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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 a psychotherapeutic agent and the second compound is a anticonvulsant.
Also disclosed are methods of affecting weight loss, increasing
energy expenditure, increasing satiety in an individual, or suppressing
the appetite of an individual, comprising identifying an individual
in need thereof and treating that individual with a psychotherapeutic
agent and an anticonvulsant.
Weight Loss Patent Claims
1. A pharmaceutical composition for the prevention of weight gain
associated with the use of a psychotherapeutic agent comprising
a first compound and a second compound, wherein said first compound
is a psychotherapeutic agent and said second compound is an anticonvulsant.
2. The pharmaceutical composition of claim 1, wherein said psychotherapeutic
agent is olanzapine or a pharmaceutically acceptable salt, ester,
amide, or prodrug thereof.
3. The pharmaceutical composition of claim 1, wherein said anticonvulsant
is selected from the group consisting of topiramate, zonisamide,
and pharmaceutically acceptable salts or prodrugs thereof, and combinations
thereof.
4. The pharmaceutical composition of claim 1, wherein said first
compound is a pyschotherapeutic agent and said second compound is
a zonisamide.
5. The pharmaceutical composition of claim 4, wherein said first
compound is olanzapine.
6. The pharmaceutical composition of claim 1, wherein said first
compound is olanzapine and said second compound is zonisamide.
8. The pharmaceutical composition of claim 1, wherein said first
compound is olanzapine and said second compound is a combination
of zonisamide and bupropion.
9. A method of preventing weight loss associated with the use of
a psychotherapeutic agent, comprising identifying an individual
in need thereof and treating that individual with a first compound
and a second compound, wherein said first compound is a psychotherapeutic
agent and said second compound is an anticonvulsant.
10. The method of claim 9, wherein the psychotherapeutic agent
is olanzapine or a pharmaceutically acceptable salt, ester, amide,
or prodrug thereof, and said anticonvulsant is zonisamide.
11. The method of claim 9, wherein said first compound is olanzapine
and said second compound is a combination of zonisamide and bupropion.
12. A method of suppressing the appetite of an individual comprising
identifying an individual in need thereof and treating that individual
with a first compound and a second compound, wherein said first
compound is a psychotherapeutic agent and said second compound is
an anticonvulsant.
13. The method of claim 12, wherein the psychotherapeutic agent
is olanzapine or a pharmaceutically acceptable salt, ester, amide,
or prodrug thereof, and said anticonvulsant is zonisamide.
14. The method of claim 12, wherein said first compound is olanzapine
and said second compound is a combination of zonisamide and bupropion.
Weight Loss Patent Description
RELATED APPLICATION
[0001] The present application is a continuation-in-part of U.S.
application Ser. No. 11/034,316, filed Jan. 11, 2005 by Gadde et
al., and entitled "COMPOSITIONS OF AN ANTICONVULSANT AND AN
ANTIPSYCHOTIC DRUG AND METHODS OF USING THE SAME FOR AFFECTING WEIGHT
LOSS," which in turn claims priority to U.S. Provisional Patent
Application Ser. No. 60/616,393, filed Oct. 5, 2004 by Gadde et
al., and entitled "COMPOSITIONS OF AN ANTICONVULSANT AND AN
ANTIPSYCHOTIC DRUG AND METHODS OF USING THE SAME FOR AFFECTING WEIGHT
LOSS," U.S. Provisional Patent Application Ser. No. 60/567,896,
filed May 3, 2004 by Ranga Krishnan, and entitled "COMPOSITIONS
FOR AFFECTING WEIGHT LOSS," U.S. Provisional Patent Application
Ser. No. 60/535,800, filed Jan. 13, 2004 by Gadde et al., and entitled
"METHOD FOR REDUCING WEIGHT GAIN RISK ASSOCIATED WITH ANTIDEPRESSANT
THERAPY," and U.S. Provisional Patent Application Ser. No.
60/535,799, filed Jan. 13, 2004 by Gadde et al., and entitled "METHOD
FOR REDUCING WEIGHT GAIN RISK ASSOCIATED WITH ANTIDEPRESSANT THERAPY,"
all 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 a psychotherapeutic agent and the second compound is an anticonvulsant.
[0010] Disclosed are also methods of reducing the risk of weight
gain associated with the use of antidepressants or other antipsychotic
drugs.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a graph showing the effect of zonisamide (10 .mu.M)
on the frequency of action currents in POMC neurons. Zonisamide
reversibly increased the activity of POMC neurons.
[0012] FIG. 2 is a graph showing the effect of olanzapine (100
nM) on the rate of action currents in POMC neurons. Olanzapine reversibly
decreased the activity of POMC neurons.
[0013] FIG. 3 is a graph showing zonisamide reversed the inhibition
of POMC neurons caused by olanzapine cotreatment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0014] Newer generation antidepressants seem less likely to be
associated with cardiovascular side effects and toxicity associated
with older generation antidepressants, such as tricyclic antidepressants
or monoamine oxidase inhibitors (MAOIs). Currently, newer generation
antidepressants include selective serotonin reuptake inhibitors
(e.g., fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
and escitalopram), venlafaxine, duloxetine, nefazodone, mianserin
setiptiline, viqualine trazodone, cianopramine, and mirtazapine.
Weight gain has been a major concern with certain of the newer antidepressants,
particularly, with paroxetine (PAXIL.RTM. PAXIL CR.RTM.)) and mirtazapine
(Fava, J. Clin. Psych. 61 (suppl. 11):37-41 (2000); Carpenter et
al, J. Clin. Psych. 60:45-49 (1999); Aronne et al, J. Clin. Psych.
64 (suppl. 8):22-29 (2003), both of which are incorporated by reference
herein in their entirety). A large proportion of patients treated
with paroxetine, mirtazapine, and other antidepressants, such as
venlafaxine (EFFEXOR.RTM., EFFEXOR XR.RTM.), gain a significant
amount of weight. Most of these patients find it difficult to lose
the weight gained as a result of treatment, even after discontinuing
use of the particular antidepressant. Weight gain is unacceptable
in patients and a major reason for noncompliance with antidepressant
therapy (Cash et al, Percep. Motor Skills 90:453-456 (2000); Deshmukh
et al, Cleveland Clinic J. Med. 70:614-618 (2003), both of which
are incorporated by reference herein in their entirety). Without
being bound by any particular theory, it is believed that potential
mechanisms for the observed weight gain include histamine H1 receptor
antagonism for mirtazapine, and anticholinergic effects in the case
of paroxetine.
[0015] Zonisamide is a marketed anticonvulsant indicated as adjunctive
therapy for adults with partial onset seizures. Without being bound
by any particular theory, it is believed that the mechanism of antiepileptic
activity appears to be: 1) sodium-channel blocking; and, 2) reduction
of inward T-type calcium currents. In addition, zonisamide binds
to the GABA/benzodiazepine receptor complex without producing change
in chloride flux. Further, zonisamide facilitates serotonergic and
dopaminergic neurotransmission and possesses a weak inhibitory effect
on carbonic anhydrase.
[0016] Zonisamide has been shown to cause significant weight loss
(comparable to marketed weight loss medications) in patients presenting
with primary obesity (Gadde et al, JAMA 289:1820-1825 (2003), incorporated
by reference herein in its entirety). It has been postulated that
it is the effect of zonisamide on the CNS concentration of serotonin,
dopamine and carbonic anhydrase that is responsible for this effect.
There is evidence that zonisamide increases serotonin and dopamine
synthesis rates (Hashiguti et al, J Neural Transm Gen Sect. 1993;93:213-223;
Okada et al, Epilepsy Res. 1992;13:113-119, both of which are incorporated
by reference herein in their entirety). There is further evidence
suggesting that zonisamide stimulates dopamine D.sub.2 receptors
(Okada et al, Epilepsy Res. 1995;22:193-205, incorporated by reference
herein in its entirety). Zonisamide was well tolerated, fatigue
being the only side effect that occurred more frequently than with
placebo treatment.
[0017] Thus, the present inventors have determined that the use
of anticonvulsants in general is effective in reducing or preventing
the weight gain associated with the use of medications such as antidepressants,
particularly newer generation of antidepressants, antihistamines,
and serotonin receptor antagonists, such as 5HT.sub.2C receptor
antagonists.
