MXPA98002001A - Antagonists of receiver 5-th3 for discine - Google Patents

Abstract

The invention provides the use of a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof for use in treating the disc

Description

ANTAGONISTS OF THE 5-HT3 RECEIVER FOR DISCINESIA Field of the Invention The invention relates to a new medical use for compounds that act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors.

Background of the Invention -HT3 receptor antagonists can be identified by methods well known in the art, for example, by their ability to inhibit 3 - (5-methyl-lH-imidazol-4-yl) -1- [1- [3H ] -methyl-lH-indol-3-yl] -1-propanone, which binds in the homogenates of the rat's entorinal cortex (following the general procedure described by G. Kilpatrick et al., Nature, 1987, 330. 746-748), and / or by its effect on the induced 5-HT reflex of Bezold-Jarisch (BJ) in the cat (following the general method described by A. Butler et al, Br. J. Pharmacol., 2 , 397-412 (1988)).

A variety of different 5-HT 3 receptor antagonists have been described, for example, those mentioned in the following patent applications (and hereinafter referred to as the compounds of Group A): REF: 27019 AU619731 AU626614 AU8658939 AU8660274 AU8716591 AU8767121 EP067770 EP158265 EP158532 EP189002 EP190920 EP191562 EP200444 EP202062 EP210840 EP212802 EP214772 EP219193 EP220011 EP221702 EP230718 EP234872 EP23588 EP237281 EP239321 EP242973 EP254584 EP255297 EP261964 EP266730 EP266899 EP276163 EP287196 EP289170 EP291172 EP294292 EP297651 EP302699 EP306148 EP306323 EP307145 EP307172 EP309423 EP311724 EP313393 EP315316 EP315390 EP317088 EP322016 EP323077 EP327307 EP327335 EP328200 EP329932 EP330788 EP330824 EP336759 EP337547 EP338650 EP339669 EP339950 EP339959 EP344015 EP345956 EP350130 EP351385 EP353983 EP356098 EP357417 EP358903 EP361317 EP361629 EP375045 EP376624 EP377238 EP378111 EP381422 EP385722 EP387431 EP392663 EP393766 EP403261 EP403882 EP405784 EP407137 EP410509 EP419397 EP420086 EP429984 EP430190 EP436245 EP454121 EP456519 EP457243 EP458636 EP469449 EP482939 EP483836 EP485962 EP490263 EP491664 EP498466 EP554794 GB2125398 GB2145416 GB2152049 GB2153821 GB2169292 GB2192885 GB2208385 GB2208862 GB2213816 GB2216516 GB2225574 GB2229182 GB2236528 GB2236751 GB2247886 US4290227 US4486441 US4657911 US4789673 US4816453 US4822881 US4826838 US4857517 US4859683 US4914207 US4920219 US4921982 US4924010 US4935511 US4963689 US4992461 US4997956 US5030646 US5063230 US5116984 US5137893 O8403281 O8801866 O8909217 O9006309 O9101316 WO9104738 O9107402 09112254 09116888 W09117161 O9205174 O9206689 O9209284 W09212149; all of which are incorporated here as a reference. The above applications also describe, in relation to the described 5-HT3 receptor antagonists, the appropriate methods of their preparation and the doses for their administration.

British Patent No. 2153821 B describes, inter alia, 1, 2, 3, 9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H -carbazole-4-one, now known as ondansetron, which can be represented by the formula (I) and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof.

