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Weight Loss Patent Abstract
Disclosed are compositions for affecting weight loss comprising
bupropion and a second compound, where the second compound causes
increased agonism of a melanocortin 3 receptor (MC3-R) or a melanocortin
4 receptor (MC4-R) compared to normal physiological conditions,
antagonizes cannabinoid receptor activity, or is useful in the treatment
of bipolar disorders. Also disclosed are methods of affecting weight
loss, increasing energy expenditure, increasing satiety in an individual,
or suppressing the appetite of an individual, comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion and a compound that enhances .alpha.-MSH
activity, antagonizes cannabinoid receptor activity, or is useful
in the treatment of bipolar disorders.
Weight Loss Patent Claims
1. A composition for affecting weight loss comprising bupropion,
or a metabolite thereof, and a second compound, wherein said second
compound causes increased agonism of a melanocortin 3 receptor (MC3-R)
or a melanocortin 4 receptor (MC4-R) compared to normal physiological
conditions, or wherein said second compound antagonizes cannabinoid
receptor activity.
2. The composition of claim 1, wherein said second compound is
selected from the group consisting of a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
3. The composition of claim 2, wherein said second compound is
selected from the group consisting of fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and
venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
4. The composition of claim 2, wherein said second compound is
sibutramine.
5. The composition of claim 1, wherein said metabolite of bupropion
is radafaxine.
6. The composition of claim 1, wherein said second compound is
a dopamine reuptake inhibitor.
7. The composition of claim 6, wherein said dopamine reuptake inhibitor
is phentermine.
8. The composition of claim 1, wherein said second compound is
a cannabinoid receptor antagonist.
9. The composition of claim 8, wherein said cannabinoid receptor
antagonist is selected from the group consisting of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-H-indol-3-yl](4-methoxyphenyl-
)methanone), LY320 135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof.
10. The composition of claim 8, wherein said cannabinoid receptor
antagonist is SR141716A (rimonabant).
11. The composition of claim 8, wherein said second compound is
AM251.
12. A composition for the treatment of obesity or for affecting
weight loss comprising bupropion, or a metabolite thereof, or a
pharmaceutically acceptable salt or prodrug thereof, and a second
compound, where the second compound is an agent useful in the treatment
of bipolar disorders.
13. The composition of claim 12, wherein said metabolite of bupropion
is radafaxine.
14. The composition of claim 12, wherein said agent useful in the
treatment of bipolar disorders is selected from the group consisting
of lithium, valproic acid, valproate, divalproex, carbamezepine,
oxycarbamezepine, lamotrogine, tiagabine, and benzodiazepines.
15. The composition of claim 12, wherein said agent useful in the
treatment of bipolar disorders is selected from the group consisting
of valproic acid, valproate, and divalproex.
16. A method of affecting weight loss, comprising identifying an
individual in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that enhances
.alpha.-MSH activity, antagonizes cannabinoid receptor activity,
or is useful in the treatment of bipolar disorders.
17. The method of claim 16, wherein said individual has a body
mass index greater than 25.
18. The method of claim 16, wherein said metabolite of bupropion
is radafaxine.
19. The method of claim 16, wherein said compound that enhances
.alpha.-MSH activity is selected from the group consisting of phentermine
and sibutramine.
20. The method of claim 16, wherein said cannabinoid receptor antagonist
is selected from the group consisting of SR141716A (rimonabant)
and AM251.
21. The method of claim 16, wherein said compound useful in the
treatment of bipolar disorders is selected from the group consisting
of valproic acid, valproate, and divalproex.
Weight Loss Patent Description
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to the U.S. Provisional Patent Application Ser. No. 60/598,558,
filed on Aug. 3, 2004, by Weber et al., and entitled "COMBINATION
OF BUPROPION AND A SECOND COMPOUND FOR AFFECTING WEIGHT LOSS,"
the entire disclosure of which is hereby incorporated by reference
herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is in the field of pharmaceutical
compositions and methods for the treatment of obesity and for affecting
weight loss in individuals.
[0004] 2. Description of the Related Art
[0005] Obesity is a disorder characterized by the accumulation
of excess fat in the body. Obesity has been recognized as one of
the leading causes of disease and is emerging as a global problem.
Increased instances of complications such as hypertension, non-insulin
dependent diabetes mellitus, arteriosclerosis, dyslipidemia, certain
forms of cancer, sleep apnea, and osteoarthritis have been related
to increased instances of obesity in the general population.
[0006] Obesity has been defined in terms of body mass index (BMI).
BMI is calculated as weight (kg)/[height (m)].sup.2. According to
the guidelines of the U.S. Centers for Disease Control and Prevention
(CDC), and the World Health Organization (WHO) (World Health Organization.
Physical status: The use and interpretation of anthropometry. Geneva,
Switzerland: World Health Organization 1995. WHO Technical Report
Series), for adults over 20 years old, BMI falls into one of these
categories: below 18.5 is considered underweight, 18.5-24.9 is considered
normal, 25.0-29.9 is considered overweight, and 30.0 and above is
considered obese.
[0007] Prior to 1994, obesity was generally considered a psychological
problem. The discovery of the adipostatic hormone leptin in 1994
(Zhang et al., "Positional cloning of the mouse obese gene
and its human homologue," Nature 1994; 372:425-432) brought
forth the realization that, in certain cases, obesity may have a
biochemical basis. A corollary to this realization was the idea
that the treatment of obesity may be achieved by chemical approaches.
Since then, a number of such chemical treatments have entered the
market. The most famous of these attempts was the introduction of
Fen-Phen, a combination of fenfluramine and phentermine. Unfortunately,
it was discovered that fenfluramine caused heart-valve complications,
which in some cases resulted in the death of the user. Fenfluramine
has since been withdrawn from the market. There has been some limited
success with other combination therapy approaches, particularly
in the field of psychological eating disorders. One such example
is Devlin, et al., Int. J. Eating Disord. 28:325-332, 2000, in which
a combination of phentermine and fluoxetine showed some efficacy
in the treatment of binge eating disorders. Of course, this disorder
is an issue for only a small portion of the population.
[0008] In addition to those individuals who satisfy a strict definition
of medical obesity, a significant portion of the adult population
is overweight. These overweight individuals would also benefit from
the availability of an effective weight-loss composition. Therefore,
there is an unmet need in the art to provide pharmaceutical compositions
that can affect weight loss without having other adverse side effects.
SUMMARY OF THE INVENTION
[0009] Disclosed are compositions for affecting weight loss comprising
bupropion, or a metabolite thereof, and a second compound, where
the second compound causes increased agonism of a melanocortin 3
receptor (MC3-R) or a melanocortin 4 receptor (MC4-R) compared to
normal physiological conditions or causes antagonism of a cannabinoid
receptor activity.
[0010] Also disclosed are methods of affecting weight loss, increasing
energy expenditure, increasing satiety in an individual, or suppressing
the appetite of an individual, comprising identifying an individual
in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that enhances
.alpha.-MSH activity or antagonizes cannabinoid receptor activity.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0011] Arcuate nucleus neurons are known to be responsive to a
wide array of hormones and nutrients, including leptin, insulin,
gonadal steroids, and glucose. In addition to potential transport
mechanisms, peripheral substances may access these neurons via arcuate
cell bodies in and projections to the median eminence, a region
considered to be a circumventricular organ, which lacks a blood-brain
barrier. Cone et al., "The arcuate nucleus as a conduit for
diverse signals relevant to energy homeostasis," Int'l Journal
of Obesity (2001) 25, Suppl 5, S63-S67.
[0012] Administration of exogenous leptin activates a number of
different neurons in hypothalamic and brainstem cell groups that
bear leptin receptor. Leptin-responsive neurons in the arcuate nucleus
include both those containing neuropeptide Y (NPY) and agouti-related
peptide (AgRP) in the medial part of the nucleus and those containing
both pro-opiomelanocortin (POMC) and its derivatives, including
.alpha.-melanocyte stimulating hormone (.alpha.-MSH), as well as
cocaine and amphetamine-related transcript (CART). Saper et al.,
"The need to feed: Homeostatic and hedonic control of eating,"
Neuron, 36:199-211 (2002).
