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Weight Loss Patent Abstract
Disclosed are compositions for affecting weight loss comprising
a first compound and a second compound, where the first compound
is an opioid antagonist and 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. 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 to antagonize opioid
receptor activity and to enhance .alpha.-MSH activity.
Weight Loss Patent Claims
1. A composition for affecting weight loss comprising a first compound
and a second compound, wherein said first compound is an opioid
antagonist and 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.
2. The composition of claim 1, wherein said opioid antagonist antagonizes
an opioid receptor selected from a .mu.-opioid receptor (MOP-R),
a .kappa.-opioid receptor, and a .delta.-opioid receptor.
3. The composition of claim 1, wherein said opioid antagonist is
selected from the group consisting of alvimopan, norbinaltorphimine,
nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine,
and pharmaceutically acceptable salts or prodrugs thereof.
4. The composition of claim 1, wherein said second compound triggers
the release of .alpha.-melanocyte stimulating hormone (.alpha.-MSH).
5. The composition of claim 4, wherein said second compound increases
the extracellular serotonin concentrations in the hypothalamus.
6. The composition of claim 5, wherein said second compound is
selected from the group consisting of a selective serotonin reuptake
inhibitor (SSR), a serotonin 2C agonist, and a serotonin 1B agonist.
7. The composition of claim 6, 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.
8. The composition of claim 1, wherein said first compound is naltrexone
and said second compound is fluoxetine.
9. The composition of claim 1, wherein said first compound is naltrexone
and said second compound is bupropion.
10. The composition of claim 9, wherein said first compound is
naltrexone and said second compound is sustained release bupropion.
11. A method of affecting weight loss, comprising identifying an
individual in need thereof, and administering to said individual
a first compound to antagonize opioid receptor activity and a second
compound to enhance .alpha.-MSH activity.
12. The method of claim 11, wherein said individual has a body
mass index greater than 25.
13. The method of claim 11, wherein said first compound is an opioid
receptor antagonist.
14. The method of claim 13, wherein the opioid receptor antagonist
is a MOP receptor antagonist.
15. The method of claim 11, wherein the opioid receptor antagonist
is selected from alvimopan, norbinaltorphimine, nalmefene, naloxone,
naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
16. The method of claim 11, wherein said second compound triggers
the release of .alpha.-MSH or increases the activity of neurons
that express .alpha.-MSH.
17. The method of claim 16, wherein said second compound is a SSRI
or a specific 5-HT receptor agonist.
18. The method of claim 17, wherein said SSRI is selected from
fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram,
sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable
salts or prodrugs thereof.
19. The method of claim 11, wherein said first compound and said
second compound are administered nearly simultaneously.
20. The method of claim 11, wherein said individual does not suffer
from depression, Prader-Willi syndrome, or binge eating disorder.
21. The method of claim 11, wherein said first compound is naltrexone
and said second compound is bupropion.
22. The method of claim 21, wherein said first compound is naltrexone
and said second compound is sustained release bupropion.
Weight Loss Patent Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
10/828,795, filed Apr. 21, 2004, which claims the benefit under
35 USC .sctn. 119(e) of U.S. Provisional Application No. 60/466,838,
filed on Apr. 29, 2003, the entire disclosures of which are incorporated
herein by reference in their 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
a first compound and a second compound, where the first compound
is an opioid antagonist and 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.
[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 to antagonize opioid
receptor activity and to enhance .alpha.-MSH 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, S63-567.
[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 weigh 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] 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.
[0019] 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.
[0020] Thus, in a first aspect, the present invention is directed
to a composition for the treatment of obesity or for affecting weight
loss comprising a first compound and a second compound, where the
first compound is an opioid antagonist and 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.
[0021] In certain embodiments, the second compound causes increased
activity of the POMC neurons, leading to greater agonism at MC3-R
and/or MC4-R.
[0022] In certain embodiments the opioid antagonist antagonizes
a .mu.-opioid receptor (MOP-R) 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.
[0023] In some embodiments the opioid antagonist is selected from
the group consisting of alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0024] In other embodiments, the opioid antagonist is a partial
opioid agonist. Compounds of this class have some agonist activity
at opioid receptors. However, because they are weak agonists, they
function as de-facto antagonists. Examples of partial opioid agonists
include pentacozine, buprenorphine, nalorphine, propiram, and lofexidine.
[0025] 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.
[0026] 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.
[0027] 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 pharmaceutically
acceptable salts or prodrugs thereof.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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 bupropion, 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, arnantadine, 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.
[0034] In certain other embodiments, the second compound is a 5-HT1b
agonist, such as sumatriptan, almotriptan, naratriptan, frovatriptan,
rizatriptan, zomitriptan, and elitriptan.
[0035] 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, fosphenyloin, phenyloin, carbamazepine, valproate,
felbamate, levetiracetam, oxcarbazepine, lamotrigine, methsuximide,
and ethosuxmide.
[0036] 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 pharmaceutically
acceptable salts or prodrugs thereof. LY320135 and SR141716A have
the following structures.
[0037] 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. bupropion and mazindol.
Alternatively, the second compound may be a combination of a SSRI
and a norepinephrine reuptake inhibitor, such as sibutramine, venlafaxine,
and duloxetine.
[0038] In certain embodiments, the second compound is an activator
of the POMC neurons. Examples of POMC activators include Ptx1 and
interleukin 1 beta, (IL-1.beta.).
[0039] 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 to antagonize opioid receptor
activity and to enhance .alpha.-MSH activity.
[0040] 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.
[0041] In some embodiments, opioid receptor activity is antagonized
by administering an opioid receptor antagonist. The opioid receptor
antagonist may be a MOP receptor antagonist. In some embodiments,
the opioid receptor antagonist is selected from alvimopan, norbinaltorphimine,
nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine,
and pharmaceutically acceptable salts or prodrugs thereof.
[0042] In some of the embodiments set forth above, .alpha.-MSH
activity is enhanced by administering a compound, where the compound
triggers release of .alpha.-MSH or increases 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 pharmaceutically acceptable salts or prodrugs thereof.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] In other embodiments, the method of the invention set forth
above is practiced with the proviso that if the opioid receptor
is antagonized using naltrexone, then release of .alpha.-MSH is
not stimulated with fluoxetine. However, the combination of naltrexone
with fluoxetine may be used to affect weight loss in individuals
who wish to lose weight, whether or not they are clinically categorized
as obese. These individuals may include those with BMI of greater
than 25, or those individuals with BMI of less than 25 who still
wish to lose additional weight. This particular combination may
also be used for the treatment of general obesity. In certain embodiments,
the individual who wishes to lose additional weight does not suffer
from binge eating disorder.
