U.S. patent application number 12/995121 was filed with the patent office on 2011-06-16 for methods for treating visceral fat conditions.
This patent application is currently assigned to Orexigen Therapeutics, Inc.. Invention is credited to Gary Tollefson.
Application Number | 20110144145 12/995121 |
Document ID | / |
Family ID | 41444868 |
Filed Date | 2011-06-16 |
United States Patent
Application |
20110144145 |
Kind Code |
A1 |
Tollefson; Gary |
June 16, 2011 |
METHODS FOR TREATING VISCERAL FAT CONDITIONS
Abstract
Disclosed are methods and compositions for treating visceral fat
conditions and/or metabolic syndrome using combinations of
naltrexone and bupropion.
Inventors: |
Tollefson; Gary;
(Indianapolis, IN) |
Assignee: |
Orexigen Therapeutics, Inc.
|
Family ID: |
41444868 |
Appl. No.: |
12/995121 |
Filed: |
May 29, 2009 |
PCT Filed: |
May 29, 2009 |
PCT NO: |
PCT/US09/45720 |
371 Date: |
February 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61057743 |
May 30, 2008 |
|
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61P 3/00 20180101; A61P
9/00 20180101; A61P 3/10 20180101; A61P 29/00 20180101; A61P 3/06
20180101; A61P 9/12 20180101; A61K 31/137 20130101; A61P 35/00
20180101; A61K 31/485 20130101; A61P 9/10 20180101; A61P 1/02
20180101; A61P 3/04 20180101; A61P 43/00 20180101; A61K 31/137
20130101; A61K 2300/00 20130101; A61K 31/485 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 3/04 20060101 A61P003/04; A61P 9/00 20060101
A61P009/00; A61P 3/06 20060101 A61P003/06; A61P 29/00 20060101
A61P029/00 |
Claims
1-62. (canceled)
63. A method of treating a visceral fat condition, comprising
administering a first and a second compound to a person who has
been identified or diagnosed as being in need of treatment for a
visceral fat condition in order to treat said visceral fat
condition, wherein said first compound is naltrexone or a
pharmaceutically acceptable salt thereof, and said second compound
is bupropion or a pharmaceutically acceptable salt thereof.
64. The method of claim 63, wherein said person has an amount of
visceral fat that increases the risk or severity of at least one
disease or condition selected from the group consisting of coronary
heart disease, cancer, diabetes, glucose intolerance,
hyperinsulinemia, hypertension, periodontal disease, and a
metabolic syndrome.
65. The method of claim 63, wherein said person has been identified
or diagnosed using a method comprising the determination of a
waist-to-hip measurement ratio of about 0.8 or greater.
66. The method of claim 63, wherein the intra-abdominal fat area of
said person, as determined by CT scanning in a single tomographic
slice at the L.sub.4-L.sub.5 level, is about 80 cm.sup.2 or
greater.
67. The method of claim 63, wherein said person has metabolic
syndrome.
68. The method of claim 67, wherein said person has been identified
or diagnosed using a method comprising identifying said person as
having at least three patient characteristics selected from the
group consisting of abdominal obesity, elevated triglyceride
levels, decreased high-density lipoprotein (HDL) cholesterol
levels, high blood pressure, and impaired fasting blood
glucose.
69. The method of claim 68, wherein one of said patient
characteristics is abdominal obesity.
70. The method of claim 63, wherein said treatment of a visceral
fat condition comprises at least one effect selected from the group
consisting of a reduction of abdominal obesity, a reduction of
triglyceride levels, an increase of high-density cholesterol
levels, a reduction in blood pressure, an improvement in fasting
blood glucose levels, a reduction of susceptibility to a heart
disease, and a reduction of inflammation.
71. The method of claim 63, wherein said person is viscerally
obese.
72. The method of claim 63, wherein the body mass index of said
person is greater than about 30.
73. The method of claim 63, wherein the body mass index of said
person is less than about 30.
74. The method of claim 63, wherein said first compound and said
second compound are administered together in a single dosage
form.
75. The method of claim 63, wherein said first compound and said
second compound are administered in separate dosage forms.
76. The method of claim 75, wherein said first compound is
administered prior to or subsequent to said second compound.
77. The method of claim 63, wherein the amount of said naltrexone
or pharmaceutically acceptable salt thereof is in the range of from
about 4 mg to about 50 mg per day.
78. The method of claim 63, wherein the amount of said bupropion or
pharmaceutically acceptable salt thereof is in the range of from
about 50 mg to about 600 mg per day.
79. The method of claim 63, wherein the amount of said naltrexone
or pharmaceutically acceptable salt thereof is in the range of from
about 4 mg to about 50 mg per day, and wherein the amount of said
bupropion or pharmaceutically acceptable salt thereof is in the
range of from about 50 mg to about 600 mg per day.
80. The method of claim 79, wherein at least one of said naltrexone
or pharmaceutically acceptable salt thereof and said bupropion or
pharmaceutically acceptable salt thereof is in a sustained-release
formulation.
81. The method of claim 79, wherein each of said naltrexone or
pharmaceutically acceptable salt thereof and said bupropion or
pharmaceutically acceptable salt thereof is in a sustained-release
formulation.
82. A method of treating a visceral fat condition, comprising
administering a first and a second compound to a person who has
been identified or diagnosed as being in need of treatment for a
visceral fat condition in order to treat said visceral fat
condition, wherein said first compound is naltrexone or a
pharmaceutically acceptable salt thereof and said second compound
is bupropion or a pharmaceutically acceptable salt thereof, wherein
the amount of said naltrexone or pharmaceutically acceptable salt
thereof is in the range of from about 4 mg to about 32 mg per day
and the amount of said bupropion or pharmaceutically acceptable
salt thereof is in the range of from about 50 mg to about 400 mg
per day, wherein each of said naltrexone or pharmaceutically
acceptable salt thereof and said bupropion or pharmaceutically
acceptable salt thereof is in a sustained-release formulation, and
wherein said first compound and said second compound are
administered together in a single dosage form.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] Embodiments of the present invention relate to methods and
compositions for reducing visceral fat and/or treating metabolic
syndrome.