[0013] The leptin-responsive POMC neurons in the arcuate nucleus
are thought to cause anorexia and weight reduction by means of the
action of .alpha.-MSH on melanocortin 3 and/or 4 receptors (MC3-R,
MC4-R). The highest MC3-R expression level is in the hypothalamus
and limbic system, whereas MC4-R mRNA is expressed in virtually
all major brain regions. Some of the metabolic effects resulting
from stimulation of MC4-R are decreased food intake and an increase
in energy expenditure through stimulation of thyrotropin-releasing
hormone and activation of the sympathetic nervous system. Targeted
deletion of the MC4-R gene produces obesity, hyperphagia, hyperinsulinemia,
and reduced energy expenditure. Targeted deletion of MC3-R results
in increased adiposity due to decreased energy expenditure. Korner
et al., "The emerging science of body weight regulation and
its impact on obesity treatment," J. Clin. Invest. 111(5):565-570
(2003). Thus, increased concentrations of .alpha.-MSH in the central
nervous system (CNS) increase its action on MC3-R and/or MC4-R and
result in a suppressed appetite.
[0014] POMC neurons also release .beta.-endorphin when they release
.alpha.-MSH. .beta.-endorphin is an endogenous agonist of the .mu.-opioid
receptors (MOP-R), found on the POMC neurons. Stimulation of MOP-R
decreases the release of .alpha.-MSH. This is a biofeedback mechanism
that under normal physiological conditions controls the concentration
of .alpha.-MSH in the CNS. Thus, blocking MOP-R by opioid antagonists
will break the feedback mechanism, which results in continued secretion
of .alpha.-MSH and an increase in its concentration in the CNS.
[0015] A second population of neurons in the arcuate nucleus tonically
inhibits the POMC neurons. These POMC-inhibiting neurons secrete
NPY, the neurotransmitter .gamma.-aminobutyric acid (GABA), and
AgRP. NPY and GABA inhibit POMC neurons, via NPY Y1 receptors and
GABA receptors, respectivley. Thus, within the arcuate nucleus NPY
and GABA inhibit the release of .alpha.-MSH, and therefore are stimulators
of feeding. It is known that leptin inhibits the release of GABA
from NPY terminals synapsing onto POMC neurons, whereas ghrelin,
an orexigenic peptide, stimulates the ghrelin receptors on NPY neurons
and increase the secretion of NPY and GABA onto the POMC cells,
which in turn inhibits the release of .alpha.-MSH.
[0016] AgRP stimulates food intake in the rat through antagonism
of the interaction of .alpha.-MSH at MC4-R. Expression of the AgRP
gene is suppressed by leptin.
[0017] Serotonin, also known as 5-hydroxytryptamine or 5-HT, activates
the POMC neurons to secrete .alpha.-MSH. However, serotonin is taken
up and removed from action by specific transporters so that a single
serotonin molecule has short term effects. It is known that selective
serotonin re-uptake inhibitors (SSRIs) prevent the uptake of serotonin
and increase its concentrations in the CNS. Thus, SSRIs also increase
the secretion of .alpha.-MSH and its concentrations in the CNS.
[0018] Dopamine also increases the activity of POMC neurons to
secrete .alpha.-MSH. Like serotonin, dopamine is also taken up and
removed from action so that a single dopamine molecule has short
term effect. Dopamine re-uptake inhibitors, which prevent or reduce
the uptake of dopamine, can also increase the secretion of .alpha.-MSH
and its concentrations in the CNS.
[0019] Therefore, increased secretion of .alpha.-MSH through various
mechanisms, such as serotonin re-uptake inhibition, are among the
strategies that the methods and pharmaceutical compositions of the
present invention pursue in order to produce a biochemical anorexigenic
effect.
[0020] The present invention provides a multi-faceted combination
therapy approach to the problem of weight loss. It addresses not
just single molecules, messengers, or receptors, but instead acts
on multiple points in the feeding and satiety pathway. Aspects of
the present invention are directed to increasing the concentrations
of .alpha.-MSH in the CNS by stimulating the release of .alpha.-MSH,
suppressing its metabolism, reducing the antagonism of its interaction
at MC3/4-R, and suppressing any feedback mechanisms that slow or
stop its release. Aspects of the present invention include pharmaceutical
compositions whose components achieve one or more of these functions.
The present inventors have discovered that a combination of two
or more of the compounds disclosed herein results in a synergistic
effect that affects weight loss more quickly and on a more permanent
basis.
[0021] Thus, in a first aspect, the present invention is directed
to a composition for the treatment of obesity or for affecting weight
loss comprising bupropion, or a metabolite thereof, or a pharmaceutically
acceptable salt or prodrug thereof, and a second compound, where
the second compound causes increased agonism of a melanocortin 3
receptor (MC3-R) or a melanocortin 4 receptor (MC4-R) compared to
normal physiological conditions.
[0022] In another aspect, the present invention is directed to
a composition for the treatment of obesity or for affecting weight
loss comprising bupropion, or a metabolite thereof, or a pharmaceutically
acceptable salt or prodrug thereof, and a second compound, where
the second compound is a cannabinoid receptor antagonist.
[0023] In yet another aspect, the the present invention is directed
to a composition for the treatment of obesity or for affecting weight
loss comprising bupropion, or a metabolite thereof, or a pharmaceutically
acceptable salt or prodrug thereof, and a second compound, where
the second compound is an agent useful in the treatment of bipolar
disorders.
[0024] In some embodiments, the second compound is not a compound
that causes increased agonism of a melanocortin 3 receptor (MC3-R)
or a melanocortin 4 receptor (MC4-R) compared to normal physiological
conditions, while in other embodiments, the second compound is not
a cannabinoid receptor antagonist.
[0025] Bupropion, whose chemical name is (.+-.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone,
is the active ingredient in the drugs marketed as ZYBAN.RTM. and
WELLBUTRIN.RTM., and is usually administered as a hydrochloride
salt. Throughout the present disclosure, whenever the term "bupropion"
is used, it is understood that the term encompasses bupropion as
a free base, or as a physiologically acceptable salt thereof. Bupropion
may be administered orally as 75 mg or 100 mg tablets, or as 100
mg or 150 mg tablets in a sustained release formulation. Preparing
tablets containing other dosages of bupropion is well within the
skill of those of ordinary skill in the art.
[0026] The metabolites of bupropion suitable for inclusion in the
methods and compositions disclosed herein include the erythro- and
threo-amino alcohols of bupropion, the erythro-amino diol of bupropion,
and morpholinol metabolites of bupropion. In some embodiments, the
metabolite of bupropion is (.+-.)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.
In some embodiments the metabolite is (-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol,
while in other embodiments, the metabolite is (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.
Preferably, the metabolite of bupropion is (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol,
which is known by its common name of radafaxine. The scope of the
present invention includes the above-mentioned metabolites of bupropion
as a free base, or as a physiologically acceptable salt thereof.
[0027] In certain embodiments, the second compound causes increased
activity of the POMC neurons, leading to greater agonism at MC3-R
and/or MC4-R.
[0028] In certain embodiments compositions and the methods described
herein cause weight loss in a mammal. The mammal may be selected
from the group consisting of mice, rats, rabbits, guinea pigs, dogs,
cats, sheep, goats, cows, primates, such as monkeys, chimpanzees,
and apes, and humans.
[0029] The term "pharmaceutically acceptable salt" refers
to a formulation of a compound that does not cause significant irritation
to an organism to which it is administered and does not abrogate
the biological activity and properties of the compound. Pharmaceutical
salts can be obtained by reacting a compound of the invention with
inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical
salts can also be obtained by reacting a compound of the invention
with a base to form a salt such as an ammonium salt, an alkali metal
salt, such as a sodium or a potassium salt, an alkaline earth metal
salt, such as a calcium or a magnesium salt, a salt of organic bases
such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
and salts thereof with amino acids such as arginine, lysine, and
the like.