[0047] In some embodiments, the treating step of the above method
comprises administering to the individual a first compound and a
second compound, where the first compound is an opioid antagonist
and the second compound enhances .alpha.-MSH activity.
[0048] In some embodiments the first compound and the second compound
are administered more or less simultaneously. In other embodiments
the first compound is administered prior to the second compound.
In yet other embodiments, the first compound is administered subsequent
to the second compound.
[0049] In certain embodiments, the first compound and the second
compound are administered individually. In other embodiments, the
first compound 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 the first
compound and the other one is the second compound.
[0050] In some embodiments, the compositions of the present invention
are a combination of the following compounds:
[0051] a SSRI in combination with 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,
or a peptide, such as PYY, PYY.sub.3-36, or leptin;
[0052] Serotonin in combination with a dopamine reuptake inhibitor,
a dopamine/norepinephrine reuptake inhibitor, an opioid antagonist,
a partial opioid agonist, or a GABA inhibitor;
[0053] a dopamine reuptake inhibitor in combination with a norepinephrine
reuptake inhibitor, a norepinephrine releaser, a norepinephrine
agonist, an opioid antagonist, a partial opioid agonist, a GABA
inhibitor, an adenosine compound, a cholinergic receptor antagonist,
or a peptide, such as PYY, PYY.sub.3-36, or leptin;
[0054] a dopamine/norepinephrine reuptake inhibitor in combination
with an opioid antagonist, a partial opioid agonist, a GABA inhibitor,
or a peripherally acting weight loss agent such as metformin;
[0055] a dopamine agonist in combination with an opioid antagonist,
a partial opioid agonist, a GABA inhibitor, or a peptide, such as
PYY, PYY.sub.3-36, or leptin.
[0056] 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.
[0057] 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 to antagonize
opioid receptor activity and to enhance .alpha.-MSH activity.
[0058] In some embodiments, the treating step of the above method
comprises administering to the individual a first compound and a
second compound, where the first compound is an opioid antagonist
and the second compound enhances .alpha.-MSH activity.
[0059] In some embodiments the first compound and the second compound
are administered nearly simultaneously. In other embodiments the
first compound is administered prior to the second compound. In
yet other embodiments, the first compound is administered subsequent
to the second compound.
[0060] 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
to antagonize opioid receptor activity and to enhance .alpha.-MSH
activity.
[0061] In some embodiments, the treating step of the above method
comprises administering to the individual a first compound and a
second compound, where the first compound is an opioid antagonist
and the second compound enhances .alpha.-MSH activity.
[0062] In some embodiments the first compound and the second compound
are administered nearly simultaneously. In other embodiments the
first compound is administered prior to the second compound. In
yet other embodiments, the first compound is administered subsequent
to the second compound.
[0063] 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 to antagonize
opioid receptor activity and to enhance .alpha.-MSH activity.
[0064] In some embodiments, the treating step of the above method
comprises administering to the individual a first compound and a
second compound, where the first compound is an opioid antagonist
and the second compound enhances .alpha.-MSH activity.
[0065] In some embodiments the first compound and the second compound
are administered nearly simultaneously. In other embodiments the
first compound is administered prior to the second compound. In
yet other embodiments, the first compound is administered subsequent
to the second compound.
[0066] 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.
[0067] 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 a selective serotonin reuptake
inhibitor (SSRI).
[0068] Data from previous structure-activity relationship (SAR)
studies within the family of .mu. opioid antagonists may be used
as a guide to determine which antagonists to use and the optimal
position or positions on the antagonist molecules to attach the
tether such that potency and selectivity of the antagonist will
remain high. Similarly, SAR data within the family of SSRIs may
be used as a guide to determine which inhibitors to use and the
optimal position or positions on the inhibitors to attach the tether
such that potency and selectivity remain high. The tether or linker
moiety is chosen from among those of demonstrated utility for linking
bioactive molecules together. Disclosed herein are representative
opioid antagonists, linkers and SSRI molecules that can be attached
together in different combinations to form heterobivalent therapeutic
molecules.
[0069] Structure-activity relationships of the opioid agonists
and antagonists have been reviewed. See for example, Zimmerman,
D. M.; Leander, J. D. J. Med. Chem. 1990, 33, 895; Portoghese, P.
S. J. Med. Chem. 1992, 35, 1927; Carroll, F. I. J. Med. Chem. 2003,
46, 1. The opioid antagonists, nalmefene (1), naltrexone (2), naloxone
(3) and naltrexamine (4) are thebaine-derived structures that share
a common opiate-type template. .mu.-Subtype selective opioid antagonists
are of considerable current interest as agents for the treatment
of obesity (Glass, M. J.; Billington, C. J.; Levine, A. S. Neuropeptides
1999, 33, 350) and CNS disorders (Reneric, J. P.; Bouvard, M. P.
CNS Drugs 1998, 10, 365).
[0070] N-Methyl and N-2-phenylethyl substituted opioids tend to
show opioid agonist activity whereas N-allyl and N-cyclopropylmethyl
substituted analogs tend to show opioid antagonist activity. Any
N-attached linker moiety will be larger than methyl. Provided that
the linker moiety does not mimic 2-phenylethyl, such linked opioids
are expected to behave as opioid antagonists. Therefore, the nitrogen
atom of nalmefene and naltrexone (and naloxone) is a suitable site
for attachment of a linker moiety. Less SAR information is available
with regard to substitution at other sites on these opioids, however,
attachment of the linker unit to one or the other of the carbon
atoms bearing one or more hydrogen atoms remains an option.
[0071] Both nalmefene and naltrexone are potent .mu.-opioid antagonists.
The only structural difference is that nalmefene has a methylene
group in place of the ketone oxygen atom in naltrexone. It is thus
postulated that significant changes in structure at the ketone oxygen
site in naltrexone do not significantly affect antagonist potency.
Therefore, a linker may be attached to the methylene group in nalmefene
without significant reduction in antagonist potency. Carbonyl derivatives
of naloxone are well known and include symmetrical azine (.dbd.N--N.dbd.),
mixed azine (Schmidhammer, H.; Kaspar, F.; Marki, A.; Borsodi, A.
Helv. Chim. Acta 1994, 77, 999), hydazone (Hahn, E. F.; Itzhak,
Y.; Nishimura, S.; Johnson, N.; Pasternak, G. W. J. Pharm. Exper.