[0018] Aspects of the present invention provide, at least in part,
methods of reducing the risk of weight gain associated with antidepressant
therapy. These methods involve the use of weight-loss promoting
anticonvulsants. The methods of the present invention are also effective
against individuals who have gained weight irrespective of the use
of antidepressants.
[0019] 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 a psychotherapeutic agent and the second compound
is an anticonvulsant.
[0020] In certain embodiments, the anticonvulsant is effective
in reducing convulsions 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.
[0021] In some embodiments the psychotherapeutic agent is an antidepressant,
an antimigrane, an antibipolar, an antimania drug, a mood stabilizer,
or an antiepileptic. Examples of antidepressants include paroxetine
and mirtazapine. Examples of antimigrane drugs include sumatriptan,
zolmitriptan, elatriptan and other triptans. Examples of antibipolar
drugs include lithium, valproate, carbamezepine, oxycarbamezepine,
lamotrogine, tiagabine, olanzapine, clozapine, risperidone, quetiapine,
aripiprazole, ziprasidone, and benzodiazepines. In a some embodiments,
the psychotherapeutic agent comprises a salt of lithium. In other
embodiments, the psychotherapeutic agent is valproate, which includes
both the salt of valproate and the free acid form of valproic acid.
Also included are pharmaceutically acceptable salts or prodrugs
of these drugs, extended release formulations of the above drugs,
as well as combinations of the above drugs. In some embodiments,
the lithium salt may be lithium carbonate or lithium citrate. In
some embodiments, the lithium drug is in an extended release formulation.
[0022] In some embodiments, the present invention is directed to
compositions comprising zonisamide and a salt of lithium, as described
herein and in formulations described herein. In other embodiments,
the present invention is directed to compositions comprising zonisamide
and valproic acid, or a pharmaceutically acceptable salt, such as
different salts of valproate, ester, amide, or prodrugs thereof.
[0023] In certain embodiments, the antidepressant is a compound
of Formula I where
[0024] W is nitrogen, CH, oxygen, or sulfur;
[0025] R.sub.1 is selected from the group consisting of hydrogen,
optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-8
cycloalkyl, optionally substituted C.sub.2-6 alkenyl, optionally
substituted C.sub.2-6 alkynyl, optionally substituted C.sub.1-6
alkoxyalkyl, and optionally substituted aryl and arylalkyl;
[0026] R.sub.2, R.sub.3, R.sub.4, and R.sub.5, are each independently
selected from the group consisting of hydrogen, halogen, optionally
substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-6 alkyloxy,
optionally substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-6 alkynyl, optionally substituted C.sub.1-6-alkoxyalkyl,
optionally substituted C.sub.1-6 alkylthio, perhaloalkyl, CN, COR.sub.10,
CONHR.sub.10, heteroalkyl, and NO.sub.2;
[0027] R.sub.6, R.sub.7, R.sub.8, and R.sub.9, are each independently
selected from the group consisting of hydrogen, halogen, optionally
substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-6 alkyloxy,
optionally substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-6 alkynyl, optionally substituted C.sub.1-6-alkoxyalkyl,
optionally substituted C.sub.1-6 alkylthio, perhaloalkyl, CN, COR.sub.10,
CONHR.sub.10, heteroalkyl, and NO.sub.2.
[0028] 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.
[0029] 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
(polyamino acid) bonded to an acid group where the peptide is metabolized
to provide the active moiety.
[0030] In another embodiment, the antidepressant is a tricyclic
antidepressants. Examples of tricyclic antidepressants include,
but are not limited to, imipramine, desipramine, trimipramine, nortriptyline,
clomipramine, doxepin, amitriptyline, maprotiline, pro triptyline,
dothiapen, setiptiline, cianopramine, and maprotiline. Maprotiline,
a very effective antidepressant, is not used widely because it carries
risk of seizures. The combination of maprotiline and zonisamide
or other anticonvulsants has the added benefit of reducing the risk
of seizures, in addition to reducing the risk of weight gain due
to the use of the antidepressant. The same is also true for combining
zonisamide with clomipramine, another tricyclic associated with
a relatively higher risk of seizures.
[0031] In further embodiments, the antidepressant is a monoamine
oxidase inhibitor (MAO inhibitor). Examples of MAO inhibitors include,
but are not limited to, phenelzine (Nardil.RTM.), tranylcypromine
(Pamate.RTM.), isocarboxazid (Marplan.RTM.), moclobemide (Aurorix.RTM.),
brofaromine, cimoxatone, clorgyline, and lazabemide.
[0032] In certain embodiments, the antihistamine is one of setiptilinie,
teciptiline, ORG 8282 (Organon, Netherlands), or MO 8282 (Mochida,
Japan).
[0033] In some embodiments, the 5HT.sub.2C receptor antagonist
is selected from colozapine, N-desmethylclozapine, and clozapine-N-oxide.
[0034] In some embodiments, the second compound is an anticonvulsant.
Examples of anticonvulsants include barbiturates, benzodiazepines,
GABA analogues, hydantoins, miscellaneous anticonvulsants, phenyltriazines,
and succinimides. An example of a barbiturate includes pentobarbital.
Examples of benzodiazepines include clonazepam, clorazepate, benzodiazepine,
and diazepam. Examples of GABA analogues include tiagabine, pregabalin,
and gabapentin. Examples of hydantoins include fosphenyloin, phenyloin,
and 5,5-Diphenylhydantoin. Examples of miscellaneous anticonvulsants
include carbamazepine, valproate, valproic acid, divalproex, felbamate,
levetiracetam, carbamazepine, topiramate, oxcarbazepine, and zonisamide.
An example of a phenyltriazine is lamotrigine. Examples of succinimides
include methsuximide and ethosuximide. Also included are extended
release formulations of the above drugs, pharmaceutically acceptable
salts or prodrugs thereof, as well as combinations of the above
drugs.
[0035] In one embodiment, the present invention is directed to
a composition for the treatment of obesity or for affecting weight
loss comprising zonisamide and mirtazapine. In another embodiment,
the present invention is directed to a composition for the treatment
of obesity or for affecting weight loss comprising zonisamide and
paroxetine. In yet another embodiment, the present invention is
directed to a composition for the treatment of obesity or for affecting
weight loss comprising zonisamide and venlafaxine.
[0036] In certain embodiments, the present invention is directed
to a composition for affecting weight loss or for preventing weight
gain comprising zonisamide and mirtazapine. In other embodiments,
the present invention is directed to a composition for affecting
weight loss or for preventing weight gain comprising bupropion and
mirtazapine. In further embodiments, the present invention is directed
to a composition for affecting weight loss or for preventing weight
gain comprising zonisamide and setiptiline. In other embodiments,
the present invention is directed to a composition for affecting
weight loss or for preventing weight gain comprising bupropion and
setiptiline. In additional embodiments, the present invention is
directed to a composition for affecting weight loss or for preventing
weight gain comprising zonisamide, bupropion, and mirtazapine. In
yet other embodiments, the present invention is directed to a composition
for affecting weight loss or for preventing weight gain comprising
zonisamide, bupropion, and setiptiline.
[0037] Throughout the present disclosure, when a particular compound
is mentioned by name, for example, zonisamide, bupropion, setiptiline,
mirtazapine, or valproate, it is understood that the scope of the
present disclosure encompasses pharmaceutically acceptable salts,
esters, amides, or prodrugs of the named compound. Also, if the
named compound comprises a chiral center, the scope of the present
disclosure also includes compositions comprising the racemic mixture
of the two enantiomers, as well as compositions comprising each
enantiomer individually substantially free of the other enantiomer.
Thus, for example, contemplated herein is a composition comprising
the S enantiomer substantially free of the R enantiomer, or a composition
comprising the R enantiomer substantially free of the S enantiomer.
