PHARMACEUTICAL COMPOSITIONS

Abstract

This invention relates to the use of low doses of (+)--dihydrotetrabenazine for the treatment of movement disorders, such as Tourette's syndrome.

Claims

1. A method of treating a movement disorder in a subject in need thereof, which treatment comprises the steps of: (a) administering to the subject an initial daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof, wherein the initial daily dosage is an amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)--dihydrotetrabenazine free base; (b) carrying out a clinical evaluation of the subject for efficacy and side effects arising from the treatment; (c) where the clinical evaluation (b) has established that an increased daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof is desirable, administering an increased daily dosage which is greater than the initial daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)--dihydrotetrabenazine free base; or, where the clinical evaluation has established that an increased daily dosage is not desirable, either maintaining the initial daily dosage, reducing the dosage, or discontinuing the treatment; (d) where an increased daily dosage has been administered, carrying out a further clinical evaluation of the subject for efficacy and side effects arising from the treatment with the increased daily dosage; (e) where the further clinical evaluation (d) has established that a further increased daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof is desirable, administering a further increased daily dosage which is greater than an immediately preceding daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)--dihydrotetrabenazine free base; or, where the clinical evaluation has established that a further increased daily dosage is not desirable, maintaining the immediately preceding daily dosage, reducing the immediately preceding dosage or discontinuing the treatment; and (f) optionally repeating steps (d) and (e) as often as desired until an optimum daily dosage is reached.

2. A method according to claim 1 wherein the initial daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof, is an amount corresponding to from 0.5 mg to 3 mg of (+)--dihydrotetrabenazine free base.

3. A method according to claim 2 wherein the initial daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof, is an amount corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)--dihydrotetrabenazine free base.

4. A method according to claim 1 wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 3 mg of (+)--dihydrotetrabenazine free base.

5. A method according to claim 4 wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)--dihydrotetrabenazine free base.

6. A method according to claim 1 wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 3 mg of (+)--dihydrotetrabenazine free base.

7. A method according to claim 6 wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)--dihydrotetrabenazine free base.

8. A method according to claim 1 wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof, which is an amount corresponding to no greater than 20 mg of (+)--dihydrotetrabenazine free base.

9. A method according to claim 8 wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof, which is an amount corresponding to no greater than 10 mg of (+)--dihydrotetrabenazine free base.

10. A method according to claim 1 wherein the treatment comprises determining an approximate weight of the subject and: (i) when the subject has a weight of 30 kg to 50 kg, administering a maximum (e.g. optimized) daily amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 2 mg to 7.5 mg of (+)--dihydrotetrabenazine free base; (ii) when the subject has a weight of 50 kg to 75 kg, administering a maximum (e.g. optimized) daily amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 5 mg to 10 mg of (+)--dihydrotetrabenazine free base; (iii) when the subject has a weight of 75 kg to 95 kg, administering a maximum (e.g. optimized) daily amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 7.5 mg to 15 mg of (+)--dihydrotetrabenazine free base; or (iv) when the subject has a weight of greater than 95 kg, administering a maximum (e.g. optimized) daily amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 15 mg to 20 mg of (+)--dihydrotetrabenazine free base the amount of (+)--dihydrotetrabenazine administered per day is from 15 mg to 20 mg.

11. A method of treating a movement disorder in a subject in need thereof, which treatment comprises administering to the subject an effective amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, wherein the said effective amount corresponds to an amount of (+)--dihydrotetrabenazine free base of from 0.05 mg/kg to 0.3 mg/kg per day.

12. A method according to claim 1 wherein the daily dosage, daily amount or effective amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered to the subject is sufficient to cause a level of blocking of between 50% and 85% of VMAT2 proteins in the subject.

13. A method according to claim 11 wherein the daily dosage, daily amount or effective amount of (+)--dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered to the subject is sufficient to cause a level of blocking of between 50% and 85% of VMAT2 proteins in the subject.

14. A method according to claim 1 wherein the movement disorder is selected from tardive dyskinesia, Tourette's syndrome and Huntington's disease.