Therapeutics 1985, 235, 846-50), semicarbazone and thiosemicarbazone
derivatives (Kolb, V. M.; Koman, A.; Neil, A. Pharmaceutical Res.
1985, 6, 266-71). Naloxazone, the hydrazone of naloxone, is an irreversible,
selective and long acting antagonist of the .mu.-1 subclass of the
opioid receptors (Pasternak, G. W.; Hahn, E. F. J. of Med. Chem.
1980, 23, 674-6). Certain of the derivatives are potent .mu. opioid
antagonists while others are potent agonists.
[0072] Naltrexamine (4) has been linked by attachment of its primary
amino group to a wide variety of other molecules producing, for
example, a fluorogenic opioid receptor affinity label (Le Bourdonnec,
B.; El Kouhen, R.; Lunzer, M. M.; Law, P. Y.; Loh, H. H.; Portoghese,
P. S.; J. Med. Chem.; 2000; 43; 2489-2492), an extensive series
of nonequilibrium opioid agonists and antagonists (Sayre, L. M.;
Larson, D. L.; Takemori, A. E.; Portoghese, P. S. J. Med. Chem.
1984, 27, 1325), and a series of potent bivalent opioid antagonists
(Erez, M.; Takemori, A. E.; Portoghese, P. S. J. Med. Chem. 1982,
25, 847-849). Consequently, the primary amino group of naltrexamine
constitutes a suitable site for attachment of a linker moiety.
[0073] A limited SAR for fluoxetine (5) has been published in U.S.
Pat. No. 4,214,081, incorporated by reference herein in its entirety.
N-Methylfluoxetine (6) shows comparable potency and selectivity
to that of fluoxetine toward inhibition of serotonin reuptake. Therefore,
attachment of a linker to the nitrogen atom of fluoxetine can result
in retention of the potency and selectivity of fluoxetine itself.
However, the present disclosure is not limited to the fluoxetine
series of SSRIs. It is envisaged that a variety of SSRI molecules
such as paroxetine (Dechant, K. L.; Clissold, S. P. Drugs, 1991,
41, 225-253) or one or the other of the bivalent SSRIs described
by Kozikowski et al. (Tamiz, A. P.; Zhang, J.; Zhang, M.; Wang,
C. Z.; Johnson, K. M.; Kozikowski, A. P. J. Am. Chem. Soc. 2000,
122, 5393-5394; Tamiz, A. P.; Bandyopadhyay, B. C.; Zhang, J.; Flippen-Anderson,
J. L.; Zhang, M.; Wang, C. Z.; Johnson, K. M.; Tella, S.; Kozikowski,
A. P. J. Med. Chem. 2001, 44, 1615-1622) may also be utilized to
construct the heterobivalent therapeutic molecules of this invention.
[0074] Examples of linkers reported in the scientific literature
include methylene (CH.sub.2).sub.n linkers (Hussey, S. L.; Muddana,
S. S.; Peterson, B. R.; J. Am. Chem. Soc. 2003; 125; 3692-3693;
Tamiz, A. P.; Bandyopadhyay, B. C.; Zhang, J.; Flippen-Anderson,
J. L.; Zhang, M.; Wang, C. Z; Johnson, K. M.; Tellar, S.; Kozikowski,
A. P. J. Med. Chem. 2001, 44, 1615-1622), oligo ethyleneoxy O(--CH.sub.2CH.sub.2O--).sub.n
units used to link naltrexamine to other opioids, glycine oligomers
of the formula --NH--(COCH.sub.2NH).sub.nCOCH.sub.2CH.sub.2CO--
(NHCH.sub.2CO).sub.nNH-- used to link opioid antagonists and agonists
together ((a) Portoghese, P. S.; Ronsisvalle, G.; Larson, D. L.;
Yim, C. B.; Sayre, L. M.; Takemori, A. E. Life Sci. 1982, 31, 1283-1286.
(b) Portoghese, P. S.; Larson, D. L.; Sayre, L. M.; Yim, C. B.;
Ronsisvalle, G.; Tarn, S. W.; Takemori, A. E. J. Med. Chem. 1986,
29, 1855-1861), hydrophilic diamines used to link opioid peptides
together (Stepinski, J.; Zajaczkowski, I.; Kazem-Bek, D.; Temeriusz,
A.; Lipkowski, A. W.; Tam, S. W. Internat. J. of Peptide & Protein
Res. 1991, 38, 588-92), rigid double stranded DNA spacers (Paar,
J. M.; Harris, N. T.; Holowka, D.; Baird, B. J. Immunol. 2002, 169,
856-864) and the biodegradable linker poly (L-lactic acid) (Klok,
H.-A.; Hwang, J. J.; Iyer, S. N.; Stupp, S. I. Macromolecules 2002,
35, 746-759). The attachment of the tether to the antagonist can
result in the antagonist achieving a favorable binding orientation.
The linker itself may or may not be biodegradable. The linker may
take the form of a prodrug and be tunable for optimal release kinetics
of the linked drugs. The linker may be either conformationally flexible
throughout its entire length or else a segment of the tether may
be designed to be conformationally restricted (Portoghese, P. S.;
Ronsisvalle, G.; Larson, D. L.; Takemori, A. E. J. Med. Chem. 1986,
29, 1650-1653).
[0075] In Scheme 1 below, naltrexone (2) is used in the linking
reaction. As a consequence of the Wittig reaction, a double bond
replaces the carbonyl group in naltrexone. The net result is fluoxetine
linked with a flexible methylene linker to a nalmefene molecule
by way of the nalmefene double bond.
[0076] Reductive amination of fluoxetine with an .omega.-bromoaldehyde
such as 11-bromoundecanal 6 (n=9) gives bromoamine 7 (n=9), best
stored as the hydrobromide salt to prevent an unwanted slow macrocyclization
side reaction by way of attack of the free amino group on the carbon
bearing the bromine atom. Reaction of 7 with triphenylphosphine
gives the intermediate phosphonium salt, which upon reaction with
butyllithium generates the corresponding ylid 8 (n=9). A Wittig
reaction between 8 and the ketone group of naltrexone (2) gives
the linked molecule 9 containing a fluoxetine unit coupled to what
is now a nalmefene unit. The expected mixture of cis, trans isomers
about the newly introduced double bond is separable by standard
chromatographic techniques. If racemic fluoxetine is used, then
a mixture of two optically active diastereomers of 9 will be produced
owing to the fact that a single enantiomer 2 of naltrexone was used.
