Method of treatment

The use of &lsqb;R-(Z)&rsqb;-&agr;-(methoxyimino)-&agr;-(1-azabicyclo&lsqb;2.2.2&rsqb;oct-3-yl)acetonitrile or a pharmaceutically acceptable salt thereof for the treatment of psychosis or other neuropsychiatric symptoms.

BIOLOGICAL DATA Amphetamine Induced Hyperactivity and Catalepsy in the Rat Materials Male Sprague Dawley rats from Charles River UK Ltd were used in all experiments. The rats were allowed to acclimatise to their housing conditions (12 h light/dark cycle with ad lib food and water; 6 rats per cage) for at least 5 days before experiments. On the day of use, rats weighed 220-340 g. Dexamphetamine sulphate (Lot No. 33H844) was obtained from Sigma Chemical Co. UK. and dissolved in 0.9% w/v saline. Haloperidol (Lot No. 37F-00123) was obtained from Sigma Chemical Co. UK. and dissolved with an equal weight of (&plus;)-tartaric acid in water. &lsqb;R-(Z)&rsqb;-&agr;-(methoxyimino)-&agr;-(1-azabicyclo &lsqb;2.2.2&rsqb;oct-3-yl)acetonitrile monohydrochloride (Compound (I)) is described in EP-A-0392803 as the oxalate salt. Compound (I) was dissolved in 0.9% w/v saline. All drug doses refer to the base equivalent. Methods 1. Amphetamine-Induced Hyperactivity Rat locomotor activity was measured in 2 racks of “AM logger” AM 1052 activity monitors (Linton Instrumentation). Each rack held 8 individual perspex boxes (42 cm×21 cm×21 cm) containing a thin bed of sawdust. For each box, 8 infra red light beams traversed the short axis and 4 infra red light beams traversed the long axis. The light beams were focussed on to photoelectric cells. Each rack of monitors was controlled by a 386 microcomputer using AMLOGGER “Activity Monitor Data Logger Version 4.02” software. Rats (n&equals;8 per treatment group) were weighed and injected with saline or test drug in a volume of 2 ml/kg po. and then placed in the locomotor activity boxes for a period of habituation. After 25-30 minutes, the rats were injected with saline (1 ml/kg sc) or dexamphetamine sulphate (0.4 mg/kg) and then returned to the locomotor activity boxes. Locomotor activity was then monitored for a further 60 minutes in 5 min blocks. After discarding the first 5 minute block so as to minimise handling artefacts, the total beam break tally for the final 55 min. was subjected to log 10 transformation before being analysed by 1 factor analysis of variance and Dunnett's t-test for multiple comparisons. ED50 with 95% confidence intervals were calculated from the log10 transformed data using a statistical package (GETED50CI) in RSE (Bolt, Beranek and Newman Inc, 1992). 2. Catalepsy For catalepsy experiments, rats (n&equals;6 per treatment group) were weighed and injected with saline or test drug in a volume of 2 ml/kg po., and then returned to their home cages. Haloperidol was included in the experiment as a positive control. At 30, 60 and 90 minutes post dose, the rats were positioned so that their hind-legs contacted the bench surface, and their fore-legs were located over the horizontal bar. A maximum measurement time of 120 sec. was used, after which, if the rats were still on the bar, they were returned to their home cages. A rat was considered to be cataleptic if it remained on the bar for at least 30 sec. at the 90 min. time point. Data was analysed by logistic regression analysis in SAS-RA (Version 2.1) (SAS Institute Inc., Cary, N.C., USA). Results In the amphetamine-induced hyperactivity model, a standard behavioural test which is predictive of antipsychotic efficacy, Compound (I) (0.01-0.3 mg/kg po; 30 min pretreatment) caused a dose related reversal of amphetamine-induced hyperactivity in the rat which reached significance (P<0.01) at a dose of 0.3 mg/kg. The ED 50 for this inhibitory effect was 0.25 mg/kg (95% CI&equals;0.14-0.75). Activity in this model indicates utility in the treatment of psychosis. Conversely, in the above catalepsy test predictive of neuroleptic-induced extrapyramidal side-effects, Compound (I) did not produce catalepsy when tested 90 min after dosing in the rat at doses up to 0.3 mg/kg po, wheras haloperidol produced catalepsy in 6 of 6 rats at 2.8 mg/kg. The data suggest that Compound (I) may possess behaviour modifying effects consistent with antipsychotic activity at doses which would not produce extrapyramidal side-effects, indicating potential use in the treatment of psychosis. Clinical