Pharmacological treatment of obsessive-compulsive disorder

Abstract

The present invention relates to a compound of the following formula (I): ##STR00001##
or a pharmaceutically acceptable salt thereof,
for use in the prevention or treatment of obsessions and/or compulsions in an individual.

Claims

1. A method for the treatment of obsessions and/or compulsions in an individual, comprising administering to the individual a therapeutically effective quantity of at least one compound of the following formula (III): ##STR00007## or the pharmaceutically acceptable salt thereof, at a dose which treats obsessions and/or compulsions, wherein the compound or pharmaceutically acceptable salt thereof is administered at a dose regimen of from 10 mg/kg/d to 200 mg/kg/d.

2. The method of claim 1, for the treatment of obsessive-compulsive disorder (OCD).

3. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in a form suitable for administration by the oral or rectal route.

4. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in the form of a powder, sachets, tablets, capsules or suppositories.

5. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for treating obsessions and/or compulsions.

6. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for treating obsessions and/or compulsions comprising selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or neuroleptics.

7. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for treating obsessions and/or compulsions comprising escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, clomipramine, haloperidol or risperidone.

8. A method for the treatment of obsessions and/or compulsions in an individual, comprising administering to the individual a therapeutically effective quantity of at least one compound of the following formula (III): ##STR00008## or the pharmaceutically acceptable salt thereof, wherein the compound of formula (III) or the pharmaceutically acceptable is administered at a unit dose which is not a sub-therapeutic amount for mood stabilization treatment of epilepsy or epileptic symptoms, wherein the compound or pharmaceutically acceptable salt thereof is administered at a dose regimen of from 10 mg/kg/d to 200 mg/kg/d.

9. The method of claim 8, for the treatment of obsessive-compulsive disorder (OCD).

10. The method of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is in a form suitable for administration by the oral or rectal route.

11. The method of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is in the form of a powder, sachets, tablets, capsules or suppositories.

12. The method of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for preventing or treating obsessions and/or compulsions.

13. The method of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for treating obsessions and/or compulsions comprising selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or neuroleptics.

14. The method of claim 8, wherein the compound or pharmaceutically acceptable salt thereof is in combination with at least one additional compound intended for treating obsessions and/or compulsions comprising escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, clomipramine, haloperidol or risperidone.

15. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered at a unit dose which is not a sub-therapeutic amount for mood stabilization treatment of epilepsy or epileptic syndrome.

16. A method for the treatment of obsessions and/or compulsions, comprising administering to the individual a therapeutically effective quantity of at least one compound of the following formula (III): ##STR00009## or a pharmaceutically acceptable slat thereof, at a dose which treats obsessions and/or compulsions, wherein the compound or pharmaceutically acceptable salt thereof is administered at a dose regimen of from 10 mg/kg/d to 200 mg/kg/d.

17. A method for the treatment of obsessions and/or compulsions involving repetitive behavior in an individual, comprising administering to the individual a therapeutically effective quantity of at least one compound of the following formula (III): ##STR00010## or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered at a dose regimen of from 10 mg/kg/d to 200 mg/kg/d.

Description

DESCRIPTION OF THE FIGURE

(1) FIG. 1 represents the influence of stiripentol (STP) and clomipramine administered i.p. at different doses (horizontal axis, in mg/kg) on the marble-burying behavior in mice (vertical axis). Each bar represent the meansem. The number of animals used appears in brackets. *p<0.05 compared to vehicle group (Veh) (ANOVA or Kruskall Wallis test followed by Dunnett's test or Dunn's method respectively).

EXAMPLE

(2) Marble-burying behavior in the rodent is considered to be a model of obsessive-compulsive disorder (OCD) and is commonly used to assess the activity of candidate compounds in the prevention or treatment of OCD (Ishimaru et al. (1995) Jpn. J. Pharmacol. 68:65-70; Gaikwad & Parle (2010) Asian Journal of Pharmaceutical and Clinical Research 3:101-103; Prajapati et al. (2011) Pharmacognosy Res. 3:62-66). Accordingly, the effects of stiripentol and clomipramine, chosen as positive reference, on marble-burying behavior were investigated in mice. In addition, because the motor behavior can interfere with the burying behavior, the effects of stripentol in the rota rod test and spontaneous locomotion have been also evaluated.

1 METHODS

(3) 1.1 Animals

(4) Six-week old NMRI mice (30-32 g) were purchased from Janvier breeding (Le Genest-St Isle; France). Mice were housed ten per translucent polypropylene cage (internal dimensions; 37.5 cm37.5 cm180 cm, LWH) under standard laboratory conditions (222 C., 12-h light/dark cycle, lights on at 7:00 AM) with food (AO4, SAFE, France) and tap water available ad libitum. No less than one week of rest followed their arrival. All animal procedures were carried out in accordance with the European Community council directive of 24 of Nov. 1986 (86/609/EEC) for the care and use of laboratory animals and the French government guidelines (authorization C60-159-04December, 2009).