[0030] A "prodrug" refers to an agent that is converted
into the parent drug in vivo. Prodrugs are often useful because,
in some situations, they may be easier to administer than the parent
drug. They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved solubility
in pharmaceutical compositions over the parent drug, or may demonstrate
increased palatability or be easier to formulate. An example, without
limitation, of a prodrug would be a compound of the present invention
which is administered as an ester (the "prodrug") to facilitate
transmittal across a cell membrane where water solubility is detrimental
to mobility but which then is metabolically hydrolyzed to the carboxylic
acid, the active entity, once inside the cell where water-solubility
is beneficial. A further example of a prodrug might be a short peptide
(polyaminoacid) bonded to an acid group where the peptide is metabolized
to provide the active moiety.
[0031] In certain embodiments, the second compound in the pharmaceutical
compositions of the present invention triggers the release of .alpha.-melanocyte
stimulating hormone ((.alpha.-MSH). The second compound may increase
the extracellular serotonin concentrations in the hypothalamus.
In some embodiments, the second compound is selected from the group
consisting of a selective serotonin reuptake inhibitor (SSRI), a
serotonin 2C agonist, and a serotonin 1B agonist. In further embodiments,
the second compound is selected, e.g., from the group consisting
of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
escitalopram, sibutramine, duloxetine, and venlafaxine, and a pharmaceutically
acceptable salt or prodrug thereof.
[0032] The terms "serotonin 1B receptor," "serotonin
2C receptor," "5-HT1b receptor," and "5-HT2c
receptor" refer to receptors found more commonly in rodents.
It is understood by those of skill in the art that other mammals
have serotonin receptors on various neurons that are analogous in
function and form to these receptors. Agonists or antagonists at
these non-rodent, preferably human, serotonin receptors are within
the scope of the present invention.
[0033] In certain embodiments, the second compound suppresses the
expression of the AgRP gene or the production or release of agouti-related
protein (AgRP). In some of these embodiments, the second compound
suppresses the activity of neurons that express AgRP.
[0034] In other embodiments, the second compound suppresses the
expression of the NPY gene or the production or release of neuropeptide
Y (NPY). In some of these embodiments, the second compound suppresses
the activity of neurons that express NPY. In further embodiments,
the second compound is selected from the group consisting of NPY
antagonists, ghrelin antagonists, and leptin. In certain other embodiments,
the second compound agonizes NPY Y2 receptor.
[0035] In some embodiments, the second compound is an NPY receptor
antagonist. In certain embodiments, the receptor is NPY Y1, while
in other embodiments the receptor is NPY Y5. In some embodiments,
the NPY receptor antagonist is S-2367, a compound developed by Shionogi
Co. Ltd. of Japan.
[0036] In certain embodiments, the second compound is selected
from .alpha.-MSH, melanotan, MT II (melanotan II, disclosed in U.S.
Pat. No. 5,674,839, which is hereby incorporated by reference in
its entirety), PT141 (developed by Palatin Technologies), the cyclic
peptide Maltose Binding Peptide 10 (MBP10), and HS014. MT II has
the structure Ac-Nle.sup.4-Asp.sup.5-His6-D-Phe.sup.7-Arg.sup.8-Trp.sup.9-Lys.sup.10-.a-
lpha.-MSH(4-10)-NH.sub.2. PT141 has the structure Ac-Nle-Asp-His-DPhe-Arg-Trp-Lys-OH.
HS014 has the structure cyclic [AcCys.sup.11, D-Nal.sup.14, Cys.sup.18,
Asp-NH.sub.2.sup.22]-.beta.-MSH(11-22) (as described in, for example,
Kask et al., Biochem. Biophys. Research Comm 245, 90-93 (1998)).
[0037] Other embodiments of the present invention include those
in which the second compound is selected from the group consisting
of a .gamma.-amino butyric acid (GABA) inhibitor, a GABA receptor
antagonist, and a GABA channel antagonist. By "GABA inhibitor"
it is meant a compound that reduces the production of GABA in the
cells, reduces the release of GABA from the cells, or reduces the
activity of GABA on its receptors, either by preventing the binding
of GABA to GABA receptors or by minimizing the effect of such binding.
The GABA inhibitor may be a 5-HT1b agonist or another agent that
inhibits the activity of NPY/AgRP/GABA neurons. In addition, the
GABA inhibitor may suppress the expression of the AgRP gene, or
the GABA inhibitor may suppress the production or release of AgRP.
It is, however, understood that a 5-HT1b agonist may inhibit the
NPY/AgRP/GABA neuron (and therefore activate POMC neurons) without
acting as an inhibitor of the GABA pathway.
[0038] In certain other embodiments the GABA inhibitor increases
the expression of the POMC gene. In some of these embodiments, the
GABA inhibitor increases the production or release of pro-opiomelanocortin
(POMC) protein. In certain other of these embodiments, the GABA
inhibitor increases the activity on POMC expressing neurons. In
some embodiments, the GABA inhibitor is topiramate.
[0039] In other embodiments the second compound is a dopamine reuptake
inhibitor. Phentermine is an example of a dopamine reuptake inhibitor.
In certain other embodiments, the second compound is a norepinephrine
reuptake inhibitor. Examples of norepinephrine reuptake inhibitors
include thionisoxetine, and reboxetine. Other embodiments include
those in which the second compound is a dopamine agonist. Some dopamine
agonists that are available on the market include cabergoline, amantadine,
lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
In further embodiments, the second compound is a norepinephrine
releaser, for example diethylpropion, or a mixed dopamine/norepinephrine
reuptake inhibitor, for example, atomoxatine.
[0040] In certain other embodiments, the second compound is a 5-HT1b
agonist, such as sumatriptan, almotriptan, naratriptan, frovatriptan,
rizatriptan, zomitriptan, and elitriptan.
[0041] In further embodiments, the second compound is an anticonvulsant.
The anticonvulsant may be selected from the group consisting of
zonisamide, topiramate, nembutal, lorazepam, clonazepam, clorazepate,
tiagabine, gabapentin, fosphenytoin, phenytoin, carbamazepine, valproate,
felbamate, levetiracetam, oxcarbazepine, lamotrigine, methsuximide,
and ethosuxmide.
[0042] In some embodiments, the second compound is a cannabinoid
receptor antagonist. Examples of this group of compounds include
AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-(2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and a pharmaceutically
acceptable salt or prodrug thereof. LY320135 and SR141716A have
the following structures.
[0043] In certain embodiments, the present invention relates to
a combination of bupropion and rimonabant. In other embodiments,
the present invention relates to a combination of radafaxine and
rimonabant.
[0044] In some embodiments, the second compound is an agent useful
in the treatment of bipolar disorders, which is selected from the
group consisting of lithium, valproic acid, valproate, divalproex,
carbamezepine, oxycarbamezepine, lamotrogine, tiagabine, and benzodiazepines.
In certain embodiments, the second compound is selected from the
group consisting of valproic acid, valproate, and divalproex. Divalproex
sodium is marketed as DEPAKOTE.RTM. by Abbot Laboratories.
[0045] In certain embodiments, the present invention relates to
a combination of bupropion and divalproex. In other embodiments,
the present invention relates to a combination of radafaxine and
divalproex.
[0046] In certain embodiments, the second compound itself may be
a combination of two or more compounds. For example, the second
compound may be a combination of a dopamine reuptake inhibitor and
a norepinephrine reuptake inhibitor, e.g. mazindol. Alternatively,
the second compound may be a combination of a SSRI and a norepinephrine
reuptake inhibitor, such as sibutramine, venlafaxine, and duloxetine.
[0047] In certain embodiments, the second compound is an activator
of the POMC neurons. Examples of POMC activators include Ptx1, leukemia
inhibitory factor (LIF), and interleukin 1 beta, (IL-1.beta.).