[0003] 2. Description of the Related Art
[0004] Health risks associated with obesity can depend on how and
where the fat is stored. Cutaneous fat refers to fat that is near
the skin's surface. Visceral fat, which may also be referred to as
intra-abdominal or subcutaneous fat, typically surrounds internal
organs. In contrast to subcutaneous fat, visceral fat has been
shown to be a risk factor associated with a variety of serious
medical disorders.
[0005] For example, whether a person is obese (BMI>30) or not,
they can still experience visceral fat accumulation in the
abdominal cavity (particularly, in the mesentery and/or in the
greater omentum). This accumulation, in turn, is often positively
correlated with elevated values of serum cholesterol, triglyceride,
and/or blood glucose measured by the glucose tolerance test.
Visceral fat accumulation also often positively correlates with the
systolic and diastolic blood pressures, and accordingly is related
to a heightened risk of diseases such as hypertension, diabetes,
and hyperlipemia (see, e.g., Fujioka, S., et al. Metabolism, 36
54-59, 1987; Matsuzawa, Y., et al. Progress in Obesity Research,
309-312, 1990). These diseases are therefore thought to be treated,
cured and/or prevented by decreasing visceral fat, by inhibiting
visceral fat accumulation, and/or improving body fat distribution
(see, e.g., Bray, G. A., Obesity Research, 3, Suppl. 4, 425S-434S,
1995). Hence, there is a need for an effective pharmacotherapy for
decreasing visceral fat.
SUMMARY OF THE INVENTION
[0006] In some embodiments, a method of treating a visceral fat
condition is provided. The method can include identifying a person
in need thereof; and administering to the person naltrexone and
bupropion in dosages that together are effective to treat the
visceral fat condition. Identifying the person in need of treatment
can include determining that the person is viscerally obese and/or
determining that the person has an amount of visceral fat that
increases the risk and/or severity of at least one disease or
condition selected from coronary heart disease, cancer, diabetes,
glucose intolerance, hyperinsulinemia, hypertension, periodontal
disease and a metabolic syndrome. Identifying the person in need of
treatment can include determining a patient waist-to-hip
measurement ratio. The patient's waist-to-hip measurement ratio can
be about 0.8 or greater. Identifying the person in need of
treatment can include analyzing one or more test selected from a
computed tomography (CT) scan, a magnetic resonance imaging scan,
and an ultrasonogram. The intra-abdominal fat area of the person,
as determined by CT scanning in a single tomographic slice at the
L.sub.4-L.sub.5 level can be about 80 cm.sup.2 or greater.
Identifying the person in need of treatment can include determining
that the body mass index of the person is greater than about 25,
greater than about 27, greater than about 30, or greater than about
40. Naltrexone and bupropion can be administered together in a
single dosage form. The bupropion dosage for an adult human can
advantageously be in the range of from about 100 mg to about 600
mg, for example, about 100 mg, about 150 mg, about 200 mg, about
250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg,
about 500 mg, about 550 mg, or about 600 mg. The naltrexone dosage
for an adult human can be in the range of from about 4 mg to about
50 mg, for example, about 4 mg, about 8 mg, about 16 mg, about 32,
mg or about 48 mg. Identifying the person in need of treatment can
include determining that the person has metabolic syndrome (also
known as Syndrome X), which can include identifying at least three
patient characteristics selected from abdominal obesity, elevated
triglyceride levels, decreased high-density lipoprotein (HDL)
cholesterol levels, high blood pressure, and impaired fasting blood
glucose. The naltrexone and bupropion can be administered in
dosages that together are effective to result in at least one
effect selected from a reduction of abdominal obesity, a reduction
of triglyceride levels, an increase of high-density cholesterol
levels, a reduction in blood pressure, and an improvement in
fasting blood glucose levels. In some cases, the body mass index of
the person can be greater than about 25 (definition of overweight),
greater than about 27, greater than about 30 (definition of
obesity) or greater than about 40, whereas in other cases the body
mass index of the patient can be less than about 30 (non-obese). In
any case, visceral fat and its health consequences can be present.
The naltrexone and bupropion can be administered in dosages that
together are effective to additionally result in a reduction of
inflammation, which can include reduction of the serum level of
interleukin 6 and/or a reduction of the serum level of C-reactive
protein. Such factors are believed to mediate cardiovascular risk.
Thus, the naltrexone and bupropion can be administered in dosages
that together are effective in reducing the person's susceptibility
to a heart disease.
[0007] A method of treating a visceral fat condition can also
include administering naltrexone or a pharmaceutically acceptable
salt thereof and bupropion or a pharmaceutically acceptable salt
thereof to a person who has been identified or diagnosed as being
in need of treatment for a visceral fat condition in order to treat
the visceral fat condition. Naltrexone or a pharmaceutically
acceptable salt thereof can be administered in an amount effective
to enhance the treatment effect of bupropion or a pharmaceutically
acceptable salt thereof compared to the administration of bupropion
or a pharmaceutically acceptable salt thereof alone. Bupropion or a
pharmaceutically acceptable salt thereof can be administered in an
amount effective to enhance the treatment effect of naltrexone or a
pharmaceutically acceptable salt thereof compared to the
administration of naltrexone or a pharmaceutically acceptable salt
thereof alone. The person can have an amount of visceral fat that
increases the risk and/or severity of at least one disease or
condition selected from coronary heart disease, cancer, diabetes,
glucose intolerance, hyperinsulinemia, hypertension, periodontal
disease, and a metabolic syndrome. The person can previously have
been identified or diagnosed using a method comprising the
determination of a waist-to-hip measurement ratio. The waist-to-hip
measurement ratio can be about 0.8 or greater. The person can
previously have been identified or diagnosed using a method
comprising analyzing one or more test selected from a computed
tomography (CT) scan, a magnetic resonance imaging scan, and an
ultrasonogram. The intra-abdominal fat area of the person, as
determined by CT scanning in a single tomographic slice at the
L.sub.4-L.sub.5 level, can be about 80 cm.sup.2 or greater. The
person can have metabolic syndrome. Metabolic syndrome could have
been identified or diagnosed using a method comprising identifying
at least three patient characteristics selected from abdominal
obesity, elevated triglyceride levels, decreased high-density
lipoprotein (HDL) cholesterol levels, high blood pressure, and
impaired fasting blood glucose. The treatment of a visceral fat
condition can reduce the person's susceptibility to a heart
disease. This reduction can include a reduction of inflammation, a
reduction in the serum level of interleukin 6, and/or a reduction
of the serum level of C-reactive protein. The person can be
viscerally obese. In some cases, the body mass index of the person
can be greater than about 30 (i.e., obese). In some cases, the body
mass index of the person can be greater than about than about 40.
