is normetanephrine or a normetanephrine precursor.
15. The medicament of claim 14, in which the normetanephrine
metabolic precursor is 4-hydroxy-3-methoxyphenylserine,
particularly L-threo-3-(4-hydroxy-3-methoxyphenyl)-serine.
16. The medicament of claim 13, in which the second antidepressant
is a norepinephrine reuptake inhibitor.
17. The medicament of claim 16, in which the norepinephrine
reuptake inhibitor is imipramine, desipramine or reboxetine.
18. The medicament of claim 16 in which the norepinephrine reuptake
inhibitor is nortriptyline, maprotiline, protriptyline,
trimipramine or venlafaxine.
19. The medicament of claim 16, in which the norepinephrine
reuptake inhibitor is amitriptyline, amoxapine, doxepin,
nefazodone, or lamotrigine.
20. The medicament of claim 13, in which the norepinephrine uptake
2 inhibitor and the second antidepressant are formulated in a
single medicament.
21. The medicament of claim 13 in which the norepinephrine uptake 2
inhibitor is combined with a selective serotonin reuptake
inhibitor.
22. The medicament of claim 13 in which the norepinephrine uptake 2
inhibitor is combined with a monoamine oxidase inhibitor.
23. The medicament of claim 14 or claim 15 further comprising a
peripheral decarboxylase inhibitor.
24. The medicament of claim 23 in which the peripheral
decarboxylase inhibitor is carbidopa.
25. A method of treating depression by administering to a patient
in need of such treatment an antidepressant amount of a
norepinephrine uptake 2 inhibitor, or a precursor thereof.
26. A method of making a medicament for treating depression by
including in the medicament a depression counteracting amount of a
norepinephrine uptake 2 inhibitor or precursor thereof.
27. The method of claim 25 or claim 26 in which the precursor to a
norepinephrine uptake 2 inhibitor is 4H-3MePS, particularly
L-threo-3-(4H-3MePS).
28. The method of claim 27 further comprising administering a
peripheral decarboxylase inhibitor.
29. The method of any of the foregoing claims further comprising
administration of an alpha.sub.2-adrenergic receptor antagonist in
conjunction with the norepinephrine uptake 2 inhibitor.
30. The method of claim 29 in which the alpha.sub.2-adrenergic
receptor antagonist is idazoxan.
Description
TECHNICAL FIELD
[0001] This invention is in the general field of central nervous
system medications, particularly antidepressants.
BACKGROUND
[0002] Norepinephrine is released from presynaptic noradrenergic
neurons into the synapse. One therapy for clinical depression is
administration of drugs known as norepinephrine reuptake
inhibitors, such as imipramine, desipramine, or reboxetine, which
inhibit the reuptake of norepinephrine into the presynaptic neuron
("uptake 1"), the main mechanism of inactivating norepinephrine at
the synapse. Reuptake inhibition thus increases synaptic
norepinephrine levels. [Bolden-Watson and Richelson, Life Sciences,
52:1023-1029 (1993), hereby incorporated by reference, discloses a
method for determining reuptake inhibition.]Typically these drugs
are administered chronically and there may be a significant delay,
e.g. 4-6 weeks, between the onset of therapy and clinical
improvement.
[0003] Other therapies feature the administration of other classes
of drugs, such as monoamine oxidase (MAO) inhibitors or selective
serotonin reuptake inhibitors.
[0004] In a study of depressed patients treated with the
antidepressant imipramine, there was a gradual increase in urinary
levels of normetanephrine, the O-methylated metabolite of
norepinephrine, during the period of definitive clinical
improvement from depression-Schildkraut et al., American Journal of
Psychiatry, 123:690-700 (1966).
SUMMARY
[0005] Norepinephrine present in the synapse or other extraneuronal
spaces can also be taken up into glia and other cells by a
mechanism known as uptake 2 or extraneuronal uptake. In glia (and
other cells), such norepinephrine may be converted to its
O-methylated metabolite, normetanephrine, which is an inhibitor of
uptake 2. Administration of compounds that lead to an increase in
brain levels of norepinephrine uptake 2 inhibitors will enhance the
antidepressant effect of norepinephrine reuptake inhibitors.
