Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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This invention relates to methods for the treatment of cocaine
craving.
Cocaine is a highly addictive pyschostimulant that causes sensations
of euphoria and craving, resulting in physiological as well as psychological
damage. Although cocaine use leads to a multitude of physiological
complications, its primary target of action is the central nervous system.
Cocaine withdrawal following abstinence causes, among other symptoms,
an intense craving for the abused drug, which in turn frequently results in
the relapse into renewed drug use. Epidemiological studies point to a high
1 S incidence of multiple substance abuse among cocaine users, a finding that
has significant societal and medical repercussions.
To date, approved pharmacotherapies for cocaine abuse and
dependence have proven scarce despite the acute need for such therapies.
Summary of the Invention
In general, the invention features methods for treating stimulant
dependencies, such as cocaine craving, by administering a therapeutically-
effective amount of a dopamine agonist, for example, pramipexole.
In one aspect, the invention provides a method of treating a patient
(for example, a human) with a stimulant dependency by administering a
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therapeutically-effective amount of pramipexole to the patient. In preferred
embodiments of this aspect, the stimulant dependency is a stimulant craving
and the stimulant is cocaine.
In a related aspect, the invention provides a method of treating a
human diagnosed with cocaine craving by administering a therapeutically-
effective amount of pramipexole to the human.
In preferred embodiments of both of the above aspects of the
invention, the method further includes administering a therapeutically-
effective amount of an antidepressant or an anticonvulsant, for example,
lamotrigine.
By "treating" is meant the medical management of a patient with the
intent that a cure, amelioration, or prevention of a dependency or a relapse
or associated disease, pathological condition, or disorder will result. This
term includes active treatment, that is, treatment directed specifically
toward improvement of the dependency or associated cure of a disease,
pathological condition, or disorder, and also includes causal treatment, that
is, treatment directed toward removal of the cause of the dependency or
associated disease, pathological condition, or disorder. In addition, this
term includes palliative treatment, that is, treatment designed for the relief
of symptoms rather than the curing of the dependency, disease, pathological
condition, or disorder; preventive treatment, that is, treatment directed to
prevention of the dependency or associated disease, pathological condition,
or disorder; and supportive treatment, that is, treatment employed to
supplement another specific therapy directed toward the improvement of the
dependency or associated disease, pathological condition, or disorder. The
term "treating" also includes symptomatic treatment, that is, treatment
directed toward constitutional symptoms of the dependency or an associated
disease, pathological condition, or disorder.
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By "stimulant" is meant any substance that temporarily increases
functional activity, and preferably cardiac, respiratory, cerebral, nervous,
vascular, motor, or vasomotor functional activity. Preferred stimulants
include, without limitation, cocaine, amphetamines, methamphetamine, and
methylphenidate.
By "therapeutically-effective amount" is meant an amount of a
pramipexole compound sufficient to produce a healing, curative, or
ameliorative effect either in the treatment of a stimulant dependency or in
the symptoms of a stimulant dependency, for example, cocaine craving.
By "dependency" is meant any form of behavior that indicates an
altered or reduced ability to make decisions resulting, at least in part, from
the use of stimulants. Representative forms of dependency behavior may
take the form of antisocial, inappropriate, or illegal behavior and include
those behaviors directed at the desire, planning, acquiring, and use of
1 S stimulants. This term also includes the psychic craving for a drug that
may
or may not be accompanied by a physiological dependency, as well as a
state in which there is a compulsion to take a drug, either continuously or
periodically, in order to experience its psychic effects or to avoid the
discomfort of its absence. Forms of "dependency" include habituation, that
is, an emotional or psychological dependence on a compound to obtain
relief from tension and emotional discomfort, as well as physical or
physiological dependence, that is, use of a compound to prevent withdrawal
symptoms.
By "craving" is meant a behavior that reflects a consuming desire,
longing, or yearning for a stimulant. This term may refer to aspects of
behaviors that are components of a dependency.
The present invention provides a number of advantages.
Importantly, it provides one of the first therapeutics for the treatment of
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stimulant cravings (such as cocaine craving). In addition, the pramipexole
utilized herein is non-toxic, is pharmocokinetically understood, and is
known to be well tolerated by humans, as is evidenced by its approval for
the treatment of Parkinson's Disease.
Brief Description of the Drawing
Figure 1 is a schematic illustration of the molecular structure of
pramipexole, marketed as Mirapex in the United States.
The invention described herein features methods involving the
administration of pramipexole (or other dopamine-D3/D2 agonists) for the
treatment of stimulant dependency, and preferably for the treatment of
cocaine craving and its symptoms, as well as cocaine dependency and
associated self destructive behaviors.
