Weight loss abstract
The present invention features a novel therapy for effecting weight
loss which involves treating a subject with a sympathomimetic agent
(e.g., phentermine or a phentermine-like drug) in combination with
an anticonvulsant sulfamate derivative (e.g., topiramate) such that
the subject experiences weight loss.The combination methods of the
present invention also are effective against symptoms associated
with Syndrome X. The invention also features pharmaceutical compositions
and kits for use in the practice of these novel therapies.
Weight loss claims
I claim:
1. A pharmaceutical composition comprising about 50 mg to 250 mg
topiramate and about 5 mg to about 15 mg phentermine.
2. The composition of claim 1, comprising about 100 mg to 250 mg
topiramate.
3. The composition of claim 2, comprising about 100 mg to 200 mg
topiramate.
4. The composition of claim 1, comprising a dosage form that provides
immediate release of the phentermine and controlled release of the
topiramate.
5. The composition of claim 4, wherein the dosage form comprises
a core containing the topiramate and a coating containing the phentermine.
6. The composition of claim 4, wherein the dosage form provides
for delayed release of the topiramate.
7. The composition of claim 6, wherein the dosage form additionally
provides for sustained release of the topiramate.
8. A method for effecting weight loss in a subject comprising administering
to the subject a maintenance dose of topiramate in the range of
about 50 mg to 250 mg daily and a daily dose of phentermine in the
range of about 5 mg to 15 mg.
9. The method of claim 8, wherein the maintenance dose of topiramate
is in the range of about 100 to 250 mg daily.
10. The method of claim 8, wherein the maintenance dose of topiramate
is in the range of about 100 to 200 mg daily.
11. The method of claim 8, wherein the subject is overweight.
12. The method of claim 8, wherein the subject is obese.
13. The method of claim 8, wherein the subject is neither overweight
nor obese.
14. The method of claim 8, wherein the phentermine and the topiramate
are administered separately.
15. The method of claim 14, wherein the phentermine and the topiramate
are administered at different times of the day.
16. The method of claim 15, wherein the phentermine is administered
in the morning and the topiramate is administered at least once
later in the day.
17. The method of claim 8, wherein the phentermine is contained
in an immediate release dosage form.
18. The method of claim 17, wherein the topiramate is contained
in an immediate release dosage form or a controlled release dosage
form.
19. The method of claim 18, wherein the topiramate is contained
in a controlled release dosage form.
20. The method of claim 19, wherein the controlled release dosage
form is a delayed release dosage form.
21. The method of claim 19, wherein the controlled release dosage
form is a sustained release dosage form.
22. The method of claim 8, wherein the daily dose of phentermine
is about 15 mg per day.
23. The method of claim 8, wherein the phentermine and the topiramate
are administered orally.
24. The method of claim 8, wherein the phentermine and the topiramate
are administered transdermally.
25. The method of claim 8, wherein the phentermine and the topiramate
are administered by injection.
26. The method of claim 8, wherein the phentermine and the topiramate
are administered simultaneously.
27. The method of claim 26, wherein the phentermine and the topiramate
are contained in a single pharmaceutical formulation.
28. The method of claim 27, wherein the pharmaceutical formulation
contains a unit dosage of phentermine and a unit dosage of topiramate.
29. The method of claim 28, wherein the unit dosages are unit daily
dosages, such that the formulation is administered once daily.
30. The method of claim 27, wherein the formulation provides for
immediate release of the phentermine and controlled release of the
topiramate.
31. The method of claim 30, wherein the formulation is composed
of an oral dosage form that comprises a core containing the topiramate
and a coating containing the phentermine.
32. The method of claim 30, wherein the controlled release formulation
provides for delayed release of the topiramate.
33. The method of claim 32, wherein the controlled release formulation
additionally provides for sustained release of the topiramate, such
that a physiologically effective blood level of topiramate is sustained
over an extended time period.
34. The method of claim 30, wherein the controlled release formulation
provides for sustained release of the topiramate, such that a physiologically
effective blood level of topiramate is sustained over an extended
time period.
35. The method of claim 30, wherein the controlled release formulation
is composed of granules, hydrogels, matrix formulations, and combinations
thereof.
36. The method of claim 30, wherein the controlled release formulation
comprises about 5 mg to about 15 mg phentermine and about 100 mg
to 200 mg topiramate.
37. The method of claim 30, further including a barrier between
the core and the coating to limit drug release from the core.
38. A method for effecting weight loss in a subject, comprising
administering to the subject: (a) a daily dose of phentermine in
the range of about 5 mg to 15 mg; and (b) a therapeutically effective
amount of topiramate that is gradually increased, over an extended
time period, from an initial daily dosage up to a final daily dosage
suitable for continued maintenance therapy, wherein the final daily
dosage is in the range of about 50 mg to 250 mg.
39. The method of claim 38, wherein the initial daily dosage is
about 25 mg.
40. The method of claim 38, wherein the final daily dosage is in
the range of about 100 mg to 250 mg.
41. The method of claim 40, wherein the final daily dosage is in
the range of about 100 mg to 200 mg.
42. The method of claim 39, wherein the final daily dosage is in
the range of about 100 mg to 250 mg.
43. The method of claim 42, wherein the final daily dosage is in
the range of about 100 mg to 200 mg.
44. The method of claim 38, wherein the therapeutically effective
amount of topiramate administered to the subject is increased on
an approximately weekly basis over said extended time period.
45. The method of claim 44, wherein the topiramate is administered
at an initial daily dosage of 25 mg 5 7 days, at 50 mg daily for
the next 5 7 days, at 100 mg daily for the next 6 8 days, and about
100 mg to 150 mg daily for the next 20 26 days, and then at a maintenance
dose of 100 mg to 200 mg daily.
46. A method of treating at least one side effect associated with
obesity comprising administering to an obese subject a therapeutically
effective daily dose of topiramate in the range of about 50 mg to
250 mg daily and a therapeutically effective daily dose of phentermine
in the range of about 5 mg to 15 mg, such that at least one side
effect associated with obesity is effectively treated.
47. The method of claim 46, wherein the daily dose of topiramate
is in the range of about 100 to 250 mg.
48. The method of claim 47, wherein the daily dose of topiramate
is in the range of about 100 mg to 200 mg.
49. A kit comprising a packaged combination of phentermine and
topiramate, and instructions for a patient to carry out drug administration
to achieve weight loss, wherein the phentermine and topiramate are
present in separate and discrete dosage forms, and further wherein
the topiramate dosage forms each contain about 50 mg to 250 mg topiramate
and the phentermine dosage forms each contain about 5 mg to 15 mg
phentermine.
50. The kit of claim 49, wherein the topiramate dosage forms each
contain about 100 mg to 250 mg topiramate.
51. The kit of claim 50, wherein the topiramate dosage forms each
contain about 100 mg to 200 mg topiramate.
52. A kit comprising a sealed package of controlled release dosage
forms each containing about 50 mg to 250 mg topiramate and about
5 mg to 15 mg phentermine, wherein the dosage forms provide for
immediate release of the phentermine and delayed release of the
topiramate.
53. The kit of claim 52, wherein the dosage forms each contain
about 100 mg to 250 mg topiramate.
54. The kit of claim 53, wherein the dosage forms each contain
about 100 mg to 200 mg topiramate.