[0048] In certain embodiments, the present invention relates to
a combination of bupropion and olanzapine. In other embodiments,
the present invention relates to a combination of bupropion and
Zyprexa.RTM.. Further embodiments relate to a combination of radafaxine
and olanzapine, or to a combinatione of radafaxine and Zyperxa.RTM..
[0049] In certain embodiments, the compositions of the present
invention comprise a third compound, where the third compound is
selected from the group of compounds described above for the second
compound. In some embodiments, the composition of the invention
comprises bupropion, zonisamide, and Zyprexa.RTM.. In other embodiments,
the composition of the invention comprises radafaxine, zonisamide,
and Zyprexa.RTM..
[0050] In another aspect, the present invention relates to a method
of affecting weight loss, comprising identifying an individual in
need thereof and treating that individual with a combination of
bupropion, or a metabolite thereof, and a compound that enhances
.alpha.-MSH activity.
[0051] In another aspect, the present invention relates to a method
of affecting weight loss, comprising identifying an individual in
need thereof and treating that individual with a combination of
bupropion, or a metabolite thereof, and a compound that antagonizes
cannabinoid receptor activity.
[0052] In yet another aspect, the present invention is directed
to a method of affecting weight loss, comprising identifying an
individual in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that is an
agent useful in the treatment of bipolar disorders.
[0053] In certain embodiments, the individual has a body mass index
(BMI) greater than 25. In other embodiments, the individual has
a BMI greater than 30. In still other embodiments, the individual
has a BMI greater than 40. However, in some embodiments, the individual
may have a BMI less than 25. In these embodiments, it may be beneficial
for health or cosmetic purposes to affect weight loss, thereby reducing
the BMI even further.
[0054] In some of the embodiments set forth above, the compound
that enhances .alpha.-MSH activity does so by triggering the release
of .alpha.-MSH or increasing the activity of neurons that express
.alpha.-MSH. In some embodiments, the compound is a selective serotonin
reuptake inhibitor (SSRI) or a specific 5-HT receptor agonist. Examples
of SSRIs that can be used in the present invention include fluoxetine,
fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine,
duloxetine, and venlafaxine, and a pharmaceutically acceptable salt
or prodrug thereof.
[0055] In other embodiments, the compound is a .gamma.-amino butyric
acid (GABA) inhibitor. The GABA inhibitor may be a 5-HT1b receptor
agonist. The GABA inhibitor may suppress the expression of the AgRP
gene, or it may suppresses the production or release of AgRP. The
GABA inhibitor may suppress the expression or release of NPY. In
certain embodiments, the GABA inhibitor suppresses the activity
of neurons that express AgRP. For example, the GABA inhibitor may
be topiramate, 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinec-
arboxylic acid hydrochloride (NNC-711), or vigabatrin.
[0056] In certain embodiments, the method of invention set forth
above is practiced with the proviso that the individual is not suffering
from Prader-Willi syndrome or binge eating disorder. Thus, some
embodiments of the invention are to be distinguished from combination
therapy involving SSRI anti-depressants (e.g., fluoxetine) used
to treat physiological eating disorders such as binge eating disorder
or Prader-Willi syndrome. In these embodiments, the target population
is the population of individuals needing or desiring weight loss,
apart from needing treatment for Prader-Willi syndrome or binge
eating disorder.
[0057] Individuals suffering from depression may gain weight as
a result of their depression. In addition, certain depressed individuals
gain weight as a side effect of the depression therapy. In certain
embodiments, the method of invention set forth above is practiced
with the proviso that the individual is not suffering from depression.
In some embodiments, the individual's overweight state was not caused
by treatment for depression.
[0058] In some embodiments, the treating step of the above method
comprises administering to the individual a combination of bupropion,
or a metabolite thereof, and a second compound, where the second
compound enhances .alpha.-MSH activity.
[0059] In some embodiments, the treating step of the above method
comprises administering to the individual a combination of bupropion,
or a metabolite thereof, and a second compound, where the second
compound antagonizes cannabinoid receptor activity.
[0060] In some embodiments, the treating step of the above method
comprises administering to the individual a combination of bupropion,
or a metabolite thereof, and a second compound, where the second
compound is an agent useful in the treatment of bipolar disorders.
[0061] In some embodiments bupropion, or a metabolite thereof,
and the second compound are administered more or less simultaneously.
In other embodiments bupropion, or a metabolite thereof, is administered
prior to the second compound. In yet other embodiments, bupropion,
or a metabolite thereof, is administered subsequent to the second
compound.
[0062] In certain embodiments, bupropion, or a metabolite thereof,
and the second compound are administered individually. In other
embodiments, bupropion, or a metabolite thereof, and the second
compound are covalently linked to each other such that they form
a single chemical entity. The single chemical entity is then digested
and is metabolized into two separate physiologically active chemical
entities, one of which is bupropion, or a metabolite thereof, or
a pharmaceutically acceptable salt or prodrug thereof, and the other
one is the second compound.
[0063] In some embodiments, the compositions of the present invention
are a combination of bupropion, or a metabolite thereof, and one
or more of the following compounds: a SSRI, a dopamine reuptake
inhibitor, a dopamine/norepinephrine reuptake inhibitor, a norepinephrine
reuptake inhibitor, an opioid antagonist, a partial opioid agonist,
GABA inhibitor, a peripherally acting weight loss agent such as
metformin, a peptide, such as PYY, PYY.sub.3-36, or leptin, a cannabinoid
receptor antagonist, and an NPY receptor antagonist, e.g., an NPY
Y5 receptor antagonist, such as S-2367.
[0064] Examples of norepinephrine agonists include phendimetrazine
and benzphetamine. Examples of adenosine compounds include all xanthine
derivatives, such as adenosine, caffeine, theophylline, theobromine,
and aminophylline. An example of a cholinergic receptor antagonist
is nicotine.
[0065] In another aspect, the present invention relates to a method
of increasing satiety in an individual comprising identifying an
individual in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that enhances
.alpha.-MSH activity.
[0066] In another aspect, the present invention relates to a method
of increasing satiety in an individual comprising identifying an
individual in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that antagonizes
cannabinoid receptor activity.
[0067] In yet another aspect, the present invention is directed
to a method of increasing satiety in an individual, comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion, or a metabolite thereof, and a compound
that is an agent useful in the treatment of bipolar disorders.
[0068] In some embodiments, the treating step of the above method
comprises administering to the individual bupropion, or a metabolite
thereof, and a second compound, where the second compound enhances
.alpha.-MSH activity.
[0069] In some embodiments bupropion, or a metabolite thereof,
and the second compound are administered nearly simultaneously.
In other embodiments bupropion, or a metabolite thereof, is administered
prior to the second compound. In yet other embodiments, bupropion,
or a metabolite thereof, is administered subsequent to the second
compound.
[0070] In yet another aspect, the present invention relates to
a method of suppressing the appetite of an individual comprising
identifying an individual in need thereof and treating that individual
with a combination of bupropion, or a metabolite thereof, and a
compound that enhances .alpha.-MSH activity.
[0071] In yet another aspect, the present invention relates to
a method of suppressing the appetite of an individual comprising
identifying an individual in need thereof and treating that individual
with a combination of bupropion, or a metabolite thereof, and a
compound that antagonizes cannabinoid receptor activity.
[0072] In yet another aspect, the present invention is directed
to a method of suppressing the appetite of an individual, comprising
identifying an individual in need thereof and treating that individual
with a combination of bupropion, or a metabolite thereof, and a
compound that is an agent useful in the treatment of bipolar disorders.
[0073] In some embodiments, the treating step of the above method
comprises administering to the individual bupropion, or a metabolite
thereof, and a second compound, where the second compound enhances
.alpha.-MSH activity.
[0074] In some embodiments bupropion, or a metabolite thereof,
and the second compound are administered nearly simultaneously.