Particular examples of the compounds within Group A include the compounds of Group B, particularly: endo-N- (8-methyl-azabicyclo [3.2.1] oct-3-yl) 2,3-dihydro-2-oxo-lH-benzimidazole-i-carboxamide (itasetron); endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) 2,3-dihydro-3-ethyl-2-oxo-lH-benzimidazole-l-carboxamide (BIMU 1); endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl indole-3-carboxylate (tropisetron); endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methylimidazol-3 -carboxamide (granisetron); trans-hexahydro-8- (3-indolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one (dolasetron) preferably in the form of its mesylate; endo-5-chloro-2,3-dihydro-2,2-dimethyl-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -7-benzofuran carboxamide (zatosetron); 4-amino-N- [1-azabicyclo (2.2.2) oct-3-yl] -5-chloro-2-methoxybenzamide (zacopride), more preferably (R) zacopride; 4- [N- (l-azabicyclo [2.2.2] octan-3- (5) -yl)] 2 -chloro-cis 5a- (s) -9a- (s) -5a, 6, 7, 8, 9,9a-hexahydrobenzofuran carboxamide (RG-12915); 4-amino-5-chloro-N- [2-pyrrolidylamethyl] -2,3-dihydrobenzo [b] furan-7-carboxamide (ADR-851); 4-amino-N- [1-azabicyclo [2.2.1] oct-3-yl] -5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide (ADR-882); (R) -5- [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole (Y 060); (±) -N- (1-azabicyclo [2.2.2] oct-3-yl) -6-chloro-4-methyl-3-OXO-3,4-dihydro-2H-l, -4-benzoxazine-8 -carboxamide (azasetron); endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydro-3, 3-dimethyl-indole-1-carboxamide (BRL 46470); and 2,3,4,5-tetrahydro-5-methyl-2- [(5-methyl-1H-imidazol-4-yl) methyl] -lH-pyrido [4, 3-b] indol-1-one ( alosetron), preferably as its hydrochloride; 6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2- [(5-methyl-1H-imidazol-4-yl) methyl] -lH-pyrido [4, 3-b] indole-1 -one (lurosetron), in particular in the form of mesylate dihydrate; 4H-pyrido (3.2, 1-jk) carbazole-11 (8H) -one, 5, 6, 9, 10-tetrahydro-10 ((2-methyl-lH-imidazol-1-yl) methyl-, ( R) - (cilansetron) benzamide, 4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- ((1-methyl-2-butynyl) ) oxy) -, monohydrochloride, (3 (S) -endo) (E-3620); irido (1, 2 -a) indole-6 (7H) -one, 8,9-dihydro-10-methyl-7- ((5-rt? ethyl-lH-imidazol-4-yl) methyl-, monohydrochloride, (+) - (FK-1052), benzamide, 4-amino-N-1-azabicicio (2.2.2.) Oct-3-il-5-chloro-2-cyclopropylmethoxy) -, (+/-) - ( pancopride), -and 8-methyl-8-azabicyclo (3.2.1) oct-3-yl ester of 7-methyl-1H-indole-3-carboxylic acid.

It will be appreciated by the skilled person that as a result of the use of different naming conventions of chemical products (eg, IUPAC, CA) a compound in group B can be referred to by a different chemical name within the corresponding patent application in Group A.

Other examples of 5-HT3 receptor antagonists, for use in accordance with the invention include the compounds of Group C, namely: lH-indole, 2,3-dihydro-l- ((4,5,6,7-tetrahydro-lH-benzimidazol-5-yl) carbonyl) -, monohydrochloride, (R) - (YM-114); ÍH-Benzimidazole, 1- (phenylmethyl) -2- (1-piperazinyl) - (lerisetron); endo-3,9-dimethyl-3,9-diazabicyclo (3.3.1) non-7-yl-lH-indazole-3-carboxamide dihydrochloride (N-3389); RS-25259; endo-8-methyl-8-azabicyclo (3.2.1) oct-3-yl-1-isobutyl-2-oxo-l, 2-dihydro-4-quinnuclidinecarboxylate (KF-18259); 2-methoxy-4-amino-5-chloro-N- hydrochloride (hexahydro-lH, 2,5-beta-methane-3 alpha, 6 alpha-cyclopenta (c) -pyrrol-4-alpha-4- (R) -yl benzamide (SC-52491); (3aS) - (2- ((S) -1-azabicyclo (2.2.2) oct-3-yl) -2, 3,3a, 4, 5, 6 hydrochloride hexahydro-lH-benz (de) isoquinolin-1-one; endo-1-Cyclohexyl-N- (8-methyl-8-azabicyclo (3.2.1) or an-3-yl) -4-oxo-1,4 -dihydroquinoline-3-carboxamide (mirisetron); 6-amino-5-chloro-1-isopropyl-2- (4-methyl-1-piperazinyl) benzimidazole dimaleate (KB-6933); hydrochloride of (+) - endo-4 - (propionyloxy) -6- (4-fluorophenyl) -1-azabicyclo (3.3.1) non-6-ene (GYKI-46903) and 3- (2- (4'-piperonylpiperazinyl) indole) carboxyaldehyde (VA-) 21B7).

The 5-HT3 receptor antagonists are known to be useful in the treatment of a variety of conditions involving 5-HT3 receptor mediation mechanisms, including in particular emesis.

Abnormal involuntary movements or dyskinesias include, inter alia, tremor, chorea (San Vito dance), myoclonus and tics. In addition to these categories of dyskinesia, there is a particular set of involuntary movements known as tardive dyskinesia or tardive dyskinesia induced by medications.

Tremor is an abnormal involuntary tremor or vibration. It can be characterized as a sinusoidal rhythmic movement of a part of the body caused by regular and rhythmic muscle contractions.