In other cases, the body mass index of the patient can be less than
about 30 (i.e., non-obese). In any case, visceral fat and its
health consequences can be present. Naltrexone or a
pharmaceutically acceptable salt thereof and bupropion or a
pharmaceutically acceptable salt thereof can be administered
together in a single dosage form, or can be administered in
separate dosage forms. Naltrexone or a pharmaceutically acceptable
salt thereof can be administered prior to, concurrently with, or
subsequent to bupropion or a pharmaceutically acceptable salt
thereof. The bupropion dosage for an adult human can advantageously
be in the range of from about 100 mg to about 600 mg, i.e., about
100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg,
about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550
mg, or about 600 mg. The naltrexone dosage for an adult human can
be in the range of from about 4 mg to about 50 mg, i.e., about 4
mg, about 8 mg, about 16 mg, about 32 mg, or about 48 mg.
Naltrexone can be a sustained-release naltrexone and/or bupropion
can be a sustained-release bupropion.
[0008] In some embodiments, a method of administering visceral fat
treatment to a patient is provided. The method includes advising
the patient or a care provider that combined therapy with bupropion
and naltrexone is effective to treat a visceral fat condition; and
administering naltrexone and bupropion to the patient in dosages
that together are effective to treat the visceral fat condition.
Advising the patient or care provider can include providing written
information. The written information can include a label or product
insert. Advising the patient or care provider can further include
advising that the dosages of naltrexone and bupropion are together
effective to result in weight loss.
[0009] In some embodiments, a method of treating metabolic syndrome
is provided, comprising identifying a person suffering from
metabolic syndrome; and administering to the person naltrexone and
bupropion in dosages that together are effective to treat metabolic
syndrome. Determining that the person has metabolic syndrome can
include identifying at least three patient characteristics selected
from abdominal obesity, elevated triglyceride levels, decreased
high-density lipoprotein (HDL) cholesterol levels, high blood
pressure, and impaired fasting blood glucose. One of the
characteristics can be abdominal obesity. The naltrexone and
bupropion can be administered in dosages that together are
effective to result in at least one effect selected from a
reduction of abdominal obesity, a reduction of triglyceride levels,
an increase of high-density cholesterol levels, a reduction in
blood pressure, and an improvement in fasting blood glucose levels.
The naltrexone and bupropion can be administered together in a
single dosage form. The dosage of the bupropion can be in the range
of from about 100 mg to about 600 mg. The dosage of the bupropion
can be about 100 mg, about 150 mg, about 200 mg, about 250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500
mg, about 550 mg or about 600 mg. The dosage of the naltrexone can
be in the range of from about 4 mg to about 50 mg, for example,
about 4 mg, about 8 mg, about 16 mg, about 32 mg or about 48
mg.
[0010] These and other embodiments are described in greater detail
below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows average change in visceral body mass following
various treatments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0012] The term "visceral fat" as used herein has its ordinary
meaning as understood by those skilled in the art and includes the
fat in the abdominal region which is inside the peritoneal cavity,
and thus is distinct from "subcutaneous fat". Visceral fat can be
assessed, either qualitatively or quantitatively, by standard
assays known to those of ordinary skill in the art, for example, by
computer tomography (CT), magnetic resonance imaging (MRI),
ultrasonography, and/or determinations of subject waist-to-hip
measurement ratios.
[0013] The term "visceral fat condition" as used herein refers to
various diseases, conditions and disorders associated with the
presence of excessive amounts of visceral fat. An individual having
a visceral fat condition thus has an unhealthy amount of visceral
fat, e.g., an amount that correlates with increased risk or
severity of a disease, condition or disorder associated with the
presence of visceral fat. For example, visceral fat is associated
with diseases and conditions such as obesity, coronary heart
disease, cancer, diabetes, glucose intolerance and hyperinsulinemia
(see Montague, C T et al., 2000, Diabetes 49:883-888); hypertension
(see Watanabe et al., 2003, Clin Exp Hypertens 25:199-208);
periodontal disease (see Wood N et al., 2003, J Clin Periodontol
30:321-327); and metabolic syndromes, such as type II diabetes (see
Goodpaster, B H et al., 2003 Diabetes Care 26:372-379). The
aforementioned articles are hereby incorporated by reference in
their entireties and particularly for the purpose of describing
visceral fat conditions. Without being bound by any particular
theory, visceral fat is thought (at least) to put a greater fatty
acid burden on the liver, causing, complicating, and/or aggravating
various diseases and conditions.
[0014] The term "selective visceral fat condition" as used herein
refers to various diseases, conditions, and disorders associated
with the presence of excessive amounts of visceral fat, but not
with the presence of excessive amounts of non-visceral (e.g.,
subcutaneous) fat. For example, a person suffering from visceral
obesity but not from obesity in general is suffering from a
selective visceral fat condition.