Data (Retrospective Analysis) Compound (I) has been assessed in clinical trials of Alzheimer's disease. In addition to investigating the effects on cognition and global functioning, scales to assess effects of Compound (I) on behavioural symptoms commonly found in Alzheimer patients (which include delusions, hallucinations, agitation, anxiety, depression, apathy, elation, disinhibition, irritability and wandering) were prospectively included in two of the trials. The prospectively defined analysis of these studies indicated a positive effect of Compound (I) on behaviour. A retrospective meta-analysis on the combined data was then conducted and effects on individual symptoms assessed. Results are shown in Table 1 (a negative score denotes an improvement and a positive score denotes a deterioration). 1 TABLE 1 All Patients (NB: Statistical analyses were not conducted on the individual symptoms) *p value *p value Parameter/ (Active vs (Active vs Dose Placebo 25 &mgr;g bid placebo) 50 &mgr;g uid placebo) Total NPI &plus;2.5 &plus;0.7 0.064 &plus;0.3 0.026 Agitation −0.2 −0.5 −0.6 Apathy −0.7 −1.1 −1.5 Depression −0.3 −0.3 −0.6 Delusions −0.9 −0.7 −0.6 Hallucinations 0 −1.5 −0.7 Wandering −0.7 −1.2 −1.0 Anxiety −0.8 −0.9 −1.5 Elation 0.1 −1.1 −1.9 Disinhibition 0 −0.7 −0.7 Irritability −0.6 −0.4 −0.9 *No adjustment has been made for multiple comparisons Country adjusted differences were calculated as the difference between the adjusted least square means; allowing estimates from each country to be combined in a manner whereby the most precise estimate is given more weight. This analysis showed a statistically significant improvement following treatment with Compound (I) 50 &mgr;g uid compared with placebo, on the NPI total score (country adjusted difference: −2.1; p&equals;0.026; 95% confidence interval: −4.1, −0.3). The analysis of the difference between Compound (I) 25 &mgr;g bid and placebo was in favour of Compound (I) but failed to achieve statistical significance (country adjusted difference: −1.8; p&equals;0.064; 95% confidence interval −3.8, 0.1). Improvements were also seen in individual symptoms, for example in psychotic symptoms (hallucinations, agitation) and other neuropsychiatric symptoms often observed in Alzheimer's disease. Following this analysis, a further retrospective analysis was conducted on the subgroup of patients who presented with severe behavioural disturbance at the start of the study (defined as a baseline NPI score>20). Country adjusted differences were calculated as the difference between the adjusted least square means; allowing estimates from each country to be combined in a manner whereby the most precise estimate is given more weight. In this subgroup, the effects of Compound (I) on behaviour were even more marked (see Table 2). Thus, a statistically and clinically significant improvement was seen in total NPI score compared with placebo at both 25 &mgr;g bid (country adjusted difference: −7.18; p&equals;0.043; 95% confidence interval: −14.1, −0.2) and 50 &mgr;g uid (country adjusted difference: −7.86; p&equals;0.019; 95% confidence interval: −14.4, −1.3) and marked improvements were also seen on individual symptoms, for example in psychotic symptoms (hallucinations, agitation) and other neuropsychiatric symptoms often observed in Alzheimer's disease, for example apathy, anxiety, disinhibition and wandering. 2 TABLE 2 Endpoint Scores: Change from baseline (Patients with baseline NPI > 20) (NB: Statistical analyses were not conducted on the individual symptoms) *p value *p value Parameter/ (Active vs (Active vs Dose Placebo 25 &mgr;g bid Placebo) 50 &mgr;g uid Placebo) Total NPI &plus;1.7 −4.0 0.043 −6.1 0.019 Agitation −0.1 0 −0.6 Apathy −0.1 −1.4 −1.6 Depression −0.7 0 −1.1 Delusions −1.3 −0.8 −1.4 Hallucinations −0.4 −2.1 −1.4 Wandering −0.2 −1.7 −1.3 Anxiety −0.5 −1.9 −1.8 Elation &plus;0.6 −1.7 −2.5 Disinhibition &plus;0.4 −0.8 −1.1 Irritability −0.9 −0.7 −1.2 *No adjustment has been made for multiple comparisons These results suggest that Compound (I) may have efficacy in the treatment of psychosis in Alzheimer's disease, more particularly in patients with severe behavioural disturbance and also in the treatment of other neuropsychiatric behaviours commonly observed in patients suffering from AD, more particularly those with severe behavioural disturbance.