By "substantially free" it is meant that the composition
comprises less than 10%, or less than 8%, or less than 5%, or less
than 3%, or less than 1% of the minor enantiomer. If the named compound
comprises more than one chiral center, the scope of the present
disclosure also includes compositions comprising a mixture of the
various diastereomers, as well as compositions comprising each diastereomer
substantially free of the other diastereomers. Thus, for example,
commercially available mirtazapine is a racemic mixture comprising
two separate enantiomers. The recitation of "mirtazapine"
throughout this disclosure includes compositions that comprise the
racemic mixture of mirtazapine, the compositions that comprise the
(+) enantiomer substantially free of the (-) enantiomer, and the
compositions that comprise the (-) enantiomer substantially free
of the (+) enantiomer.
[0038] In another aspect, the present invention relates to a method
of affecting weight loss, comprising identifying an individual in
need thereof and treating that individual with a psychotherapeutic
agent and an anticonvulsant. The psychotherapeutic agent and the
anticonvulsant are as described above.
[0039] 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 some of these embodiments, it may
be beneficial for health or cosmetic purposes to affect weight loss,
thereby reducing the BMI even further. In some embodiments, the
individual has reached the above BMI as the result of antidepressant
therapy. In other embodiments, the individual has reached the above
BMI without the use of antidepressants.
[0040] 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 a psychotherapeutic
agent and the second compound is a anticonvulsant.
[0041] 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.
[0042] 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.
[0043] In certain embodiments, the first compound is zonisamide
and the second compound is mirtazapine. In other embodiments, the
first compound is bupropion and the second compound is mirtazapine.
In further embodiments, the first compound is zonisamide and the
second compound is setiptiline. In other embodiments, the first
compound is bupropion and the second compound is setiptiline. In
additional embodiments, the first compound is a combination of zonisamide
and bupropion and the second compound is mirtazapine. In yet other
embodiments, tthe first compound is a combination of zonisamide
and bupropion and the second compound is setiptiline.
[0044] In some embodiments, the first compound is zonisamide and
the second compound is a salt of lithium, as described herein and
in formulations described herein. In other embodiments, the first
compound is zonisamide and the second compound is valproic acid,
or a pharmaceutically acceptable salt, such as different salts of
valproate, ester, amide, or prodrugs thereof.
[0045] In some embodiments, the first compound is topiramate and
the second compound is a salt of lithium, as described herein and
in formulations described herein. In other embodiments, the first
compound is topiramate and the second compound is valproic acid,
or a pharmaceutically acceptable salt, such as different salts of
valproate, ester, amide, or prodrugs thereof.
[0046] In another aspect, the present invention relates to a method
of increasing satiety in an individual comprising identifying an
individual in need thereof and treating that individual with a first
compound and a second compound, where the first compound is a psychotherapeutic
agent and the second compound is an anticonvulsant.
[0047] 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.
[0048] 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
by administering to the individual a first compound and a second
compound, where the first compound is a psychotherapeutic agent
and the second compound is a anticonvulsant.
[0049] 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.
[0050] In certain embodiments, the first compound is zonisamide
and the second compound is mirtazapine. In other embodiments, the
first compound is bupropion and the second compound is mirtazapine.
In further embodiments, the first compound is zonisamide and the
second compound is setiptiline. In other embodiments, the first
compound is bupropion and the second compound is setiptiline. In
additional embodiments, the first compound is a combination of zonisamide
and bupropion and the second compound is mirtazapine. In yet other
embodiments, tthe first compound is a combination of zonisamide
and bupropion and the second compound is setiptiline.
[0051] 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 by administering
to the individual a first compound and a second compound, where
the first compound is a psychotherapeutic agent and the second compound
is a anticonvulsant.
[0052] 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.
[0053] 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.
[0054] Aspects of the present invention also relate to methods
of reducing the risk of weight gain associated with the administration
of antidepressants, antihistamines, or serotonin receptor antagonists.
Other aspects of the invention further relate to methods of minimizing
metabolic risk factors associated with weight gain, such as hypertension,
diabetes and dyslipidaemia. In one embodiment, the methods comprise
administering to a mammal receiving an antidepressant an amount
of zonisamide, or other weight-loss promoting anticonvulsant, sufficient
to reduce the weight gain risk associated with the antidepressant.
In an alternative embodiment, the methods comprise administering
to mammal receiving an antidepressant a combination of zonisamide
or topiramate, or other weight-loss promoting anticonvulsant (including
agents that block kainate/AMPA (D,L-.alpha.-amino-3-hydroxy-5-methyl-isoxazole
propionic acid) subtype glutamate receptors), and bupropion, or
other compound that enhances the activity of norepinephrine and/or
dopamine via uptake inhibition or other mechanism, in an amount
sufficient to reduce the weight gain risk associated with the antidepressant.
[0055] In certain embodiments, methods of the present invention
are directed to reducing the risk of weight gain in an individual
who already is on antidepressant therapy, or is about to begin antidepressant
therapy. In these embodiments, in addition to the antidepressant,
the individual is administered a composition comprising an anticonvulsant
and a psychotherapeutic drug, as described herein, where the psychotherapeutic
drug is not an antidepressant. Thus, in some embodiments, the individual
who is taking mirtazapine or setiptiline is administered a composition
comprising zonisamide or a composition comprising zonisamide and
bupropion. In other embodiments, the individual who is taking mirtazapine
or setiptiline is administered a composition comprising zonisamide
or a composition comprising zonisamide and valproate. In further
embodiments, the individual who is taking mirtazapine or setiptiline
is administered a composition comprising zonisamide or a composition
comprising zonisamide and venlafaxine.
[0056] In certain embodiments, the weight gain risk-reducing agents
for use in the methods of the present invention include zonisamide
or topiramate (and pharmaceutically acceptable salts thereof). In
other embodiments, other methane-sulfonamide derivatives, such as
those described in U.S. Pat. No. 4,172,896, or other sulfamates
(including sulfamate-substituted monosaccharides), such as those
described in U.S. Pat. No. 4,513,006, incorporated by reference
herein in its entirety, are used.
[0057] In further embodiments, the weight gain risk-reducing agent
is bupropion; while in other embodiments, compounds disclosed in
U.S. Pat. Nos. 3,819,706 and 3,885,046, both of which are incorporated
by reference herein in their entirety, are used. In additional embodiments,
the weight gain risk-reducing agent is a compound that enhances
the activity of norepinephrine and/or dopamine, such as by reuptake
inhibition or other mechanism. All of the above-mentioned U.S. patents
are.
[0058] Compounds that enhance the activity of norepinephrine and/or
dopamine include norepinephrine agonists, such as phendimetrazine
and benzphetamine; norepinephrine reuptake inhibitors such as atomoxetine,
bupropion, radafaxine, thionisoxetine, and reboxetine; dopamine
agonists, such as cabergoline, amantadine, lisuride, pergolide,
ropinirole, pramipexole, and bromocriptine; norepinephrine releasers,
for example diethylpropion; a mixed dopamine/norepinephrine reuptake
inhibitor, for example, bupropion; a combination of a dopamine reuptake
inhibitor and a norepinephrine reuptake inhibitor, e.g. bupropion
and mazindol; or a combination of a selective serotonin reuptake
inhibitor (SSRI) and a norepinephrine reuptake inhibitor, such as
sibutramine, venlafaxine, and duloxetine.
[0059] Mammals suitable for treatment in accordance with the instant
invention can be receiving any antidepressant associated with weight
gain. Typically, however, the antidepressant is a newer generation
antidepressant (e.g., a selective serotonin uptake inhibitor (e.g.,
fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and
escitalopram), venlafaxine, nefazodone, and mirtazapine)), particularly,
paroxetine or mirtazapine.
[0060] The amount of weight gain risk-reducing agent(s) administered
in the pharmaceutical compositions described herein can vary with
the patient, the antidepressant that the patient is receiving, the
route of administration and the result sought. Optimum dosing regimens
for particular patients can be readily determined by one skilled
in the art.
[0061] In accordance with the invention, the combination of, for
example, zonisamide or topiramate and bupropion (including sustained
release preparations) provides an effective means of minimizing
metabolic risks associated with weight gain and/or antidepressant
use (e.g., type II diabetes). The combination can be more effective
than, for example, zonisamide or topiramate treatment alone and
with fewer side effects. Neuropharmacologically, all three major
nerve transmitters that regulate appetite and weight, i.e., serotonin,
norepinephrine and dopamine, are targeted with the combination of,
for example, bupropion and zonisamide or topiramate. Side effects
of, for example, zonisamide or topiramate (such as somnolence, psychomotor
slowing, cognitive impairment, fatigue and depression) can be offset
by insomnia, activation, psychomotor agitation and antidepressant
effects of, for example, bupropion. On the other hand, zonisamide
or topiramate, for example, can reduce the seizure risk associated
with, for example, bupropion. Lower doses of both types of medication
can be used in the combination treatment, thereby further reducing
the overall side effect burden.