15. A method according to claim 14 wherein the movement disorder is Tourette's Syndrome.

16. A method according to claim 14 wherein the movement disorder is Huntington's Disease.

17. A method according to claim 1 wherein the (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof is administered to the subject once per day.

18. A method according to claim 1 wherein the (+)--dihydrotetrabenazine or pharmaceutically acceptable salt thereof is not administered in combination with a therapeutically effective amount of amantadine.

19. A method according to claim 1 wherein the subject is a human subject from 5 years old to 16 years old, having a weight of 80 kg or less, for example a weight in the range from 17 kg to 70 kg.

20. A unit dosage form comprising from 0.5 mg to 3 mg of (+)--dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0159] FIG. 1 is a plot of % VMAT2 binding vs body weight after administration of doses of 7.5 mg, 15 mg and 22.5 mg of (+)--dihydrotetrabenazine to human subjects.

[0160] FIG. 2 is a plot of % VMAT2 binding vs amounts of (+)--dihydrotetrabenazine administered to human subjects in mg/kg body weight.

[0161] FIG. 3 shows the average total distance traveled by rats when treated with vehicle (with or without amphetamine induction) and (+)--dihydrotetrabenazine at doses of 0.5, 1, 1.5 and 2 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below.

[0162] FIG. 4 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (+)--dihydrotetrabenazine at doses of 0.5, 1, 1.5 and 2 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below.

[0163] FIG. 5 shows the average total distance traveled by rats when treated with vehicle (with or without amphetamine induction) and (+)--dihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.

[0164] FIG. 6 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (+)--dihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.

[0165] FIG. 7 shows the average total distance traveled by rats when treated with vehicle and (+)--dihydrotetrabenazine at a dose of 2.5 mg/kg or 5 mg/kg and risperidone at a dose of 1 mg/kg in rats without amphetamine induction, as described in Example 2, Study 3 below.

[0166] FIG. 8 shows the average total stereotypic behaviour by rats when treated with vehicle and (+)--dihydrotetrabenazine at a dose of 2.5 mg/kg or 5 mg/kg and risperidone at a dose of 1 mg/kg in rats without amphetamine induction, as described in Example 2, Study 3 below.

[0167] FIG. 9 shows the average total distance traveled by rats when treated with vehicle and (+)--dihydrotetrabenazine and Valbenazine each at a dose of 1 mg/kg or 1.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.

[0168] FIG. 10 shows the average total stereotypic behaviour by rats when treated with vehicle and (+)--dihydrotetrabenazine and Valbenazine each at a dose of 1 mg/kg or 1.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.

EXAMPLES

[0169] The following non-limiting examples illustrate the synthesis and properties of the (+)-alpha-dihydrotetrabenazine salt of the invention.

Example 1

[0170] (+)--Dihydrotetrabenazine in defined amounts was administered by oral dosing to five human volunteers. In four of the volunteers, blood sample were taken at 30, 60, 120 and 180 minutes after drug administration. Blood samples were not taken from the fifth volunteer. At 60 minutes after drug administration, PET scans were initiated and these were stopped at 120 minutes after drug administration.

[0171] The experiment was carried out at dosages of 7.5 mg, 15 mg and 22.5 mg.

Results

[0172] Table 1 shows the plasma concentrations in nanogrammes/ml of (+)--dihydrotetrabenazine in five human subjects, 0.5, 1, 1.5, 2 and 3 hours after a dose of 7.5 mg, 15 mg and 22.5 mg. Table 2 shows the % VMAT2 blocking following administration of 7.5 mg, 15 mg and 22.5 mg of (+)--dihydrotetrabenazine in all five subjects.