Chemists skilled in the art will recognize that the (CH.sub.2).sub.9
linker may be varied in length and/or contain substituents by beginning
with a different bromoaldehyde. Thus, pharmacological properties
may be optimized. Molecule 9 is stable under physiological conditions.
Opioid antagonist activity will be due to the covalently linked
nalmefene unit and not due to free nalmefene released as a result
of some cleavage reaction. Similarly, SSRI activity will be due
to the covalently linked fluoxetine unit and not due to free fluoxetine
released as a result of some cleavage reaction.
[0077] An analogous reaction sequence may be used in which the
bromoaldehyde is derived from an oligo ethylene glycol as shown
in Scheme 2 below. For example, tetraethylene glycol (10 n=2) is
converted into bromide 11 (n=2), which is then oxidized under Swern
conditions to aldehyde 12 (n=2). Substitution of aldehyde 12 for
aldehyde 6 in Scheme 1 will give a series of irreversibly linked
molecules in which the linker is more hydrophilic than that in molecules
9. Generation of the ylid in the oligo ethylene glycol series and
the subsequent Wittig reaction is performed at reduced temperature
to avoid .beta.-elimination of the alkoxy group. If racemic fluoxetine
is used, then a mixture of two optically active diastereomers of
13 will be produced owing to the fact that a single enantiomer 2
of naltrexone was used. Chemists skilled in the art will recognize
that the (OCH.sub.2CH.sub.2).sub.n linker may be varied in length
by beginning with a different bromoaldehyde 12. Thus, pharmacological
properties may be optimized. Molecule 13 is stable under physiological
conditions.
[0078] In Scheme 3, another linking method beginning with tetraethylene
glycol is illustrated as an example of a variety of oligo ethylene
glycols that may be used. Adapting the chemistry of Sashiwa et al.
(Sashiwa, H.; Shigemasa, Y.; Roy, R. Macromolecules 2000, 33, 6913),
tetraethylene glycol may be converted into acetal 14 (n=2) and subsequently
into aldehyde 15. Reductive amination of fluoxetine with aldehyde
15 gives the fluoxetine derivative 16. Reduction of azide 16 to
amine 17 and then reductive amination with naltrexone gives molecule
18 in which a fluoxetine unit is linked irreversibly by a flexible
oligo ethyleneoxy unit to .beta.-naltrexamine (after separation
of the .alpha. and .beta. isomers). If racemic fluoxetine is used,
then a mixture of two optically active diastereomers of 18 will
be produced owing to the fact that a single enantiomer 2 of naltrexone
was used. Chemists skilled in the art will recognize that the (OCH.sub.2CH.sub.2).sub.n
linker may be varied in length by beginning with a different oligo
ethylene glycol 10. Thus, pharmacological properties may be optimized.
Molecule 18 should be stable under physiological conditions.
[0079] Scheme 4 illustrates a synthetic route to fluoxetine linked
to nalmefene by way of the N-cyclopropyl group of nalmefene. The
readily available t-butyldimethylsilyl protected noroxymorphone
(19) is synthesized from morphine (Ninan, A.; Sainsbury, M. Tetrahedron
1992, 48, 6709-16), and then subjected to a reductive amination
reaction with the commercially available cyclopropanecarboxaldehyde
20 (Aldrich, largely trans) giving ester 21. Wittig methyleneation
gives ester 22, which is hydrolyzed to give acid 23. Activation
of acid 23 with an appropriate carbodiimide and then N-acylation
of fluoxetine derivative 17 (Scheme 3) gives 25, deprotection of
which with Bu.sub.4NF gives the novel molecule 26. Chemists skilled
in the art will recognize that the (OCH.sub.2CH.sub.2).sub.n linker
may be varied in length by beginning with a different aldehyde azide
15 in the synthesis of 17. Thus, pharmacological properties may
be optimized. Molecule 26 should be stable under physiological conditions.
[0080] Alternatively, ester 22 may be reduced to aldehyde 24 using
DIBAL at -78.degree. C. Reductive amination of aldehyde 24 with
amine 17 gives molecule 27 after removal of the TBDMS protecting
group. Chemists skilled in the art will recognize that the (OCH.sub.2CH.sub.2).sub.n
linker may be varied in length by beginning with a different aldehyde
azide 15 in the synthesis of 17. Thus, pharmacological properties
may be optimized. Molecule 27 should be stable under physiological
conditions.
[0081] If the Wittig methyleneation step is omitted in the above
sequence, then an analog of 26, namely ketone 28, is formed in which
the methylene group of 26 is replaced by a carbonyl group. The result
is a naltrexone unit linked to a fluoxetine unit by way of a flexible,
hydrophilic (CH.sub.2CH.sub.2O).sub.n linker in the form of compound
28. Chemists skilled in the art will recognize that the (OCH.sub.2CH.sub.2).sub.n
linker may be varied in length by beginning with a different aldehyde
azide 15 in the synthesis of 17. Thus, pharmacological properties
may be optimized. Molecule 28 is stable under physiological conditions.
[0082] Scheme 5 illustrates how fluoxetine may be linked to .beta.-naltrexamine
using a combination of linkers, namely the flexible glycine-based
linkers 29 exploited by Portoghese et al. and the oligo ethylene
glycol linkers used in the schemes above. Thus carboxyl activation
of 29 with a suitable carbodiimide followed by monocondensation
with .beta.-naltrexamine gives amide 30. Reactivation of 30 followed
by condensation with amine 17 (Scheme 3) gives molecule 31. Portoghese
reports that symmetrical amides derived from linker 29 and .beta.-naltrexamine
are effective .mu.-opioid receptor antagonists. Chemists skilled
in the art will recognize that the --NH--(COCH.sub.2NH).sub.n-1
ICOCH.sub.2CH.sub.2CO--(NHCH.sub.2CO).sub.nNH-- linker may be varied
in length by beginning with a different glycine-based linking unit
29 in the synthesis of 30. Thus, pharmacological properties may
be optimized. Molecule 31 is stable under physiological conditions.
[0083] Reaction of bromide 7 (Scheme 1) with Mg in dry THF will
give Grignard reagent 32, reaction of which with the carbonyl group
of naltrexone gives adduct 33 after separation of the two diastereomers
produced at the newly created chiral center. Adduct 33 contains
a fluoxetine segment linked to a N-cyclopropylmethyl-normorphine
unit by way of a flexible methylene linker. Chemists skilled in
the art will recognize that the (CH.sub.2).sub.9 linker may be varied
in length by beginning with a different bromoaldehyde for the synthesis
of bromide 7. Thus, pharmacological properties may be optimized.