Weight loss description
BACKGROUND OF THE INVENTION
About 97 million adults in the United States are overweight or
obese. The medical problems caused by overweight and obesity can
be serious and often life-threatening, and include diabetes, shortness
of breath, gallbladder disease, hypertension, elevated blood cholesterol
levels, cancer, arthritis, other orthopedic problems, reflux esophagitis
(heartburn), snoring, sleep apnea, menstrual irregularities, infertility
and heart trouble. Moreover, obesity and overweight substantially
increase the risk of morbidity from hypertension, dyslipidemia,
type 2 diabetes, coronary heart disease, stroke, gallbladder disease,
osteoarthritis and endometrial, breast, prostate, and colon cancers.
Higher body weights are also associated with increases in all-cause
mortality. Most or all of these problems are relieved or improved
by permanent significant weight loss. Longevity is likewise significantly
increased by permanent significant weight loss.
Weight loss treatments vary depending, at least in part, on the
degree of weight loss one is attempting to achieve in a subject
as well as on the severity of overweight or obesity exhibited by
the subject. For example, treatments such as low-fat diet and/or
regular exercise are often adequate in cases where a subject is
only mildly overweight. Such treatments can be enhanced by controlled
use of over-the-counter appetite suppressants including caffeine,
ephedrine and phenylpropanolamine (Acutrim.RTM., Dexatrim.RTM.).
Moreover, prescription medications including amphetamine, diethylpropion
(Tenuate.RTM.), mazindol (Mazanor.RTM., Sanorex.RTM.), phentermine
(Fastin.RTM., Ionamin.RTM.), phenmetrazine (Preludin.RTM.), phendimetrazine
(Bontrol.RTM., Plegine.RTM., Adipost.RTM., Dital.RTM., Dyrexan.RTM.,
Melfiat.RTM., Prelu-2.RTM., Rexigen Forte.RTM.), benzphetamine (Didrex.RTM.)
and fluoxetine (Prozac.RTM.) are often used in the treatment of
seriously overweight and/or obese subjects or patients. However,
such treatments, at best, result in only .about.5 10% weight loss
(when accompanied with diet and exercise). Moreover, most of these
treatments ultimately prove inadequate because they are either dangerous,
ineffective or quickly lose their anorexient effect.
At least one class of these prescription medications, the phentermines
(Fastin.RTM., Ionamin.RTM.), have been used as monotherapy in the
treatment of obesity for about 30 years. The phentermines are members
of a class of drugs known as the sympathomimetics for their ability
to mimic stimulation of the central nervous system. The phentermines
act on the hypothalamus, an appetite control center of the brain.
Phentermine monotherapy can increase weight loss when used in combination
with diet and exercise, as compared to diet and exercise alone.
However, the drug loses effectiveness after about two weeks and,
in fact, is not approved by the FDA for use beyond six weeks. Moreover,
weight loss may not be permanent, especially after the drug is discontinued.
Phentermine treatment is also associated with side effects including
nervousness, irritability, headache, sweating, dry-mouth, nausea,
and constipation.
In general, available weight loss drugs have limited efficacy and
some clinically significant side effects. Studies of the weight
loss medications dexfenfluramine (Guy-Grand, B. et al. (1989) Lancet
2:1142 5), orlistat (Davidson, M. H. et al. (1999) JAMA 281:235
42), sibutramine (Bray, G. A. et al. (1999) Obes. Res. 7:189 98),
and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591 5)
have shown similar effectiveness. Studies for each demonstrated
a weight loss of about 5% of body weight for drug compared with
placebo. Other serious considerations limit the clinical use of
these drugs. Dexfenfluramine was withdrawn from the market because
of suspected heart valvulopathy, orlistat is limited by GI side
effects, sibutramine can cause hypertension, and phentermine has
limited efficacy.
Various combination therapies that include phentermine as one of
the agents have been investigated and have met with mixed success.
The phentermines were, up until around 1997, often prescribed along
with fenfluramine (Pondimin.RTM.) or dexfenfluramine (Redux.RTM.),
nicknamed "fen", as a combination therapy known as fen-phen.
Fenfluramine is a potent releaser of serotonin from serotonergic
neurons which acts on a cerebral appetite center. When combined
with phentermine, fenfluramine had the effect of enhancing and extending
the anorexient action of phentermine. However in 1997, the Food
and Drug Administration ("FDA") asked manufacturers to
withdraw Pondimin.RTM. and Redux.RTM. due to studies which strongly
suggested that the drugs cause damage to the mitral valve of the
heart and pulmonary hypertension.
More recently, it has been suggested that phentermine in combination
with anti depressants is a potentially effective therapy for effecting
weight loss, U.S. Pat. No. 5,795,895. In particular, the anti-depressants
suggested for use in this new combination therapy are members of
a class of compounds known as selective serotonin reuptake inhibitors
(SSRIs) which include fluoxetine (Prozac.RTM.), sertraline (Zoloft.RTM.),
fluvoxamine maleate (Luvox.RTM.) and trazodone hydrochloride (Desyrel.RTM.).
The combination therapy is also suggested to treat coexisting depression
and/or obsessive-compulsive disorder.
Phentermine has also recently been tested in combination with bupropion
(Wellbutrin.RTM.) for the treatment of obesity. Bupropion is an
antidepressant that inhibits dopamine reuptake, as compared to serotonin
uptake. It is also used to treat Attention Deficit Disorder (ADHD),
bipolar depression, chronic fatigue syndrome, cocaine addiction,
nicotine addiction, and lower back pain. While bupropion alone had
a modest effect as a weight loss agent (when prescribed to patients
following a 1200 calorie per day diet), patients receiving phentermine
in combination with bupropion experienced no greater weight loss
than those receiving bupropion alone. Moreover, bupropion use has
been associated with drug-induced seizures causing it to be removed
from the market by the FDA for at least five years before its re-introduction
in 1989.
Accordingly, there exists a need for new, more effective weight
loss treatments which are accompanied by fewer adverse or undesirable
side effects or less serious side effects. In particular, there
exists a need for developing medical weight loss treatments which
can potentially lower major endpoints such as death and/or myocardial
infarction rates by directly treating obesity rather than treating
the consequences of obesity (e.g., diabetes, hypertension, hyperlipidemia),
as is currently the practice.
SUMMARY OF THE INVENTION
The present invention features a novel therapy for effecting weight
loss which involves treating a subject with a sympathomimetic agent
in combination with an anticonvulsant sulfamate derivative such
that the subject experiences weight loss. In one aspect, the sympathomimetic
agent is a compound having anorectic activity (e.g., amphetamine,
methamphetamine, benzphetamine, phentermine, chlorphentermine, diethylpropran,
phenmetrazine, and phendimetrazine). Preferably, the sympathomimetic
agent is the drug phentermine (nicknamed "phen"). In another
aspect, the anticonvulsant sulfamate derivative is the drug topiramate.
The combination methods of the present invention also are effective
against symptoms associated with Syndrome X. Accordingly, in another
aspect the invention features methods for treating Syndrome X with
a combination of a sympathomimetic agent and an anticonvulsant sulfamate
derivative (e.g., phentermine and topiramate, respectively) such
that at least one symptom associated with Syndrome X is beneficially
affected. Moreover, the combination methods of the present invention
have been shown to have beneficial side effects, such as ameliorating
sleep apnea and lowering blood pressure, blood glucose, blood lipid,
and Hgb A1C levels. Accordingly, in another aspect the invention
features methods for treating at least one side effect associated
with obesity. In a preferred embodiment, at least one side effect
of obesity is treated with a combination of a sympathomimetic agent
in combination with an anticonvulsant sulfamate derivative.