[0062] With regard to the pharmacokinetics of zonisamide, its renal
excretion and minimal potential for inhibition or induction of hepatic
microsomal enzymes, are favorable qualities in the concept of combination
use with antidepressants, particularly newer generation antidepressants.
[0063] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of a psychotherapeutic agent
and an anticonvulsant, as described above, or comprising a linked
molecule, as described herein, and a physiologically acceptable
carrier, diluent, or excipient, or a combination thereof.
[0064] Details of some embodiments of the appropriate routes of
administration and compositions suitable for same can be found in,
for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231,
5,427,798, 5,358,970 and 4,172,896, as well as in patents cited
therein, all of which are incorporated by reference herein in their
entirety, including any drawings.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] Pharmaceutical preparations which can be used orally, including
sublingually, which include 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.
[0078] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0083] 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.
[0084] 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.
[0085] A pharmaceutical carrier for the hydrophobic compounds of
the invention is a cosolvent system comprising benzyl alcohol, a
nonpolar surfactant, a water-miscible organic polymer, and an aqueous
phase. A common cosolvent system used is the VPD co-solvent system,
which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without destroying
its solubility and toxicity characteristics. Furthermore, the identity
of the co-solvent components may be varied: for example, other low-toxicity
nonpolar surfactants may be used instead of POLYSORBATE 80.TM.;
the fraction size of polyethylene glycol may be varied; other biocompatible
polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone;
and other sugars or polysaccharides may substitute for dextrose.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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 6000 mg
of each ingredient, preferably between 1 mg and 5000 mg, e.g. 25
to 5000 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 2500 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.
[0091] In some embodiments, the dosage range for lithium carbonate,
for an oral dose, will result in blood levels of lithium being between
about 0.5 and about 1.5 meq/l. In a preferred embodiment, the lithium
carbonate dosage range, for an oral dose, will be about 900 mg/day.
[0092] In certain embodiments, the dosage range for valproate,
for an oral dose, is in the range of about 250 to about 5000 mg/day.
In a preferred embodiment, the valproate dosage range, for an oral
dose, will be about 1500 mg/day.
[0093] In further embodiments, the dosage range for zonisamide,
for an oral dose, is in the range of about 25 to about 600 mg per
day. In some embodiments, the dosage is 25 mg per day. In other
embodiments, the dosage is 50 mg per day. In yet other embodiments,
the dosage is 100 mg per day.
[0094] In further embodiments, the dosage range for mitrazepine,
for an oral dose, is in the range of about 5 to about 500 mg per
day. In some embodiments, the dosage is 8 mg per day. In other embodiments,
the dosage is 16 mg per day. In yet other embodiments, the dosage
is 32 mg per day. In some embodiments, the dosage is 15 mg per day.
In other embodiments, the dosage is 30 mg per day. In yet other
embodiments, the dosage is 45 mg per day.
[0095] In other embodiments, the dosage range for venlafaxinor
venlafaxin XR, for an oral dose, is in the range of about 20 mg
to about 600 mg per day. In some embodiments, the dosage is 25 mg
per day. In other embodiments, the dosage is 37.5 mg per day. In
yet other embodiments, the dosage is 50 mg per day. In some embodiments,
the dosage is 75 mg per day. In other embodiments, the dosage is
100 mg per day. In yet other embodiments, the dosage is 150 mg per
day.
[0096] 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.
[0097] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen that maintains
plasma levels above the MEC for 10-90% of the time, preferably between
30-90% and most preferably between 50-90%.
[0098] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0099] 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.
[0100] 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.
[0101] 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.
[0102] All documents and other information sources cited above
are hereby incorporated in their entirety by reference, as are Gadde
et al, Obesity Res. 9:544-551 (2001) and Gadde et al, JAMA 289:1820-1825
(2003).
SOME EMBODIMENTS OF THE INVENTION
[0103] Some of the embodiments of the present invention are as
follows:
[0104] 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 a psychotherapeutic agent
and said second compound is an anticonvulsant.
[0105] In the second embodiment, the invention relates to the composition
of the first embodiment, wherein said psychotherapeutic agent is
selected from the group consisting of lithium carbonate, lithium
citrate, valproate, mixtures thereof, and pharmaceutically acceptable
salts or prodrugs thereof.
[0106] In the third embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound is selected
from the group consisting of a barbiturate, benzodiazepine, GABA
analogue, hydantoins, anticonvulsant, phenyltriazine, succinimide,
pharmaceutically acceptable salts or prodrugs thereof, and combinations
thereof.
[0107] In the fourth embodiment, the invention relates to the composition
of the third embodiment, wherein said barbiturate is pentobarbital
or pharmaceutically acceptable salts or prodrugs thereof.
[0108] In the fifth embodiment, the invention relates to the composition
of the third embodiment, wherein said benzodiazepine is selected
from the group consisting of clonazepam, alprazolam, chlordiazepoxide,
clorazepate, diazepam, halazepam, lorazepam, oxazepam, prazepam,
flurazepam, temazepam, triazolam, pharmaceutically acceptable salts
or prodrugs thereof, and combinations thereof.
[0109] In the sixth embodiment, the invention relates to the composition
of the third embodiment, wherein said GABA analogue is selected
from the group consisting of tiagabine, gabapentin, pregabalin,
pharmaceutically acceptable salts or prodrugs thereof, and combinations
thereof.
[0110] In the seventh embodiment, the invention relates to the
composition of the third embodiment, wherein said hydantoin is selected
from the group consisting of fosphenyloin, phenyloin, 5,5-Diphenylhydantoin,
pharmaceutically acceptable salts or prodrugs thereof, and combinations
thereof.
[0111] In the eighth embodiment, the invention relates to the composition
of the third embodiment, wherein said miscellaneous anticonvulsant
is selected from the group consisting of carbamazepine, valproate,
valproic acid, divalproex, felbamate, levetiracetam, carbamazepine,
topiramate, oxcarbazepine, zonisamide, pharmaceutically acceptable
salts or prodrugs thereof, and combinations thereof.
[0112] In the ninth embodiment, the invention relates to the composition
of the third embodiment, wherein said phenyltriazine is lamotrigine.
[0113] In the tenth embodiment, the invention relates to the composition
of the third embodiment, wherein said succinimide is selected from
the group consisting of methsuximide, ethosuximide, and combinations
thereof.
[0114] In the eleventh embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is a pyschotherapeutic agent and said second compound is a zonisamide.
[0115] In the twelfth embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is lithium carbonate or lithium citrate and said second compound
is zonisamide.
[0116] In the thirteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is valproate and said second compound is zonisamide.
[0117] In the fourteenth embodiment, the invention relates to the
composition of the twelfth or thirteenth embodiment, wherein the
zonisamide is in a time-release formulation.
[0118] In the fifteenth embodiment, the invention relates to a
method of affecting weight loss, comprising identifying an individual
in need thereof and treating that individual with a psychotherapeutic
agent and an anticonvulsant.
[0119] In the sixteenth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein said individual has
a body mass index greater than 25.
[0120] In the seventeenth embodiment, the invention relates to
the method of the fifteenth embodiment, wherein the psychotherapeutic
agent is selected from the group consisting of lithium carbonate,
lithium citrate, and valproate, extended release formulations of
the above drugs, and combinations of the above drugs.
[0121] In the eighteenth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein the anticonvulsant is
selected from the group consisting of barbiturates, benzodiazepines,
GABA analogues, hydantoins phenyltriazines, and succinimides, and
pharmaceutically acceptable salts or prodrugs thereof.
