Therapeutic uses of melatonin

Details Therapeutic uses of melatonin Therapeutic uses of melatonin

2001-11-26

2003-05-20

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S226200, C514S225500, C514S225800, C514S437000, C514S252130, C514S327000, C514S211130, C514S233500, C514S220000, C514S258100

Reexamination Certificate

active

06566389

ABSTRACT:

This is a 371 of PCT UK 00/00296 filed May 24, 2000.
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a method and pharmaceutical formulation for treating tardive dyskinesia
Tardive dyskinesia (TD) is an involuntary movement disorder, which develops in a high percentage of patients who have been treated with neuroleptic drugs. A number of articles have appeared in the literature suggesting an inverse relationship between melatonin secretion and the incidence of TD symptoms. However, to the best of our knowledge, in only one instance has administration of exogenous melatonin been attempted in this connection, in which it was found that whereas treatment with haloperidol of pinealectomized rats resulted, in significantly more severe movement disorder than in unoperated control rats, subsequent administration of melatonin (4 mg, i.p.) was associated with a non-significant reduction of the severity of movements within one hour (Sabdyk, R., et al., Int. J. Neurosci., 1989, 48 (3-4): 303-8). The amount of melatonin used in this non-significant result was equivalent to more than 1000 mg for a 70 kg human, so that it is not surprising that subsequent attempts at TD therapy have avoided the use of exogenous melatonin. In U.S. Pat. No. 5,691,324 to Sandyk, R., for example, TD is one of a number of conditions, related to deficient serotonin transmission and impaired melatonin function, which is treated by administering to a patient a composition which increases serotonin neurotransmission, followed by applying a magnetic field to the brain. The entire contents of U.S. Pat. No. 5,691,324 are incorporated herein by reference.
It has now surprisingly been found, in relation to tardive dyskinesia, that exogenous melatonin produces a significant therapeutic effect in humans, at a dosage rate which is at least one order of magnitude lower (taking into account the average weight of humans in relation to laboratory animals) than that used in the report in Int. J. Neurosci., mentioned above.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical formulation which comprises, in addition to at least one carrier, diluent or adjuvant, at least one neuroleptic compound in an amount effective to exert a neuroteptic effect in a patient requiring such treatment, and melatonin in an amount effective to ameliorate or prevent symptoms of tardive dyskensia developing in the patient.
In another aspect, the invention provides use of melatonin in the manufacture of a medicament for the prevention or treatment of symptoms of tardive dyskensia in a patient. The medicament preferably takes the form of a pharmaceutical formulation, which includes at least one of the following additional components (a) and (b): (a) at least one carrier, diluent or adjuvant (b) at least one neuroleptic compound in an amount effective to exert a neuroleptic effect in a patient requiring such treatment. Further in accordance with the invention, a method for preventing or treating symptoms of tardive dyskensia in a patient, comprises administering melatonin to a patient exhibiting such symptoms or liable otherwise to develop such symptoms, in an amount effective to ameliorate or prevent symptoms of tardive dyskensia developing in the patient.
DETAILED DESCRIPTION OF THE INVENTION
The medicament/pharmaceutical formulation may be administered in any convenient form, such as one adapted for oral, rectal, parenteral or transdermal administration. It may be e.g. in unit dosage form. In a particular embodiment, the melatonin is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rate.
The amount of melatonin presently contemplated for use in preventing or treating tardive dyskinesia will be the amount found to be effective for this purpose, presently believed to be, in the case of oral administration, more than 0.5 mg and no more than 100 mg daily, eg. 0.5-50 mg, preferably 2.5-20 mg, and for parenteral or transdermal administration, between 0.1 and 50 mg. In accordance with the invention, an effective amount of melatonin may be formulated e.g. together with an effective dosage of a neuroleptic drug. The present medicament/pharmaceutical formulation may comprise also at least one melatonin receptor modifier and/or melatonin profile modifier.
Once the concept of the present invention for treatment or prevention of TD using melatonin is known according to the present invention, no inventive skill would be required to ascertain the range of effective amounts of melatonin for the present purpose, for various routes of administration. Where the pharmaceutical formulation includes at least one neuroleptic compound, this may for example be selected from such compounds containing at least one of the following ring systems, namely, piperidine, pirperazine, morpholine, 5,6,7,8-tetrahydroindole, phenothiazine and thioxanthene Exemplary neuroleptic compounds are chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, haloperidol, loxapine, molindone (c.f. Table 1), and clothiapine, clozapine, olanzapine, risperidone and zuclopenthixol acetate, and their pharmaceutically acceptable salts).
TABLE 1
Neuroleptic Compounds
Daily Dosage*
Modes of
Intramuscular
Compound
possible
usual
Administration
single dosage*
Chlorpromazine+
 25-2000
300-800 
oral; parenteral,
20-50
rectal, SR
Triflupromazine+
25-300
100-150 
oral, parenteral
20-60
Mesoridazine besylate
25-300
75-300
oral, parenteral
25
Piperacetazine
 5-200
20-160
oral
—
Thioridazine+
20-800
200-600 
oral
—
Acetophenazine maleate
20-600
60-120
oral
—
Fluphenazine+
0.5-30  
1-20
oral, parenteral
1.25-2.5 
Perphenazine
4-64
8-32
oral, parenteral, SR
 5-10
Trifluoperazine+
2-60
6-20
oral, parenteral
1-2
Chlorprothixene
30-600
50-400
oral, parenteral
25-50
Thiothixene+
6-60
6-30
oral, parenteral
2-4
Haloperidol
 1-100
6-20
oral, parenteral
2-5
Loxapine succinate
20-250
60-100
oral, parenteral
12.5-50  
Molindone+
12-225
50-100
oral
—
*mg + hydrochloride SR = sustained release (oral)


REFERENCES:
Database Medline ISSN 00207454 abstract. Sandyk, R., et al., “Magnetic fields in the treatment of Parkinson's disease,”International Journal of Neuroscience, 63(1-2):141-150, Mar. 1992.
Abstract of Jeste et al., “Conventional vs. Newer Antipsychotics in elderly Patients,”Am. J. Geriatr Psychiatry, 7:70-76, Feb. 1999.

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