[0015] As used herein, "treatment" or "treating" refers to
inhibiting or reversing the progression of a disease, condition, or
disorder, e.g., visceral obesity, or delaying the onset of a
disease, condition, or disorder, e.g., visceral obesity, whether
physically, e.g., stabilization of a discernible symptom,
physiologically, e.g., stabilization or reduction of a physical
parameter, or both. As used herein, the terms "treatment,"
"treating," and the like, refer to obtaining a desired
pharmacologic and/or physiologic effect. The effect can be
prophylactic in terms of completely or partially preventing a
disease or condition, or a symptom thereof and/or can be
therapeutic in terms of a partial or complete reversal,
amelioration, or cure for a disease, condition or disorder and/or
of an adverse affect attributable to the disease, condition or
disorder. "Treatment" or "treating," as used herein, encompasses
any treatment of a disease, condition, or disorder in a human, and
includes: decreasing the risk of death due to the disease;
preventing the disease or disorder from occurring in a subject
which may be predisposed to the disease but has not yet been
diagnosed as having it; inhibiting the disease or disorder, i.e.,
arresting its development (e.g., reducing the rate of disease
progression); and relieving the disease, i.e., causing regression
of the disease. Therapeutic benefits of the treatment methods
described herein include reducing the risk of onset or severity of
visceral fat conditions as well as improvements in appearance
(e.g., the treatment can be a "cosmetically effective" treatment,
which can be further associated with improved physical appearance,
psychological benefits, emotional benefits, and the like).
[0016] As used herein, "enhance," "enhancement," or "enhancing"
refers to improving and/or augmenting the therapeutic effect of a
compound in the treatment of a disease, condition, or disorder
(e.g., a visceral fat condition). A first compound can enhance a
second compound by allowing less of the second compound to be
administered with an equivalent therapeutic effect. A first
compound can enhance a second compound by generating a therapeutic
effect that is greater than the therapeutic effect of the second
compound administered alone. In some cases, the combination of a
first and a second compound has less than an additive therapeutic
effect. For example, amounts of naltrexone and bupropion can be
selected such that the combination reduces a visceral fat condition
to an extent that is less than the sum of naltrexone and bupropion
administered alone. In some cases, the combination of a first and a
second compound has an additive therapeutic effect. For example,
amounts of naltrexone and bupropion can be selected such that the
combination reduces a visceral fat condition to an extent that is
approximately equal to the sum of naltrexone and bupropion
administered alone. In some cases, the combination of a first and a
second compound has a synergistic therapeutic effect. For example,
amounts of naltrexone and bupropion can be selected such that the
combination reduces a visceral fat condition to an extent that is
more than the sum of naltrexone and bupropion administered
alone.
[0017] The term "subcutaneous fat" as used herein has its ordinary
meaning as understood by those skilled in the art and includes fat
deposited just under the skin, e.g., under the skin of the thigh
area.
[0018] The term "bupropion" as used herein, unless the context
indicates otherwise, includes free bupropion, active bupropion
metabolites (including, but not limited to, hydroxybupropion, and
the amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion), prodrug esters, amides, and
pharmaceutically acceptable salts of bupropion, such as (but not
limited to) bupropion hydrochloride and bupropion hydrobromide.
Bupropion can be formulated as an immediate-release form or a
controlled-release form, e.g., a sustained-release form. Bupropion
can be formulated for once daily administration.
[0019] The term "naltrexone" as used herein, unless the context
indicates otherwise, includes free naltrexone, active naltrexone
metabolites (including, but not limited to, 6 beta-naltrexol),
prodrug esters, amides, and pharmaceutically acceptable salts
thereof. Naltrexone can be formulated as an immediate-release form
or a controlled-release form, e.g., a sustained-release form as
described in U.S. Patent Publication No. 2007-0281021 A1, which is
hereby incorporated by reference in its entirety and particularly
for the purpose of describing sustained-release forms of
naltrexone.
[0020] In various embodiments, naltrexone and bupropion are
coadministered to a person. Naltrexone and bupropion can be
formulated and administered in various ways. See, e.g., U.S. Pat.
Nos. 5,512,593 and 5,817,665, as well as U.S. Patent Publication
Nos. 2004-0254208 and 2006-0142290, all of which are hereby
incorporated by reference in their entireties and particularly for
the purpose of describing formulations of naltrexone and bupropion
and methods of administering them. Naltrexone and bupropion can be
combined into a single dosage form, e.g., in a multilayer tablet as
described in U.S. application Ser. No. 11/937,421, filed Nov. 8,
2007, which is hereby incorporated by reference in its entirety and
particularly for the purpose of describing multilayer dosage forms
comprising naltrexone and bupropion. Alternatively, naltrexone and
bupropion can be administered as separate dosage forms, e.g., as
described in U.S. application Ser. No. 11/937,367, filed Nov. 8,
2007, which is hereby incorporated by reference in its entirety and
particularly for the purpose of describing methods of administering
naltrexone and bupropion as separate dosage forms. For example,
naltrexone can be administered prior to, concurrently with, or
subsequent to bupropion. Coadministration of naltrexone and
bupropion, whether simultaneous or temporally separated, should be
done so as to provide the two drugs in the blood stream
simultaneously, in effective amounts. The dosages discussed herein,
when administered simultaneously, provide one example of such
effective amounts. One or both of naltrexone and bupropion can be
administered with another weight-reducing agent and/or visceral-fat
reducing agent. One or both of the naltrexone and bupropion can be
in a sustained-release form. For example, in a preferred
embodiment, sustained-release naltrexone and sustained-release
bupropion are administered concurrently, e.g., as described in U.S.
application Ser. Nos. 11/937,421 and 11/937,367.
[0021] In some embodiments, one or both of the compounds are
formulated for parenteral administration by injection, e.g., by
bolus injection or continuous infusion. Formulations for injection
can be presented in unit dosage form, e.g., in ampoules or in
multi-dose containers, with an added preservative. The compounds
can take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, and can contain formulatory agents such as
suspending, stabilizing, and/or dispersing agents. In some
embodiments, a once-monthly injectable form of naltrexone
(commercially available under the tradename VIVITROL.RTM.) is used
for the methods and compositions described herein.