Described below is an example of the successful use of pramipexole
for the treatment of cocaine craving and related symptoms. This example is
provided for the purpose of illustrating the invention, and should not be
construed as limiting.
Mr. A, a 34 year-old single, successful business man, was referred
for evaluation of possible bipolar disorder. Currently depressed, he had in
the previous year brought financial ruin on himself by a pattern of cocaine
freebasing and sexual and other extravagance that absorbed nearly one
million dollars.
Along with current major depression, persisting cocaine craving but
rare use, and a question of past primary or secondary (to substance abuse)
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mania, he manifested an extraordinary movement disorder with constant
restlessness and thrashing of his legs, leaving the inner aspects of his knees
and thighs bruised and discolored with hematomas in various stages of
evolution and resolution.
For the restless legs, he had consulted a neurologist who diagnosed
"pre-parkinsonism" presumed secondary to neurological damage from
cocaine. The disfiguring movements limited his ability to return to and
conduct business.
Previously, he had failed to respond to or tolerate most of the new
generation of antidepressants. Treatment was begun with lamotrigine up to
200 mg with modest improvement in mood. Given his severe restless legs
syndrome and persisting depression, pramipexole was added, titrated to 1.5
mg a day in divided doses.
In response to this treatment, his leg movements quieted
substantially, his mood brightened, and he reported that these were the first
days in a year that he awoke without craving cocaine, a benefit sustained for
one year on this drug, combined with 75 mg of lamotrigine. During the
subsequent year, Mr. A. reported one day of non-compliance when he was
out of town without his medication. That night, for the first time, he dreamt
about cocaine and the next day experienced a renewed craving on
awakening which resolved when treatment was restored.
Although he faces an array of financial and business challenges, his
mood following treatment is nearly euthymic, his leg movements at worst
resemble mild restlessness, and his cocaine craving remains abolished.
These dramatic results demonstrate that dopamine agonists, like
pramipexole, represent treatments for cocaine craving, and may be
particularly useful for patients with comorbid refractory depression.
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Pramipexole and Other Dopamine Agonists
The synthesis of pramipexole is described in U.S. Patent No.
4,886,812 and European Patent 186 087. Pramipexole is a non-ergot
derivative which may be used at a range of between about 1.5 mg to 6.0 mg
per day, and is preferably administered between about 1.5 mg and 4.5 mg
per day. Higher dosages may be used with the concomitant risk of potential
side effects.
Other formulations for treatment or prevention of stimulant
dependency or craving, such as cocaine craving, as described herein, may
take the form of a dopamine agonist compound that may be combined with
a pharmaceutically-acceptable diluent, Garner, stabilizer, or excipient.
Conventional pharmaceutical practice is employed to provide suitable
formulations or compositions to administer such compositions to patients.
Oral administration is preferred, but any other appropriate route of
administration may be employed, for example, parenteral, intravenous,
subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic,
intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal,
intranasal, or aerosol administration. Therapeutic formulations may be in
the form of liquid solutions or suspensions (as, for example, for intravenous
administration); for oral administration, formulations may be in the form of
liquids, tablets or capsules; and for intranasal formulations, in the form of
powders, nasal drops, or aerosols.
Methods well known in the art for making formulations are
described, for example, in "Remington: The Science and Practice of
Pharmacy" (19th ed.) ed. A.R. Gennaro AR., 1995, Mack Publishing
Company, Easton, PA. Formulations for parenteral administration may, for
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example, contain excipients, sterile water, saline, polyalkylene glycols such
as polyethylene glycol, oils of vegetable origin, or hydrogenated
napthalenes.
If desired, slow release or extended release delivery systems may be
utilized. Biocompatible, biodegradable lactide polymer, lactide/glycolide
copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used
to control the release of the compounds. Other potentially useful parenteral
delivery systems include ethylene-vinyl acetate copolymer particles,
osmotic pumps, implantable infusion systems, and liposomes. Formulations
for inhalation may contain excipients, for example, lactose, or may be
aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether,
glycocholate and deoxycholate, or may be oily solutions for administration
in the form of nasal drops, or as a gel.
In general, a dopamine agonist for use in the methods of the
invention is administered at a dosage appropriate to the effect to be
achieved and is typically administered in unit dosage form. As noted above,
the preferred route of administration for most indications is oral.
An effective quantity of a dopamine agonist-containing compound of
the invention is employed to treat the stimulant dependency or craving, for
example, cocaine craving as described herein. The exact dosage of the
compound may be dependent, for example, upon the age and weight of the
recipient, the route of administration, and the severity and nature of the
symptoms to be treated. In general, the dosage selected should be sufficient
to prevent, ameliorate, or treat the condition, or one or more symptoms
thereof, without producing significant toxic or undesirable side effects.