The invention also features pharmaceutical compositions including
therapeutically effective amounts of a sympathomimetic agent in
combination with an anticonvulsant sulfamate derivative. Kits including
the pharmaceutical compositions of the present invention are also
featured (e.g., kits including the compositions packaged in a daily
dosing regimen).
Combination therapy according to the invention provides an effective
and efficient treatment for bringing about weight loss while, quite
unexpectedly, simultaneously enabling a reduction in the effective
dosage of each drug administered and minimizing the potential side
effects of each individual drug. Administering topiramate with phentermine
according to the invention, for example, is very effective in bringing
about weight loss using a daily dose of topiramate that, a particularly
preferred embodiment, is at most about half of the recommended daily
dose of the drug (400 mg, for Topamax.RTM.) and a daily dose of
phentermine that is also significantly reduced relative to the recommended
daily dose (from 37.5 mg daily to 5 15 mg daily). At the same time,
weight loss is achieved efficiently and the common side effects
of each drug are substantially reduced. Applicant is unaware of
any teaching suggesting the combination therapy of the invention;
in fact, the 1999 Physicians' Desk Reference pertaining to phentermine
specifically states that the drug is useful only in the context
of short-term monotherapy and recommends not co-administering the
drug with any other active agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a novel combination therapy
for effecting weight loss in a subject. In particular, the present
invention provides methods which involve treating the subject with
a therapeutically effective amount of a combination of a sympathomimetic
agent (e.g., phentermine or a phentermine-like compound) and an
anticonvulsant sulfamate derivative (e.g., topiramate). The methods
are particularly useful for the treatment of overweight and/or obesity,
as well as in the treatment of Syndrome X.
The phrase "therapeutically effective amount" as used
herein refers to the amount of an agent, compound, drug, composition,
or combination of the invention which is effective for producing
some desired therapeutic effect upon administration to a subject
or patient (e.g., a human subject or patient). The phrase "administering
to a subject" or "administering to a patient" refers
to the process of introducing an agent, compound, drug, composition
or combination of the invention into the subject or patient's body
via an art-recognized means of introduction (e.g., orally, transdermally,
via injection, etc.).
The term "sympathomimetic agent" is a term of art and
refers to agents or compounds which mimic or alter stimulation of
the sympathetic nervous system (e.g., stimulates the peripheral
nervous system) of an organism (e.g., mimic the stimulation naturally
effected by physical activity, psychological stress, generalized
allergic reaction and other situations in which the organism is
provoked).
Preferred sympathomimetic agents for use in the present invention
as well as there general clinical uses or effects are set forth
in Table I.
TABLE-US-00001 TABLE I SYMPATHOMIMETIC AGENTS AND CLINICAL USES
THEREOF.sup..dagger. MAIN CLINICAL USES ##STR00001## .alpha.ReceptorA
N P V .beta.ReceptorB C CNS, 0 Phenylethylamine H H H Epinephrine
3-OH, 4-OH OH H CH.sub.3 A, P, V B, C Norepinephrine 3-OH, 4-OH
OH H H P Epinine 3-OH, 4-OH H H CH.sub.3 Dopamine 3-OH, 4-OH H H
H P Dabutamine 3-OH, 4-OH H H 1 * C Nordefrin 3-OH, 4-OH OH CH.sub.3
H V Ethylnorepinephrine 3-OH, 4-OH OH CH.sub.2CH.sub.3 H B Isoproterenol
3-OH, 4-OH OH H CH(CH.sub.3).sub.2 B, C Protokylol 3-OH, 4-OH OH
H 2 * B Isoetharine 3-OH, 4-OH OH CH.sub.2CH.sub.3 CH(CH.sub.3).sub.2
B Metaproterenol 3-OH, 5-OH OH H CH(CH.sub.3).sub.2 B Terbutaline
3-OH, 5-OH OH H C(CH.sub.3).sub.3 B Metaraminol 3-OH OH CH.sub.3
H P Phenylephrine 3-OH OH H CH.sub.3 N, P Tyramine 4-OH H H H Hydroxyamphetamine
4-OH H CH.sub.3 H N, P C Methoxyphenamine 2-OCH.sub.3 H CH.sub.3
CH.sub.3 B Methoxamine 2-OCH.sub.3, 5-OCH.sub.3 OH CH.sub.3 H P
Albuterol 3-CH.sub.2OH, 4-OH OH H C(CH.sub.3).sub.3 B Amphetamine
H CH.sub.3 H CNS, 0 Methamphetamine H CH.sub.3 CH.sub.3 P CNS, 0
Benzphetamine H CH.sub.3 CH.sub.3 0 Ephedrine OH CH.sub.3 CH.sub.3
N, P B, C Phenylpropanolamine OH CH.sub.3 H N Mephentermine H 4
* CH.sub.3 N, P Phentermine H 4 * H 0 Chlorphentermine 4-Cl H 4
* H 0 Fenfluramine 3-CF.sub.3 H CH.sub.3 C.sub.2H.sub.5 0 Tuaminoheptane
CH.sub.3(CH.sub.2).sub.3 H CH.sub.3 H N Propylhexedrine 5 * H CH.sub.3
CH.sub.3 N Diethylpropran 6 * Phenmetrazine 7 * 0 Phendimetrazine
8 * 0 1 ##STR00002## 2 ##STR00003## 3 ##STR00004## 4 ##STR00005##
5 ##STR00006## 6 ##STR00007## 7 ##STR00008## 8 ##STR00009## .alpha.
Activity A = Allergic reactions (includes .beta. action) N = Nasal
decongestion P = Pressor (may include .beta. action) V = Other local
vasoconstriction (e.g. in local anesthesia) .beta. Activity B =
Bronchodilator C = Cardiac CNS = Central nervous system 0 = Anorectic
* Numbers bearing an asterisk refer to the substituents numbered
in the bottom rows of the table; substituent 5 replaces the phenyl
rings, and 6, 7 and 8 are attached directly to the phenyl ring,
replacing the ethylamine side chain. .sup..dagger.The .alpha. and
.beta. in the prototype formula refer to positions of the C atoms
in the ethylamine side chain.
In preferred embodiments, the sympathomimetic agent has anorexient
properties (e.g., suppresses appetite) or is anorectic without significant
toxicity to a subject or patient (e.g., a human) at therapeutically
effective doses. In a more preferred embodiment, the sympathomimetic
agent has anorexient properties (e.g., suppresses appetite) or is
anorectic without loss of efficacy or without adverse or undesirable
side effects to a subject or patient (e.g., a human subject or patient)
at therapeutically effective doses when prescribed in combination
with topiramate. In yet another embodiment, the sympathomimetic
agent is phentermine or a phentermine-like compound. As defined
herein, a phentermine-like compound is a compound structurally related
to phentermine (e.g., an analog or derivative) which maintains an
anorectic activity similar to that of phentermine. A preferred phentermine-like
compound is chlorphentermine. In yet another embodiment, the sympathomimetic
agent is amphetamine or an amphetamine-like compound. As used herein,
an "amphetamine-like compound" is a compound structurally
related to amphetamine (e.g., an analog or derivative) which maintains
an anorectic effect of amphetamine. In yet another embodiment, the
sympathomimetic agent is phenmetrazine or a phenmetrazine-like compound.