The chorea consists of a continuous flow of irregular, spasmodic and explosive movements that flit from one part of the body to another in a random sequence. Each contraction of the muscle is brief and often appears as a fragment of what could have been a normal movement, and is quite unpredictable in time or location.

Myoclonus consists of rapid muscle spasms such as shock, often repetitive and sometimes rhythmic.

Tics are similar to myoclonic spasms in appearance, but they are repetitive, stereotyped movements that can be imitated voluntarily and can be kept in check by an effort of will at the expense of mounting an internal tension.

Tardive dyskinesia is typically marked by repetitive involuntary movements of the facial, buccal, oral or cervical muscles.

Current medical therapies for dyskinesia, particularly where dyskinesia is the only feature of the disease (eg, benign (hereditary) essential and benign essential tremor (myoclonus)), include alcohol, benzodiazepines such as diazepam, lorazepam and clonazepam; and b-adrenergic receptor antagonists such as propranolol. Other dyskinesias are often a facet of another neurological disorder, and the treatment of dyskinesia follows that appropriate for the relevant neurological disorder. For example, the treatment of tremor caused by Parkinson's disease can be by dopaminergic agents such as levodapa and anitmuscarinic agents such as benzenexol.

However, many patients obtain little or no relief from such agents. In addition, the profiles of the side effects of these medications severely limit their clinical use. Thus, there is a real need to develop new medicines for the treatment of dyskinesia.

Description of the invention Surprisingly, it has now been found that 5-HT3 receptor antagonists are also useful in the treatment of dyskinesia.

According to one aspect of the invention, therefore, a 5-HT3 receptor antagonist, or a pharmaceutically acceptable derivative thereof, is provided for use in the treatment of dyskinesia.

By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt or solvate of a 5-HT 3 receptor antagonist, or any other compound, which upon administration to the patient, is capable of delivering (directly or indirectly) a 5-HT 3 receptor antagonist. HT3, or an active metabolite or residue thereof.

In a preferred aspect, the invention provides a Group A compound or a pharmaceutically acceptable derivative thereof, more preferably a group B compound or a pharmaceutically acceptable derivative thereof, for use in the treatment of dyskinesia.

In a further preferred aspect, the invention therefore provides ondansetron or a pharmaceutically acceptable derivative thereof, for use in the treatment of dyskinesia.

Suitable pharmaceutically acceptable salts of ondansetron include acid addition salts formed with organic or inorganic acids (for example, hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthates, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarbalylates, citrates, fumarates and maleates), and solvates (for example hydrates) thereof.

In a preferred embodiment of the present invention, ondansetron is used in the form of its hydrochloride, more preferably its hydrochloride dihydrate.

In another preferred embodiment of the present invention, ondansetron is employed in the form of its free base.

It will be appreciated by those skilled in the art that ondansetron contains a chiral center (shown by * in formula (I)) and that ondansetron therefore exists in the form of optical isomers (ie, enantiomers). The invention includes all isomers of ondansetron and their pharmaceutically acceptable derivatives, including all tautomeric and optical forms and mixtures thereof, including racemic mixtures.

Each type of dyskinesia can be caused by a variety of diseases. It may be accompanied by other neurological deficiencies, or abnormal involuntary movements may occur isolated and constitute the disease. The 5-HT3 receptor antagonists are particularly useful in the treatment of tremor, chorea, myoclonus, tics and tardive dyskinesia.

The tremor includes tremor at rest, postural tremor, and intention tremor. The resting tremor may be caused by, for example, Parkinson's disease, post-encephalic parkinsonism, drug-induced parkinsonism and other extrapyramidal diseases. Postural tremor can be caused by, for example, physiological tremor; exaggerated physiological, tremor attributable to for example, thyrotoxicosis, anxiety states, alcohol, medications (such as sympathomimetics, antidepressants and lithium) and heavy metal poisoning (such as mercury); hyperthyroidism, structural brain disorder attributable to, for example, severe brain injuries, Wilson's disease and neurosyphilis; and benign (hereditary) essential tremor. The intention tremor can be caused by, for example, cerebellum or brainstem disease attributable to for example, multiple sclerosis (MS), spinocerebellar degenerations, vascular disorder and tumor.

Chorea includes Sydenham's chorea, Huntington's disease, benign hereditary chorea, symptomatic chorea, drug-induced chorea, and hemiballism (hemicorea).