[0022] In various embodiments, the present invention relates to a
method of treating a visceral fat condition, comprising identifying
a person in need thereof and administering to the person naltrexone
and bupropion in dosages that together are effective to treat the
visceral fat condition. Methods can comprise diagnosing a patient
with a visceral fat condition and/or a selective visceral fat
condition and administering or providing to the person naltrexone
and bupropion in dosages that together are effective to treat the
condition. The effectiveness of the treatment can be evidenced by a
reduction in visceral fat and/or a reduction in the risk and/or
severity of the disease, condition or disorder associated with the
presence of the visceral fat. Changes in visceral fat level can be
determined by comparing measurements of visceral fat before and
after a period of visceral fat treatment as described herein, using
a visceral fat measurement technique such as computed tomography
(CT), magnetic resonance imaging (MRI), ultrasonography, and/or
measuring a change in a treated patient's waist-to-hip measurement
ratio. In an embodiment, treatment as described herein results in
reductions in visceral fat and subcutaneous fat that are about the
same (non-selective), and generally results in overall weight loss.
A selective reduction in visceral fat results in a greater
reduction in visceral fat than subcutaneous fat, and can even be
accompanied by no loss or a gain in subcutaneous fat. Thus, a
selective reduction in visceral fat typically involves a
redistribution of fat, accompanied by an overall loss of body fat
in some situations, whereas in others the redistribution is not
accompanied by an overall loss of body fat. Redistribution of body
fat is, without being held to theory, one possible explanation for
reduction of visceral fat in a subject without an overall reduction
in body weight or BMI, which can be due to, for example, a
proportional or non-proportional increase in subcutaneous fat.
[0023] In general, a decrease in the waist measurement of a treated
person that is greater than the decrease in hip measurement
indicates that visceral fat is selectively reduced. For example, a
selective reduction in visceral fat is indicated where the waist
diameter measurement decreases by at least about 1 cm more than the
hip measurement, or at least about 2 cm or more than the hip
measurement, e.g., about 3 cm to about 5 cm or more than the hip
measurement. The waist measurement (or "abdominal perimeter") takes
into account both visceral and subcutaneous fat, while the hip
measurement takes into account primarily subcutaneous fat. A
selective reduction in visceral fat can be evaluated by, for
example, determining a reduction of a waist-to-hip measurement
ratio from greater than about 1 (where the measurement of the waist
circumference and the measurement of the hip circumference are
about the same) to a ratio of less than about 1 (wherein the
measurement of the waist circumference is less than the measurement
of the hip circumference). A selective reduction in visceral fat
can also be evaluated by, for example, determining a reduction in
the waist-to-hip measurement ratio of greater than about 2%,
including about 3% to about 100%, such as by about 4% to about 98%.
In some embodiments, a reduction in the waist-to-hip measurement
ratio is greater than about 2%, about 5%, about 10%, about 15%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, about 95%, or about 100%. The
percentage reduction in the waist-to-hip measurement ratio can be
calculated as one hundred times one minus the patient's initial
waist-to-hip ratio divided by the patient's final waist-to-hip
ratio (100*(1-R.sub.i/R.sub.f)).
[0024] Some embodiments of the invention are directed to methods of
treating visceral obesity, comprising identifying a person in need
of a reduction in visceral fat and administering bupropion and
naltrexone to the person in dosages that together are effective to
treat the visceral obesity. Visceral obesity is a visceral fat
condition in which an overweight or obese person has an excess of
visceral fat, e.g., the ratio of visceral fat to subcutaneous fat
is higher for the viscerally obese person than for the average
non-obese person or person having obesity primarily attributed to
subcutaneous fat. Those skilled in the art understand that an obese
person is not necessarily viscerally obese, and that a person who
has a visceral fat condition is not necessarily obese. Obesity and
overweight refer to conditions, as defined by the United States
Centers for Disease Control, which are presently defined as an
adult subject (a subject of about 20 years of age or older) who
presents with a body-mass index (BMI) of about 30 or greater (for
obesity) or 25 or greater (for overweight). It will be readily
appreciated by those skilled in the art that the BMI-based
definition of obesity can be modified to reflect changes in
understanding of the condition or practices in the field, and such
changes to the BMI-based definitions of obesity and overweight are
contemplated herein. For subjects of about 2 to 20 years in age,
obesity and overweight are determined using a BMI-for-age
calculation, which is plotted on gender specific growth charts
(such as those available from the United States Centers for Disease
Control). In an embodiment, a viscerally obese person has a BMI of
about 30 or greater and a waist-to-hip measurement ratio that is
greater than about 1.
[0025] Some embodiments of the invention are directed to methods of
treating a metabolic syndrome. For example, in an embodiment,
naltrexone and bupropion are administered, as described herein, to
reduce visceral fat (either the absolute amount of visceral fat or
the ratio of visceral fat to subcutaneous fat), and to reduce a
symptom, condition, disorder or disease (e.g., a heart disease)
associated with a metabolic syndrome. Metabolic syndrome (also
known as Syndrome X) represents a group of risk factors that have
been linked to obesity and insulin resistance, and are present in
about 47 million Americans. This syndrome can increase the risk of
later developing diabetes or cardiovascular disease and can be
reduced by a loss in excess body weight. Metabolic syndrome (see
Adult Treatment panel Guidelines III) is a condition associated
with a subject having three or more of the following symptoms:
abdominal obesity, elevated triglyceride levels, decreased
high-density lipoprotein (HDL) cholesterol levels, high blood
pressure, and impaired fasting blood glucose. Abdominal obesity can
be manifested for men as greater than a 40-inch waist and for women
as greater than a 35-inch waist. Impaired fasting blood glucose can
be manifested as 110 mg/dL or higher. Elevated triglyceride levels
can be manifested as fasting triglyceride levels of 150 mg/dL or
higher. Decreased HDL cholesterol levels can be manifested for men
as less than 40 mg/dL and for women as less than 50 mg/dL. High
blood pressure can be manifested as 130/85 or higher. Treatment can
increase or decrease the measurement of at least one symptom of
metabolic syndrome to an amount that no longer falls above or below
the threshold to qualify as a symptom. For example, treatment can
reduce a waist measurement to less than about 40 inches for a man
or less than about 35 inches for a woman, decrease fasting blood
glucose to less than about 110 mg/dL, decrease triglyceride level
to less than about 150 mg/dL, increase HDL cholesterol level to
more than about 40 mg/dL for a man or more than about 50 mg/dL for
a woman, and/or reduce blood pressure to less than about 130/85. In
some embodiments, treatment reduces the measurement of one or more
symptoms such that a subject no longer qualifies as having
metabolic syndrome. For example, in some embodiments, the subject
has all five symptoms prior to treatment, but only two symptoms
during and/or after treatment. In some embodiments, the subject has
three symptoms prior to treatment, but has no symptoms during
and/or after treatment.