As defined herein, a "phenmetrazine-like compound" is
a compound structurally related to phenmetrazine (e.g., an analog
or derivative) which maintains an anorectic effect of phenmetrazine.
A preferred phenmetrazine-like compound is phendimetrazine. Analogs
and/or derivatives of the compounds of the present invention can
be tested for their ability to suppress appetite (e.g., suppress
food intake) in a subject (e.g., a mammalian subject).
In an exemplary preferred embodiment, the sympathomimetic agent
is selected from the group consisting of amphetamine, methamphetamine,
benzphetamine, phenylpropanolamine, phentermine, chlorphentermine,
diethylpropion, phenmetrazine, and phendimetrazine (as set forth
in Table I. In a particularly preferred embodiment, the sympathomimetic
agent is phentermine. It is also within the scope of the present
invention to utilize other sympathomimetic agents including pseudo
ephedrine (a stereoisomer of ephedrine, SUDAFED.RTM.), methylphenidate
(RITALIN.RTM.) and other CNS stimulants including, for example,
caffeine.
The terms "anticonvulsant sulfamate derivative" and "anticonvulsant
sulfamate derivatives" are terms of art and refer to a class
of sulfamate-derived compounds that possess anticonvulsant activity
and have an art-recognized use in the treatment of epilepsy. In
particular, the anticonvulsant sulfamate derivatives are monosaccharide
derivatives with sulfamate functionality. The anticonvulsant sulfamate
derivatives for use in the present invention have one or more of
the following modes of activity: modulation of voltage-dependent
sodium conductance; potentiation of gamma-aminobutyric acid-evoked
currents; inhibition of the kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid (AMPA) subtype of the glutamate receptor; and/or inhibition
of carbonic anhydrase (e.g, a mechanism by which the anticonvulsant
derivative of the present invention may decrease the sensation of
taste). The anticonvulsant sulfamate derivatives for use in the
present invention are described further in U.S. Pat. Nos. 4,513,006,
5,384,327, 5,498,629, 5,753,693 and 5,753,694, as are methods of
synthesizing such anticonvulsant sulfamate derivatives. The aforementioned
patents are incorporated by reference herein in their entireties.
In preferred embodiments, the anticonvulsant sulfamate derivative
is a compound having the following formula (I):
##STR00010## wherein:
X is CH.sub.2 or O;
R.sub.1 is H or alkyl; and
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently H or lower
alkyl, with the proviso that when X is O, then R.sub.2 and R.sub.3
and/or R.sub.4 and R.sub.5 together may be a methylenedioxy group
of the following formula (II):
##STR00011##
in which R.sub.6 and R.sub.7 are the same or different and are
H or lower alkyl, or are joined to form a cyclopentyl or cyclohexyl
ring.
R.sub.1 in particular is hydrogen or alkyl of about 1 to 4 carbons,
such as methyl, ethyl, and isopropyl. Alkyl includes both straight
and branched chain alkyl. Alkyl groups R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6 and R.sub.7 are about 1 to 3 carbons and include
methyl, ethyl, isopropyl and n-propyl.
A particular group of compounds of the formula (II) are those wherein
X is oxygen and both R.sub.2 and R.sub.3, and R.sub.4 and R.sub.5
together are methylenedioxy groups of the formula (II), wherein
R.sub.6 and R.sub.7 are both hydrogen, both alkyl, or combine to
form a spiro cyclopentyl or cyclohexyl ring, in particular, where
R.sub.6 and R.sub.7 are both alkyl such as methyl. A second group
of compounds are those wherein X is CH.sub.2 and R.sub.4 and R.sub.5
are joined to form a benzene ring. A third group of compounds of
the formula (I) are those wherein both R.sub.2 and R.sub.3 are hydrogen.
In preferred embodiments, the anticonvulsant sulfamate derivatives
have anorexient properties (e.g., suppress appetite) without significant
toxicity to a subject or patient (e.g., a human) at therapeutically
effective doses. In a more preferred embodiment, the anticonvulsant
sulfamate derivatives have anorexient properties (e.g., suppress
appetite) without significant adverse or undesirable side effects
to a subject or patient (e.g., a human) at therapeutically effective
doses when prescribed in combination with phentermine. In a particularly
preferred embodiment the anticonvulsant sulfamate derivative is
topiramate (Topamax.RTM.). Topiramate, also referred to in the art
as 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfamate,
has been demonstrated in clinical trials of human epilepsy to be
effective as an adjunctive therapy or as monotherapy in treating
simple and complex partial seizures and secondarily generalized
seizures (E. Faught et al. (1995) Epilepsia 36(suppl 4):33; S. Sachdeo
et al. (1995) Epilepsia 36(suppl 4):33) and is currently marketed
for the treatment of simple and complex partial seizure epilepsy
with or without secondary generalized seizures.
Dosages, Administration and Pharmaceutical Compositions:
The choice of appropriate dosages for the drugs used in combination
therapy according to the present invention can be determined and
optimized by the skilled artisan, e.g., by observation of the patient,
including the patient's overall health, the response to the combination
therapy, and the like. Optimization, for example, may be necessary
if it is determined that a patient is not exhibiting the desired
therapeutic effect or conversely, if the patient is experiencing
undesirable or adverse side effects that are too many in number
or are of a troublesome severity.
The sympathomimetic drug (e.g., a drug set forth in Table I) is
prescribed at a dosage that is at most that which is routinely used
by the skilled artisan (e.g., physician) to promote the desired
therapeutic effect of the drug, when the drug is used as a monotherapy.
Preferably, an anticonvulsant sulfamate derivative (e.g., a compound
having formula (I) is prescribed at a lower dosage than routinely
used by the skilled artisan (e.g., physician) to promote the desired
therapeutic effect of the drug, when the drug is used as a monotherapy
(e.g., in the treatment of epilepsy). A sympathomimetic drug or
anticonvulsant sulfamate derivative may be prescribed, for example,
at a dose of 5 1000, preferably 10 1500, more preferably 20 1000,
and most preferably 25 50 mg daily In the preferred embodiment,
wherein the anticonvulsant sulfamate derivative is topiramate, the
maintenance dose given is at least 50 mg daily, and should be less
than 400 mg daily; preferably, the maintenance dose should be in
the range of about 50 mg to 250 mg daily, more preferably in the
range of about 100 mg to 250 mg daily, and optimally in the range
of about 100 mg to 200 mg daily. By "maintenance dose"
is meant an ongoing daily dose given to a patient, typically after
gradually increasing the daily dose from an initial, low dosage,
over an extended time period, e.g., on the order of several weeks.
It is especially advantageous to formulate compositions of the
invention in unit dosage form for ease of administration and uniformity
of dosage. The term "unit dosage forms" as used herein
refers to physically discrete units suited as unitary dosages for
the individuals to be treated. That is, the compositions are formulated
into discrete dosage units each containing a predetermined, "unit
dosage" quantity of an active compound calculated to produce
the desired therapeutic effect in association with the required
pharmaceutical carrier. The specifications of the novel unit dosage
forms of the invention are dependent on the unique characteristics
of the composition containing the anticonvulsant or sympathomimetic
agent and the particular therapeutic effect or effects to be achieved.
Dosages can further be determined by reference to the usual dose
and manner of administration of the ingredients. It is also within
the scope of the present invention to formulate a single physically
discrete dosage form having each of the active ingredients of the
combination treatment (e.g., a single dosage form having anticonvulsant
and sympathomimetic agent).