Myoclonus includes generalized myoclonus, such as progressive myoclonic encephalopathies, static myoclonic encephalopathies, myoclonic epilepsies, benign (hereditary) essential myoclonus, and focal myoclonus (segmental).

Tics include simple tics, complex multiple tics (eg, Gilles de la Tourette syndrome), and symptomatic tics.

Tardive dyskinesia may develop after the treatment of for example, psychotic disorders (such as schizophrenia and mania) with neuroleptics such as phenothiazines; and cognitive disorders such as dementia (eg, Parkinson's disease), with dopaminergic agents such as levodopa. Tardive dyskinesia may persist after withdrawal of treatment.

In a preferred aspect, the invention provides a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment of tremor.

In another preferred aspect, the invention provides a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment of benign (hereditary) essential tremor.

Benign (hereditary) essential tremor can occur at any age and is often inherited as an autosomal dominant characteristic. It is characterized by the postural tremor of the arms and head, although the jaw, tongue, legs and trunk may also be affected.

In a further preferred aspect, the invention provides a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment of intention tremor.

In another aspect, the invention provides a method of treating a mammal including man, who suffers from dyskinesia, which comprises the administration of an effective amount of the receptor antagonist or a pharmaceutically acceptable derivative thereof.

In another aspect, the invention provides the use of a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of dyskinesia.

Within the above aspects and preferred aspects of the invention, the use of a Group A 5-HT3 receptor antagonist, more preferably a Group B 5-HT3 receptor antagonist, and most preferably ondansetron is most preferred.

It is understood that reference to treatment includes treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.

Conveniently, a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof, can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus, a 5-HT3 receptor antagonist or a pharmaceutically acceptable derivative thereof may for example be formulated for oral, sublingual, buccal, parenteral, rectal or intranasal administration, or in a form suitable for administration by inhalation or insufflation (and either through the mouth or nose) or in a form appropriate for topical administration.

For oral administration, the pharmaceutical compositions can take the form of for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg, magnesium stearate, talc or silica); disintegrated (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be present as a dry product for constitution with water or other suitable vehicle before use. Said liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methyl cellulose or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters or ethyl alcohol); and conservatives (e.g., propyl or methyl p-hydroxybenzoates or sorbic acid).

For oral administration the compositions may take the form of tablets or lozenges formulated in a conventional manner.

A 5-HT3 receptor antagonist, or a pharmaceutically acceptable derivative thereof, can be formulated for parenteral administration by injection, conveniently an intravenous, intramuscular or subcutaneous injection for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, optionally with an added preservative.

Compositions for parenteral administration may take such forms as suspensions, solutions or emulsions in aqueous or oily vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the compositions may be in dry form such as a freeze-dried, crystalline or solid powder for constitution with an acceptable carrier, eg, sterile, pyrogen-free water or isotonic saline before use. They can be presented, for example, in sterile vials or vials.

A 5-HT3 receptor antagonist, or a pharmaceutically acceptable derivative thereof can also be formulated in rectal compositions such as suppositories or retention enemas.

Tablets for sublingual formulation can be formulated in a conventional manner.

For intranasal administration, or administration by inhalation or insufflation, a 5-HT 3 receptor antagonist, or a pharmaceutically acceptable derivative thereof can be formulated in a conventional manner.

For topical administration, the pharmaceutical compositions can be liquid, for example solutions, suspensions or emulsions presented in the form of creams or gels.

In addition to the formulations previously described, a 5-HT 3 receptor antagonist, or a pharmaceutically acceptable derivative thereof can also be formulated as a depot preparation. Such extended-action formulations can be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compositions can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or poorly soluble derivatives for example, a sparingly soluble salt.

Pharmaceutical formulations of ondansetron or a pharmaceutically acceptable derivative thereof can be prepared, for example, according to British Patent UK No. GB 2153821B, the publication of European Patent Application No. 276559 or the Publication of International Patent Applications Nos. 094/27599, 096/15785 or W096 / 15786.

It will be appreciated that the precise therapeutic dose of a 5-HT3 receptor antagonist, expressed in the form of its free base, will depend on the age and condition of the patient and the nature of the dyskinesia to be treated, and will ultimately be at the physician's discretion. to attend him However, in general, effective doses for the treatment of dyskinesia, in particular tremor, will be in the range of 0.001 to 500 mg, such as 0.01 to 100 mg, preferably 0.05 to 50 mg, for example 0.5 to 25 mg per unit dose, which could be administered in single or divided doses, for example, from 1 to 4 times a day.

