USE OF MOXONIDINE FOR THE TREATMENT OF DEPRESSION

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.

Description: 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 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, maleic, 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. 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 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 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. 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.

Claims: 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.

Inventors: O'NEILL MICHAEL FRANCIS, O'NEILL, MICHAEL, FRANCIS
Applicants: LILLY CO ELI, NEILL MICHAEL FRANCIS O, ELI LILLY AND COMPANY LIMITED, O'NEILL, MICHAEL, FRANCIS
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D403