Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF ANXIETY DISORDERS
The invention belongs to the fields of
pharmaceutical chemistry and central nervous system
medicine, and provides a method of treatment for anxiety
disorders.
Anxiety disorders represent the most prevalent type
of psychiatric disorders in the United States. Anxiety
disorders include panic disorder, obsessive-compulsive
disorder, post-traumatic stress disorder, specific phobia,
social phobia, and generalized anxiety disorder. All are
characterized by uneasiness, a sense of fearfulness, and
distress for no apparent reason. These disorders, if left
untreated, reduce the quality of life and productivity of
patients suffering from them. In the United States alone,
more than 23 million people suffer from anxiety disorders.
The cost to society from these disorders is staggering,
estimated in 1990 at X46.6 billion in the United States alone
in direct and indirect costs.
Currently available methods for treating anxiety
disorders include behavioral therapy, cognitive therapy, and
relaxation techniques. These methods typically take a
considerable amount of time to achieve their desired effect.
To increase the rate of recovery, these methods may be used in
combination with one of a number of medications. Currently
used medications include benzodiazepines, beta-blockers,
buspirone, monoamine oxidase inhibitors, serotonin reuptake
inhibitors, and tricyclic antidepressants, all. of which have
liabilities associated with their use. The benzodiazepines
are potentially habit forming and can cause drowsiness; beta-
blockers cannot be used if the patient has certain pre-
existing medical conditions such as asthma, congestive heart
failure, diabetes, vascular disease, hyperthyroidism, or
angina pectoris; buspirone has a long induction period before
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its beneficial effects are realized; patients taking monoamine
oxidase inhibitors are under strict dietary constraints and
there is the potential for drug interactions, low blood
pressure, moderate weight gain, reduced sexual response, and
insomnia; the serotonin reuptake inhibitors can cause nausea,
nervousness, and delayed ejaculation; and the tricyclic
antidepressants can cause dry mouth, constipation, blurry
vision, difficulty in urination, dizziness, low blood
pressure, and moderate weight gain. New methods for treating
anxiety disorders are needed which avoid or diminish the
liabilities of current therapies.
The present invention provides a method for the
treatment of anxiety disorders which comprises administering
to a mammal in need of such treatment an effective amount of
a selective norepinephrine reuptake inhibitor.
The present invention also provides a method for
the prevention of anxiety disorders which comprises
administering to a mammal susceptible to said disorders an
effective amount of a selective norepinephrine reuptake
inhibitor.
The present invention provides a method for the
treatment or prevention of anxiety disorders that relies on
a novel mechanism of action. This method comprises treating
a mammal suffering from or susceptible to anxiety disorders
with a compound that is a selective norepinephrine reuptake
inhibitor. This mechanism is operative in mammals and the
preferred mammal is a human.
A further embodiment of this invention comprises
the administration of a composition that exhibits selective
norepinephrine reuptake inhibitor activity. The composition
may be composed of one or more agents that, individually or
together, are selective inhibitors of norepinephrine
reuptake.
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The present invention also provides the use of a
selective norepinephrine reuptake inhibitor for the
preparation of a medicament useful for the treatment or
prevention of anxiety disorders.
The present invention further provides the use of
a selective norepinephrine reuptake inhibitor for the
preparation of a medicament useful for the treatment of
anxiety disorders with cpmorbid Attention-deficit
Hyperactivity Disorder.
Many compounds, including those discussed at
length below, are selective norepinephrine reuptake
inhibitors, and no doubt many more will be identified in the
future. In the practice of the present invention, it is
intended to include reuptake inhibitors which show 50%
effective concentrations of about 1000 nM or less, in the
protocol described by Wong et al., Drug Development
Research, 6, 397 (1985). The norepinephrine reuptake
inhibitors useful for the method of the present invention
are characterized in being selective for the inhibition of
neurotransmitter reuptake relative to their ability to act
as direct agonists or antagonists at other receptors.
Norepinephrine reuptake inhibitors useful for the method of
the present invention include, but are not limited to:
Tomoxetine, (R)-(-)-N-methyl-3-(2-methylphenoxy)-
3-phenylpropylamine, is usually administered as the
hydrochloride salt. Tomoxetine was first disclosed in U.S.