[0122] In the ninteenth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein the anticonvulsant is
selected from the group consisting of pentobarbital, clonazepam,
clorazepate, benzodiazepine, diazepam, tiagabine, gabapentin, pregabalin,
fosphenyloin, phenyloin, phenyloin, 5,5-Diphenylhydantoin, carbamazepine,
valproate, valproic acid, divalproex, felbamate, levetiracetam,
carbamazepine, topiramate, oxcarbazepine, zonisamide, lamotrigine,
methsuximide, ethosuximide, extended release formulations of the
above drugs, and combinations of the above drugs.
[0123] In the twentieth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0124] In the twenty first embodiment, the invention relates to
the method of the fifteenth embodiment, wherein said first compound
is administered prior to said second compound.
[0125] In the twenty second embodiment, the invention relates to
the method of the fifteenth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0126] In the twenty third embodiment, the invention relates to
a method of increasing satiety in an individual comprising identifying
an individual in need thereof and treating that individual with
a first compound and a second compound, wherein said first compound
is a psychotherapeutic agent and said second compound is a anticonvulsant.
[0127] In the twenty fourth embodiment, the invention relates to
the method of the twenty third embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0128] In the twenty fifth embodiment, the invention relates to
the method of the twenty third embodiment, wherein said first compound
is administered prior to said second compound.
[0129] In the twenty sixth embodiment, the invention relates to
the method of the twenty third embodiment, wherein said first compound
is administered subsequent to said second compound.
[0130] In the twenty seventh embodiment, the invention relates
to a method of increasing energy expenditure in an individual comprising
identifying an individual in need thereof and treating that individual
with a first compound and a second compound, wherein said first
compound is a psychotherapeutic agent and said second compound is
an anticonvulsant.
[0131] In the twenty eighth embodiment, the invention relates to
the method of the twenty seventh embodiment, wherein said first
compound and said second compound are administered nearly simultaneously.
[0132] In the twenty ninth embodiment, the invention relates to
the method of the twenty seventh embodiment, wherein said first
compound is administered prior to said second compound.
[0133] In the thirtieth embodiment, the invention relates to the
method of the twenty seventh embodiment, wherein said first compound
is administered subsequent to said second compound.
[0134] In the thirty first embodiment, the invention relates to
a method of suppressing the appetite of an individual comprising
identifying an individual in need thereof and treating that individual
with a first compound and a second compound, wherein said first
compound is a psychotherapeutic agent and said second compound is
an anticonvulsant.
[0135] In the thirty second embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0136] In the thirty third embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
is administered prior to said second compound.
[0137] In the thirty fourth embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
is administered subsequent to said second compound.
[0138] In the thirty fifth 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 lithium carbonate and zonisamide.
[0139] In the thirty sixth 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 valproate and zonisamide.
[0140] In the thirty seventh embodiment, the invention relates
to the method of the thirty fifth or thirty sixth embodiments, wherein
the individual has a BMI greater than 30.
[0141] In the thirty eighth embodiment, the invention relates to
the method of the thirty fifth or thirty sixth embodiments, wherein
the individual has a BMI greater than 25.
[0142] In the thirty ninth embodiment, the invention relates to
the method of the thirty fifth or thirty sixth embodiments, wherein
the lithium carbonate or valproate is in a time-release formulation.
[0143] In the fortieth embodiment, the invention relates to the
method of the thirty fifth or thirty sixth embodiments, wherein
the plasma concentration level of both the lithium carbonate or
valproate and zonisamide follow a similar concentration profile.
[0144] In the forty first embodiment, the invention relates to
the method of the thirty ninth embodiment, wherein the lithium carbonate
or valproate and the zonisamide are administered substantially simultaneously.
[0145] In the forty second embodiment, the invention relates to
the method of the thirty ninth embodiment, wherein the lithium carbonate
or valproate is administered prior to the zonisamide.
[0146] In the forty third embodiment, the invention relates to
the method of the thirty ninth embodiment, wherein the lithium carbonate
or valproate is administered subsequent to the zonisamide.
EXAMPLES
[0147] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Use of Zonisamide Alone
[0148] Individuals taking an antidepressant, or about to take an
antidepressant, who have gained weight as the result of the use
of the antidepressant, or are susceptible to gain weight as the
result of the use of the antidepressant, are identified. Each individual
is instructed to take one 25 mg tablet of zonisamide on a daily
basis, in addition to the antidepressant therapy.
[0149] 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.
[0150] The dosage of zonisamide can be from about 25 mg to about
800 mg per day, generally given once per day or divided (e.g., equally)
into multiple doses. Preferably, the dose is from about 100 mg to
about 600 mg per day, more preferably, the dose is from about 200
mg to about 400 mg per day. However, it may be necessary to use
dosages outside these ranges. Zonisamide tablets are usually made
and marketed in 25 mg, 50 mg, and 100 mg doses. Individual tablets,
or combination of tablets can be used to achieve the desired dosing.
Example 2
Use of Topiramate Alone
[0151] Individuals taking an antidepressant, or about to take an
antidepressant, who have gained weight as the result of the use
of the antidepressant, or are susceptible to gain weight as the
result of the use of the antidepressant, are identified. Each individual
is instructed to take one 25 mg tablet of topiramate on a daily
basis, in addition to the antidepressant therapy.
[0152] 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.
[0153] The dosage of topiramate can be from about 25 mg to about
1600 mg, preferably from about 50 mg to about 600 mg, more preferably
from about 100 mg to about 400 mg. However, it may be necessary
to use dosages outside these ranges.
Example 3
Combination of Zonisamide and Mitrazepine
[0154] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one tablet of zonisamide on
a daily basis, in addition to one tablet of mitrazepine on a daily
basis. Initially, the drugs are administered as follows: 8 mg mitrazepine
and 64 mg zonisamide; or 16 mg mitrazepine and 128 mg zonisamide;
or 32 mg mitrazepine and 252 mg zonisamide; generally with an mitrazepine/zonisamide
ratio of 1:8.
[0155] 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.
[0156] If the initial dosages are not effective, they can be increased.
Example 4
Combination of Zonisamide and Paroxetine
[0157] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one tablet of zonisamide on
a daily basis, in addition to one tablet of paroxetine on a daily
basis. Initially, the drugs are administered as follows: 10 mg paroxetine
and 60 mg zonisamide; or 20 mg paroxetine and 120 mg zonisamide;
or 30 mg paroxetine and 180 mg zonisamide; or 40 mg paroxetine and
240 mg zonisamide; generally with an paroxetine/zonisamide ratio
of 1:6.
[0158] 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.
[0159] If the initial dosages are not effective, they can be increased.
Example 5
Combination of Zonisamide and Lithium Carbonate
[0160] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 25 mg tablet of zonisamide
on a daily basis, in addition to one 300 mg tablet of lithium carbonate
on a daily basis.
[0161] 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.
[0162] If the initial dosage is not effective, then the zonisamide
dosage can be increased by approximately 25 mg per day. If the initial
dosage results in a more rapid weight loss than the above rate,
the dosage of each of zonisamide or lithium carbonate can be reduced.
[0163] In some cases, it is beneficial to administer one dose of
zonisamide per day in conjunction with two or three or more doses
of lithium carbonate throughout the day. Lithium carbonate may also
be in a time-release formulation where the dose is administered
once a day, but lithium carbonate gradually enters the blood stream
throughout the day, or in the course of a 12 hour period.
[0164] The above procedure can be followed using lithium citrate,
or any other pharmaceutically acceptable salt of lithium, instead
of lithium carbonate.
Example 6
Combination of Zonisamide and Lithium Carbonate
[0165] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 25 mg tablet of zonisamide
on a daily basis. In addition, each individual is instructed to
take one 300 mg tablet of lithium carbonate on a daily basis.
[0166] 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.
It is recommended that serum creatinine be checked periodically.
[0167] If the initial dosage is not effective, then the lithium
carbonate dosage can be increased so as to achieve blood levels
of 0.5 to 1.5 meq/l. If the initial dosage results in a more rapid
weight loss than the above rate, the dosage of each of zonisamide
or lithium carbonate can be reduced.
[0168] The above procedure can be followed using lithium citrate,
or any other pharmaceutically acceptable salt of lithium, instead
of lithium carbonate.
Example 7
Combination of Zonisamide and Valproate
[0169] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 50 mg tablet of zonisamide
on a daily basis, in addition to one 500 mg tablet of valproate
on a daily basis.