TABLE-US-00001 TABLE 1 Time Subject # (h) 1 2 3 4 5 6 Body 112 76 129 59 91 68 Weight (kg) Dose (oral) 7.5 mg 0.5 BLQ 0.531 0.216 8.43 6.68 BLQ 1 0.94 13.7 4.35 15.0 9.8 3.77 1.5 2.39 10.8 6.91 20.7 13.5 3.06 2 2.44 14.0 5.03 17.6 10.7 4.33 3 3.01 22.2 6.96 19.6 11.2 9.18 15 mg 0.5 4.02 7.99 1.2 26.7 15.6 5.41 1 11.1 22.8 14.3 53.8 34.2 10.6 1.5 10.7 46.4 17.9 42.5 27.1 16.1 2 10.2 35.7 12.0 53.3 31.8 17.4 3 10.6 46.5 18.2 60.2 27.1 14.9 22.5 mg 0.5 9.61 5.23 9.04 ND 55.3 5.58 1 18.0 21.8 34.7 ND 45.1 8.01 1.5 16.8 36.2 29.8 ND 46.2 5.87 2 14.9 40.2 26.3 ND 41.9 12.5 3 13.2 51.8 17.3 ND 42.5 18.7 BLQBelow level of quantitation, NDNot done

TABLE-US-00002 TABLE 2 Subject # 1 2 3 4 5 6 Body 112 76 129 59 91 68 Weight (kg) Dose 7.5 mg 54 73 62 84 73 60 (oral) 15 mg 73 83 69 89 79 76 22.5 mg 75 82 74 ND 82 62

[0173] Although in subjects with a lower body weight, higher (+)--dihydrotetrabenazine blood plasma concentrations were observed for a given dose, it can be seen that even in heavier individuals, at least 50% % VMAT2 blocking was observed at doses as low as 7.5 mg and, in lighter individuals, significantly higher % VMAT2 binding was. It was also observed that during the period of PET scanning, average plasma levels of less than 15 ng/ml gave rise to % VMAT2 binding of at least 50%.

[0174] The data demonstrate that very low doses of (+)--dihydrotetrabenazine resulting in plasma concentrations of less than 15 ng/ml can still give high levels of VMAT2 blocking.

[0175] The data for subjects 1 to 5 were used to prepare plots (FIG. 1) of % VMAT2 binding against body weight at the three dosage levels and plots (FIG. 2) of % VMAt2 binding against the amount (in mg/kg body weight) of (+)--dihydrotetrabenazine administered. The data for subject 6, which are somewhat anomalous, were not included in FIG. 1 or FIG. 2.

[0176] FIG. 1 shows the % VMAT2 binding against body weight for each dose of (+)--DHTBZ administered (7.5 mg, 15 mg and 22.5 mg) based on the data above. As can be seen, for a given dose there is a good correlation between body weight and % VMAT2 binding.

[0177] FIG. 2 shows the % VMAT2 binding against the amount of (+)--DHTBZ per kg of the body weight of the subject based on the data above. Again it can be seen that there is a good correlation between amount of (+)--DHTBZ per weight of the subject (mg/kg value) and % VMAT2 binding.

[0178] Therefore, it is expected that the amount of (+)--DHTBZ that needs to be administered to provide a given VMAT2 binding level will depend greatly on the weight of the subject.

Example 2Comparison of the Effect of Dihydrotetrabenazines and Risperidone on Amphetamine-Induced Hyperlocomotion

[0179] Dopaminergic models for Tourette's syndrome use systemic or focal administration of dopamine agonists such as amphetamine. After injection with amphetamine, a test animal expresses stereotypic behaviour. In particular, involvement of a dopaminergic system implicated in Tourette's syndrome wild type mice and rats can be stimulated with amphetamine and the resulting hyperactivity and stereotypes can be reversed with dopamine antagonists such as risperidone and haloperidol (Tourette's syndromeAnimal Models for Screening, Charles River Discovery Research Services, Finland).

[0180] Amphetamine produced a rise in extracellular concentrations of brain dopamine and concomitant behavioural manifestations in the rat and other species. At relatively low doses (1.2 ng/kg i.p.) amphetamine increases locomotor behaviour, ceases movement and gives way to a stationary posture accompanied by highly repetitive rapid head movements. This latter non-locomotor phase of stimulation is referred to as focused stereotypy. The stereotypy can last for over an hour and is usually followed by a period of locomotor stimulation (Schiorring 1971).