Patent #4,314,081. The word "tomoxetine" will be used here
to refer to any acid addition salt or the free.base of the
molecule. See, for example, Gehlert, et al., Neuroscience
Letters, 157, 203-206 (1993), for a discussion of
tomoxetine's activity as a norepinephrine~reuptake
inhibitor;
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The compounds of formula I:
\ X
O
\ NAY
/ , H
I
wherein X is C1-C4 alkylthio, and Y is C1-C~ alkyl or a
pharmaceutically acceptable salt thereof. The compounds of
formula I were described in U.S. Patent 5,281,624, of
Gehlert, Robertson, and Wong, and in Gehlert, et al., Life
Sciences, 55'(22), 1915-1920, (1995). The compounds are
there taught to be inhibitors of norepinephrine reuptake in
the brain. It is also explained that the compounds exist as
stereoisomers, and that they accordingly include not only
the racemates, but also the isolated individual isomers as
well as mixtures of the individual isomers. For example,
the compounds of formula I include the following exemplary
species:
. N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propyl-
amine benzoate;
(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)-
propylamine hydrochloride;
(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propyl-
amine;
N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propyl-
amine malonate;
(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)-
propylamine naphthalene-2-sulfonate;
(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenyl-
propylamine; and
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Reboxetine (EdronaxTM) , 2- [cc- (2-ethoxy)phenoxy-
benzyl]morpholine, is usually administered as the racemate.
It was first taught by U.S. Patent 4,229,449, which
describes its utility for the treatment of depression.
Reboxetine is a selective norepinephrine reuptake inhibitor.
The term "reboxetine" will be used here to refer to any acid
addition salt or the free base of the molecule existing as
the racemate or either enantiomer.
While all compounds exhibiting norepinephrine
~ reuptake inhibition are useful for the methods of the
present invention, certain are preferred. It is preferred
that the norepinephrine reuptake inhibitor is selective for
norepinephrine over other neurotransmitters. It is
especially preferred that the norepinephrine reuptake
inhibitor be selected from tomoxetine, reboxetine, or (R)-N-
methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine. The use
of tomoxetine hydrochloride for the methods of the present
invention is the most preferred embodiment of the present
invention.
It will be understood by the skilled reader that
most or all of the compounds used in the present invention
are capable of forming salts, and that the salt forms of
pharmaceuticals are commonly used, often because they are
more readily crystallized and purified than are the free
bases. In all cases, the use of the pharmaceuticals
described above as salts is contemplated in the description
herein, and often is preferred, and the pharmaceutically
acceptable salts of all of the compounds are included in the
names of them.
Many of the compounds used in this invention are
amines, and accordingly react with any of a number of
inorganic and organic acids to form pharmaceutically
acceptable acid addition salts. Since some of the free
amines of the compounds of this invention are typically oils
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at room temperature, it is preferable to convert the free
amines to their pharmaceutically acceptable acid addition
salts for ease of handling and administration, since the
latter are routinely solid at room temperature. Acids
commonly employed to form such salts are inorganic acids
such as hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulfuric acid, phosphoric acid, and the like, and
organic acids, such as p-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic
acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate,
isobutyrate, caproate, heptanoate, propiolate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,
chlorobenzoate, me.thylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, b-hydroxybutyrate,
glycollate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate
and the like. Preferred pharmaceutically acceptable salts
are those formed with hydrochloric acid.
The dosages of the drugs used in the present
invention must, in the final analysis, be set by the
physician in charge of the case using knowledge of the
drugs, the properties of the drugs in combination as
. determined in clinical trials, and the characteristics of
the patient including diseases other than that for which the
physician is treating the patient. General outlines of the
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dosages, and some preferred dosages, can and will be
provided here.
Tomoxetine: from about 5 mg/day to about 200
mg/day; preferably in the range from about 60 to about 150
mg/day; more preferably from about 60 to about 130 mg/day;
and still more preferably from about 60 to about 120 mg/day;
Compounds of formula I: from about 0.01 mg/kg to
about 20 mg/kg; preferred daily doses will be from about
0.05 mg/kg to 10 mg/kg; ideally from about 0.1 mg/kg to
about 5 mg/kg;
Reboxetine: from about 1 to about 30 mg, once to
four times/day; preferred, from about 5 to about 30 mg
once/day.