Molecule 33 is stable under physiological conditions.
[0084] Throughout the above schemes, one should be able to employ
N-desmethylfluoxetine (34), or any other derivative of fluoxetine,
in place of fluoxetine. The resulting linked fluoxetine unit is
identical to that of fluoxetine itself except that the methyl group
of fluoxetine is replaced by a longer chain that is part of the
linker. When necessary due to the use of strongly basic reagents
or when chemoselectivity toward a primary amino group elsewhere
in the molecule is required, one may protect the intermediate fluoxetine
secondary amino group by use of the N-[2-(trimethylsilyl)ethoxy]methyl
(SEM) group (Zeng, Z.; Zimmerman, S. C. Tetrahedron Lett. 1988,
29, 5123) as illustrated in Scheme 7.
[0085] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of an opioid antagonist 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0104] 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.
[0105] 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.
[0106] 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 80T.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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
[0113] 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%.
[0114] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0115] 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.
[0116] 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.
[0117] 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
[0118] Some of the embodiments of the present invention are as
follows:
[0119] In the first embodiment, the invention relates to a composition
for affecting weight loss comprising a first compound and a second
compound, wherein said first compound is an opioid antagonist and
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.
[0120] In the second embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist antagonizes
an opioid receptor in a mammal.
[0121] In the third embodiment, the invention relates to the composition
of the second embodiment, wherein said opioid receptor is selected
from a .mu.-opioid receptor (MOP-R), a .kappa.-opioid receptor,
and a .delta.-opioid receptor.
[0122] In the fourth embodiment, the invention relates to the composition
of the second embodiment, wherein said opioid antagonist antagonizes
a .mu.-opioid receptor (MOP-R) in a mammal.
[0123] In the fifth embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist is selected
from the group consisting of alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0124] In the sixth embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist is a partial
opioid agonist.
[0125] In the seventh embodiment, the invention relates to the
composition of the sixth embodiment, wherein said partial opioid
agonist is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
[0126] In the eighth embodiment the invention relates to the composition
of the first embodiment, wherein said second compound triggers the
release of .alpha.-melanocyte stimulating hormone (.alpha.-MSH).
[0127] In the ninth embodiment, the invention relates to the composition
of the eighth embodiment, wherein said second compound increases
the extracellular serotonin concentrations in the hypothalamus.
[0128] In the tenth embodiment, the invention relates to the composition
of the ninth 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.
[0129] In the eleventh embodiment, the invention relates to the
composition of the tenth 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.
[0130] In the twelfth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the expression of the AgRP gene or the production or
release of agouti-related protein (AgRP).
[0131] In the thirteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the activity of neurons that express AgRP.
[0132] In the fourteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the expression of the NPY gene or the production or release
of neuropeptide Y (NPY).
[0133] In the fifteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the activity of neurons that express NPY.
[0134] In the sixteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
is selected from the group consisting of NPY Y1 receptor antagonists,
ghrelin antagonists, and leptin.
[0135] In the seventeenth embodiment, the invention relates to
the composition of the first embodiment wherein said second compound
agonizes NPY Y2 receptor.
[0136] In the eighteenth embodiment, the invention relates to the
composition of the first 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.
[0137] In the nineteenth embodiment, the invention relates to the
composition of the eighteenth embodiment, wherein said GABA inhibitor
is a 5-HT1b agonist, which may be selected from sumatriptan, almotriptan,
naratriptan, frovatriptan, rizatriptan, zomitriptan, and elitriptan.
[0138] In the twentieth embodiment, the invention relates to the
composition of the eighteenth embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0139] In the twenty first embodiment, the invention relates to
the composition of the eighteenth embodiment, wherein said GABA
inhibitor suppresses the production or release of AgRP.
[0140] In the twenty second embodiment, the invention relates to
the composition of the eighteenth embodiment, wherein said GABA
inhibitor increases the expression of the POMC gene.
[0141] In the twenty third embodiment, the invention relates to
the composition of the eighteenth embodiment, wherein said GABA
inhibitor increases the production or release of .alpha.-MSH from
pro-opiomelanocortin (POMC) neurons.
[0142] In the twenty fourth embodiment, the invention relates to
the composition of the eighteenth embodiment, wherein said GABA
inhibitor increases the activity of POMC expressing neurons.
[0143] In the twenty fifth embodiment, the invention relates to
the composition of the eighteenth embodiment, wherein the GABA inhibitor
is topiramate.
[0144] In the twenty sixth embodiment the invention relates to
the composition of the first embodiment, wherein said second compound
is a dopamine reuptake inhibitor.
[0145] In the twenty seventh embodiment, the invention relates
to the composition of the twenty sixth embodiment, wherein said
dopamine reuptake inhibitor is phentermine.
[0146] In the twenty eighth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a norepinephrine reuptake inhibitor.
[0147] In the twenty ninth embodiment, the invention relates to
the composition of the twenty eighth embodiment, wherein said norepinephrine
reuptake inhibitor is selected from bupropion, thionisoxetine, and
reboxetine.
[0148] In the thirtieth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
is a dopamine agonist.
[0149] In the thirty first embodiment, the invention relates to
the composition of the thirtieth embodiment, wherein said dopamine
agonist is selected from the group consisting of cabergoline, amantadine,
lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
[0150] In the thirty second embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a norepinephrine releaser.
[0151] In the thirty third embodiment, the invention relates to
the composition of the thirty second embodiment, wherein said norepinephrine
releaser is diethylpropion.
[0152] In the thirty fourth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a combination of a dopamine reuptake inhibitor and a norepinephrine
reuptake inhibitor.
[0153] In the thirty fifth embodiment, the invention relates to
the composition of the thirty fourth embodiment, wherein said second
compound is selected from bupropion and mazindol.
[0154] In the thirty sixth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a combination of a SSRI and a norepinephrine reuptake inhibitor.
[0155] In the thirty seventh embodiment, the invention relates
to the composition of the thirty sixth embodiment, wherein said
second compound is selected from sibutramine, venlafaxine, and duloxetine.
[0156] In the thirty eighth embodiment, the invention relates to
the composition of the first embodiment, wherein said first compound
is naltrexone and said second compound is fluoxetine.