Accordingly, one aspect of the invention features co-administration
and co-formulation of a compound that inhibits norepinephrine
uptake 2 (or a precursor thereof) together with another
antidepressant compound, particularly a norepinephrine reuptake
inhibitor (acting at uptake 1). The uptake 2 inhibitor or precursor
may be normetanephrine or a normetanephrine precursor that crosses
the blood-brain barrier where it is converted to normetanephrine,
the latter being a norepinephrine uptake 2 inhibitor that increases
the level of extraneuronal norepinephrine in the brain. The effect
of other antidepressants should also be enhanced by the use of
norepinephrine uptake 2 inhibitors. Among the other antidepressants
to be evaluated are MAO inhibitors and selective serotonin reuptake
inhibitors.
[0006] In clinical studies of depressed patients treated with the
norepinephrine reuptake inhibitor antidepressant desipramine, we
have found that after one week of treatment, there were small
decreases in urinary levels of norepinephrine and normetanephrine.
However, by the fourth week of treatment with desipramine, urinary
levels of norepinephrine and normetanephrine showed statistically
significant increases, and these increases were even more
pronounced and statistically significant after six weeks of
treatment with desipramine. Similar findings were observed in
studies of levels of norepinephrine in plasma during treatment with
desipramine in these patients. (Plasma levels of normetanephrine
were not measured in these studies.)
[0007] Without wishing to bind ourselves to a specific molecular
mechanism to the exclusion of other mechanisms, various substances
such as normetanephrine block uptake of norepinephrine via uptake
2. Moreover, such uptake 2 inhibitors complement norepinephrine
uptake 1 inhibitors, in that each works independently to enhance
extraneuronal norepinephrine levels in the brain. The invention
therefore further increases levels of norepinephrine present at the
synapse and surrounding extraneuronal spaces, thereby providing a
more rapid antidepressant effect for norepinephrine reuptake
inhibitors.
[0008] Again, without wishing to bind ourselves exclusively to a
mechanism of action, we note the following regarding the
invention's ability to reduce the time required for clinical
antidepressant effects from the administration of norepinephrine
reuptake inhibitors. Reuptake inhibition at uptake 1 sites
initially results in an increase of norepinephrine at the synapse.
This results in the activation of presynaptic
alpha.sub.2-adrenergic receptors as well as somatodendritic
alpha.sub.2-adrenergic receptors on noradrenergic neuronal cell
bodies in the locus coeruleus (the nucleus containing
norepinephrine cell bodies in the brain), and the consequent
feedback inhibition of locus coeruleus firing rates and
norepinephrine release from presynaptic noradrenergic neurons. Over
time, the continued presence of norepinephrine in the synapse
produces a decrease in the sensitivity of these
alpha.sub.2-adrenergic receptors, and this decrease in the
sensitivity of presynaptic and somatodendritic
alpha.sub.2-adrenergic receptors contributes to an increase of
locus coeruleus firing rates and an increased release of
norepinephrine from presynaptic neurons--Linner et al., Biological
Psychiatry 46: 766-774 (1999); Schildkraut et al., Science,
168:867-869 (1970)--further enhancing synaptic levels of
norepinephrine during long-term administration of norepinephrine
reuptake inhibitor drugs and enhancing clinical antidepressant
effects. By directly inhibiting norepinephrine uptake 2, the
invention will further enhance the accumulation of norepinephrine
in the synapse and extraneuronal spaces and should reduce the time
required for clinical improvement during the administration of
norepinephrine reuptake (uptake 1) inhibitors. Moreover
administration of an alpha.sub.2-adrenergic receptor antagonist
(e.g. idazoxan) in conjunction with a norepinephrine uptake 2
inhibitor (with or without a norepinephrine reuptake (uptake 1)
inhibitor) would further enhance the accumulation of norepinephrine
in the synapse and extraneuronal spaces.