All of the compounds concerned are orally available
and are normally administered orally, and so oral
administration is preferred. However, oral administration is
not the only route or even the only preferred route. For
example, transdermal administration may be very desirable for
patients who are forgetful or petulant about taking oral
medicine. Compounds of Formula I may also be administered by
the percutaneous, intravenous, intramuscular, intranasal or
intrarectal route, in particular circumstances. The route of
administration may be varied in any way, limited by the
physical properties of the drugs, the convenience of the
patient and the caregiver, and other relevant circumstances
(Remington's Pharmaceutical Sciences, 18th Edition, Mack
Publishing Co. (1990)).
The pharmaceutical compositions are prepared in a
manner well known in the pharmaceutical art. The carrier or
excipient may be a solid, semi-solid, or liquid material that
can serve as a vehicle or medium for the active ingredient.
Suitable carriers or excipients are well known in the art. The
pharmaceutical composition may be adapted for oral,
inhalation, parenteral, or topical use and may be administered
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to the patient in the form of tablets, capsules, aerosols,
inhalants, suppositories, solutions, suspensions, or the like.
The compounds of the present invention may be
administered orally, for example, with an inert diluent or
capsules or compressed into tablets. For the purpose of oral
therapeutic administration, the compounds may be incorporated
with excipients and used: in the form of tablets, troches,
capsules, elixirs, suspensions, syrups, wafers, chewing gums
and the like. These preparations should contain at least 40 of
the compound of the present invention, the active ingredient,
but may be varied depending upon the particular form and may
conveniently be between 4% to about 70o of the weight of the
unit. The amount of the compound,present in compositions is
such that a suitable dosage will be obtained. Preferred
compositions and preparations according to the present
invention may be determined by a person skilled in the art.
The tablets, pills, capsules, troches, and the like
may also contain one or more of the following adjuvants:
binders such as microcrystalline cellulose, gum tragacanth or
gelatin; excipients such as starch or lactose, disintegrating
agents such as alginic acid, Primogel, corn starch and the
like; lubricants such as magnesium stearate or Sterotex;
glidants such as colloidal silicon dioxide; and sweetening
agents such as sucrose or saccharin may be added or a
flavoring agent such as peppermint, methyl salicylate or
orange flavoring. V~Ihen the dosage unit form is a capsule, it
may contain, in addition to materials of the above type, a
liquid carrier such as polyethylene glycol or a fatty oil.
Other dosage unit forms may contain other various materials
that modify the physical form of the dosage unit, for example,
as coatings. Thus, tablets or pills may be coated with sugar,
shellac, or other coating agents. A syrup may contain, in
addition to the present compounds, sucrose as a sweetening
agent and certain preservatives, dyes and colorings and
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flavors. Materials used in preparing these various
compositions should be pharmaceutically pure and non-toxic in
the amounts used.
A formulation useful for the administration of R-(-
)-N-methyl 3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane
hydrochloride (tomoxetine) comprises a dry mixture of R-(-)-N-
methyl 3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane
hydrochloride with a diluent and lubricant. A starch, such as
pregelatinized corn starch, is a suitable diluent and a
silicone oil, such as dimethicone, a suitable lubricant for
use in hard gelatin capsules. Suitable formulations are
prepared containing about 0.4 to 26% R-(-)-N-methyl 3-((2-
methylphen-yl)oxy)-3-phenyl-1-aminopropane hydrochloride,
about 73 to 99o starch, and about 0.2 to 1.0% silicone oil.
25 The following tables illustrate particularly preferred
formulations:
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Ingredient (%) 2.5 5 mg 10 18 20 25 40 60
mg mg mg mg mg mg mg
R-(-)-N-methyl
3-
((2-meth-
ylphenyl)oxy)-3- -
phenyl-1- 1.24 2.48 4.97 8.94 9.93 12.4 19.8 22.1
aminopropane 2 7 2
hydrochloride
Dimethicone 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Pregelatinized 98.2 97.0 94.5 90.5 89.5 87.0 79.6 77.3
Starch 6 2 3 6 7 8 3 8
Ingredient 2.5 5 mg 10 18 20 25 40 60
(mg/capsule) mg mg mg mg mg mg mg
R-(-)-N-methyl
3-
((2-meth-
ylphenyl)oxy)-3-
phenyl-1- 2.86 5.71 11.4 20.5 22.8 28.5 45.7 68.5
aminopropane 3 7 5 7 1 6
hydrochloride
Dimethicone 1.15 1.15 1.15 1.15 1.15 1.15 1.15 1.55
Pregelatinized 225. 223. 217. 208. 206. 200. 183. 239.