In other embodiments bupropion, or a metabolite thereof, is administered
prior to the second compound. In yet other embodiments, bupropion,
or a metabolite thereof, is administered subsequent to the second
compound.
[0075] In another aspect, the present invention relates to a method
of increasing energy expenditure in an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion, or a metabolite thereof, and a compound
that enhances .alpha.-MSH activity.
[0076] In another aspect, the present invention relates to a method
of increasing energy expenditure in an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion, or a metabolite thereof, and a compound
that antagonizes cannabinoid receptor activity.
[0077] In yet another aspect, the present invention is directed
to a method of increasing energy expenditure in an individual, comprising
identifying an individual in need thereof and treating that individual
with a combination of bupropion, or a metabolite thereof, and a
compound that is an agent useful in the treatment of bipolar disorders.
[0078] In some embodiments, the treating step of the above method
comprises administering to the individual bupropion, or a metabolite
thereof, and a second compound, where the second compound enhances
.alpha.-MSH activity.
[0079] In some embodiments bupropion, or a metabolite thereof,
and the second compound are administered nearly simultaneously.
In other embodiments bupropion, or a metabolite thereof, is administered
prior to the second compound. In yet other embodiments, bupropion,
or a metabolite thereof, is administered subsequent to the second
compound.
[0080] In certain embodiments, in the compositions or methods disclosed
herein, the second compound does not trigger the release of .alpha.-melanocyte
stimulating hormone (.alpha.-MSH). In some embodiments, the second
compound does not increase the extracellular serotonin concentrations
in the hypothalamus. In further embodiments, the second compound
is not a selective serotonin reuptake inhibitor (SSRI), is not a
serotonin 2C agonist, or is not a serotonin 1B agonist. In some
embodiments, the second compound is not fluoxetine, is not fluvoxamine,
is not sertraline, is not paroxetine, is not citalopram, is not
escitalopram, is not sibutramine, is not duloxetine, or is not venlafaxine.
[0081] In certain embodiments, in the compositions or methods disclosed
herein, the second compound does not suppress the expression of
the AgRP gene or the production or release of agouti-related protein
(AgRP). In some of these embodiments, the second compound does not
suppress the activity of neurons that express AgRP.
[0082] In other embodiments, in the compositions or methods disclosed
herein, the second compound does not suppress the expression of
the NPY gene or the production or release of neuropeptide Y (NPY).
In some of these embodiments, the second compound does not suppress
the activity of neurons that express NPY. In further embodiments,
the second compound is not an NPY antagonist, is not a ghrelin antagonist,
or is not leptin. In certain other embodiments, the second compound
does not agonize NPY Y2 receptor.
[0083] In some embodiments, in the compositions or methods disclosed
herein, the second compound is not an NPY receptor antagonist. In
certain embodiments, the second compound is not an NPY Y1 receptor
antagonist, while in other embodiments the second compound is not
an NPY Y5receptor antagonist. In some embodiments, the NPY receptor
antagonist is not S-2367.
[0084] In other embodiments, in the compositions or methods disclosed
herein, the second compound is not a GABA inhibitor, is not a GABA
receptor antagonist, or is not a GABA channel antagonist.
[0085] In certain other embodiments, in the compositions or methods
disclosed herein, the GABA inhibitor does not increase the expression
of the POMC gene. In some of these embodiments, the GABA inhibitor
does not increase the production or release of POMC protein. In
certain other of these embodiments, the GABA inhibitor does not
increase the activity on POMC expressing neurons. In some embodiments,
the GABA inhibitor is not topiramate.
[0086] In other embodiments, in the compositions or methods disclosed
herein, the second compound is not a dopamine reuptake inhibitor.
In other embodiments, the dopamine reuptake inhibitor is not phentermine.
In certain other embodiments, the second compound is not a norepinephrine
reuptake inhibitor. In other embodiments, the norepinephrine reuptake
inhibitor is not thionisoxetine or is not reboxetine. In further
embodiments, the second compound is not a dopamine agonist. In some
embodiments, the dopamine agonist is not cabergoline, is not amantadine,
is not lisuride, is not pergolide, is not ropinirole, is not pramipexole,
or is not bromocriptine. In further embodiments, the second compound
is not a norepinephrine releaser. In some embodiments, the norepinephrine
releaser is not diethylpropion. In certain embodiments, the second
compound is not a mixed dopamine/norepinephrine reuptake inhibitor.
In some embodiments, the mixed dopamine/norepinephrine reuptake
inhibitor is not atomoxatine.
[0087] In certain other embodiments, in the compositions or methods
disclosed herein, the second compound is not a 5-HT1b agonist. In
some embodiments, the 5-HT1b agonist is not sumatriptan, is not
almotriptan, is not naratriptan, is not frovatriptan, is not rizatriptan,
is not zomitriptan, or is not elitriptan.
[0088] In further embodiments, in the compositions or methods disclosed
herein, the second compound is not an anticonvulsant. In some embodiments,
the anticonvulsant is not zonisamide, is not topiramate, is not
nembutal, is not lorazepam, is not clonazepam, is not clorazepate,
is not tiagabine, is not gabapentin, is not fosphenytoin, is not
phenytoin, is not carbamazepine, is not valproate, is not felbamate,
is not levetiracetam, is not oxcarbazepine, is not lamotrigine,
is not methsuximide, or is not ethosuxmide.
[0089] In some embodiments, in the compositions or methods disclosed
herein, the second compound is not a cannabinoid receptor antagonist.
In some embodiments, cannabinoid receptor antagonist is not AM251,
is not AM281, is not AM630, is not LY320135, or is not SR141716A.
[0090] In certain embodiments, in the compositions or methods disclosed
herein, the second compound is not an activator of the POMC neurons.
In some embodiments, the activator of the POMC neurons is not Ptx1
or is not IL-1.beta..
[0091] In certain embodiments disclosed herein, an individual is
given a pharmaceutical composition comprising a combination of two
or more compounds to affect weight loss. In some of these embodiments,
each compound is a separate chemical entity. However, in other embodiments,
the two compounds are joined together by a chemical linkage, such
as a covalent bond, so that the two different compounds form separate
parts of the same molecule. The chemical linkage is selected such
that after entry into the body, the linkage is broken, such as by
enzymatic action, acid hydrolysis, base hydrolysis, or the like,
and the two separate compounds are then formed.
[0092] Thus, in another aspect, the present invention relates to
synthetic routes to novel molecules in which an opioid antagonist
is linked by a flexible linker to another compound disclosed herein.
[0093] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of bupropion, or a metabolite
thereof, and a compound that causes increased agonism of a melanocortin
3 receptor (MC3-R) or a melanocortin 4 receptor (MC4-R) compared
to normal physiological conditions, as described above, or comprising
a linked molecule, as described herein, and a physiologically acceptable
carrier, diluent, or excipient, or a combination thereof.
[0094] The term "pharmaceutical composition" refers to
a mixture of a compound of the invention with other chemical components,
such as diluents or carriers. The pharmaceutical composition facilitates
administration of the compound to an organism. Multiple techniques
of administering a compound exist in the art including, but not
limited to, oral, injection, aerosol, parenteral, and topical administration.
Pharmaceutical compositions can also be obtained by reacting compounds
with inorganic or organic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid
and the like.
[0095] The term "carrier" defines a chemical compound
that facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier
as it facilitates the uptake of many organic compounds into the
cells or tissues of an organism.
[0096] The term "diluent" defines chemical compounds
diluted in water that will dissolve the compound of interest as
well as stabilize the biologically active form of the compound.
Salts dissolved in buffered solutions are utilized as diluents in
the art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low concentrations,
a buffered diluent rarely modifies the biological activity of a
compound.
[0097] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0098] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical compositions
where they are mixed with other active ingredients, as in combination
therapy, or suitable carriers or excipient(s). Techniques for formulation
and administration of the compounds of the instant application may
be found in "Remington's Pharmaceutical Sciences," Mack
Publishing Co., Easton, Pa., 18th edition, 1990.