[0009] Normetanephrine also may be a biological alpha.sub.2
adrenoreceptor antagonist--Lenz et al., Canadian Journal of
Physiology and Pharmacology 69: 929-937 (1991)--and, as an
alpha.sub.2-adrenergic receptor antagonist, normetanephrine may
increase both locus coeruleus firing rates and the rate of release
of norepinephrine from presynaptic neurons. Thus, normetanephrine
may contribute to clinical antidepressant effects by
pharmacological mechanisms in addition to or other than blocking
uptake 2.
[0010] Uptake 2 inhibitors or precursors that are particularly
useful are those that cross the blood/brain barrier where they are
converted to normetanephrine, the latter being a compound that acts
to inhibit uptake 2. Specific normetanephrine precursors that are
useful according to the invention include those metabolized via a
pathway that includes the conversion of
L-threo-3-(4-hydroxy-3-methoxyphenyl)-serine ("L-threo-4H-3MePS")
into normetanephrine by an L-aromatic amino acid decarboxylase
present in the brain. In one detailed embodiment, the invention
features the use of 4H-3MePS itself (particularly
L-threo-4H-3MePS).
[0011] The invention can be used in conjunction with compounds
blocking peripheral decarboxylation of 4H-3MePS (such as
carbidopa), a process that would otherwise convert some 4H-3MePS
into normetanephrine, which is less able to cross the blood/brain
barrier. Preferably, the norepinephrine reuptake inhibitor
component of the combination is imipramine, desipramine, or
reboxetine. Other norepinephrine reuptake inhibitors that can be
used include nortriptyline, maprotiline, protriptyline,
trimipramine, and venlafaxine. Still other candidates include
amitriptyline, amoxapine, doxepin, nefazodone, and lamotrigine.
[0012] Advantageously, the norepinephrine uptake 2 inhibitor and
the second antidepressant are formulated in a single
medicament.
[0013] A second aspect of the invention features administering an
uptake 2 inhibitor (or a precursor thereof, such as
L-threo-4H-3MePS), that provides antidepressant effect by
itself.
[0014] The details of one or more embodiments of the invention are
set forth in the detailed description below. Other features,
objects, and advantages of the invention will be apparent from the
description and drawings, and from the claims.
DESCRIPTION OF DRAWINGS
[0015] FIG. 1 shows the in vivo conversion of 4H-3MePS to
normetanephrine.
DETAILED DESCRIPTION
[0016] I. The uptake 2 inhibitor or precursor thereof
[0017] The uptake 2 inhibitor or precursor thereof can be
normetanephrine or normetanephrine metabolic precursors that are
metabolized via a pathway concluding with the conversion of
L-threo-3- (4-hydroxy-3-methoxyphenyl)-serine ("L-threo-4H-3MePS")
into normetanephrine by an L-aromatic amino acid decarboxylase
present in the brain. While we do not rule out the possibility that
there may be other compounds in the pathway that would be useful in
the invention, we have identified 4H-3MePS itself as the preferred
precursor compound. The formula of 4H-3MePS and its conversion to
normetanephrine are illustrated in FIG. 1.
[0018] The compound can be obtained from commercially available
starting materials by the general method described in U.S. Pat. No.
3,723,514, which is hereby incorporated by reference. Optically
active 4H-3MePS (particularly the L-threo-stereoisomer) may be
obtained by reacting a derivative of racemic 4H-3MePS with an
optically active base or an optically active acid, as described in
the '514 patent.
[0019] Those skilled in the art will understand that, in addition
to normetanephrine precursors, other uptake 2 inhibitors or
precursors could be used. For example, normetanephrine itself,
formulated in a way that crosses the blood/brain barrier could be
used. Finally, the normetanephrine precursors may be replaced by or
co-administered with other uptake 2 inhibitors, such as cortisol,
cimetidine, clonidine, quinine, metanephrine,
3-O-methylisoprenaline, amphetamine, phenethylamine,
phenoxybenzamine, phentolamine, prazosin.