The method of administration of compositions or combinations of
the invention will depend, in particular, on the type of sympathomimetic
agent used and the chosen anticonvulsant sulfamate derivative. The
sympathomimetic agent and the anticonvulsant sulfamate derivative
may be administered together in the same composition or simultaneously
or sequentially in two separate compositions. Also, one or more
sympathomimetic agents or one or more anticonvulsant sulfamate derivatives
may be administered to a subject or patient either in the form of
a therapeutic composition or in combination, e.g., in the form of
one or more separate compositions administered simultaneously or
sequentially. The schedule of administration will be dependent on
the type of sympathomimetic agent(s) and anticonvulsant sulfamate
derivative(s) chosen. For example, a sympathomimetic agent can have
a stimulant effect and the degree of such stimulant effect may vary
depending on the sympathomimetic agent chosen. Accordingly, a sympathomimetic
agent having a significant stimulant effect might be administered
earlier in the day than administration of a sympathomimetic agent
having a lesser stimulant effect. Likewise, an anticonvulsant sulfamate
derivative can have a sedative effect and the degree of such sedative
effect may vary depending on the anticonvulsant sulfamate derivative
chosen. Accordingly, an anticonvulsant sulfamate derivative having
a significant sedative effect might be administered later in the
day than administration of an anticonvulsant sulfamate derivative
having a lesser sedative effect. Moreover, sympathomimetic agents
and/or anticonvulsant agents having lesser stimulant or sedative
effects, respectively, may be administered simultaneously.
Sympathomimetic agents and/or anticonvulsant sulfamate derivatives
can also be administered along with a pharmaceutically acceptable
carrier. As used herein "pharmaceutically acceptable carrier"
includes any solvents, dispersion media, coatings, antibacterial
and antifungal agents, isotonic and absorption delaying agents,
and the like. The use of such media and agents for pharmaceutically
active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active compound,
use thereof in compositions of the invention is contemplated.
A sympathomimetic agent alone, or in combination with an anticonvulsant
sulfamate derivative in the form of a composition, is preferably
administered orally. When the composition(s) are orally administered,
an inert diluent or an assimilable edible carrier may be included.
The composition and other ingredients may also be enclosed in a
hard or soft shell gelatin capsule, compressed into tablets, or
incorporated directly into the individual's diet. For oral therapeutic
administration, the composition may be incorporated with excipients
and used in the form of ingestible tablets, buccal tablets, troches,
capsules, elixirs, suspensions, syrups, wafers, and the like. The
percentage of the compositions and preparations may, of course,
be varied. The amount of active compound in such therapeutically
useful compositions is such that a suitable dosage will be obtained.
In a particularly preferred embodiment, the present invention includes
pharmaceutical composition comprising a therapeutically effective
amount of a sympathomimetic agent and an anticonvulsant sulfamate
derivative. In one embodiment, the present invention includes a
therapeutically-effective amount of a sympathomimetic agent and
an anticonvulsant sulfamate derivative packaged in a daily dosing
regimen (e.g., packaged on cards, packaged with dosing cards, packaged
on blisters or blow-molded plastics, etc.). Such packaging promotes
products and increases patient compliance with drug regimens. Such
packaging can also reduce patient confusion. The present invention
also features such kits further containing instructions for use.
The tablets, troches, pills, capsules and the like may also contain
a binder, an excipient, a lubricant, or a sweetening agent. Various
other materials may be present as coatings or to otherwise modify
the physical form of the dosage unit. For instance, tablets, pills,
or capsules may be coated with shellac, sugar, or both. Of course,
any material used in preparing any dosage unit form should be pharmaceutically
pure and substantially non-toxic in the amounts employed.
A sympathomimetic agent, alone or in combination with an anticonvulsant
sulfamate derivative, can also be administered in a convenient manner
such as by injection (subcutaneous, intravenous, etc.), inhalation,
transdermal application, or rectal administration. Depending on
the route of administration, the composition containing the sympathomimetic
agent and/or anticonvulsant sulfamate derivative may be coated with
a material to protect the compound from the action of acids and
other natural conditions which may inactivate the compounds or compositions.
To administer the compositions, for example, transdermally or by
injection, it may be necessary to coat the composition with, or
co-administer the composition with, a material to prevent its inactivation.
For example, the composition may be administered to an individual
in an appropriate diluent or in an appropriate carrier such as liposomes.
Pharmaceutically acceptable diluents include saline and aqueous
buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions
as well as conventional liposomes (Strejan et al. (1984) J. Neuroimmunol.
7:27). To administer the compositions containing the sympathomimetic
agents and/or anticonvulsant sulfamate derivatives parenterally
or intraperitoneally, dispersions can be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations may contain a
preservative to prevent the growth of microorganisms.
Compositions suitable for injectable use include sterile aqueous
solutions (where water-soluble) or dispersions and sterile powders
for the extemporaneous preparation of sterile injectable solutions
or dispersion. In all cases, the composition must be sterile and
must be fluid to the extent that easy syringeability exists. It
must be stable under the conditions of manufacture and storage and
must be preserved against the contaminating action of microorganisms
such as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyetheylene glycol, and
the like), suitable mixtures thereof, and vegetable oils. The proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. Prevention
of the action of microorganisms can be achieved by various antibacterial
and antifungal agents. In many cases, it will be preferable to include
isotonic agents, for example, sugars, polyalcohols such as mannitol,
sorbitol, sodium chloride in the composition. Prolonged absorption
of the injectable compositions can be brought about by including
in the composition an agent which delays absorption, for example,
aluminum monostearate and gelatin.
A preferred aspect of the present invention features prescribing
phentermine in combination with topiramate to effect weight loss
and/or to treat Syndrome X and/or a subset of symptoms thereof.
Phentermine is administered at a daily dosage of about 5 60 mg,
including but not limited to, doses of 8, 10, 15, 20, 25, 30, 35,
40, 45, 50, and 55 mg daily. It is strongly preferred, however,
that the amount of phentermine administered be in the range of about
5 to about 15 mg daily, since within that dosage range, therapeutic
efficacy is maintained within the context of the present combination
therapy, and the side effects of the drug are minimized.
Preferably, the phentermine is taken by the patent in the morning
and more preferably, is taken before breakfast. The phentermine
is best taken in the morning because the drug is a stimulant as
well as an appetite suppressant. When phentermine is prescribed
(e.g., as part of the combination therapy described herein), physicians
should be aware and may want to advise patients that the drug can
be mildly habit forming. Phentermine can also cause increased nervousness,
increased energy, irritability and, rarely, insomnia. Stopping phentermine
may also cause tiredness lasting for up to 1 2 weeks. Phentermine
can also raise blood pressure (e.g., during the early phases of
treatment).