[0099] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, or intestinal administration; parenteral
delivery, including intramuscular, subcutaneous, intravenous, intramedullary
injections, as well as intrathecal, direct intraventricular, intraperitoneal,
intranasal, or intraocular injections.
[0100] Alternately, one may administer the compound in a local
rather than systemic manner, for example, via injection of the compound
directly in the renal or cardiac area, often in a depot or sustained
release formulation. Furthermore, one may administer the drug in
a targeted drug delivery system, for example, in a liposome coated
with a tissue-specific antibody. The liposomes will be targeted
to and taken up selectively by the organ.
[0101] The pharmaceutical compositions of the present invention
may be manufactured in a manner that is itself known, e.g., by means
of conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0102] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the active
compounds into preparations which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration
chosen. Any of the well-known techniques, carriers, and excipients
may be used as suitable and as understood in the art; e.g., in Remington's
Pharmaceutical Sciences, above.
[0103] For injection, the agents of the invention may be formulated
in aqueous solutions, preferably in physiologically compatible buffers
such as Hanks's solution, Ringer's solution, or physiological saline
buffer. For transmucosal administration, penetrants appropriate
to the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0104] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable
the compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions
and the like, for oral ingestion by a patient to be treated. Pharmaceutical
preparations for oral use can be obtained by mixing one or more
solid excipient with pharmaceutical combination of the invention,
optionally grinding the resulting mixture, and processing the mixture
of granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, gum tragacanth,
methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents
may be added, such as the cross-linked polyvinyl pyrrolidone, agar,
or alginic acid or a salt thereof such as sodium alginate.
[0105] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene
glycol, and/or titanium dioxide, lacquer solutions, and suitable
organic solvents or solvent mixtures. Dyestuffs or pigments may
be added to the tablets or dragee coatings for identification or
to characterize different combinations of active compound doses.
[0106] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in admixture
with filler such as lactose, binders such as starches, and/or lubricants
such as talc or magnesium stearate and, optionally, stabilizers.
In soft capsules, the active compounds may be dissolved or suspended
in suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers may be added. All
formulations for oral administration should be in dosages suitable
for such administration.
[0107] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0108] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs
or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin for use
in an inhaler or insufflator may be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0109] The compounds may be formulated for parenteral administration
by injection, e.g., by bolus injection or continuous infusion. Formulations
for injection may be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents.
[0110] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be prepared
as appropriate oily injection suspensions. Suitable lipophilic solvents
or vehicles include fatty oils such as sesame oil, or synthetic
fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl cellulose,
sorbitol, or dextran. Optionally, the suspension may also contain
suitable stabilizers or agents which increase the solubility of
the compounds to allow for the preparation of highly concentrated
solutions.
[0111] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0112] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing conventional
suppository bases such as cocoa butter or other glycerides.
[0113] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0114] A pharmaceutical carrier for the hydrophobic compounds of
the invention is a cosolvent system comprising benzyl alcohol, a
nonpolar surfactant, a water-miscible organic polymer, and an aqueous
phase. A common cosolvent system used is the VPD co-solvent system,
which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without destroying
its solubility and toxicity characteristics. Furthermore, the identity
of the co-solvent components may be varied: for example, other low-toxicity
nonpolar surfactants may be used instead of POLYSORBATE 80.TM.;
the fraction size of polyethylene glycol may be varied; other biocompatible
polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone;
and other sugars or polysaccharides may substitute for dextrose.
[0115] Alternatively, other delivery systems for hydrophobic pharmaceutical
compounds may be employed. Liposomes and emulsions are well known
examples of delivery vehicles or carriers for hydrophobic drugs.
Certain organic solvents such as dimethylsulfoxide also may be employed,
although usually at the cost of greater toxicity. Additionally,
the compounds may be delivered using a sustained-release system,
such as semipermeable matrices of solid hydrophobic polymers containing
the therapeutic agent. Various sustained-release materials have
been established and are well known by those skilled in the art.
Sustained-release capsules may, depending on their chemical nature,
release the compounds for a few weeks up to over 100 days. Depending
on the chemical nature and the biological stability of the therapeutic
reagent, additional strategies for protein stabilization may be
employed.
[0116] Many of the compounds used in the pharmaceutical combinations
of the invention may be provided as salts with pharmaceutically
compatible counterions. Pharmaceutically compatible salts may be
formed with many acids, including but not limited to hydrochloric,
sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts
tend to be more soluble in aqueous or other protonic solvents than
are the corresponding free acid or base forms.
[0117] Pharmaceutical compositions suitable for use in the present
invention include compositions where the active ingredients are
contained in an amount effective to achieve its intended purpose.
More specifically, a therapeutically effective amount means an amount
of compound effective to prevent, alleviate or ameliorate symptoms
of disease or prolong the survival of the subject being treated.
Determination of a therapeutically effective amount is well within
the capability of those skilled in the art, especially in light
of the detailed disclosure provided herein.
[0118] The exact formulation, route of administration and dosage
for the pharmaceutical compositions of the present invention can
be chosen by the individual physician in view of the patient's condition.
(See e.g., Fingl et al. 1975, in "The Pharmacological Basis
of Therapeutics", Ch. 1 p. 1). Typically, the dose range of
the composition administered to the patient can be from about 0.5
to 1000 mg/kg of the patient's body weight. The dosage may be a
single one or a series of two or more given in the course of one
or more days, as is needed by the patient. Note that for almost
all of the specific compounds mentioned in the present disclosure,
human dosages for treatment of at least some condition have been
established. Thus, in most instances, the present invention will
use those same dosages, or dosages that are between about 0.1% and
500%, more preferably between about 25% and 250% of the established
human dosage. Where no human dosage is established, as will be the
case for newly-discovered pharmaceutical compounds, a suitable human
dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other
appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
[0119] Although the exact dosage will be determined on a drug-by-drug
basis, in most cases, some generalizations regarding the dosage
can be made. The daily dosage regimen for an adult human patient
may be, for example, an oral dose of between 0.1 mg and 500 mg of
each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200
mg or an intravenous, subcutaneous, or intramuscular dose of each
ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg
and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical
compositions of the present invention or a pharmaceutically acceptable
salt thereof calculated as the free base, the composition being
administered 1 to 4 times per day. Alternatively the compositions
of the invention may be administered by continuous intravenous infusion,
preferably at a dose of each ingredient up to 400 mg per day. Thus,
the total daily dosage by oral administration of each ingredient
will typically be in the range 1 to 2000 mg and the total daily
dosage by parenteral administration will typically be in the range
0.1 to 400 mg. Suitably the compounds will be administered for a
period of continuous therapy, for example for a week or more, or
for months or years.
[0120] Dosage amount and interval may be adjusted individually
to provide plasma levels of the active moiety which are sufficient
to maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will depend
on individual characteristics and route of administration. However,
HPLC assays or bioassays can be used to determine plasma concentrations.
[0121] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably between
30-90% and most preferably between 50-90%.
[0122] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0123] The amount of composition administered will, of course,
be dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0124] The compositions may, if desired, be presented in a pack
or dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or dispenser
device may be accompanied by instructions for administration. The
pack or dispenser may also be accompanied with a notice associated
with the container in form prescribed by a governmental agency regulating
the manufacture, use, or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the drug for
human or veterinary administration. Such notice, for example, may
be the labeling approved by the U.S. Food and Drug Administration
for prescription drugs, or the approved product insert. Compositions
comprising a compound of the invention formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an appropriate
container, and labeled for treatment of an indicated condition.
[0125] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present invention. Therefore, it should be
clearly understood that the forms of the present invention are illustrative
only and are not intended to limit the scope of the present invention.