[0170] 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.
[0171] If the initial dosage is not effective, then the zonisamide
dosage can be increased by approximately 30 mg per day, though not
exceeding 600 mg total per day. If the initial dosage results in
a more rapid weight loss than the above rate, the dosage of each
of zonisamide or valproate can be reduced.
[0172] In some cases, it is beneficial to administer one dose of
zonisamide per day in conjunction with two or three or more doses
of valproate throughout the day. Valproate may also be in a time-release
formulation where the dose is administered once a day, but valproate
gradually enters the blood stream throughout the day, or in the
course of a 12 hour period.
Example 8
Combination of Zonisamide and Valproate
[0173] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 50 mg tablet of zonisamide
on a daily basis. In addition, each individual is instructed to
take one 250 mg tablet of valproate on a daily basis.
[0174] 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.
[0175] If the initial dosage is not effective, then the valproate
dosage can be increased by 20 mg intervals up to 3000 mg per day.
If the initial dosage results in a more rapid weight loss than the
above rate, the dosage of each of zonisamide or valproate can be
reduced.
Example 9
Combination of Zonisamide and Olanzapine
[0176] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one tablet of zonisamide on
a daily basis, in addition to one tablet of olanzapine on a daily
basis. Initially, the drugs are administered as follows: 5 mg olanzapine
and 60 mg zonisamide, or 10 mg olanzapine and 120 mg zonisamide;
generally with an olanzapine/zonisamide ratio of 1:12.
[0177] 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.
[0178] If the initial dosages are not effective, they can be increased.
Example 10
Combination of Zonisamide and Risperidone
[0179] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one tablet of zonisamide on
a daily basis, in addition tablet of risperidone on a daily basis.
Initially, the drugs are administered as follows: 0.5 mg risperidone
and 30 mg zonisamide, 1 mg risperidone and 60 mg zonisamide, or
2 mg risperidone and 120 mg zonisamide; generally with an olanzapine/zonisamide
ratio of 1:60.
[0180] 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.
[0181] If the initial dosages are not effective, they can be increased.
Example 11
Zonisamide and/or Bupropion Prevent the Weight Gain Associated
with Mirtazapine or Setiptiline Treatment
Background
[0182] Mirtazapine shows considerable promise as a therapy for
sleep apnea, but it causes weight gain in some patients. This weight
gain limits the use of mirtazapine as a therapy for sleep apnea
or as an antidepressant. Addition of zonisamide, or bupropion, or
zonisamide plus bupropion, to concomitant mirtazapine treatment
decreases the weight gain associated with mirtazapine, in a rodent
model of mirtazapine-induced weight gain.
[0183] The melanocortin system controls energy balance. Mirtazapine
and setiptiline change the activity of melanocortin circuits. Zonisamide,
or bupropion, or zonisamide plus bupropion reverse this change in
neuronal activity.
[0184] The melanocortin system consists of Proopiomelanocortin
(POMC) neurons, the cognate melanocortin receptors (MC4 R) and the
agouti-related peptide neurons in the arcuate nucleus of the hypothalamus.
It is well established in humans and animals that the melanocortin
system controls energy balance and the most common genetic cause
of obesity in humans is congenital lack of MC4 R.
[0185] It has recently been shown that many compounds that influence
energy balance modify the activity of melanocortin circuits. In
particular, it has been shown that bupropion and zonisamide increase
the electrophysiological activity of POMC neurons. As part of this
research some of the receptors that can regulate the activity of
POMC neurons have been identified; specifically it has been shown
that 5-HT 2C and 5-HT 1B receptors increase the activity of POMC
neurons as does dopamine D2 R. The clear role of 5-HT 2CR in regulating
the activity of POMC neurons suggests that compounds like mirtazapine,
which is an antagonist at this receptor, modify energy balance to
induce an anabolic state, favoring weight gain.
In Vivo Pharmacology
[0186] We have developed a model to pre-clinically test the effects
of mirtazapine on body weight gain. Dose-ranging studies are performed
to determine the dose that best demonstrates the weight gain caused
by mirtazapine or by setiptiline in the "rat-weight gain assay".
Zonisamide, or bupropion, or zonisamide plus bupropion are tested
to decrease the weight gain seen in response to concomitant mirtazapine
or setiptiline therapy. Initially, a dose of 30 mg/kg of zonisamide
(bid) is used, but the dose in the experiment ranges from 20 mg/kg
to 90 mg/kg (bid). Bupropion is used initially at a dose of 190
mg/kg/day, the dose in the experiment ranges from 50-190 mg/kg/day.
Mirtazapine or setiptiline are used as solutions in minipumps. The
concentration of the solution ranges between 0.1 .mu.M to 10 mM.
In some experiments, the concentration is calculated to provide
a dose of about 1 mg/kg/day. In certain experiments, the concentration
is 10 .mu.M.
[0187] In a 4.times.3 design rats receive implants that secrete
mirtazapine, or setiptiline, or vehicle. Some rats also receive
co-treatment with saline, some receive zonisamide, some receive
bupropion, and others receive co-treatment with zonisamide plus
bupropion. In this way cohorts of 10 rats receive all possible combinations
of the weight loss drug(s) with mirtazapine or setiptiline. TABLE-US-00001
Rat numbers and groups Weight loss agent Vehicle Setiptiline (tbd)
Mirtazapine (tbd) Vehicle 10 10 10 Zonisamide (tbd) 10 10 10 Bupropion
(tbd) 10 10 10 Zonisamide (tbd) + 10 10 10 Bupropion (tbd)
Electrophysiology
[0188] The electrophysiological response of POMC neurons to mirtazapine
and to setiptiline is determined. It is then determined if co-treatment
with zonisamide, or bupropion, or zonisamide plus bupropion prevents
the expected decrease in POMC activity due to mirtazapine or setiptiline.
[0189] Preliminary data show that sub-threshold doses of zonisamide
and bupropion synergistically inhibit acute food intake in mice,
which is further evidence of powerful synergy between zonisamide
and bupropion to inhibit food intake in mice after a 16 hr fast.
[0190] In other preclinical experiments it has been shown that
zonisamide and bupropion each inhibit food intake. These effects
had faded by 4 hours, but the combination was effective when each
compound alone was ineffective. The weight reducing effects of zonisamide
and bupropion have also been well demonstrated in humans (Gadde
et al, 2003; Gadde et al, 2001).
[0191] It has also been shown that zonisamide in combination with
bupropion strongly increases the electrophysiological activity of
POMC neurons in brain slices from POMC-EGFP mice. It has been shown
that a large increase in rate of spontaneous action potentials in
POMC neurons would be expected to stimulate significant secretion
of a-MSH from POMC neurons, and consequent activation of MC4 R--to
inhibit food intake and decrease body weight gain.
Procedures
In Vivo Pharmacology
[0192] Female Sprague-Dawley rats weighing about 300 grams at the
start of the experiment are used. Under isoflurane anesthesia, Alzet
osmotic minipumps (2 ml2) are implanted subcutaneously between the
shoulder blades. The rats are returned to their home cages after
recovery. The minipumps deliver 5 .mu.L per hour for 14 days. A
range of doses of mirtazapine (from 0.1 to 20 mg/kg/day dissolved
in DMSO/saline) are used. Animals are housed individually and supplied
with standard laboratory chow. Food consumed and animal weights
are recorded every 3 days, to minimize disruption of the animals.
[0193] We have already shown in mice that bupropion, zonisamide,
and zonisamide plus bupropion have pronounced effects on food intake
after intra-peritoneal injection. We will develop chronic infusion
methods to test the effects of bupropion, or zonisamide and zonisamide
plus bupropion on weight gain over 14 days using the following groups:
[0194] 7 groups of 6 rats (6 doses of mirtazapine (0.1, 0.5, 1,
5, 10, 20 mg/kg), +saline)
[0195] The doses of zonisamide, and bupropion, and zonisamide plus
bupropion that cause weight loss in this rat model in the preliminary
studies are determined; the co-treatment experiments (mirtazapine
plus zonisamide plus bupropion) are then performed.
Electrophysiology
[0196] The electrophysiological activity of Proopiomelanocortin
(POMC) neurons in brain slices from POMC-EGFP mice are recorded.