Administration of topiramate at dosages of .gtoreq.400 mg daily
results is promotion of undesirable side effects (e.g., sedation,
mental clouding). Accordingly, in the method of the invention, topiramate
is prescribed at a maintenance dose of at least 50 mg to less than
400 mg daily, preferably about 50 mg to 250 mg daily, more preferably
100 mg to 250 mg daily, and optimally 100 mg to 200 mg daily, as
noted above. In another preferred embodiment, the dosage of topiramate
is increased gradually at the outset of the therapy in order to
reduce the chance of undesirable side effects associated with higher
doses of the drug. In an exemplary embodiment, the topiramate is
administered at a dose of 25 mg daily for about the first 5 7 days
(e.g., 6 days) of treatment, at a dose of about 50 mg daily for
the next 5 7 days (e.g., 6 days), at a dose of 100 mg daily for
about the next 6 8 days (e.g., 7 days) and about 100 150 mg daily
for the next 20 26 days. From this point forward, the topiramate
can be administered at a dose of 100 250 mg daily, preferably 100
200 mg daily. A particularly preferred dose for continued therapy
is about 200 mg of topiramate daily. In another exemplary embodiment,
the topiramate is of an immediate release form. In yet another exemplary
embodiment, the topiramate is of a sustained release form.
In a preferred embodiment, topiramate is taken later in the day
than the phentermine. Preferably, the patient takes the topiramate
just before supper or later in the evening. Topiramate is best given
later in the day because the drug can be sedating. In other embodiments,
the topiramate is given BID (e.g., twice daily), TID (three times
daily) or QID (four time daily). When prescribing topiramate, physicians
should be aware and may want to advise patients that the drug can
cause tiredness, fatigue, dizziness, difficulty with speech or finding
words, difficulty concentrating, difficulty with balance, and/or
numbness or tingling in the hands or feet. Less common side effects
are nausea, coordination problems, abdominal pain, slowed thinking
nervousness, depression, breast pain, painful periods, double or
blurred vision, palpitations, low white blood count and kidney stones.
A physician should also advise patients that the drug may not be
taken if the patient is also taking Diamox (acetazolamide). No female
patient should become pregnant while taking this drug as it may
cause birth defects. If a female patient misses a period she should
immediately discontinue taking the medication and inform the physician.
Female patients should not be treated according to the methods of
the present invention if breast-feeding a child. Patients should
not drink alcohol or take sedating medications while taking topiramate
since excess sedation can occur. Patients should also refrain from
performing dangerous tasks (e.g. operating heavy machinery or driving)
until they are comfortable with the side effects of the full dose
(e.g., 200 mg daily). Patients should be advised not to increase
the dosage beyond what is prescribed. Topiramate is not habit forming.
Yet another embodiment of the present invention features pharmaceutical
compositions (e.g., for oral administration) comprising phentermine
and topiramate in a single pharmaceutical formulation. Such compositions
may be preferred, for example, to increase patient compliance (e.g.,
by reducing the number of administrations necessary to achieve the
desired pharmacologic effect.)
In a preferred embodiment, the pharmaceutical composition includes
phentermine in an immediate release form and further includes topiramate
in a controlled release formulation. As defined herein, an "immediate
release formulation" is one that has been formulated to allow,
for example, the phentermine, to act as quickly as possible. Preferred
immediate release formulations include, but are not limited to,
readily dissolvable formulations. As defined herein, a "controlled
release formulation" includes a pharmaceutical formulation
that has been adapted such that drug release rates and drug release
profiles can be matched to physiological and chronotherapeutic requirements
or alternatively, has been formulated to effect release of a drug
at a programmed rate. Preferred controlled release formulations
include, but are not limited to, granules, delayed release granules,
hydrogels (e.g., of synthetic or natural origin), other gelling
agents (e.g., gel-forming dietary fibers), matrix-based formulations
(e.g., formulations comprising a polymeric material having at least
one active ingredient dispersed therethrough), granules within a
matrix, polymeric mixtures, granular masses, and the like.
In one embodiment, a controlled release formulation is a delayed
release form. As defined herein, a "delayed release form"
is formulated in such a way as to delay, for example, topiramate's
action for an extended period of time. A delayed release form can
be formulated in such a way as to delay the release of an effective
dose of topiramate for 4, 8, 12, 16 or 24 hours following the release
of phentermine. In yet another preferred embodiment, a controlled
release formulation is a sustained release form. As defined herein,
a "sustained release form" is formulated in such a way
as to sustain, for example, the topiramate's action over an extended
period of time. A sustained release form can be formulated in such
a way as to provide an effective dose of topiramate (e.g., provide
a physiologically effective blood level) over a 4, 8, 12, 16 or
24 hour period.
Preferred compositions include a tablet core consisting essentially
topiramate, said core being in association with a layer of phentermine.
Preferably, the core has a delayed or sustained dissolution rate.
In an exemplary embodiment, a tablet can comprise a first layer
containing, for example, phentermine (e.g., in an immediate release
formulation) and a core containing, for example, topiramate in a
delayed release or sustained release formulation. Other exemplary
embodiments can include, for example, a barrier between the first
layer and core, said layer serving the purpose of limiting drug
release from the surface of the core. Preferred barriers prevent
dissolution of the core when the pharmaceutical formulation is first
exposed to gastric fluid. For example, a barrier can comprise a
disintegrant, a dissolution-retarding coating (e.g., a polymeric
material, for example, an enteric polymer), or a hydrophobic coating
or film, and/or can be selectively soluble in either the stomach
or intestinal fluids. Such barriers permit the topiramate to leach
out slowly and can cover substantially the whole surface of the
core.
The above-described pharmaceutical compositions are designed to
release the two effective agents of the combination therapy of the
present invention sequentially, i.e., releasing topiramate after
releasing phentermine, both agents being contained in the same pharmaceutical
composition. Preferred amounts of phentermine and topiramate are
as described above with particularly preferred compositions comprising
unit daily dosages of from about 5 mg to about 15 mg phentermine
and from about 100 mg to 200 mg topiramate.
Pharmaceutical compositions so formulated may contain additional
additives, suspending agents, diluents, binders or adjuvants, disintegrants,
lubricants, glidants, stabilizers, coloring agents, flavoring agents,
etc. These are conventional materials that may be incorporated in
conventional amounts.
In one embodiment, a method of the present invention is carried
out, practiced, or performed such that weight loss in the subject
or patient occurs. Accordingly, the methods of the present invention
are particularly useful for the treatment of overweight or obese
patients. As defined herein, "overweight" subjects or
patients are between about 1 and 20 percent overweight (e.g., weighs
1 20% in excess of their ideal body weight). Also as defined herein,
an "obese" subject or patient is greater than 20 percent
overweight (e.g., weighs >20% in excess of his or her ideal body
weight). Alternatively, the methods of the present invention are
useful in the treatment of subjects or patients in need of losing
weight, but who are not necessarily overweight or obese. For example,
it may be desirable to achieve weight loss in subjects or patients
having arthritis or prostheses such that the individual experiences
fewer or less severe adverse effects resulting from bearing weight.
The combination therapies of the present invention will generally
be administered until the patient has experienced the desired weight
loss, and preferably has achieved an ideal body weight. Alternatively,
the combination therapies of the present invention can be administered
until the patient has achieved a weight loss of 5 10%, 10 15%, 15
20%, or 20 25% of their initial body mass (e.g. patient's starting
weight).
The present inventor has also recognized that the combination therapy
of the present invention ameliorates symptoms associated with Syndrome
X. Syndrome X consists of a complex of medical problems that are
largely associated with obesity, including, hypertension, diabetes
or glucose intolerance and insulin resistance, hyperlipidemia, and
often tiredness and sleepiness associated with sleep apnea. Patients
are often treated with combinations of antihypertensives, lipid
lowering agents, insulin or oral diabetic drugs, and various mechanical
and surgical methods for treating sleep apnea. However, such treatments
are often costly and do not treat the underlying problem of obesity.