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Combination with Other Therapeutics
One particular source of pramipexole is Pharmacia & Upjohn, Inc.
which markets Mirapex (Pramipexole Dihydrochloride) tablets which have
the molecular structure shown in Figure 1. Examples of other dopamine
agonists include, but are not limited to, amantadine, bromocriptine,
cabergoline, lisuride, pergolide, ropinirole, quinpirole, or quinelorane.
Pramipexole, or any other dopamine agonist, may be administered as a
monotherapy, or in combination with other compounds, for the treatment of
multiple substance abuse or other physiological or psychological conditions.
In one particular example, the dopamine agonist (e.g. pramipexole)
may be administered in combination with an antidepressant, anticonvulsant,
antianxiety, antimanic, antipyschotic, antiobsessional, sedative-hypnotic, or
stimulant medication. Examples of these medications include, but are not
limited to, the antianxiety medications alprazolam, buspirone hydrochloride,
chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium,
desipramine hydrochloride, diazepam, halazepam, hydroxyzine
hydrochloride, hydroxyzine pamoate, lorazepam, meprobamate, oxazepam,
prazepam, prochlorperazine maleate, prochlorperazine, prochlorperazine
edisylate, and trimipramine maleate; the anticonvulsants amobarbital,
amobarbital sodium, carbamazepine, chlordiazepoxide, chlordiazepoxide
hydrochloride, clorazepate dipotassium, diazepam, divalproex sodium,
ethosuximide, ethotoin, gabapentin, lamotrigine, magnesium sulfate,
mephenytoin, mephobarbital, methsuximide, paramethadione, pentobarbital
sodium, phenacemide, phenobarbital, phenobarbital sodium, phensuximide,
phenytoin, phenytoin sodium, primidone, secobarbital sodium,
trimethadione, valproic acid, and clonazepam; the antidepressants
amitriptyline hydrochloride, amoxapine, bupropion hydrochloride,
clomipramine hydrochloride, desipramine hydrochloride, doxepin
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hydrochloride, fluoxetine, fluvoxamine, imipramine hydrochloride,
imipramine pamoate, isocarboxazid, lamotrigine, maprotoline
hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride,
phenelzine sulfate, protriptyline hydrochloride, sertraline hydrochloride,
tranylcypromine sulfate, trazodone hydrochloride, trimipramine maleate,
and venlafaxine hydrochloride; the antimanic medications lithium carbonate
and lithium citrate; the antiobsessional medications fluvoxamine, and
clomipramine hydrochloride; the antipsychotic medications acetophenazine
maleate, chlorpromazine hydrochloride, chlorprothixene, chlorprothixene
hydrochloride, clozapine, fluphenazine decanoate, fluphenazine enathrate,
fluphenazine hydrochloride, haloperidol decanoate, haloperidol, haloperidol
lactate, lithium carbonate, lithium citrate, loxapine hydrochloride, loxapine
succinate, mesoridazine besylate, molindone hydrochloride, perphenazine,
pimozide, prochlorperazine maleate, prochlorperazine, prochlorperazine
edisylate, promazine hydrochloride, risperidone, thioridazine, thioridazine
hydrochloride, thiothixene, thiothixene hydrochloride, and trifluoperzine
hydrochloride; the sedative-hypnotic medications amobarbital, amobarbital
sodium, aprobarbital, butabarbital, chloral hydrate, chlordiazepoxide,
chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam,
diphenhydramine, estazolam, ethchlorvynol, flurazepam hydrochloride,
glutethimide, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam,
methotrimeprazine hydrochloride, midazolam hydrochloride, non
prescription, oxazepam, pentobarbital sodium, phenobarbital, phenobarbital
sodium, quazepam, secobarbital sodium, temazepam, triazolam, and
zolpidem tartrate; and the stimulants dextroamphetamine sulfate,
methamphetamine hydrochloride, methylphenidate hydrochloride and,
pemoline.
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All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same extent as if
each independent publication or patent application was specifically and
individually indicated to be incorporated by reference.
While the invention has been described in connection with specific
embodiments thereof, it will be understood that it is capable of further
modifications and this application is intended to cover any variations, uses,
or adaptations of the invention following, in general, the principles of the
invention and including such departures from the present disclosure that
come within known or customary practice within the art to which the
invention pertains and may be applied to the essential features hereinbefore
set forth, and follows in the scope of the appended claims.
Other embodiments are within the claims.
What is claimed is:
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