[0026] Naltrexone and bupropion can be administered, as described
herein as at least part of a prophylactic (prior to onset) and/or
cosmetic treatment, wherein the prophylactic and/or cosmetic
treatment comprises a relative or absolute reduction of visceral
fat. In some instances, the prophylactic and/or cosmetic treatment
further comprises weight loss, which may or may not be
substantially proportional to the reduction in visceral fat.
[0027] Various embodiments are directed to a method of
administering a weight loss therapy to a patient, comprising
advising the patient or a care provider that combined therapy with
bupropion and naltrexone is effective to treat a visceral fat
condition. For example, a patient or a care provider can be advised
that treatment with naltrexone and bupropion as described herein
results in a reduction of visceral body fat and a reduction in the
risk and/or severity of at least one disease or condition selected
from coronary heart disease, cancer, diabetes, glucose intolerance,
hyperinsulinemia, hypertension, periodontal disease and a metabolic
syndrome (such as a reduction of abdominal obesity, a reduction of
triglyceride levels, an increase of high-density cholesterol
levels, a reduction in blood pressure, an improvement in fasting
blood glucose levels, a reduction of inflammation, and/or a
reduction of the patient's susceptibility to heart disease). The
advising can include providing written information. The written
information can comprise a label, instructions, or a package
insert.
[0028] The methods described herein are directed to the treatment
of subjects having an excess of visceral fat, which can be
manifested as an excessive ratio of visceral fat to subcutaneous
fat, by an excessive percentage of total body fat that is
attributed to visceral fat, or by an absolute amount of visceral
fat that is excessive. For example, the excess of visceral fat can
be a level that the subject or a physician considers to be
undesirable and/or unhealthy. In certain embodiments, the subjects
are obese or overweight, whereas in other embodiment, they are not.
The excessively high visceral fat content can include a fat content
that increases the risk of medical diseases, conditions, or
disorders. The excessively high visceral fat content can include a
fat content that is determined to be too high for cosmetic
purposes. Identification of the patient can comprise determining or
measuring a visceral fat characteristic of a patient. The visceral
fat characteristic can include a waist circumference and/or a
waist-to-hip ratio. The visceral fat characteristic can be
determined at least partially by analyzing one or more of a
computed tomography scan, a magnetic resonance imaging scan, and an
ultrasonogram.
[0029] Naltrexone and bupropion can be administered as described
herein to a patient with a waist circumference that is about 80 cm
or greater, about 85 cm or greater, about 90 cm or greater, about
95 cm or greater, or about 100 cm or greater. In a preferred
embodiment, treatment reduces a patient's waist circumference to
less than about 80 cm, or more preferably to less than about 70 cm.
Naltrexone and bupropion can be administered as described herein to
a patient with a waist-to-hip ratio circumference that is about 0.8
or greater, about 0.85 or greater, about 0.9 or greater, about 0.95
or greater, or about 1 or greater. Naltrexone and bupropion can be
administered as described herein to a patient with a waist-to-hip
ratio circumference that is about 0.8 or greater, about 0.85 or
greater, about 0.9 or greater, about 0.95 or greater, or about 1 or
greater. In a preferred embodiment, treatment reduces a patient's
the waist-to-hip ratio circumference to less than about 0.8, or
more preferably to less than about 0.7. Naltrexone and bupropion
can be administered as described herein to a patient with an
intra-abdominal fat area, as estimated by CT scanning in a single
tomographic slice at the L.sub.4-L.sub.5 level of about 80 cm.sup.2
or greater, about 100 cm.sup.2 or greater, about 120 cm.sup.2 or
greater, or about 130 cm.sup.2 or greater. In a preferred
embodiment, treatment reduces a patient's tomographic slice at the
L.sub.4-L.sub.5 level to less than about 80 cm.sup.2, or more
preferably to less than about 70 cm.sup.2.
[0030] In certain embodiments, the subjects are obese or
overweight, whereas in other embodiments, they are not. For
example, patients can have a BMI greater than about 25, greater
than about 27, greater than about 30, greater than about 40, less
than about 30, less than about 40 and/or less than about 50.
[0031] Visceral fat levels of subjects can be determined by various
techniques known to those skilled in the art. Visceral fat of
subjects can be directly measured. Visceral obesity can be
diagnosed by determining a subject's waist-to-hip measurement
ratio. Generally, measurements are taken of the waist and hip and a
ratio is compared to published tables which reflect the amount of
risk for certain diseases or conditions associated with visceral
obesity. The waist measurement, i.e., belt size, can also be used
by itself. Changes in visceral fat levels in a subject (e.g., a
"decrease in visceral fat") in response to treatment can be
determined by a subject's waist-to-hip measurement ratio. The waist
measurement (or "abdominal perimeter") takes into account both
visceral and subcutaneous fat, while the hip measurement takes into
account only subcutaneous fat.