[0020] The ability of a compound to inhibit uptake 2 of
norepinephrine can be verified by the general methods described in
Russ et al., Eur. J. Neurosci. 8:1256-1264 (1996), or Streich et
al. Naunyn-Schmiedeberg's Arch Pharmacol., 353:328-333 (1996), each
of which is hereby incorporated by reference.
[0021] II. Co-administration with reuptake inhibitors or other
antidepressants
[0022] As noted, the normetanephrine precursor or other uptake 2
inhibitors or precursors may be combined with norepinephrine
reuptake inhibitors, i.e., those that inhibit norepinephrine uptake
1. Specifically, the uptake 2 inhibitor or precursor may be
combined with: imipramine, desipramine, or reboxetine. Other
norepinephrine reuptake inhibitors are: nortriptyline, maprotiline,
protriptyline, trimipramine, and venlafaxine. Still other reuptake
inhibitors include: amitriptyline, amoxapine, doxepin, nefazodone,
and lamotrigine.
[0023] The normetanephrine precursors may also be combined with
other antidepressants such as monoamine oxidase inhibitors
(phenelzine, tranylcypromine, isocarboxazid, selegiline
(L-deprenyl)) or selective serotonin reuptake inhibitors
(fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram).
Other compounds that can be evaluated for use in the invention
include: stimulants (e.g., amphetamine) or other drugs that
presumably have antidepressant effect such as adinazolam,
adrafinil, amineptine, befloxatone, brofaromine, bupropion,
captopril (capoten), clomipramine, corticotropin-releasing factor
(CRF) antagonists, dothiepin (prothiaden), duloxetine, fengabine,
flesinoxan, idazoxan, inositol, lofepramine, mianserin (bolvidon,
norval), medifoxamine, milnacipran, minaprine, mirtazapine,
moclobemide, modafanil, ondansetron (zofran), ProzacII, ritanserine
(tisterton), rolipram, roxindole, S-adenosyl-L-methionine (SAMe),
substance P antagonists, sulpiride (dogmatil), sunepitron,
tianeptine, and trazodone.
[0024] III. Administration of the uptake 2 inhibitor or
precursor
[0025] The compounds to be administered can be formulated into a
suitable pharmaceutical preparation by known techniques. For
example the '514 patent discloses tablet and capsule formulations.
Such formulations typically comprise the active agent (or the agent
in a salt form) and a pharmaceutically acceptable carrier. As used
herein the language "pharmaceutically acceptable carrier" is
intended to include any and all solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents, and the like, compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active compound, use thereof in the compositions is contemplated.
Supplementary active compounds can also be incorporated into the
compositions.
[0026] A pharmaceutical composition of the invention is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include oral, intravenous,
intradermal, subcutaneous, transdermal (topical), transmucosal
(e.g. intranasal), and rectal.
[0027] By far the most convenient route of administration is oral
(ingestion). Oral compositions generally include an inert diluent
or an edible carrier. They can be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches, or capsules.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition. The tablets,
pills, capsules, troches and the like can contain any of the
following ingredients, or compounds of a similar nature: a binder
such as microcrystalline cellulose, gum tragacanth or gelatin; an
excipient such as starch or lactose, a disintegrating agent such as
alginic acid, Primogel, or corn starch; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon
dioxide; a sweetening agent such as sucrose or saccharin; or a
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring.
[0028] In one embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation and Nova
Pharmaceuticals, Inc. Liposomal suspensions can also be used as
pharmaceutically acceptable carriers. These can be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811.
[0029] It is especially advantageous to formulate oral compositions
in dosage unit form for ease of administration and uniformity of
dosage. Dosage unit form as used herein refers to physically
discrete units suited as unitary dosages for the subject to be
treated; each unit containing a predetermined quantity of active
compound calculated to produce the desired therapeutic effect in
association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are
dictated by and directly dependent on the unique characteristics of
the active compound and the particular therapeutic effect to be
achieved, and the limitations inherent in the art of compounding
such an active compound for the treatment of individuals.
[0030] The pharmaceutical compositions can be included in a
container, pack, or dispenser together with instructions for
administration.
[0031] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *