Use of darifenacin to enhance cognitive functions

Abstract: Darifenacin, and its pharmaceutically acceptable salts, are useful in the treatment of cognitive impairment. The invention also discloses the use of combinations of darifenacin, or a pharmaceutically acceptable salt thereof, with an acetylcholinesterase inhibitor, in the treatment of cognitive impairment.

Description: This invention relates to a new use of darifenacin and its pharmaceutically acceptable salts. Darifenacin is (S)-2-{1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide and is disclosed in European Patent N° 0388054, Examples 1B and 8, and is referred to therein as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine. It is indicated in the treatment of urinary incontinence and irritable bowel syndrome and has the following structure: It has now been found that darifenacin, and its pharmaceutically acceptable salts, is able to enhance cognition. It is therefore indicated in the treatment of cognitive impairment, and as a cognition enhancer in persons not suffering from cognitive impairment. Thus, according to the present invention, there is provided the use of darifenacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cognitive impairment. Causes of cognitive impairment which may be mentioned are Alzheimer's disease and age-related memory disorder. The invention further provides a method of enhancing cognition in a person not suffering from cognitive impairment, which comprises administering an effective amount of darifenacin, or a pharmaceutically acceptable salt thereof, to that person. The invention further provides a method of treatment of cognitive impairment, which comprises administering a therapeutically effective amount of darifenacin, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. In the present indication, a suitable dosage of darifenacin, or a pharmaceutically acceptable salt thereof, for a 70 kg person, is in the range 3.75-40 mg daily, for example 7.5-30 mg daily. The dosage may be administered in, say, 3 divided doses or in a single controlled release formulation (such as described in International Patent Application N° PCT/EP96/03719). Conventional dosage forms and modes of administration are described in EP 0388054. Example Comparison of the effects of darifenacin and oxybutynin upon cognitive function in the elderly A. Methods Study design Thirty six elderly (65+ years) subjects with urge incontinence were planned to complete this single centre, double blind, placebo controlled, parallel group out-patient study. Patients received one of three treatment conditions: placebo; darifenacin (in the form of its hydrobromide salt, 5 mg tid) or oxybutynin (10 mg daily; 2.5 mg in the morning and afternoon and 5 mg in evening). The final dose was given on the morning of day 12 and this was double the usual morning dose (i.e. 10 mg darifenacin or 5 mg oxybutynin). CDR testing schedule a. Training Training on the CDR system took place prior to the first day of the trial in order to familiarise the volunteers with the procedure and overcome the initial learning variability. Four training sessions were planned for each volunteer, two being conducted during the screening period and two on another day prior to day 0. b. Study days The CDR assessments were completed on days 0, 10, 12 and on the post study follow-up. On days 10 and 12 the assessments were conducted 45-60 minutes after the morning or afternoon dose, with all assessments being conducted at approximately the same time of day. Cognitive assessments The CDR Computerised Cognitive Assessment System A selection of tasks from the CDR computerised cognitive assessment system was administered, parallel forms of the tests being presented on each testing session. All tasks were computer-controlled, the information being presented on high resolution monitors, and the response recorded via response modules containing two buttons, one marked 'NO' and the other 'YES'. The tests administered included the following: Choice Reaction Time: Either the word 'NO' or the word 'YES' was presented on the monitor and the volunteer was instructed to press the corresponding button as quickly as possible. There were 30 trials for each of which the stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. Statistics Summary statistics were computed for each assessment by dose condition. For each measure and for each volunteer the assessment conducted prior to the first dose on day 0 was then used as a baseline and subtracted from all subsequent data to compute 'change from day 0' scores. Summary statistics were also computed for these data by dose condition. The latter data were plotted to give a visual representation of the data. The data were subjected to an ANOVA with main effects of treatment group (COND) and study data (DAY). The treatment groups were compared using the LSMEANS statement: darifenacin and oxybutynin were separately compared with placebo and the two active treatments were also compared. B. Results Data Collected 24 patients completed the study. Seven of these patients were randomised to receive darifenacin, eight to receive oxybutynin and nine placebo. In addition, two patients (numbers 2 and 39) completed up to the day 10 assessment. Both these patients were randomised to receive darifenacin. Their data were not included in the main analysis. The data for the Choice Reaction Time test is illustrated in Figure 1. C. Conclusion Darifenacin made a statistically significant improvement in cognitive function as measured by the Choice Reaction Time test. This result was consistent with an earlier study involving young volunteers.

Claims: Use of darifenacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cognitive impairment. The use as claimed in claim 1, wherein the cognitive impairment results from Alzheimer's disease. The use as claimed in claim 1, wherein the cognitive impairment results from age-related memory disorder. Use of darifenacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing cognition in a person not suffering from cognitive impairment.

Inventors: ALLEN MICHAEL JOHN, JOHNSON BRIAN FRANK, LEAKER BRIAN ROBERT, WALLIS ROBERT MICHAEL, ALLEN, MICHAEL JOHN, JOHNSON, BRIAN FRANK, LEAKER, BRIAN ROBERT, WALLIS, ROBERT MICHAEL
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P25, A61P43, C07D405