[0032] Visceral fat can be also assessed both qualitatively and
quantitatively, by standard assays known to one of ordinary skill
in the art, for example, by computer tomography (CT) scans of, for
example, the abdomen. Where desired, CT scans can be used to assess
both visceral and subcutaneous fat. In such instances, it can be
useful to determine the ratio of visceral fat to subcutaneous fat
as part of determination of whether a subject is amenable to
therapy, and/or to monitor therapy according to the invention.
Visceral fat can be assessed by CT scanning in a single tomographic
slice at the L.sub.4-L.sub.5 level. Visceral fat can be assessed at
least partially by analyzing one or more of a magnetic resonance
imaging scan and an ultrasonogram.
[0033] Normal subjects, i.e., those not displaying obesity, large
amounts of visceral fat, or a visceral-fat disease, condition or
disorder, who can be amenable to the methods and compositions of
the invention can be identified by any method for predicting
obesity, visceral fat, or a visceral-fat disease, condition or
disorder, including, but not limited to, genetic tests and
screening of family histories.
[0034] The patient can be suffering from a visceral-fat condition.
For example, the patient can be suffering from, or at risk of
suffering from, one or more of coronary heart disease, certain
cancers, diabetes, glucose intolerance, hyperinsulinemia,
hypertension, periodontal disease, metabolic abnormalities, and
diabetes. The condition can be related to the patient being
overweight. The condition can also be inhibited by weight loss. In
some embodiments, the patient is being administered a different
medication which causes an increase in relative or absolute values
of visceral fat.
[0035] Naltrexone and bupropion compositions suitable for use in
the present invention include compositions in which the active
ingredients are contained in an amount effective to achieve its
intended purpose. A "therapeutically effective amount" refers to
that amount of the naltrexone and/or bupropion composition that is
sufficient to treat or manage a visceral fat condition, typically
as determined by a clinician or a physician. In some embodiments,
two or more compounds are provided separately or in a single dosage
form. In these embodiments, a therapeutically effective amount can
be determined based on the combined effects of the two or more
compounds. For example, naltrexone and bupropion can be
administered at dosages for which the combination of naltrexone and
bupropion is effective in decreasing visceral fat content, though
the dosages would be ineffective if either naltrexone or bupropion
were administered alone. In an embodiment, the amounts of
naltrexone and bupropion are selected so that the combination
provides an effect that is greater than additive, e.g.,
synergistically effective, in decreasing visceral fat content
and/or metabolic syndrome, as compared to the effect of either
naltrexone or bupropion administered alone.
[0036] The exact formulation, route of administration and dosage
for the naltrexone and bupropion compositions described herein 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.
[0037] The naltrexone and/or bupropion can be administered in a
controlled-release dosage form, e.g. a sustained-release form. The
naltrexone and/or bupropion can be administered to the patient
before, during, or after a specific meal or before, during, or
after every meal. The composition or compound can be administered
before the patient goes to sleep or in the morning. Bupropion can
be provided in various dosages, preferably in the range of from
about 100 mg to about 600 mg. Examples of bupropion dosages include
about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250
mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
500 mg, about 550 mg or about 600 mg. Naltrexone can also be
provided in various dosages, preferably in the range of from about
4 mg to about 50 mg. Examples of naltrexone dosages include about 8
mg, about 16 mg, about 32 mg, about 48 mg, or about 64 mg.
EXAMPLES
Example 1
[0038] A double-blind, placebo-controlled multi-center trial was
conducted with 285 healthy, non-diabetic, obese subjects. The
subjects were administered either bupropion 200 mg bid, placebo
(P), naltrexone 48 mg qd (N.sub.1), or bupropion 400 mg with
naltrexone 32 mg qd (BN.sub.2). 182 subjects completed 24 weeks of
treatment. A subset of 60 subjects had dual energy X-ray
absorptometry (DEXA) and multislice CT scans to measure body fat,
lean tissue and visceral fat (American Diabetes Association Annual
Meeting 2007).
[0039] The groups were matched at baseline. Markers of insulin
resistance improved more with BN.sub.2 than expected from the
weight loss alone. A robust effect on decreasing visceral fat was
also evident.
TABLE-US-00001 TABLE 1 Naltrexone & Naltrexone Bupropion
Bupropion Placebo 48 mg 400 mg 32/400 mg Weight (%) -1.1 .+-. 0.6
*** -1.74 .+-. 0.9 *** -3.14 .+-. 0.7 *** -7.1 .+-. 0.7 Waist (cm)
-1.0 .+-. 5.4 ** -3.8 .+-. 12.7.sup. -2.9 .+-. 6.0 -5.4 .+-. 7.6
Fasting Glucose 1.9 .+-. 1.3 * 3.4 .+-. 1.7 * .sup. 3.5 .+-. 1.5 *
-2.0 .+-. 1.5 (mg/dL) Insulin 0.9 .+-. 0.9 ** 1.7 .+-. 1.3 ** -0.5
.+-. 1.1 -3.0 .+-. 1.1 (mcU/mL) Triglyceride -15.0 .+-. 7.7 * -17.6
.+-. 10.4 -18.4 .+-. 9.0 * -43.6 .+-. 8.8 (mg/dL) Visceral fat (%)
-4.6 .+-. 0.6 ** -0.1 .+-. 8.7 *** .sup. -2.3 .+-. 5.1 * -13.7 .+-.
11.7 * p < 0.05, ** p < 0.01, *** p < 0.001
Example 2
[0040] Subjects (n=117) received one of six treatments: two
placebos (P+P), placebo and naltrexone (P+Nal), bupropion and
placebo (Bup+P), bupropion and naltrexone 48 mg (Bup+Nal 48),
bupropion and naltrexone 32 mg (Bup+Nal 32), or bupropion and
naltrexone 16 mg (Bup+Nal 16).
[0041] Subjects had a DEXA body scan to measure total body fat,
lean tissue and bone mineral content at baseline and at 6 months.
Subjects also had a multi-slice CT scan to determine visceral fat
volume at the same time points. The mass of selective visceral loss
can be calculated based on total fat and the volume of visceral
fat.