[0181] Administration of dopamine agonists (such as amphetamine) is known to induce behavioural stereotypes and sensorimotor gating disruption. Also, dopaminergic, cholinergic (TANs) and HDC models (subsequent to stress and/or amphetamine injection) are known to show an increase in stereotypic behaviours (Yaol et al 2016).

[0182] Amphetamine induced stereotype behaviour has also been evaluated as a model for the movement disorder condition, tardive dyskinesia (see Rubovitis et al (1972)).

[0183] The atypical antipsychotic drug risperidone is commonly used for the treatment of Tourette's syndrome and has been described (J. D. Walkup, A Guide to Tourette Syndrome Medications, Publ. 2008, The National Tourette Syndrome Association, Inc.) as being probably the best atypical antipsychotic for tic suppression with potentially less risk of motor side effects than haloperidol and fluphenazine.

[0184] Three studies were carried out to compare the effects of dihydrotetrabenazines and risperidone on amphetamine-induced and non-amphetamine-induced hyperlocomotion in rats, on the basis that, for the reasons given above, locomotor studies are useful models for Tourette's syndrome and other movement disorders.

Materials and Methods

Equipment

[0185] Open field arena, Med Associates Inc.
Plastic syringes 1 ml, Terumo. Ref: SS-01T1
Animal feeding needle 15 G, Instech Solomon, Cat: 72-4446

Sartorius Mechatronics Scale A22101, Sartorius Weighting Technology, Germany

Needle 27 G Terumo Myjector, 0.5 ml, Ref: 8300010463

[0186] Plastic syringes 3 ml, Soft-Ject, Ref: 8300005761
BD Microtainer K2EDTA tubes Ref: 365975

Matrix 0.75 ml, Alphanum Tubes, Thermo Scientific, Ref: 4274

[0187] Microplate Devices, Uniplate 24 wells, 10 ml, Ref: 734-1217
Thermo Electron Corp. Heraeus Fresco 17, refrigerated centrifuge

Test Animals

[0188] All animal experiments were carried out according to the National Institute of Health (NIH) guidelines for the care and use of laboratory animals, and approved by the National Animal Experiment Board, Finland. Male CD (Charles River Laboratories, Germany) at weight range of 200-250 g (165-200 g upon arrival) were used for the experiments. Animals were housed at a standard temperature (221 C.) and in a light-controlled environment (lights on from 7 am to 8 pm) with ad libitum access to food and water.

Methods

[0189] Locomotor activity of the rats was tested in open field arena. The open field test was performed during the rat light cycle and under a normal lighting evenly distributed to the test chambers. The paths of the rats were recorded by activity monitor (Med. Associates Inc.).

[0190] Dosing the vehicle, vehicle-amphetamine, (+)--DHTBZ or risperidone was done prior to LMA test. The rats were placed in the centre of the arena, and the path was recorded for 60 minutes.

Endpoint, Blood Samples and Tissue Processing

[0191] Within 10 minutes from the end of the test animals were euthanized by an overdose of CO.sub.2. The terminal blood sample was collected with cardiac puncture from all compound treated rats from each group excluding vehicle rats. 0.5 ml of blood was collected with syringe attached to 18 G needle and moved into precooled K2-EDTA microtubes. The EDTA microtube was inverted several times to mix up the EDTA and blood. Tubes were then immediately put on wet ice and centrifuged (Heraeus Fresco 17) within 10-15 minutes of collecting (9.61000 G/101000 RPM, +4 C. for 2 min), and 200 l of plasma was collected in 96-tube plates (Matrix Technologies ScreenMates 0.75 ml Alphanumeric Round-Bottom Storage tubes, PP) on dry ice according to sample map.

[0192] After collection of blood the neck was dislocated at the base of the skull. Brain was collected and weighed. Brain weights were recorded and the brain was frozen on dry ice on the 24 well plate.

[0193] The plasma and brain samples were stored at 80 C. until sent for analysis or destroyed.

