USE OF MOXONIDINE FOR THE TREATMENT OF DEPRESSION

UTILISATION DE MOXONIDINE POUR LE TRAITEMENT DE LA DEPRESSION

English Abstract

The use of moxonidine, or a pharmaceutically-acceptable acid addition salt
thereof, in the preparation of a medicament for treating a disorder of the
central nervous system.

French Abstract

L'invention se rapporte à l'utilisation de moxonidine, ou d'un sel d'addition acide pharmaceutiquement acceptable de moxonidine, dans la préparation d'un médicament destiné à traiter un trouble du système nerveux central.

Claims

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CLAIMS
1. The use of moxonidine, or a pharmaceutically-acceptable
acid addition salt thereof, in the
preparation of a medicament for treating a disorder
of the central nervous system.
2. The use, according to Claim 1, in which the
medicament is in unit dosage form and containing
0.01 to 2.0 mg of moxonidine.
3. A method of treating an animal, including a human,
suffering from or susceptible to depression, which
comprises administering an effective amount of
moxonidine, or a pharmaceutically-acceptable acid
addition salt thereof.

Description

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USE OF MOXONIDINE FOR .THE TREATMENT OF DEPRESSION
This invention relates to the use of moxonidine in the
treatment of depression.
Moxonidine is a well known compound described in, for
example, U.S. Patent 4,323,570, for its properties as an
anti-hypertensive. The compound has the chemical
formula 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-
yl)aminopyrimidine.
It has now been found that moxonidine is indicated for
use in the treatment of depression.
Thus the invention comprises the use of moxonidine, or a
pharmaceutically-acceptable acid addition salt thereof,
in the treatment of depression. More particularly, the
invention comprises the use of moxonidine, or a
pharmaceutically-acceptable acid addition salt thereof,
in the preparation of a medicament for treating
depression.
It has been found in test models that moxonidine
significantly modulates the alpha 2-adrenoceptors, and
has adrenoceptor agonist properties. This is
demonstrated in the well-known forced swim test as

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described, for example, by Cervo et al. (1992),
Neuropharmacology, 31, 331-335.
As mentioned above, moxonidine is the compound 4-chloro-
6-methoxy-2-methyl-5-(2-imidazolin-2-yl)aminopyrimidine,
and can also be utilised in pharmaceutically-acceptable
acid addition salt form. Suitable acid addition salts
are the pharmaceutically acceptable, non-toxic addition
salts with suitable acids, such as those with inorganic
acids, for example hydrochloric, hydrobromic, nitric,
sulphuric or phosphoric acids, or with organic acids,
such as organic carboxylic acids, for example,
glycollic, malefic, hydroxymaleic, fumaric, malic,
tartaric, citric, salicyclic, o-acetoxybenzoic, or
organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-
sulphonic, or naphthalene-2-sulphonic acid.
The treatment of depression includes the treatment of a
variety of related mood disorders as, for example, the
following disorders defined in the Diagnostic and
Statistical Manual of Mental Disorders, American
Psychiatric Association, Fourth Edition (DSM-IV), major
depressive episode, major depressive disorder, dysthymic
disorder, depressive disorder not otherwise specified,
bipolar disorder and cyclothymic disorder, and also
depression with anxiety.

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The identification of patients in need of treatment for
depression is a routine matter and a clinician skilled
in the art can readily determine, by the use of clinical
tests, physical examination and medical/family history,
if a patient is in need of treatment.
For the purpose of the invention, moxonidine may be
administered by various routes, for example by the oral
or rectal route, topically or parenterally, for example
by injection or infusion, being usually employed in the
form of a pharmaceutical composition. Such compositions
are prepared in a manner well known in the
pharmaceutical art. In making the composition the
active ingredient will usually be mixed with a carrier,
or diluted by a carrier, and/or enclosed within a
carrier which may, for example, be in the form of a
capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, semi-
solid, or liquid material which acts as a vehicle,
excipient or medium for the active ingredient. Thus,
the composition may be in the form of tablets, lozenges,
sachets, cachets, elixirs, suspensions, aerosols (as a
solid or in a liquid medium), ointments containing for
example up to 10~ by weight of the active compound, soft
and hard gelatin capsules, suppositories, injection
solutions, suspensions, sterile packaged powders and as

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a topical patch. The preferred formulations are for
oral dosage and are especially in table or capsule form.
Some examples of suitable carriers are lactose,
dextrose, sucrose, sorbitol, mannitol, starches,
ethylcellulose, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, syrup, methyl cellulose,
methyl- and propyl- hydroxybenzoate, talc magnesium
stearate and mineral oil. The compositions of the
injection may, as is well known in the art, be
formulated so as to provide quick, sustained or delayed
release of the active ingredient after administration to
the patient.
Where the composition is formulated in unit dosage form,
it is preferred that each unit dosage form contains from
0.01 mg to 2.0 mg, for example, from 0.05 mg to 1.0 mg,
such quantities referring to the active ingredient as
free base. The term 'unit dosage form' refers to
physically discrete units suitable as unit dosages for
human subjects and animals, each unit containing a
predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association
with the required pharmaceutical carrier.
The active compound is effective over a wide dosage
range and, for example, dosages per day will normally

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fall within the range of from 0.01 to 2.0 mg, more
usually in the range of from 0.1 to 1.0 mg. Usually one
dose a day, preferably in the morning, is sufficient.
However, it will be understood that the amount
administered will be determined by the physician in the
light of the relevant circumstances including the
condition to be treated and the chosen route of
administration, and therefore the above dosage ranges
are not intended to limit the scope of the invention in
any way.
The following Example illustrates the activity of
moxonidine in a mouse model.
EXAMPLE
Female mice were kept in the holding facility for
two weeks before experimental use. Immobility was
measured in 11 beakers filled with 600 ml of water at
23° C. (10 cm depth). Time spent immobile was measured
with a stopwatch.
Animals were removed from their home cages and placed in
individual holding cages (10 x 15 x 13 cm) for at least
60 minutes prior to the beginning of the experiment.

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Animals were dosed with moxonidine and returned to the
holding cases for 30 minutes. When the pretreatment
time had elapsed, the animals were placed in the beakers
and the time spent immobile was recorded.
The animals were placed in the beakers for 5 minutes.
Immobility was not measured for the first minute as all
animals swam at this period almost irrespective of
treatment. A minimum of six animals was tested for each
group.
Moxonidine significantly reduced the time spent immobile
in the forced swim test. Moxonidine was active at all
doses tested (2.5-10 mg/kg). The effect observed was
equivalent to 10 mg/kg of imipramine included as a
positive control.