The POMC neurons in these mice are identified by the expression
of green fluorescent protein (EGFP) in these, and only these, cells.
The frequency of action potentials in these neurons are recorded
using standard electrophysiological techniques. In particular loose
cell attached patch configuration is used to determine action potential
frequency, whilst minimally disturbing the cells.
[0197] It has been shown that zonisamide, or bupropion, or zonisamide
plus bupropion increase the activity of POMC neurons. The basal
activity is recorded, and then mirtazapine or setiptiline is added
to the tissue bath to determine the effect of the antidepressant
on the activity of POMC neurons. If mirtazapine or setiptiline inhibits
the activity of POMC neurons, the increase in neuronal activity
by treating the brain slices with bupropion, or zonisamide or zonisamide
plus bupropion is tested.
Example 12
Zonisamide Prevents the Weight Gain Associated with Olanzapine
Treatment
Background
[0198] In this experiment, the effect of co-treatment with drug
combinations on the weight gain associated with olanzapine use is
tested. Specifically, addition of zonisamide to concomitant olanzapine
treatment is shown to decrease the weight gain associated with olanzapine,
in a validated rodent model of olanzapine-induced weight gain.
[0199] The melanocortin system consists of Proopiomelanocortin
(POMC) neurons, the cognate melanocortin receptors (MC4 R) and the
agouti-related peptide neurons in the arcuate nucleus of the hypothalamus.
It is well established in humans and animals that the melanocortin
system controls energy balance, and the most common genetic cause
of obesity in humans is congenital lack of MC4 R. It has recently
been shown that many compounds that influence energy balance modify
the activity of melanocortin circuits. In particular, it has been
shown that increases the electrophysiological activity of POMC neurons.
It has also been shown that cannabinoid antagonists activate this
same circuitry. We have identified some of the receptors that can
regulate the activity of POMC neurons; in particular we have shown
that 5-HT 2C and 5-HT 1 B receptors increase the activity of POMC
neurons as does dopamine D2 R. The clear role of D2 R and 5-HT 2CR
in regulating the activity of POMC neurons shows that compounds
like olanzapine, which is an antagonist at both these receptors,
modify energy balance to induce an anabolic state, favoring weight
gain.
In Vivo Pharmacology
[0200] Female Sprague-Dawley rats, weighing about 235 grams at
the start of the experiment were used. They were trained to sham
injections, using the zonisamide vehicle for 2 weeks before the
study commenced. Under isoflurane anesthesia, Alzet osmotic minipumps
(2 ml2) were implanted subcutaneously, between the shoulder blades.
The rats were subsequently returned to their home cages after recovery.
The minipumps delivered 5 .mu.L per hour for 14 days. Olanzapine
was dissolved in 1.5% lactic acid in dH.sub.2O. Zonisamide was dissolved
in 10% DMSO, 13.4% EtOH, 20.1% PPG, and 66.5% saline. Olanzapine
dose was 1.75 mg/day. The animals were housed individually and supplied
with standard laboratory chow. Food consumed and animal weights
were recorded every days. There were 5 animals in the control (vehicle)
group, 5 animals in the zonisamide only group, 4 animals in the
olanzapine only group, and 6 animals in the olanzapine+zonisamide
group.
[0201] We have already shown in mice that zonisamide has pronounced
effects on food intake over 24 hrs after intra-peritoneal injection.
[0202] Rats were allowed to recover after pump implantation, and
then received twice daily injections of zonisamide 26 mg/kg. Their
food intake and body weight were calculated daily for 15 days.
[0203] The results of these studies are shown below: TABLE-US-00002
Cumulative Change in Body Weight Olanzapine + Vehicle Zonisamide
Olanzapine Zonisamide Day Mean SEM Mean SEM Mean SEM Mean SEM 1.00
6.10 2.64 9.74 2.98 7.44 3.74 3.33 2.35 4.00 19.24 5.16 20.24 2.94
21.04 3.56 12.13 4.36 5.00 17.14 6.39 17.60 2.97 19.22 5.15 12.67
3.57 6.00 19.76 6.49 19.34 4.05 20.56 6.18 12.05 2.65 7.00 23.96
5.78 20.18 2.62 30.88 4.83 15.67 3.96 8.00 22.80 5.81 17.32 2.97
27.56 6.28 10.40 3.68 9.00 25.80 4.44 13.66 3.40 32.94 7.83 20.50
3.05 10.00 24.78 7.24 14.62 6.02 34.98 6.35 16.45 3.28 11.00 26.60
6.59 16.46 3.60 33.40 6.46 18.55 2.44 12.00 27.14 6.46 21.08 3.27
40.76 7.91 18.58 2.43 13.00 29.68 6.35 24.26 3.56 38.84 9.07 24.83
2.31 14.00 34.04 6.33 27.52 3.63 43.28 8.60 21.65 2.60 15.00 28.70
5.61 25.70 6.26 41.64 9.34 22.22 3.70
[0204] TABLE-US-00003 Change in Food Intake Post Pump Implant Olanzapine
+ Vehicle Zonisamide Olanzapine Zonisamide Day Mean SEM Mean SEM
Mean SEM Mean SEM 1.00 15.84 1.68 12.48 1.79 16.56 1.29 15.17 0.68
2.00 32.34 1.96 30.10 2.99 39.82 1.93 35.22 1.22 5.00 52.72 2.65
46.02 4.13 62.30 4.36 52.60 1.35 6.00 71.82 2.68 58.24 3.16 86.14
6.02 72.82 1.74 7.00 87.88 4.27 72.10 3.32 105.74 7.17 89.98 3.63
8.00 101.70 5.52 86.88 3.28 119.30 7.12 107.47 2.58 9.00 121.84
5.99 104.86 3.57 144.98 8.35 125.95 2.16 10.00 139.82 6.03 123.66
3.31 161.16 9.37 144.15 3.22 11.00 157.54 5.33 140.40 3.10 180.96
10.62 158.10 4.73 12.00 175.35 4.59 160.36 2.10 201.42 10.92 177.27
4.81 13.00 195.70 3.66 177.70 5.53 224.38 11.57 197.35 6.06 14.00
217.93 3.84 186.25 10.97 241.48 12.45 219.13 5.98
[0205] TABLE-US-00004 Change in Food Intake Olanzapine + Vehicle
Zonisamide Olanzapine Zonisamide Day Mean SEM Mean SEM Mean SEM
Mean SEM 1.00 16.16 1.43 17.88 1.12 15.22 1.67 16.48 1.07 4.00 69.44
2.49 78.44 2.59 75.54 2.83 67.20 5.06 5.00 89.38 3.17 97.88 2.81
96.16 3.13 88.70 5.31 6.00 105.22 4.76 110.36 3.19 112.72 3.67 103.87
5.17 7.00 121.72 5.01 127.98 4.42 135.98 3.82 123.92 5.27 8.00 142.10
5.75 143.90 5.41 158.46 6.05 141.30 5.67 9.00 161.20 5.80 156.12
4.45 182.30 7.59 161.52 6.14 10.00 177.26 6.80 169.98 4.13 201.90
8.36 178.68 7.50 11.00 191.08 7.94 184.76 4.61 215.46 8.46 196.17
6.33 12.00 211.22 8.71 202.74 5.32 241.14 9.96 214.65 5.18 13.00
229.20 8.68 221.54 5.30 257.32 11.13 232.85 5.59 14.00 246.92 7.80
238.28 5.35 277.12 12.17 246.80 6.88
Electrophysiology
[0206] The electrophysiological activity of Proopiomelanocortin
(POMC) neurons in brain slices from POMC-EGFP mice was recorded.
The POMC neurons in these mice are identified by the expression
of green fluorescent protein (EGFP) in these, and only these, cells.
The frequency of action potentials in these neurons were recorded
using standard electrophysiological techniques. In particular, loose
cell attached patch configuration is used to determine action current
frequency, whilst minimally disturbing the cells.
[0207] It has been shown that zonisamide increases the activity
of POMC neurons, as shown in FIG. 1. The basal activity was recorded,
and then olanzapine (100 nM) was added to the tissue bath to determine
the effect of olanzapine on the activity of POMC neurons. Olanzapine
reduced the activity of POMC neurons, as shown in FIG. 2). Pharmacological
data show that olanzapine decreases the activity of POMC neurons.