[0042] The average change in visceral body mass is shown in FIG. 1
for the four treatments. Patients receiving Bup+Nal 32 experienced
a dose-related loss in visceral body mass. Statistically
significant improvements were also observed in several important
metabolic parameters including: plasma glucose, serum insulin and
plasma triglycerides.
TABLE-US-00002 TABLE 2 Baseline Weight, BMI and Weight
Circumference Bup + Nal Bup + Bup + P + P P + Nal Bup + P 48 Nal 32
Nal 16 Weight (kg) 98.8 96.3 101.4 92.9 98.3 92.7 Mean BMI (kg/m2)
34.7 35.3 35.8 34.0 35.1 34.4 Mean Waist 105.8 104.3 107.7 102.1
103.5 102.0 Circumference (cm) Change in -- -1.5 1.9 -3.7 -2.3 -3.8
Waist Circumference (cm) Change in -- -1.4 1.8 -3.5 -2.2 -3.6 Waist
Circumference (%) vs. placebo
TABLE-US-00003 TABLE 3 Change from Baseline, Visceral Adipose Mass
Bup + Nal Bup + Bup + Bup + P + P P + Nal Bup + P 48 Nal 32 Nal 16
Nal # Change from Baseline -4.6 -0.1 -2.3 -16.7 -13.7 -15.5 -14.7
Mean (SD), Visceral (9.6) (8.7) (5.1) (15.2) (11.7) (14.9) (12.9)
Adipose Mass P-Value* 0.064 0.971 -.278 0.027 <0.001 0.009
<0.001 LS Mean (SE){circumflex over ( )} -1.2 3.5 0.2 -11.0
(2.7) (3.5) (4.3) (2.1) P-value (vs. B + N)* 0.003 <0.001
0.024
TABLE-US-00004 TABLE 4 Change from Baseline, Total Body Adipose
Mass Bup + Nal Bup + Bup + Bup + P + P P + Nal Bup + P 48 Nal 32
Nal 16 Nal # Change from Baseline -4.0 -3.2 -4.1 -15.7 -12.2 -16.0
-13.7 Mean (SD), Total (7.1) (6.9) (4.1) (13.2) (8.4) (8.4) (9.3)
Body Adipose Mass P-Value* 0.035 0.150 0.026 0.020 <0.001
<0.001 <0.001 LS Mean (SE){circumflex over ( )} -1.9 -1.5
-2.6 -11.0 (2.2) (2.7) (3.1) (1.7) P-value (vs. B + N)* <0.001
<0.001 0.010
TABLE-US-00005 TABLE 5 Metabolic Parameters Placebo Naltrexone
Bupropion Bup + Nal 32 Plasma Glucose (mg/dL) 1.9 .+-. 1.3* 3.4
.+-. 1.7** 3.5 .+-. 1.5** -2.0 .+-. 1.5 Serum Insulin (uU/mL) 0.9
.+-. 0.9*** 1.7 .+-. 1.3*** -0.5 .+-. 1.1 -3.0 .+-. 1.1
Triglycerides (mg/dL) -15.0 .+-. 7.7** -17.6 .+-. 10.4 -18.4 .+-.
9.0 -43.6 .+-. 8.8
[0043] The results demonstrate that weight loss associated with
Bup+Nal 32 was essentially due to decreased adipose tissue, as
opposed to lean tissue. The percentage of this decrease was similar
in magnitude in both visceral and overall adipose tissue. Visceral
adipose tissue loss indicates that the combination of bupropion and
naltrexone (e.g., Bup+Nal 32) will likely benefit cardio-vascular
risk factors associated with obesity. Bupropion and naltrexone 32
mg showed a synergistic effect for weight loss and loss of visceral
adipose mass. The change in the total adipose mass and visceral
adipose mass associated with Bup+Nal 48 was not significant.
However, the group of patients receiving Bup+Nal 48 had a higher
early drop-out rate which reduced the sample size, thereby
affecting the significance calculations.
[0044] Metabolic syndrome represents a group of risk factors that
have been linked to obesity, insulin resistance and are present in
about 47 million Americans. This syndrome can increase the risk of
later developing diabetes or cardiovascular disease and can be
reduced by a loss in excess body weight.
[0045] A post-hoc evaluation was applied on the baseline prevalence
of the metabolic syndrome among 361 evaluable subjects, as defined
by the Adult Treatment Panel III Guidelines. Approximately one in
three study subjects were determined to have exhibited the
metabolic syndrome at baseline. Treatment with bupropion and
naltrexone was associated with a significantly higher rate of
subjects who no longer met metabolic syndrome criteria after 24
weeks of treatment than seen with placebo (p=0.04). Subjects were
administered the same treatments as described in Example 2. Of the
bupropion and naltrexone dosage forms, Bup+Nal 32 demonstrated the
best overall risk to benefit ratio with a decrease in metabolic
syndrome from 30% to 14% using a conservative ITT-LOCF analysis
(p<0.05). Improvements associated with the Bup+Nal 32 treatment
across the parameters defining metabolic syndrome were most
dramatic on reductions in triglycerides (0.6% P+P, -33.6% Bup+Nal
32, p<0.01) and waist circumference (-1.8% P+P, -6.4% Bup+Nal
32, p=0.06) while also favorably increasing HDL cholesterol (0.3%
P+P, 15.1% Bup+Nal 32, p<0.01). The increase in HDL cholesterol
is especially noteworthy since the literature indicates that a 1%
increase in HDL cholesterol leads to a 2% reduction in
cardiovascular risk. These data indicate that bupropion and
naltrexone dosage forms described herein, particularly the 32/400
dose, reduce the metabolic syndrome prevalence and improve
cardiovascular risk amongst those individuals with the greatest
need for risk reduction. Treatment with bupropion and naltrexone
significantly decreased the percent of the study population with
the metabolic syndrome from 31% to 15% in the pooled NB groups as
compared to only a 38% to 30% within the placebo cohort
(p=0.04).
[0046] 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.
* * * * *