[0157] In the thirty ninth embodiment, the invention relates to
the composition of the thirty eighth embodiment, wherein the naltrexone
is in a time-release formulation whereas the fluoxetine is in an
immediate release formulation.
[0158] In the fortieth embodiment, the invention relates to a method
of affecting weight loss, comprising identifying an individual in
need thereof and treating that individual to antagonize opioid receptor
activity and to enhance .alpha.-MSH activity.
[0159] In the forty first embodiment, the invention relates to
the method of the fortieth embodiment, wherein said individual has
a body mass index greater than 25.
[0160] In the forty second embodiment, the invention relates to
the method of the fortieth embodiment, wherein opioid receptor activity
is antagonized by administering an opioid receptor antagonist.
[0161] In the forty third embodiment, the invention relates to
the method of the forty second embodiment, wherein the opioid receptor
antagonist is a MOP receptor antagonist.
[0162] In the forty fourth embodiment, the invention relates to
the method of the fortieth embodiment, wherein the opioid receptor
antagonist is selected from alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0163] In the forty fifth embodiment, the invention relates to
the method of the forty second embodiment, wherein said opioid receptor
antagonist is a partial opioid agonist.
[0164] In the forty sixth embodiment, the invention relates to
the method of the forty fifth embodiment, wherein said partial opioid
agonist is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
[0165] In the forty seventh embodiment, the invention relates to
the method of the fortieth embodiment through the forty fifth 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.
[0166] In the forty eighth embodiment the invention relates to
the method of the forty seventh embodiment, wherein said compound
is a selective serotonin reuptake inhibitor (SSRI) or a specific
5-HT receptor agonist.
[0167] In the forty ninth embodiment, the invention relates to
the method of the forty eighth embodiment, wherein said 5-HT receptor
is selected from 5-HT1b receptor and 5-HT2c receptor.
[0168] In the fiftieth embodiment, the invention relates to the
method of the forty eighth embodiment, wherein said SSRI is selected
from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0169] In the fifty first embodiment, the invention relates to
the method of the forty seventh embodiment, wherein said compound
is a .gamma.-amino butyric acid (GABA) inhibitor.
[0170] In the fifty second embodiment, the invention relates to
the method of the fifty first embodiment, wherein said GABA inhibitor
is a 5-HT1b receptor agonist.
[0171] In the fifty third embodiment, the invention relates to
the method of the fifty first embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0172] In the fifty fourth embodiment, the invention relates to
the method of the fifty first embodiment, wherein said GABA inhibitor
suppresses the production or release of AgRP.
[0173] In the fifty fifth embodiment, the invention relates to
the method of the forty eighth embodiment, wherein said 5-HT agonists
inhibits the NPY/AgRP/GABA neurons.
[0174] In the fifty sixth embodiment, the invention relates to
the method of the fifty first embodiment, wherein said GABA inhibitor
suppresses the activity of neurons that express AgRP.
[0175] In the fifty seventh embodiment, the invention relates to
the method of the fifty first embodiment, wherein said GABA inhibitor
is topiramate.
[0176] In the fifty eighth embodiment, the invention relates to
the method of the forty seventh 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.
[0177] In the fifty ninth embodiment, the invention relates to
the method of the fifty eighth embodiment, wherein said compound
is not phentermine.
[0178] In the sixtieth embodiment, the invention relates to the
method of the fortieth embodiment, with the proviso that the individual
is not suffering from Prader-Willi syndrome.
[0179] In the sixty first embodiment, the invention relates to
the method of the fortieth embodiment, with the proviso that if
the opioid receptor is antagonized using naltrexone, then release
of .alpha.-MSH is not stimulated with fluoxetine.
[0180] In the sixty second embodiment, the invention relates to
the method of the fortieth embodiment, wherein said treating step
comprises administering to said individual a first compound and
a second compound, wherein said first compound is an opioid antagonist
and said second compound enhances .alpha.-MSH activity.
[0181] In the sixty third embodiment, the invention relates to
the method of the sixty second embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0182] In the sixty fourth embodiment, the invention relates to
the method of the sixty third embodiment, wherein said first compound
is administered prior to said second compound.
[0183] In the sixty fifth embodiment, the invention relates to
the method of the sixty fourth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0184] In the sixty sixth embodiment, the invention relates to
a method of increasing satiety in an individual comprising identifying
an individual in need thereof and treating that individual to antagonize
opioid receptor activity and to enhance .alpha.-MSH activity.
[0185] In the sixty seventh embodiment, the invention relates to
the method of the sixty sixth embodiment, wherein said treating
step comprises administering to said individual a first compound
and a second compound, wherein said first compound is an opioid
antagonist and said second compound enhances .alpha.-MSH activity.
[0186] In the sixty eighth embodiment, the invention relates to
the method of the sixty seventh embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0187] In the sixty ninth embodiment, the invention relates to
the method of the sixty seventh embodiment, wherein said first compound
is administered prior to said second compound.
[0188] In the seventieth embodiment, the invention relates to the
method of the sixty seventh embodiment, wherein said first compound
is administered subsequent to said second compound.
[0189] In the seventy first 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
to antagonize opioid receptor activity and to enhance .alpha.-MSH
activity.
[0190] In the seventy second embodiment, the invention relates
to the method of the seventy first embodiment, wherein said treating
step comprises administering to said individual a first compound
and a second compound, wherein said first compound is an opioid
antagonist and said second compound enhances .alpha.-MSH activity.
[0191] In the seventy third embodiment, the invention relates to
the method of the seventy second embodiment, wherein said first
compound and said second compound are administered nearly simultaneously.
[0192] In the seventy fourth embodiment, the invention relates
to the method of the seventy second embodiment, wherein said first
compound is administered prior to said second compound.
[0193] In the seventy fifth embodiment, the invention relates to
the method of the seventy second embodiment, wherein said first
compound is administered subsequent to said second compound.
[0194] In the seventy sixth 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
to antagonize opioid receptor activity and to enhance .alpha.-MSH
activity.
[0195] In the seventy seventh embodiment, the invention relates
to the method of the seventy sixth embodiment, wherein said treating
step comprises administering to said individual a first compound
and a second compound, wherein said first compound is an opioid
antagonist and said second compound enhances .alpha.-MSH activity.
[0196] In the seventy eighth embodiment, the invention relates
to the method of the seventy seventh embodiment, wherein said first
compound and said second compound are administered nearly simultaneously.