Some Embodiments of the Invention
[0126] Some of the embodiments of the present invention are as
follows:
[0127] In the 1.sup.st embodiment, the invention relates to a composition
for affecting weight loss comprising bupropion, or a metabolite
thereof, and a second compound, wherein said second compound causes
increased agonism of a melanocortin 3 receptor (MC3-R) or a melanocortin
4 receptor (MC4-R) compared to normal physiological conditions,
or wherein said second compound antagonizes cannabinoid receptor
activity.
[0128] In the 2.sup.nd embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
triggers the release of .alpha.-melanocyte stimulating hormone (.alpha.-MSH).
[0129] In the 3.sup.rd embodiment, the invention relates to the
composition of the 2.sup.nd embodiment, wherein said second compound
increases the extracellular serotonin concentrations in the hypothalamus.
[0130] In the 4.sup.th embodiment, the invention relates to the
composition of the 3.sup.rd embodiment, wherein said second compound
is selected from the group consisting of a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
[0131] In the 5.sup.th embodiment, the invention relates to the
composition of the 4.sup.th embodiment, wherein said second compound
is selected from the group consisting of fluoxetine, fluvoxamine,
sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine,
and venlafaxine, and pharmaceutically acceptable salts or prodrugs
thereof.
[0132] In the 6.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
suppresses the expression of the AgRP gene or the production or
release of agouti-related protein (AgRP).
[0133] In the 7.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
suppresses the activity of neurons that express AgRP.
[0134] In the 8.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
suppresses the expression of the NPY gene or the production or release
of neuropeptide Y (NPY).
[0135] In the 9.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
suppresses the activity of neurons that express NPY.
[0136] In the 10.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is an NPY receptor antagonist.
[0137] In the 11.sup.th embodiment, the invention relates to the
composition of the 10.sup.th embodiment, wherein said NPY receptor
is selected from NPY Y1 receptor, NPY Y2 receptor, NPY Y4 receptor,
and NPY Y5 receptor.
[0138] In the 12.sup.th embodiment, the invention relates to the
composition of the 1.sup.th embodiment, wherein said compound is
S-2367.
[0139] In the 13.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is selected from the group consisting of ghrelin antagonists and
leptin.
[0140] In the 14.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
agonizes NPY Y2 receptor.
[0141] In the 15.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is selected from the group consisting of a .gamma.-amino butyric
acid (GABA) inhibitor, a GABA receptor antagonist, and a GABA channel
antagonist.
[0142] In the 16.sup.th embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
is a 5-HT1b agonist, which may be selected from sumatriptan, almotriptan,
naratriptan, frovatriptan, rizatriptan, zomitriptan, and elitriptan.
[0143] In the 17.sup.th embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0144] In the 18.sup.th embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
suppresses the production or release of AgRP.
[0145] In the 19.sup.th embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
increases the expression of the POMC gene.
[0146] In the 20.sup.th embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
increases the production or release of .alpha.-MSH from pro-opiomelanocortin
(POMC) neurons.
[0147] In the 21.sup.st embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein said GABA inhibitor
increases the activity of POMC expressing neurons.
[0148] In the 22.sup.nd embodiment, the invention relates to the
composition of the 15.sup.th embodiment, wherein the GABA inhibitor
is topiramate.
[0149] In the 23.sup.rd embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a dopamine reuptake inhibitor.
[0150] In the 24.sup.th embodiment, the invention relates to the
composition of the 23.sup.rd embodiment, wherein said dopamine reuptake
inhibitor is phentermine.
[0151] In the 25.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a norepinephrine reuptake inhibitor.
[0152] In the 26.sup.th embodiment, the invention relates to the
composition of the 25.sup.th embodiment, wherein said norepinephrine
reuptake inhibitor is selected from thionisoxetine and reboxetine.
[0153] In the 27.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a dopamine agonist.
[0154] In the 28.sup.th embodiment, the invention relates to the
composition of the 27.sup.th embodiment, wherein said dopamine agonist
is selected from the group consisting of cabergoline, amantadine,
lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
[0155] In the 29.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a norepinephrine releaser.
[0156] In the 30.sup.th embodiment, the invention relates to the
composition of the 29.sup.th embodiment, wherein said norepinephrine
releaser is diethylpropion.
[0157] In the 31.sup.st embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a combination of a dopamine reuptake inhibitor and a norepinephrine
reuptake inhibitor.
[0158] In the 32.sup.nd embodiment, the invention relates to the
composition of the 31.sup.st embodiment, wherein said second compound
is mazindol.
[0159] In the 33.sup.rd embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a combination of a SSRI and a norepinephrine reuptake inhibitor.
[0160] In the 34.sup.th embodiment, the invention relates to the
composition of the 33.sup.rd embodiment, wherein said second compound
is selected from sibutramine, venlafaxine, and duloxetine.
[0161] In the 35.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is a cannabinoid receptor antagonist.
[0162] In the 36.sup.th embodiment, the invention relates to the
composition of the 35.sup.th embodiment, wherein said cannabinoid
receptor antagonist is selected from the group consisting of AM251
[N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof.
[0163] In the 37.sup.th embodiment, the invention relates to the
composition of the 1.sup.st embodiment, wherein said second compound
is AM251.
[0164] In the 38.sup.th embodiment, the invention relates to a
method of affecting weight loss, comprising identifying an individual
in need thereof and treating that individual with a combination
of bupropion, or a metabolite thereof, and a compound that enhances
.alpha.-MSH activity or antagonizes cannabinoid receptor activity.
[0165] In the 39.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment, wherein said individual has
a body mass index greater than 25.
[0166] In the 40.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment, wherein .alpha.-MSH activity
is enhanced by administering a compound, wherein said compound triggers
release of .alpha.-MSH or increases the activity of neurons that
express .alpha.-MSH.
[0167] In the 41.sup.st embodiment, the invention relates to the
method of the 40.sup.th embodiment, wherein said compound is a selective
serotonin reuptake inhibitor (SSRI) or a specific 5-HT receptor
agonist.
[0168] In the 42.sup.nd embodiment, the invention relates to the
method of the 41.sup.st embodiment, wherein said 5-HT receptor is
selected from 5-HT1b receptor and 5-HT2c receptor.
[0169] In the 43.sup.rd embodiment, the invention relates to the
method of the 41.sup.st embodiment, wherein said SSRI is selected
from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0170] In the 44.sup.th embodiment, the invention relates to the
method of the 40.sup.th embodiment, wherein said compound is a .gamma.-amino
butyric acid (GABA) inhibitor.
[0171] In the 45.sup.th embodiment, the invention relates to the
method of the 44.sup.th embodiment, wherein said GABA inhibitor
is a 5-HT1b receptor agonist.
[0172] In the 46.sup.th embodiment, the invention relates to the
method of the 44.sup.th embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0173] In the 47.sup.th embodiment, the invention relates to the
method of the 44.sup.th embodiment, wherein said GABA inhibitor
suppresses the production or release of AgRP.
[0174] In the 48.sup.th embodiment, the invention relates to the
method of the 41.sup.st embodiment, wherein said 5-HT agonists inhibits
the NPY/AgRP/GABA neurons.
[0175] In the 49.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment, wherein said second compound
suppresses the activity of neurons that express NPY.
[0176] In the 50.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment, wherein said second compound
is an NPY receptor antagonist.
[0177] In the 51.sup.st embodiment, the invention relates to the
method of the 50.sup.th embodiment, wherein said NPY receptor is
selected from NPY Y1 receptor, NPY Y2 receptor, NPY Y4 receptor,
and NPY Y5 receptor.
[0178] In the 52.sup.nd embodiment, the invention relates to the
method of the 51.sup.st embodiment, wherein said compound is S-2367.
[0179] In the 53.sup.rd embodiment, the invention relates to the
method of the 44.sup.th embodiment, wherein said GABA inhibitor
suppresses the activity of neurons that express AgRP.
[0180] In the 54.sup.th embodiment, the invention relates to the
method of the 44.sup.th embodiment, wherein said GABA inhibitor
is topiramate.