Moreover, some of the treatments for diabetes including insulin
and oral diabetic agents actually aggravate Syndrome X by increasing
insulin levels, increasing appetite, and increasing weight. This
can lead to higher blood pressure and even higher cholesterol. Accordingly,
one aspect of the present invention features a method of treating
Syndrome X using the combination therapies described herein. In
one embodiment, the invention features a method of treating Syndrome
X in a subject or patient which includes treating the subject with
a therapeutically effective amount of a combination of an anticonvulsant
sulfamate derivative (e.g., topiramate) and a sympathomimetic agent
(e.g., phentermine or a phentermine-like compound), such that at
least one symptom associated with Syndrome X is treated, i.e. beneficially
affected. As defined herein, "treating or beneficially affecting
a symptom" (e.g., a symptom associated with Syndrome X) refers
to lessening, decreasing the severity of the symptom or reversing,
ameliorating, or improving the symptom (e.g., decreasing hypertension,
ameliorating diabetes, reversing glucose intolerance or insulin
resistance, lessening hyperlipidemia, or decreasing tiredness and
sleepiness associated with sleep apnea).
Treatment of Syndrome X according to the methods of the present
invention includes treating, i.e., beneficially affecting, at least
one, preferably two, more preferably three, more preferably four,
five, or six symptoms associated with Syndrome X. In a particularly
preferred embodiment, all symptoms associated with Syndrome X are
beneficially affected (e.g., lessened, reversed, ameliorated, etc.)
The present inventor has also recognized that the combination therapy
of the present invention ameliorates some side effects associated
with obesity, as described herein. Accordingly, one aspect of the
present invention features a method of treating at least one side
effect associated with obesity using the combination therapies described
herein. In one embodiment, the invention features a method of treating
at least one obesity-related side effect in a subject or patient
which includes treating the subject with a therapeutically effective
amount of a combination of an anticonvulsant sulfamate derivative
(e.g., topiramate) and a sympathomimetic agent (e.g., phentermine
or a phentermine-like compound), such that at least one obesity-related
side effect is effected. As defined herein, a "side effect
associated with obesity" includes a symptom or disorder in
a subject (e.g., a patient) which is secondary and/or results from
(e.g., directly and/or indirectly results from) a medical condition
for which the subject is obese and/or being treated. In a preferred
embodiment, the subject is obese and/or is being treated for obesity.
In another embodiment, the subject has at least one or more (e.g.,
two, three, four, five or more) side effect(s) selected from the
group consisting of sleep apnea, high blood pressure and high blood
sugar, high blood lipid, high Hgb A1C or other art-recognized side
effects associated with obesity.
Whether in the treatment of Syndrome X or in the practicing of
the methods of the present invention to effect weight loss (e.g.,
in the treatment of overweight and/or obesity) or in treatment of
side effects associated with obesity, it will be apparent to the
skilled artisan (e.g., physician) that monitoring of the patient
is needed to determine the effectiveness of the treatments and to
potentially modify the treatments (e.g., modify the dosing, time
of drug administration, sequence of drug administration, as defined
herein). Accordingly, in certain embodiments, the patient is monitored
about every 2 6, preferably every 3 5 and more preferably every
4 weeks. Monitoring the effective of treatment to achieve weight
loss includes, but is not limited to monitoring the subject or patient's
body weight (e.g., comparing the patient's initial body weight to
that at a follow-up visit, for example, four weeks after the initiation
of treatment). Additional features of the subject or patient's health
can also be monitored (i.e., monitoring the patient's overall health
and/or monitoring the effectiveness of treatment of an undesired
side effect of obesity) including, but not limited to the patient's
blood pressure, blood sugar, serum lipid levels, etc. Likewise,
monitoring a subject or patient for treatment of Syndrome X can
include monitoring of at least one, preferably more than one symptom
associated with Syndrome X.
This invention is further illustrated by the following examples
which should not be construed as limiting. The contents of all references,
patents, and published patent applications cited throughout this
application are hereby incorporated by reference.
EXAMPLE 1
Patients as part of the following trial were treated according
to the following dosage regimen. Patients took phentermine at a
dose of 15 mg daily throughout the weight loss program, before breakfast.
For the first 6 days, patients took one 25 mg tablet of topiramate
before supper. For the next 6 days, patients took two 25 mg tablets
of topiramate before supper. For the next 7 days (days 13 19), patients
took 100 mg before supper daily using 4 25 mg tablets of topiramate
daily. For days 20 26, patients took 150 mg of topiramate daily
consisting of one-half of a 200 mg tablet and two 25-mg mg tablets
of topiramate. From that point on, unless instructed otherwise by
the physician, patients continued to take one 200 mg topiramate
tablet daily before supper and continued the 15 mg phentermine daily
in the morning. Patients were advised to drink at least eight (8)
full glasses of water daily to reduce the risk of kidney stones
which may result from taking topiramate.
Patients were advised that while the effect of phentermine is fairly
rapid, the effect of topiramate is slower in onset. The weight reduction
effect of topiramate will continue for as long as 18 months on the
medication. That is, the patient can expect to continue gradual
weight loss for up to 18 months on the medication. Of course, weight
loss is maximal if the patient follows diet and/or exercise programs.
The weight loss should exceed 15% of the patients starting weight.
Thus, if the patient weighs about 200 pounds as of the start date,
he/she might expect to lose at least 30 pounds in a period of 12
18 months. The following patient data has been collected.
TABLE-US-00002 TABLE II Start Start Follow-Up % Follow- Patient's
Weight Blood Follow- Weight Weight Up Blood Initials Age Sex (lbs)
Pressure Up Date (lbs) Loss Pressure M.O..sup.1 48 F 182 115/70
5 weeks 177 2.7% 120/80 9 weeks 176 3.3% 110/70 T.M. 37 F 190 122/84
2 weeks, 178 6.3% 110/80 5 days 6 weeks, 168 11.6% 125/80 2 days
D.M.(A) 28 M 286 138/90 4 weeks 279 2.4% 128/86 P.L. 55 F 144 132/84
4 weeks 141 2.1% 138/85 9 weeks 137 4.9% 122/82 E.K. 52 F 181 130/100
5 weeks 175 3.3% 140/88 I.F. 41 F 196 95/60 6 weeks, 5 days D.M.(B).sup.2
56 M 295 150/80 4 weeks, 297 (+0.7%) 148/82 2 days 8 weeks, 287
2.7% 140/70 2 days .sup.1Patient M.O. was being treated with Meridia
.RTM. at the onset of the study, which continued through the first
5 weeks of the study. At the 5-week follow up, M.O. was switched
to the phentermine/topiramate regime described above. .sup.2Patient
D.M.(B) was being treated with phentermine alone at the onset of
the study and was taking the full dose of topiramate by the fourth
week of the study.
As is apparent from the above-described data, patients not previously
treated with an anorexient at the outset of the study experienced
an average of about 3.5% weight loss after only 2 6 weeks (e.g.,
patient T. M. lost 6.3% body weight, patient D. M.(A) lost 2.4%
body weight, patient P. L. lost 2.1% body weight and patient E.
K. lost 3.3% body weight). After only 6 9 weeks of treatment, patients
(not previously treated with an anorexient at the outset of the
study experienced an average of about 8.3% weight loss (e.g., patient
T. M. lost 11.6% body weight and patient P. L. lost 4.9% body weight).
The patient previously on Meridia.RTM. (patient M. O.) lost 3.3%
body weight after being enrolled in the program for 9 weeks. Moreover,
the patient previously on phentermine (patient D. M.(B)) lost a
total of 2.7% body weight after being enrolled in the program for
about 8 weeks. This particular patient reported that this is the
most significant weight loss he has achieved to date, the patient
having previously tried other conventional therapies.