[0197] In the seventy ninth embodiment, the invention relates to
the method of the seventy seventh embodiment, wherein said first
compound is administered prior to said second compound.
[0198] In the eightieth embodiment, the invention relates to the
method of the seventy seventh embodiment, wherein said first compound
is administered subsequent to said second compound.
[0199] In the eighty first embodiment, the invention relates to
a method of affecting weight loss in an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of naltrexone and fluoxetine,
[0200] provided that the individual does not suffer from Prader-Willi
syndrome or binge eating disorder.
[0201] In the eighty second embodiment, the invention relates to
the method of the eighty first embodiment, wherein the individual
has a BMI greater than 30.
[0202] In the eighty third embodiment, the invention relates to
the method of the eighty first embodiment, wherein the individual
has a BMI greater than 25.
[0203] In the eighty fourth embodiment, the invention relates to
the method of the eighty first embodiment, wherein the naltrexone
is in a time-release formulation whereas the fluoxetine is in an
immediate release formulation.
[0204] In the eighty fifth embodiment, the invention relates to
the method of the eighty fourth embodiment, wherein the plasma concentration
level of both naltrexone and fluoxetine follow a similar concentration
profile.
[0205] In the eighty sixth embodiment, the invention relates to
the method of the eighty fourth embodiment, wherein the naltrexone
and the fluoxetine are administered substantially simultaneously.
[0206] In the eighty seventh embodiment, the invention relates
to the method of the eighty fourth embodiment, wherein the naltrexone
is administered prior to the fluoxetine.
[0207] In the eighty eighth embodiment, the invention relates to
the method of the eighty fourth embodiment, wherein the naltrexone
is administered subsequent to the fluoxetine.
EXAMPLES
[0208] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Combination of Fluoxetine and Naltrexone
[0209] 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 50 mg tablet
of naltrexone on a daily basis.
[0210] 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.
[0211] 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. If the initial dosage results in a more rapid
weight loss than the above rate, the dosage of each of fluoxetine
or naltrexone can be reduced.
[0212] Fluoxetine has a physiological half life of about 9 hours,
whereas that of naltrexone is about 1.5 hours. Thus, in some cases,
it is beneficial to administer one dose of fluoxetine 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 2
Combination of Fluoxetine and Nalmefene
[0213] 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, each individual is
injected with 1 mL of a solution of 100 .mu.g of nalmefene in 1
mL of saline, intravenously, intramuscularly, or subcutaneously.
[0214] 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.
[0215] 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. In addition, the dosage of nalmefene may be
increased up to 2 mL of a solution of 1 mg of nalmefene in 1 mL
of saline. If the initial dosage results in a more rapid weight
loss than the above rate, the dosage of each of fluoxetine or nalmefene
can be reduced.
Example 3
Combination of Fluoxetine and Naloxone
[0216] 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, each individual is
injected with 1 mL of a solution of 400 .mu.g of naloxone in 1 mL
of saline, intravenously, intramuscularly, or subcutaneously.
[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 fluoxetine
dosage can be increased by 20 mg per day, though never exceeding
80 mg total per day. If the initial dosage results in a more rapid
weight loss than the above rate, the dosage of each of fluoxetine
or nalmefene can be reduced.
Example 4
Combination of Opioid Antagonist and Sibutramine
[0219] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take nalmefene, naltrexone, or
naloxone in the dosage set forth in Examples 1-3. In addition, each
individual is instructed to take 10 mg of sibutramine orally once
a day.
[0220] 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.
[0221] 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. If the initial dosage
results in a more rapid weight loss than the above rate, the dosage
of each of sibutramine, nalmefene, naltrexone, or naloxone can be
reduced.
Example 5
Combination of Opioid Antagonist and Bupropion
[0222] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take nalmefene, naltrexone, or
naloxone in the dosage set forth in Examples 1-3. In addition, each
individual is instructed to take bupropion. The usual adult does
is 300 mg per day, given three times daily. Dosing should begin
at 200 mg per day, given as 100 mg twice daily. Based on clinical
response, this dose may be increased to 300 mg per day, given as
100 mg three times daily. No single dose is to exceed 150 mg.
[0223] 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 6
Combination of Opioid Antagonist and Phentermine
[0224] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take nalmefene, naltrexone, or
naloxone in the dosage set forth in Examples 1-3. In addition, each
individual is instructed to take 37.5 mg of phentermine orally once
a day.
[0225] 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 7
Combinations with Naltrexone
[0226] In a multicenter, randomized, blinded, placebo-controlled
clinical trial with 6 groups, the following drug combinations are
tested: [0227] Group 1: Fluoxetine 60 mg po QD plus Naltrexone 50
mg po QD [0228] Group 2: Fluoxetine 60 mg po QD plus N-placebo po
QD [0229] Group 3: Bupropion-SR 150 mg po BID plus Naltrexone 50
mg po QD [0230] Group 4: Bupropion-SR 150 mg po BID plus N-placebo
po QD [0231] Group 5: P-placebo po BID plus Naltrexone 50 mg po
QD [0232] Group 6: P-placebo po BID plus N-placebo po QD
[0233] In any of the above groups, the dosage of fluoxetine may
be in the range between 6 mg and 60 mg, for example, 6 mg, 10 mg,
12 mg, 18 mg, 20 mg, 24 mg, 30 mg, 36 mg, 40 mg, 42 mg, 45 mg, 48
mg, 54 mg, and 60 mg. Bupropion may be administered in doses in
the range between 30 mg and 300 mg, for example, 30 mg, 40 mg, 50
mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg,
140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,
220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg,
and 300 mg. Naltrexone may be administered in doses in the range
between 5 mg and 50 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg,
25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg.
[0234] Subjects are evaluated as out-patients during this study.
All subjects in this trial receive diet instruction, behavior modification
advice and instruction to increase their activity, a regimen shown
to give weight loss. Subjects are randomized to receive study drugs
in various combinations.
[0235] Subjects in groups 5 and 6 cross-over to treatment with
fluoxetine plus naltrexone or bupropion SR plus naltrexone after
week 16 for the extension treatment period which provide additional
data on safety of the combination therapies.
[0236] The primary endpoint is percent and absolute change from
baseline in body weight at 16 weeks. Secondary endpoints include
weight loss at 24, 36, and 48 weeks, number and proportion of subjects
who achieve at least a 5% weight loss and a 10% weight loss (responder
analysis), changes in obesity-associated cardiovascular risk factors
(total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides,
glucose and insulin) and waist circumference, and safety and tolerability.