(5) 1.2 General Testing Conditions and Treatments.

(6) Mice were habituated to the testing room at least 60 min before any behavioural evaluation. All tests took place between 9:00 AM and 3:00 PM unless otherwise stated. The behavioural tests were performed by different well-trained experimenters who were kept unaware of the treatment administered. All experiments were performed in a randomized manner. Stiripentol (100-200 mg/kg) and clomipramine (5-20 mg/kg) were given intra-peritoneously (i.p.) 60 and 30 min respectively before testing.

(7) 1.3 Marble-Burying Behavior

(8) The marble-burying behavior of mice was conducted according to the methodology of Njung'e and Handley (1991) Pharmacol Biochem Behav 1991; 38: 63-67. Briefly, each mouse was placed individually in a polycarbonate cage (Type S-River; 26.51614 cm height) containing 20 clean glass marbles of diameter 1.5 cm evenly spaced on 5 cm deep sawdust. The cage-lid was a metal grid. No food or water was present. The marbles were cleaned with an alcohol solution (10%; v/v) between each animal. The number of marbles at least buried was counted 30 min later.

(9) 1.4 Spontaneous Locomotor Activity

(10) Testing occurred in a quiet room under a light level of approximately 400 lux. The motor activity cages (type S; River; polycarbonate; 26.51614 cm height) were made of clear plastic, changed between each animal, and containing a minimum amount of sawdust. Locomotor activity and rearing were measured by vibrations analysis and the interruption of infra-red beams respectively (ActiV-Meter; Software BIO-ACTIV; Bioseb-Vitrolles-France). The distance travelled (in cm) and the number of rearings were measured for 30 min.

(11) 1.5 Rotarod Test

(12) The rotarod test was performed in accordance with the teachings of Kohara et al. (2005) J Pharmacol Exp Ther 2005; 315: 163-169. Briefly, the rotarod consists of a 3-cm-diameter rod rotating at a fixed speed of 16 revolutions per minute (model 7600; Ugo Basile, Comerio Italy), which can be used to assess motor performance. Mice were trained to walk on the rotarod until they could complete three consecutive 120-s sessions without falling off. Mice that show a 120 s performance time were selected for drug evaluation. Animals were then given i.p. either vehicle or various doses of either compound before being placed on the rotarod. In the drug evaluation session, rotarod performance time was measured three times, up to 120 s, and the mean was adopted as the performance time for each animal. The performance of the animals on the rota rod requires skill and motor coordination.

(13) 1.6 Drugs

(14) Stiripentol (batch 167, Biocodex, France) was suspended in a saline solution of 5% tween 80 (v/v) whereas clomipramine hydrochloride (Sigma-France) was dissolved in 0.9% saline. These compounds were administered under a volume of 0.1 ml/10 g of body weight. Control animals received an equivalent volume of vehicle.

(15) 1.7 Statistical Analysis

(16) All data are expressed as meanSEM. The number of marble buried, locomotor activity and the time spent on the rot rod were analyzed by one-way analyse of variance (ANOVA) or the Kruskall Wallis procedure followed post-hoc by the Dunnett's test or Dunn's method respectively to locate the differences between the treated groups and the vehicle group. Differences were considered statistically significant when p<0.05. Statistical tests were run using SigmaStat v3.5 (SPSS, inc, Chicago, Ill., USA).

2 RESULTS

(17) As shown in FIG. 1, stripentol dose-dependently decreased the number of marbles buried [F(3.42)=5.425; p=0.003] and significance was reached for the dose of 200 mg/kg. Likewise, clomipramine significantly reduced the number of marbles buried [H(3)=20.412; p<0.001] and significance was reached at the doses of 10 and 20 mg/kg.

(18) Besides, stiripentol did not significantly modify the distance travelled up to 200 mg/kg of stiripentol. Similarly, stiripentol did not significantly impair the number of rearings up to 200 mg/kg. In addition, doses of stiripentol up to 200 mg/kg were without any significant effect on the time spent on the rot rod.

3 DISCUSSION

(19) Marble-burying behaviour of mice is considered as the marker index of compulsive behaviour, which is characteristically evident in OCD. This behaviour is an unconditioned species-specific defensive reaction in rodents, which is not associated with physical danger, and does not habituate upon repeated testing. The major finding of the present study is that stiripentol reduced marble burying behaviour. A similar reduction in the number of marbles buried was observed in mice treated with clomipramine, chosen as reference compound and clinically used as anti-compulsive agent.

(20) It is noteworthy that these anti-compulsive-like effects of stiripentol could be theoretically compromised by sedative-like or ataxic actions. However, by comparing marble burying scores with locomotor activity and rota rod measures, the inventors have shown that stiripentol inhibited marble burying at doses that did not affect motor activities. Similarly, it has been shown that the anti-compulsive effects of clomipramine were specific and unrelated to general motor effects in the mouse.

4. CONCLUSION

(21) In the OCD mouse model of marble-burial, stiripentol reduced the number of marble buried in the mouse without affecting locomotor activity.