Starch 99 14 42 28 00 28 14 89
Capsule Fill Weight230 230 230 230 230 230 230 310
Capsule Size 3 3 3 3 3 3 3 2
For the purpose of parenteral therapeutic
administration, the compounds of the present invention may be
incorporated into a solution or suspension. These preparations
typically contain at least 0.10 of a compound of the
invention, but may be varied to be between 0.1 and about 900
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of the weight thereof. The amount of the compound of formula I
present in such compositions is such that a suitable dosage
will be obtained. The solutions or suspensions may also
include one or more of the following adjuvants: sterile
diluents such as water for injection, saline solution, fixed
oils, polyethylene glycols, glycerine,~propylene glycol or
other synthetic solvents; antibacterial agents such as benzyl
alcohol or methyl paraben; antioxidants such as ascorbic acid
or sodium bisulfate; chelating agents such as ethylene
diaminetetraacetic acid; buffers such as acetates, citrates or
phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose
vials made of glass or plastic. Preferred compositions and
preparations are able to be determined by one skilled in the
art.
The compounds of the present invention may also be
administered topically, and when done so the carrier may
suitably comprise a solution, ointment, or gel base. The
base, for example, may comprise one or more of the
following: petrolatum, lanolin., polyethylene glycols, bees
wax, mineral oil, diluents such as water and alcohol, and
emulsifiers, and stabilizers. Topical formulations may
contain a concentration of the formula I, or its
pharmaceutical salt, from about 0.1 to about 10% w/v (weight
per unit volume).
Inhibition or norepinephrine reuptake
The ability of compounds to inhibit the reuptake
of norepinephrine may be measured by the general procedure
of Wong, et al., supra:
Male Sprague-Dawley rats weighing 150-250 gm are
decapitated and brains are immediately removed. Cerebral
cortices are homogenized in 9 volumes of a medium containing
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0.32 M sucrose and 10 mM glucose. Crude synaptosomal
preparations are isolated after differential centrifugation
at 1000 x g for 10 minutes and 17,000 x g for 28 minutes.
The final pellets are suspended in the same medium and kept
in ice until use within the same day.
Synaptosomal uptake of 3H-norepinephrine is
determined as follows. Cortical synaptosomes (equvalent to
1 mg of protein) are incubated at 37°C for 5 minutes in 1 mL
Krebs-bicarbonate medium containing also 10 mM glucose, 0.1
mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 nM
3H-norepinephrine. The reaction mixture is immediately
diluted with 2 mL of ice-chilled Krebs-bicarbonate buffer
and filtered under vacuum with a cell harvester (Brandel,
Gaithersburg, MD). Filters are rinsed twice with
approximately 5 mL of ice-chilled 0.9o saline and the uptake
of 3H-norepinephrine assessed by.liquid scintillation
counting. Accumulation of 3H-norepinephrine at 4°C is
considered to be background and is subtracted from all
measurements. The concentration of the test compound
required to inhibit 50% of the 3H-norepinephrine
accumulation (ICSO values) are determined by linear
regression analysis.
Anxiety disorders are a heterogeneous class of
diseases. The most common types of anxiety disorders are
described in the following paragraphs.
Panic Disorder
Panic disorder is characterized by the sudden onset
of intense apprehension, fearfulness, or terror. An attack of
panic disorder is unprovoked and may last for a discrete
period of time. During these attacks, it is not uncommon for
the victim to experience shortness of breath, palpitations,
chest pain or discomfort, choking or a smothering sensation,
and fear of losing control.
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Generalized Anxiety Disorder
Generalized anxiety disorder is characterized by at
least 6 months of persistent and excessive anxiety and worry.
It is associated with physical anxiety symptoms such as muscle
aches, fatigue, difficulty sleeping, sweating, dizziness, and
nausea.