Adverse events, laboratory parameters, vital signs, and the Hospital
Anxiety and Depression (HAD) Scale are used to monitor safety and
tolerability.
Example 8
Dose-Response Experiments
[0237] Seventy, four week old, male CS7/B16J.sup.- mice (Jackson
Laboratory), 22-30 g were sham injected daily with 0.1 mL 0.9% saline
(pH 7.4) for 1 week prior to the experiments. Animals were weighed
and randomized to 1 of 7 weight-matched dose groups (0, 1.5, 3,
5.5, 10, 18, and 30 mg/kg; n=10/group for fluoxetine; 0, 1.5, 3,
5.5, 10, 18, and 30 mg/kg; n=3/group for naltrexone) the day before
experiments began. Food was removed between 4:30-5:30 pm the day
before the experiment. Animals received a 0.3 mL bolus (fluoxetine)
or 0.1 mL bolus (naltrexone) intraperitoneal injection between 9-10:30
am, and food was provided immediately following injection. 3 animals/group
received injections on each testing day (i.e., 3 runs of 3/group;
1 run of 1/group). Food was weighed 1, 2, 4, 8, and 24 h post-injection.
Cumulative food intake .+-.SEM was calculated and analyzed using
Prizm. The SEM for these numbers was found to be between 0.0041
and 0.26. Doses were log transformed and fit to a sigmoidal curve,
food intake was expressed as a proportion of the food intake in
saline treated animals. From the curve, the EC.sub.50 at each time
point for each drug was determined.
[0238] Similar procedures as described above were followed using
fluvoxamine and nalmefene, and bupropion and naltrexone.
[0239] The results are set forth in the table below. TABLE-US-00001
Hour 1 Hour 2 Hour 4 Hour 8 Hour 24 MEAN MEAN MEAN MEAN MEAN Saline
1.00 1.00 1.00 1.00 1.00 Fluvoxamine 0.77 0.85 0.95 0.91 0.92 Nalmefene
0.0083 0.11 0.57 0.81 0.98 Fluvoxamine + 0.0041 0.019 0.42 0.79
0.99 Nalmefene Bupropion 0.32 0.64 0.97 0.96 0.99 Naltrexone 0.41
0.77 0.99 1.1 0.98 Naltrexone + Bupropion 0.042 0.34 0.89 0.97 0.95
Naltrexone 0.30 0.56 0.83 0.98 1.01 Fluoxetine 0.36 0.57 0.68 0.76
1.05 Naltrexone + Fluoxetine 0.070 0.26 0.72 0.95 1.04
Example 9
Electrophysiology Data
[0240] To test the hypothesis that drugs selectively activate POMC
neurons, we used a strain of transgenic mice expressing green fluorescent
protein (EGFP, Clontech), under the transcriptional control of mouse
Pomc genomic sequences that include a region located between -13
kb and -2 kb required for accurate neuronal expression Bright green
fluorescence (509 nm) was seen in the two CNS regions where POMC
is produced: the ARC and the nucleus of the solitary tract. Under
ultraviolet (450-480 nm) excitation, POMC neurons were clearly distinguished
from adjacent, non-fluorescent neurons visualized under infrared
optics.
[0241] 200 .mu.m thick coronal slices were cut from the ARC of
four-week old male POMC-EGFP mice. Slices were maintained in Krebs
solution (NaCl (126 mM), KCl (2.5 mM), MgCl.sub.2 91.2 mM), CaCl.sub.2.2H.sub.2O
(2.4 mM), NaH.sub.2PO.sub.4.H.sub.2O (1.2 mM), NaHCO.sub.3 (21.4
mM), glucose (11.1 mM)) at 35.degree. C. and saturated with 95%
O.sub.2 and 5% CO.sub.2 for 1 hr prior to recordings. Recordings
were made in Krebs at 35.degree. C. Slices were visualized on an
Axioskop FS2 plus (Zeiss) through standard infra red optics and
using epifluorescence through a FITC (longpass) filter set. POMC-EGFP
neurons in hypothalamic slices had a resting membrane potential
of -40 to -45 mV and exhibited frequent spontaneous action potentials.
Cell-attached recordings were made from fluorescent neurons using
an Axopatch 200B amplifier (Axon Instruments) and Clampex 8 (Axon
Instruments). Action potentials frequencies were determined using
an event detection program (Mini Analysis; Synaptosoft Inc., Decatur,
Ga.). Drugs were applied to the bath for 3 min.
[0242] Data were analyzed by determining the average firing rate
for 500 sec prior to drug addition, and analyzing treatments relative
to this frequency (that is, firing rates were normalized to the
pre-treatment frequency). The ratio's listed for the combinations
are the ratio of the effect of naltrexone in combination with the
POMC activator, relative to naltrexone alone (that is the extra
effectiveness that naltrexone conferred to the POMC activator).
Also listed are the mean effects of the drugs alone. TABLE-US-00002
Fenfluramine 2X increase (n = 6) Fenfluramine + Naltrexone 5.2X
(n = 8) Fluoxetine 3X (n = 1) Fluoxetine + Naltrexone 1.2X (n =
1) Dopamine 11X (n = 9) Dopamine + Naltrexone 1.5X (n = 3)
[0243] Naltrexone alone has a potent (7.times.) but variable effect.
many cells did not respond to naltrexone alone, but gave a significant
response to combination treatment. Heisler et al. (Science 297(5581):609-11
(2002)) show that fenfluramine alone causes a 200% effect. TABLE-US-00003
Drug Dose Effect (%) Drug Dose Effect (%) Ratio Naltrexone 1 .mu.M
29650 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M 15080 0.51 Naltrexone
1 .mu.M 2200 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M 11440
520 Naltrexone 1 .mu.M 2500 Naltrexone + Fenfluramine 1 .mu.M +
20 .mu.M 856 0.34 Naltrexone 1 .mu.M 417 Naltrexone + Fenfluramine
1 .mu.M + 20 .mu.M 5700 13.67 Naltrexone 1 .mu.M 177 Naltrexone
+ Fenfluramine 1 .mu.M + 20 .mu.M 430 2.43 Naltrexone 1 .mu.M 200
Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M 2933 14.67 Naltrexone
1 .mu.M 700 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M Naltrexone
1 .mu.M 900 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M 1831 2.03
Naltrexone 1 .mu.M 2273 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M
Naltrexone 1 .mu.M 300 Naltrexone + Fenfluramine 1 .mu.M + 20 .mu.M
920 3.07
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