Study 1

[0194] The effects on stereotypic behaviour and the distance traveled in rats following administration of (+)--dihydrotetrabenazine dosed at 0.5 mg/kg to 2 mg/kg, as well as risperidone at 1 mg/kg, were studied.

[0195] Animals were grouped as follows: [0196] Group 1: 10 rats treated with Vehicle (t=0 min) and Vehicle (t=30 min) [0197] Group 2: 10 rats treated with Vehicle (t=0 min) and Amphetamine (t=30 min) [0198] Group 3: 10 rats treated with (+)--DHTBZ 0.5 mg/kg (t=0 min) and Amphetamine (t=30 min) [0199] Group 4: 10 rats treated with (+)--DHTBZ 1 mg/kg (t=0 min) and Amphetamine (t=30 min) [0200] Group 5: 10 rats treated with (+)--DHTBZ 1.5 mg/kg (t=0 min) and Amphetamine (t=30 min) [0201] Group 6: 10 rats treated with (+)--DHTBZ 2 mg/kg (t=0 min) and Amphetamine (t=30 min) [0202] Group 7: 10 rats treated with risperidone 1 mg/kg (t=0 min) and Amphetamine (t=30 min)

Results

1. Distance Traveled

[0203] Rats dosed with either vehicle, (+)--DHTBZ 0.5 mg/kg, (+)--DHTBZ 1 mg/kg, (+)--DHTBZ 1.5 mg/kg, (+)--DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance traveled over the testing time is presented in FIG. 3.

[0204] When compared to the vehicle-vehicle group the vehicle-amphetamine was significantly different. When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ 0.5 mg/kg, (+)--DHTBZ 1 mg/kg, (+)--DHTBZ 1.5 mg/kg, (+)--DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.

2. Stereotypic Behaviour

[0205] Rats dosed with either vehicle, (+)--DHTBZ 0.5 mg/kg, (+)--DHTBZ 1 mg/kg, (+)--DHTBZ 1.5 mg/kg, (+)--DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in FIG. 4.

[0206] When compared to the vehicle-vehicle group the vehicle-amphetamine, (+)--DHTBZ 0.5 mg/kg and (+)--DHTBZ 1.5 mg/kg were significantly different. When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ 0.5 mg/kg, (+)--DHTBZ 1 mg/kg, (+)--DHTBZ 1.5 mg/kg, (+)--DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.

Conclusions

[0207] This study evaluated the effect of (+)--DHTBZ at doses 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg and 2 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.

[0208] (+)--DHTBZ at all the tested doses and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)--DHTBZ at all the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group. Both of the measured parameters suggest that (+)--DHTBZ has a sedative effect similar to risperidone.

Study 2

[0209] The effects on stereotypic behaviour and the distance traveled in rats following administration of (+)--dihydrotetrabenazine dosed at 0.1 mg/kg to 0.25 mg/kg, as well as risperidone at 1 mg/kg, were studied.

[0210] Animals were grouped as follows: [0211] Group 1: 10 rats treated with Vehicle (t=0 min) and Vehicle (t=30 min) [0212] Group 2: 10 rats treated with Vehicle (t=0 min) and Amphetamine (t=30 min) [0213] Group 3: 10 rats treated with (+)--DHTBZ 0.1 mg/kg (t=0 min) and Amphetamine (t=30 min) [0214] Group 4: 10 rats treated with (+)--DHTBZ 0.25 mg/kg (t=0 min) and Amphetamine (t=30 min) [0215] Group 5: 10 rats treated with risperidone 1 mg/kg (t=0 min) and Amphetamine (t=30 min)

Results

1 Distance Traveled

[0216] Rats dosed with either vehicle, (+)--DHTBZ 0.1 mg/kg, (+)--DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance traveled over the testing time is presented in FIG. 5.

[0217] When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different.

2 Stereotypic Behaviour

[0218] Rats dosed with either vehicle, (+)--DHTBZ 0.1 mg/kg, (+)--DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in FIG. 6.

[0219] When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ 0.1 mg/kg, (+)--DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different.

Conclusions

[0220] This study evaluated the effect of (+)--DHTBZ at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.