Specific Phobia
Specific phobia is a persistent, intense, and
irrational fear associated with a particular object or
situation that leads to avoidance of that object or situation.
Social Phobia
Social phobia is a persistent fear of one or more
situations in which the person is exposed to possible scutiny
by others and the person fears that he or she may do something
or act in a way that will be humiliating. Social phobias can
include extreme shyness.
Obsessive-Compulsive Disorder
Obsessive-compulsive disorder is characterized by
obsessions that cause anxiety and compulsions which serve to
neutralize the anxiety. Common obsessions include fear of
dirt, germs, or contamination or fear of harming someone;
common compulsions are excessive cleaning, counting, double-
checking, and hoarding.
Post-Traumatic Stress Disorder
Post-traumatic stress disorder is characterized by
the re-experiencing of an extremely traumatic event
accompanied by symptoms of increased arousal and by avoidance
of the stimuli associated with the trauma. Individuals can
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become so preoccupied with the experience that they are unable
to lead a normal life.
The diseases described above as well as other
anxiety disorders contemplated by the method of the present
invention are classified in the Diagnostic and Statistical
Manual of Mental Disorders, 4th Version, published by the
American Psychiatric Association (DSM). In such cases, the
DSM code numbers are supplied below for the convenience of the
reader.
Panic Disorder Without Agoraphobia DSM 300.01
Panic Disorder With Agoraphobia DSM 300.21
Agoraphobia Without History of Panic
Disorder DSM 300.22
Specific Phobia DSM 300.29
Social Phobia DSM 300.23
Obsessive-Compulsive Disorder DSM 300.3
Post-Traumatic Stress Disorder DSM 309.81
Acute Stress~Disorder DSM 308.3
Generalized Anxiety Disorder DSM 300.02
Anxiety Disorder Due to a General Medical
Condition DSM 293.84
Substance Induced Anxiety Disorder
Alcohol DSM 291.89
Amphetamine (or Amphetamine-Like
Substance) DSM 292.89
Caffeine DSM 292.89
Cannabis DSM 292.89
Cocaine DSM 292.89
Hallucinogen DSM 292.89
Inhalant DSM 292.89
Phencyclidine (or Phencyclidine-Like
Substance) DSM 292.89
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Sedative, Hypnotic, or Anxiolytic DSM 292.89
Other [Unknown] Substance DSM 292.89
Anxiety Disorder Not Otherwise
Specified DSM 300.00
Separation Anxiety Disorder DSM 309.22
Sexual Adversion Disorder DSM 302.79
Any of these disorders, whether presenting alone or
in combination in an individual mammal, may be treated or
prevented by the method of the present invention. The
treatment of Obsessive-Compulsive Disorder is a preferred
embodiment of the present invention.
Patients suffering from anxiety disorders also
commonly suffer concomitantly from Attention-deficit
Hyperactivity Disorder. The patient will receive benefit
from the use of norepinephrine reuptake inhibitors in the
amelioration of the symptoms of anxiety disorders regardless
of whether comorbid conditions are present. Furthermore, a
patient suffering from anxiety disorders and Attention-
deficit Hyperactivity Disorder will receive benefit in the
amelioration of symptoms of both conditions through the
method of the present invention. A further embodiment of
the present invention, therefore, is a method of treating
anxiety disorders with comorbid Attention-deficit
Hyperactivity Disorder comprising administering to a patient
in need of treatment of both anxiety disorders and
Attention-deficit Hyperactivity Disorder an effective amount
of a selective norepinephrine reuptake inhibitor.
The method of the present invention is effective
in the treatment of patients who are children, adolescents
or adults, and there is no significant difference in the
symptoms or the details of the manner of treatment among
patients of different ages. In general terms, however, for
purposes of the present invention, a child is considered to
be a patient below the age of puberty, an adolescent is
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considered to be a patient from the age of puberty up to
about 18 years of age, and an adult is considered to be a
patient of 18 years or older.
EXAMPLE 2
A female subject presented with chronic fingernail
biting. The subject was treated with 60 mg of tomoxetine
hydrochloride, twice daily for 13 consecutive days. At the
time of final assessment the subject demonstrated
significant improvement, with healthy appearing fingernails
except for one finger. The patient's chronic fingernail
biting behavior resumed upon termination of treatment with
tomoxetine hydrochloride.