Then the effect of zonisamide on the reducuction in activity caused
by zonisamide was tested by adding olanzapine plus zonisamide (10
.mu.M) to the bath. An increase in neuronal activity was observed,
as shown in FIG. 3.
Example 13
Zonisamide Plus Bupropion Prevent the Weight Gain Associated with
Olanzapine Treatment
Background
[0208] In this experiment, the effect of co-treatment with drug
combinations on the weight gain associated with olanzapine use is
tested. Specifically, addition of zonisamide or zonisamide plus
bupropion to concomitant olanzapine treatment is shown to decrease
the weight gain associated with olanzapine, in a validated rodent
model of olanzapine-induced weight gain.
[0209] The melanocortin system consists of Proopiomelanocortin
(POMC) neurons, the cognate melanocortin receptors (MC4 R) and the
agouti-related peptide neurons in the arcuate nucleus of the hypothalamus.
It is well established in humans and animals that the melanocortin
system controls energy balance, and the most common genetic cause
of obesity in humans is congenital lack of MC4 R. It has recently
been shown that many compounds that influence energy balance modify
the activity of melanocortin circuits. In particular, it has been
shown that bupropion and zonisamide increase the electrophysiological
activity of POMC neurons. It has also been shown that cannabinoid
antagonists activate this same circuitry. We have identified some
of the receptors that can regulate the activity of POMC neurons;
in particular we have shown that 5-HT 2C and 5-HT 1 B receptors
increase the activity of POMC neurons as does dopamine D2 R. The
clear role of D2 R and 5-HT 2CR in regulating the activity of POMC
neurons shows that compounds like olanzapine, which is an antagonist
at both these receptors, modify energy balance to induce an anabolic
state, favoring weight gain.
Study Design
In Vivo Pharmacology
[0210] Rats receive implants that secrete olanzapine (or vehicle
in control groups). Some also receive co-treatment with zonisamide;
others get co-treatment with zonisamide plus bupropion. Initially,
a dose of 30 mg/kg of zonisamide (bid) is used, but the dose in
the experiment ranges from 20 mg/kg to 90 mg/kg (bid). Bupropion
is used initially at a dose of 190 mg/kg/day, the dose in the experiment
ranges from 50-190 mg/kg/day. Olanzapine is used as a solution in
minipumps. The concentration of the solution ranges between 0.1
.mu.M to 10 mM. In some experiments, the concentration is calculated
to provide a dose of about 1.75 mg/kg/day. In certain experiments,
the concentration is 10 .mu.M. TABLE-US-00005 Rat numbers and groups
Weight loss agent Vehicle Olanzapine (1.75 mg/day) Vehicle 10 10
Zonisamide (tbd) 10 10 Zonisamide (tbd) + 10 10 bupropion (tbd)
[0211] Preliminary data on the effect of zonisamide combined with
bupropion on electrophysiological activity of POMC neurons in brain
slices from POMC-EGFP mice show the increase in rate of spontaneous
action potentials in POMC neurons. This large increase stimulates
significant secretion of a-MSH from POMC neurons, and consequently
activates MC4 R--to inhibit food intake and decrease body weight
gain.
Procedures
In Vivo Pharmacology
[0212] Female Sprague-Dawley rats weighing about 300 grams at the
start of the experiment are used. Under isoflurane anesthesia, Alzet
osmotic minipumps (2 ml2) are implanted subcutaneously, between
the shoulder blades. The rats are returned to their home cages after
recovery. The minipumps deliver 5 .mu.L per hour for 14 days. Olanzapine
is dissolved in 1.5% lactic acid in dH.sub.2O. Zonisamide is dissolved
in 10% DMSO, 13.4% EtOH, 20.1% PPG, and 66.5% saline. The animals
are housed individually and are supplied with standard laboratory
chow. Food consumed and animal weights are recorded every day.
[0213] It has been shown in mice that zonisamide plus bupropion
have pronounced effects on food intake over 24 hrs after intra-peritoneal
injection. Similar mini-pump based methods are developed to test
the effects of zonisamide plus bupropion on weight gain over 14
days using the following groups:
[0214] 7 groups of 6 rats (6 doses of zonisamide, +saline)
[0215] 7 groups of 6 rats (6 doses of bupropion, +saline)
[0216] The doses of zonisamide and bupropion that cause weight
loss in this rat model are determined in smaller preliminary studies.
The co-treatment experiments (olanzapine plus zonisamide plus bupropion)
are then performed. Total animals tested are: 60+42+42=144 rats.
The experiments are run three times to confirm the results.
Electrophysiology
[0217] The electrophysiological activity of Proopiomelanocortin
(POMC) neurons in brain slices from POMC-EGFP mice are recorded.
The POMC neurons in these mice are identified by the expression
of green fluorescent protein (EGFP) in these, and only these, cells.
The frequency of action potentials in these neurons are recorded
using standard electrophysiological techniques. In particular, loose
cell attached patch configuration is used to determine action potential
frequency, whilst minimally disturbing the cells.
[0218] It has been shown that zonisamide plus bupropion increase
the activity of POMC neurons. The basal activity is recorded, and
then olanzapine is added to the tissue bath to determine the effect
of olanzapine on the activity of POMC neurons. Pharmacological data
show that olanzapine decreases the activity of POMC neurons. Then
the increase in neuronal activity is tested again by treating the
brain slices with zonisamide plus bupropion.
Example 14
Case Study of Combination of Zonisamide, Lamotrogine, and Clonazepam
[0219] A 49 year-old woman having biopolar disorder, Type I, had
been treated for just over year by her psychiatrist using clonazepam
1 mg qHS, fluoxetine 20 mg qd, and lamotrogine 300 mg qD. One particular
complaint was that she had "constant thoughts of eating".
Her psychiatrist started her on zonisamide 100 mg qD. She reported
that the zonisamide significantly reduced her craving for food.
and prevented weight gain. The dose was continued and despite multiple
stressors at home, she continued to do well on the treatment regimen.
Example 15
Case Study of Combination of Zonisamide, Paroxetine, and Risperidone
[0220] A 45 year old female patient with social phobia and schizoaffective
disorder was treated with paroxetine augmented with risperidone.
She had marked increase in appetite and gained 40 pounds. A trial
of bupropion alone did not cause significant weight loss. She was
therefore started on zonisamide 100 mg, incraesed to 200 mg. In
3 weeks she lost 12 pounds. The dose was then increased to 300 mg
and then to 600 mg. In 5 months her weight returned to baseline.
The psychiatric symptoms also improved.
Example 16
Case Study of Combination of Zonisamide, Olanzapine, Valproate,
and Bupropion
[0221] A 30 year-old female patient with a diagnosis of bipolar
disorder gained 56 lbs while receiving olanzapine and valproate
over 5 years. Despite significant weight gain, as her mental illness
was effectively controlled, these medications were continued. She
was clinically obese with a BMI of 33.8 kg/m.sup.2. In an effort
to assist in weight reduction, bupropion was added at 150 mg/day
while olanzapine and valproate were continued. When bupropion dose
was raised to 300 mg/day, the patient reported feeling hyperactive;
hence, the dose was reduced back to 150 mg/day. After 6 months,
the patient lost 23.6 lbs. However, while continuing to receive
bupropion, the patient regained 10.6 lbs over the next 10 months.
At this point, zonisamide was added to her medication regimen at
100 mg/day and the dose was increased to 200 mg/day after two weeks.
The patient lost 15 lbs over the next 4 months and reported no adverse
effects. She remained free of bipolar disorder symptoms.
[0222] The case illustrates two advantages of the combination therapy
of bupropion and zonisamide. 1) Although bupropion helped in decreasing
weight gain resulting from olanzapine and valproate, the patient
could not take a higher dose (300-400 mg/day) of bupropion because
of precipitation of hypomanic symptoms. The risk of induction of
manic or hypomanic symptoms with use of antidepressant medications
in susceptible patients is well documented. 2) Zonisamide helped
in further offsetting weight gain associated with olanzapine and
valproate after the patient lost weight initially with bupropion
and regained some of weight lost.
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