In a preferred embodiment, the effective doses of ondansetron for tremor treatment will be in the range of 0.05 to 100 mg, such as 0.1 to 50 mg, preferably 0.5 to 25 mg, for example 2, 4, 8 or 16 mg of ondansetron per unit dose, which could be administered in single or divided doses, for example, from 1 to 4 times a day.

The use of ondansetron in the treatment of dyskinesia is supported in the following clinical data.

A double-blind, placebo-controlled, crossover study of intravenous ondansetron was performed in twenty patients with cerebellar tremor caused by MS, cerebellar degeneration, or drug toxicity.

Most had tremor based on cerebellar involvement from the MS, three had hereditary degenerative disorders involving the cerebellum and one had acquired lithium toxicity. The clinical information and the previous treatment of patients is detailed below in Table 1.

Patients were randomly assigned to receive intravenous ondansetron (8 mg or a placebo, consisting of normal saline). The medication was given by an intravenous bolus injection. The patients were given an alternate agent at a later interval.

The main output measure was the change in manual coordination tasks as assessed by spiral copying, copying words or line drawing, and the time to complete a nine-hole grade test. Only 12 patients had sufficient coordination to complete the nine-hole grade test.

Clinical response was measured at baseline and one hour after infusion.

Figures 1 (a), (b) and (c) represent an attempt to copy a spiral by the first patient mentioned in Table 1. Figure 1 (a) represents an attempt prior to treatment with ondansetron; Figure 1 (b) an attempt after receiving the placebo and Figure l (c) an attempt after receiving the ondansetron.

Resul ates The patient profile and clinical responses are shown in Table 1 Table 1 Keys: The improvement was measured on a simple ordinary scale: 0 = none, + = a little, ++ = moderate, +++ = too much improvement The spiral writing of this patient is shown in Figure 1 (a), 1 (b) and 1 (c); 2 The development of dystonia in this patient dissipated the enthusiasm to continue in the study; Cd = cerebellar degeneration A favorable clinical response was identified by a panel of three blind observers in 13 of 20 patients; the same observers identified a response in a patient treated with placebo. The difference was important in the complete study group (p = 0.009, Fisher's exact relation) and the MS subgroup of 16 patients, 13 of which had a response (p = 0.001).

At the completion of the scheduled task, the nine-hole grade test, patients receiving ondansetron were improved. The average time for completion of this task was 79 ± 13 (standard error) seconds in patients treated with ondansetron and 87 ± 12 seconds in patients treated with placebo (p = 0.04; Mann Whitney; an end test for even data ). An additional patient with cerebellar degeneration, also disabled to complete these tasks (Cd2, Table 1), was observed to have improved speech after treatment with ondansetron.

Patient identification of the treatment allocation was correct in 12/20 cases and this was based on efficacy. No one believed that the placebo was better (p = 0.014, Fisher's exact ratio).

The recruitment of patients was biased to select the most severely challenged patients: Most patients required walking assistance. After the study was completed, it was apparent that the best responses were seen in the least disabled patients. Among patients with MS, a better response was observed in patients with onset of more recent ataxia.

Ondansetron was well tolerated and the effect could be sustained in the long term. The withdrawal of the medication resulted in the tremor returning to pre-study levels. Nothing worked well for the tremor in these patients before the use of ondansetron.

The effect of intravenous ondansetron could be reproduced with oral ondansetron (8-16 mg).

It is noted that with respect to this date, the best method known to the applicant to carry out the invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property

Claims (10)

1. The use of a 5-HT3 receptor antagonist, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of dyskinesia.

2. The use according to claim 1, characterized in that the dyskinesia is tremor.

3. The use according to claim 2, characterized in that the tremor is a benign (hereditary) essential tremor.

4. The use according to claim 2, characterized in that the tremor is an intention tremor.

5. The use according to any of claims 1-4, characterized in that the 5-HT3 receptor antagonist is ondansetron or a pharmaceutically acceptable derivative.

6. The use according to claim 5, characterized in that ondansetron is in the form of its hydrochloride or dihydrate hydrochloride.

7. The use according to claim 5, characterized in that the ondansetron is in the form of its free base.

8. The use according to any of claims 1-4, characterized in that the 5-HT3 receptor antagonist is selected from granisetron, tropisetron, azasetron, dolasetron, alosetron or (R) zacopride.

9. A method for the treatment of a mammal, including man, suffering from dyskinesia, characterized in that it comprises the administration of an effective amount of a 5-HT 3 receptor antagonist, or a pharmaceutically acceptable derivative thereof.

10. A 5-HT3 receptor antagonist, or a pharmaceutically acceptable derivative thereof for use in the treatment of dyskinesia.