[0221] (+)--DHTBZ at 0.25 mg/kg and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)--DHTBZ at both the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.

Study 3

[0222] The effects of (+)--dihydrotetrabenazine and risperidone on in non-amphetamine induced rats was studied. Animals were grouped as follows: [0223] Group 1: 10 rats treated with Vehicle [0224] Group 2: 10 rats treated with (+)--DHTBZ 2.5 mg/kg [0225] Group 3: 10 rats treated with (+)--DHTBZ 5 mg/kg [0226] Group 4: 10 rats treated with risperidone 1 mg/kg

Results

[0227] In non-induced rats, the total movement and stereotypic behaviour in rats treated with the vehicle were comparable to (+)--dihydrotetrabenazine (see FIGS. 7 and 8). However, rats treated with risperidone had reduced total movement and reduced total stereotypic behaviour.

Study 4

[0228] The effects on stereotypic behaviour and the distance traveled in rats following administration of (+)--dihydrotetrabenazine and Valbenazine both dosed at 1 mg/kg and 1.5 mg/kg, as well as risperidone at 1 mg/kg, were studied.

[0229] Animals were grouped as follows: [0230] Group 1: 10 rats treated with Vehicle (t=0 min) and Vehicle (t=30 min) [0231] Group 2: 10 rats treated with Vehicle (t=0 min) and Amphetamine (t=30 min) [0232] Group 3: 10 rats treated with (+)--DHTBZ 1 mg/kg (t=0 min) and Amphetamine (t=30 min) [0233] Group 4: 10 rats treated with (+)--DHTBZ 1.5 mg/kg (t=0 min) and Amphetamine (t=30 min) [0234] Group 5: 10 rats treated with Valbenazine 1 mg/kg (t=0 min) and Amphetamine (t=30 min) [0235] Group 6: 10 rats treated with Valbenazine 1.5 mg/kg (t=0 min) and Amphetamine (t=30 min) [0236] Group 7: 10 rats treated with risperidone 1 mg/kg (t=0 min) and Amphetamine (t=30 min)

Results

1 Distance Traveled

[0237] Rats dosed with either vehicle, (+)--DHTBZ, Valbenazine or Risperidone were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The total distance traveled over the testing time is presented in FIG. 9.

[0238] When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ (at 1 mg/kg and 1.5 mg/kg), Valbenazine (at 1 mg/kg and 1.5 mg/kg) and risperidone 1 mg/kg were significantly different.

2 Stereotypic Behaviour

[0239] Rats dosed with either vehicle, (+)--DHTBZ 0.1 mg/kg, (+)--DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in FIG. 10.

[0240] When compared to vehicle-amphetamine group the vehicle-vehicle, (+)--DHTBZ (at 1 mg/kg and 1.5 mg/kg), Valbenazine (at 1 mg/kg and 1.5 mg/kg) and risperidone 1 mg/kg were significantly different.

Conclusions

[0241] This study evaluated the effect of (+)--DHTBZ and Valbenazine both at doses of 1 mg/kg and 1.5 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.

[0242] (+)--DHTBZ at 1 mg/kg and 1.5 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group and the corresponding dose of Valbenazine. (+)--DHTBZ at both the tested doses led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group and the corresponding dose of Valbenazine.

Comments

[0243] Studies 1 and 2 in Example 2 show the effectiveness of doses of (+)--dihydrotetrabenazine as low as 0.1 mg/kg in reducing movement in amphetamine-induced rats. It is therefore expected that such low dose regimes may also be useful in treating hyperkinetic movement disorders in humans.

[0244] Study 3 in Example 2 suggests that following administration of low doses of (+)--dihydrotetrabenazine whereas abnormal movements of the type found in movement disorders will be reduced or suppressed by the drug, normal movements will not be. This is in contrast to risperidone, a well-used treatment for movement disorders, where the levels of both normal and abnormal movements can be reduced by administration of the drug.

[0245] Study 4 in Example 2 shows the increased effectiveness of (+)--dihydrotetrabenazine over Valbenazine.

EQUIVALENTS

[0246] It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.