[0181] In the 55.sup.th embodiment, the invention relates to the
method of the 40.sup.th embodiment, wherein said compound is selected
from the group consisting of a dopamine reuptake inhibitor, a norepinephrine
reuptake inhibitor, a dopamine agonist, a norepinephrine releaser,
a combination of a dopamine reuptake inhibitor and a norepinephrine
reuptake inhibitor, and a combination of a SSRI and a norepinephrine
reuptake inhibitor.
[0182] In the 56.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment, wherein said treating step comprises
administering to said individual bupropion, or a metabolite thereof,
and a second compound, wherein said second compound enhances .alpha.-MSH
activity, or wherein said second compound antagonizes cannabinoid
receptor activity.
[0183] In the 57.sup.th embodiment, the invention relates to the
method of the 56.sup.th embodiment, wherein bupropion, or a metabolite
thereof, and said second compound are administered nearly simultaneously.
[0184] In the 58.sup.th embodiment, the invention relates to the
method of the 57.sup.th embodiment, wherein bupropion, or a metabolite
thereof, is administered prior to said second compound.
[0185] In the 59.sup.th embodiment, the invention relates to the
method of the 58.sup.th embodiment, wherein bupropion, or a metabolite
thereof, is administered subsequent to said second compound.
[0186] In the 60.sup.th embodiment, the invention relates to a
method of increasing satiety in an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion, or a metabolite thereof, and a compound
that enhances .alpha.-MSH activity or antagonizes cannabinoid receptor
activity.
[0187] In the 61.sup.st embodiment, the invention relates to the
method of the 60.sup.th embodiment, wherein said treating step comprises
administering to said individual bupropion, or a metabolite thereof,
and a second compound, wherein said second compound enhances .alpha.-MSH
activity or antagonizes cannabinoid receptor activity.
[0188] In the 62.sup.nd embodiment, the invention relates to the
method of the 61.sup.st embodiment, wherein bupropion, or a metabolite
thereof, and said second compound are administered nearly simultaneously.
[0189] In the 63.sup.rd embodiment, the invention relates to the
method of the 61.sup.st embodiment, wherein bupropion, or a metabolite
thereof, is administered prior to said second compound.
[0190] In the 64.sup.th embodiment, the invention relates to the
method of the 61.sup.st embodiment, wherein bupropion, or a metabolite
thereof, is administered subsequent to said second compound.
[0191] In the 65.sup.th embodiment, the invention relates to a
method of increasing energy expenditure in an individual comprising
identifying an individual in need thereof and treating that individual
with a combination of bupropion, or a metabolite thereof, and a
compound that enhances .alpha.-MSH activity, or antagonizes cannabinoid
receptor activity.
[0192] In the 66.sup.th embodiment, the invention relates to the
method of the 65.sup.th embodiment, wherein said treating step comprises
administering to said individual bupropion, or a metabolite thereof,
and a second compound, wherein said second compound enhances .alpha.-MSH
activity or antagonizes cannabinoid receptor activity.
[0193] In the 67.sup.th embodiment, the invention relates to the
method of the 66.sup.th embodiment, wherein bupropion, or a metabolite
thereof, and said second compound are administered nearly simultaneously.
[0194] In the 68.sup.th embodiment, the invention relates to the
method of the 66.sup.th embodiment, wherein bupropion, or a metabolite
thereof, is administered prior to said second compound.
[0195] In the 69.sup.th embodiment, the invention relates to the
method of the 66.sup.th embodiment, wherein bupropion, or a metabolite
thereof, is administered subsequent to said second compound.
[0196] In the 70.sup.th embodiment, the invention relates to a
method of suppressing the appetite of an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of bupropion, or a metabolite thereof, and a compound
that enhances .alpha.-MSH activity, or antagonizes cannabinoid receptor
activity.
[0197] In the 71.sup.st embodiment, the invention relates to the
method of the 70.sup.th embodiment, wherein said treating step comprises
administering to said individual bupropion, or a metabolite thereof,
and a second compound, wherein said second compound enhances .alpha.-MSH
activity, or antagonizes cannabinoid receptor activity.
[0198] In the 72.sup.nd embodiment, the invention relates to the
method of the 71.sup.st embodiment, wherein bupropion, or a metabolite
thereof, and said second compound are administered nearly simultaneously.
[0199] In the 73.sup.rd embodiment, the invention relates to the
method of the 71.sup.st embodiment, wherein bupropion, or a metabolite
thereof, is administered prior to said second compound.
[0200] In the 74.sup.th embodiment, the invention relates to the
method of the 71.sup.st embodiment, wherein bupropion, or a metabolite
thereof, is administered subsequent to said second compound.
[0201] In the 75.sup.th embodiment, the invention relates to the
method of the 38.sup.th embodiment through the 74.sup.th embodiment,
wherein the individual has a BMI greater than 30.
[0202] In the 76.sup.th embodiment, the invention relates to the
method of the 75.sup.th embodiment, wherein the individual has a
BMI greater than 25.
EXAMPLES
[0203] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Combination of Fluoxetine and Bupropion
[0204] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 20 mg tablet of fluoxetine
(PROZAC.RTM.) on a daily basis, in addition to one 75 mg tablet
of bupropion on a daily basis. The administered bupropion may be
in a sustained release formulation.
[0205] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
[0206] If the initial dosage is not effective, then the fluoxetine
dosage can be increased by 20 mg per day, though never exceeding
80 mg total per day. The bupropion dosage can be increased to 100
or 150 mg on a daily basis. If the initial dosage results in a more
rapid weight loss than the above rate, the dosage of each of fluoxetine
or bupropion can be reduced.
Example 2
Combination of Bupropion and Sibutramine
[0207] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take bupropion in the dosage set
forth in Example 1. In addition, each individual is instructed to
take 10 mg of sibutramine orally once a day.
[0208] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
[0209] If the initial dosage is not effective, then the sibutramine
dosage can be increased 15 mg per day. Dosages of sibutramine in
excess of 15 mg per day are not recommended. The bupropion dosage
can be increased to 100 or 150 mg on a daily basis. If the initial
dosage results in a more rapid weight loss than the above rate,
the dosage of each of sibutramine or bupropion can be reduced.
Example 3
Combination of Opioid Antagonist and Phentermine
[0210] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take bupropion in the dosage set
forth in Example 1. In addition, each individual is instructed to
take 37.5 mg of phentermine orally once a day.
[0211] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
Example 4
Combination of AM251 and Bupropion
[0212] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 20 mg tablet of AM251
on a daily basis. In addition, each individual is instructed to
take bupropion in the dosage set forth in Example 1.
[0213] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
[0214] If the initial dosage is not effective, then the AM251 dosage
can be increased by 20 mg per day, though never exceeding 80 mg
total per day. The bupropion dosage can be increased to 100 or 150
mg on a daily basis. If the initial dosage results in a more rapid
weight loss than the above rate, the dosage of each of AM251 or
bupropion can be reduced.
[0215] In some cases, it is beneficial to administer one dose of
AM251 per day in conjunction with two or three or more doses of
naltrexone throughout the day. Naltrexone may also be in a time-release
formulation where the dose is administered once a day, but naltrexone
gradually enters the blood stream throughout the day, or in the
course of a 12 hour period.
Example 5
Combination of Bupropion and DEPAKOTE.RTM.
[0216] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take bupropion in the dosage set
forth in Example 1. In addition, each individual is instructed to
take 250 mg of DEPAKOTE.RTM. orally twice a day.
[0217] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
[0218] If the initial dosage is not effective, then the DEPAKOTE.RTM.
dosage can be increased 500 mg twice a day, then to 1000 mg twice
a day, and if still greater weight loss rate is desired, to 1000
mg four times a day. The bupropion dosage can be increased to 100
or 150 mg on a daily basis. If the initial dosage results in a more
rapid weight loss than the above rate, the dosage of each of DEPAKOTE.RTM.
or bupropion can be reduced.
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