In addition to the weight loss reported above, almost all patients
enrolled in the study experienced decreased blood pressure. Moreover,
patients involved in the study who had previously taken Redux, phen-fen,
Meridia and/or other weight loss treatments report that they have
not previously experienced the benefits of the combined phentermine/topiramate
therapy. Patients report that they have no appetite, can resist
food easily, can concentrate and function at work (even in attention-intensive
jobs such as computer programming), have more energy and feel better.
Patients also report experiencing fewer side effects than any previous
weight loss treatments tried.
EXAMPLE 2
Extended results of the trial described in Example 1.
A total of thirteen patients were treated for 1 9 months with phentermine
(15 mg daily) in the morning and up to 400 mg of topiramate (median
dose 200 mg), in the evening. [Note: Patient D. M.(B) discussed
above is not included in this data as he was on phentermine treatment
prior to treatment with the combination therapy of the present invention.]
Topiramate dose was gradually increased from 25 mg per day in increments
of 25 50 mg weekly until either desirable weight loss took place
or until side effects limited dose increases. [Note: A fourteenth
patient discontinued treatment after 3 days due to nausea.] All
thirteen patients tolerated treatment well with minimal side effects.
Along with taking medication, patients were instructed to walk at
least 30 minutes three times per week and to follow a low fat diet.
No patients had taken diet medication for at least 3 months prior
to treatment. Average baseline BMI was 32.5 (range 26 48).
Average weight loss for the thirteen patients was 11.8%. For seven
patients who were on treatment the longest (range 5 9 months), the
average weight loss was 14.4%. Patients reported that they had little
or no appetite and that they actually felt better (Topiramate's
usefulness is also being investigated as a mood stabilizer) than
before therapy. Blood pressure, lipid, glucose, and Hgb A1C values
were also favorably affected by this treatment.
Table III sets forth patient data for the thirteen above-described
patients treated with the combination therapy of the present invention.
TABLE-US-00003 TABLE III Patient Data: Combination Therapy* % of
Patient Weight Baseline Current Weeks Current No. Loss BMI BMI on
Rx Status 1 7.7 38 35 10 on Rx 2 10.3 25 23 4 Finished 3 6.8 48
44 5 d/c early - dropped out 4 16.8 30 24 35 on taper 5 23.2 30
23 41 on taper 6 8 41 38 40 on Rx 7 9.7 28 25 33 on taper 8 14.4
30 26 44 on Rx 9 15.9 27 21 32 on taper 10 9 33 31 7 d/c early -
will restart 11 12.9 28 24 22 Finished 12 7 29 27 5 on Rx 13 12.1
34 31 6 on Rx *data for thirteen patients Average weight loss =
11.8% (13 patients) Average weight loss .gtoreq. 22 weeks on Rx
= 14.4% (7 patients) Average baseline BMI = 32.4
Table IV sets forth for the average blood pressure, blood glucose,
Hgb A1C and blood lipid value for the thirteen patients.
TABLE-US-00004 TABLE IV BP GLUCOSE HGBA1C CHOL TRIG mmHg mg/dL
%* mg/dL mg/dL Average Pre- 131.3/ 107 6.48 212 189 Treatment Value
85.9 Average On 122.6/ 102 5.05 210 172 Treatment Value 78.4 *Numbers
include 1 diabetic patient whose oral hypoglycemic was reduced by
50% while on the weight loss treatment.
One of the thirteen patients in the study also had severe sleep
apnea with the usual complications of daytime sleepiness and fatigue.
His symptoms have disappeared with the weight loss treatment.
Of the six patients (i.e., finished or on taper) who have completed
the combination therapy of the present invention, five of the six
achieved a body mass index (BMI) of 24 or better. The average pre-treatment
or baseline BMI for these six patients was 28. The final average
BMI was 23.3. The average weight loss was 17%.
EXAMPLE 3
The 56-year old male patient described previously (D. M.(B)) who
was initially taking phentermine alone and had topiramate added
to his regimen had a good effect from the combination. He once weighed
as much as 395 pounds. When Redux was still on the mark in the United
States, he was treated with a combination of diet, exercise, Redux
and phentermine. His lowest weight attained was 285 pounds. When
Redux was withdrawn from the market, he remained on phentermine
but gained weight back to 295 300 pounds. When topiramate was added
to his regimen, he managed to lose 25 pounds and is currently at
271 pounds, his lowest weight since he was in his 20s. He, along
with most of the patients treated so far, reported that the treatment
with topiramate and phentermine had fewer side effects and was more
effective than any previous weight loss treatment using medications
that he and others had tried. This 56-year old man exhibited lowered
blood pressure (approx. 15 mm Hg systolic and 10 mm Hg diastolic).
EXAMPLE 4
Extended results of the trial described in Examples 1 and 2.
The cumulative data from a total of seventeen patients treated
with the combination weight loss treatment of the present invention
are set forth in Table V.
TABLE-US-00005 TABLE V Patient Data: Combination Therapy* % BASE-
WEIGHT LINE CURRENT WEEKS CURRENT PATIENT LOSS BMI BMI ON Rx STATUS
1 7.7 38 35 33 on Rx 2 10.3 25 23 4 Finished 3 6.8 48 44 5 d/c early
- dropped out 4 16.8 30 24 58 on taper 5 23.2 30 23 64 on taper
6 17.5 41 33 63 on Rx 7 9.7 28 25 56 on taper 8 18.6 30 24 67 on
Rx 9 15.9 27 21 55 on taper d/c early- 10 9 33 31 7 will restart
11 12.9 28 24 22 Finished d/c early- 12 7 29 27 5 will restart d/c
early- 13 12.1 34 31 6 will restart 14 22.5 46 32 16 on Rx 15 10.1
50 45 12 on Rx 16 6.4 27 24 4 Finished 17 6.3 27 25 6 on Rx *data
for seventeen patients AVERAGE WEIGHT LOSS = 12.5% (17 patients)
AVERAGE WEIGHT LOSS .gtoreq. 22 WEEKS ON Rx = 15.3% (8 patients)
AVERAGE BASELINE BMI = 33.6
The present invention provides a novel combination therapy for
the treatment of obese or overweight patients that can result in
weight losses of greater than 5 10%, perhaps even as great as 15
20%. The therapy combines phentermine or a phentermine-like drug
with drug previously recognized for the treatment of epileptic seizures,
known as topiramate. The combination therapy results in greater
initial weight loss than other recognized therapies, potential greater
overall weight loss and can be continued for significant periods
of time with fewer and less serious side effects than other recognized
weight loss treatments. In particular, the combination therapy far
surpasses the modest anorexient effects of phentermine monotherapy
and can be continued for significant periods of time without the
loss of effectiveness experienced by patients being treated with
phentermine alone. Moreover, the combination therapy has been found
to ameliorate symptoms associated with Syndrome X and accordingly,
has potential use in the treatment of Syndrome X.
Equivalents
Those skilled in the art will recognize, or be able to ascertain
using no more than routine experimentation, many equivalents to
the specific embodiments of the invention described herein. Such
equivalents are intended to be encompassed by the following claims.
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