FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease.
FK962 is a member of a novel class of compounds that promote somatostatin production in the brain, and is being developed as a treatment for patients with Alzheimer's disease. As acetylcholinesterase inhibitors such as Aricept© (donepezil) are widely used to treat these patients, it is important to confirm that potential new medicines in this disease area can be co-administered with drugs such as Aricept. To study the effect of FK962 in combination with donepezil, touchscreen methodology was used to measure the effect on cognition in rats. Doses of FK962 and donepezil were identified that resulted in minimal cognition enhancement when given separately. There was strong evidence (p=0.002) of a treatment difference between the combination of FK962/donepezil and FK962 alone: the estimated treatment difference is 5.47 (95% CI: 2.19-8.75). There was also evidence (p=0.017) of a treatment difference between the combination of FK962/donepezil and donepezil alone: the estimated treatment difference is 4.01 (95% CI: 0.77-7.26). Therefore, a combination of low doses of FK962 and donepezil showed a significantly greater effect on cognition than low doses of either compound alone. This is the first time that FK962 has shown activity in a reward-based model of cognition. In addition, these data suggest that this compound could beneficially be given in addition to Aricept to treat Alzheimer's disease patients.
PGXIS Ltd., Aston Court, Kingsmead Business Park, Frederick Place, High Wycombe, Bucks HP11 1LA, UK. alun.mccarthy@pgxis.com
Alun D
AD
McCarthy
Ian J
IJ
Owens
Aruna T
AT
Bansal
Stephanie M
SM
McTighe
Timothy J
TJ
Bussey
Lisa M
LM
Saksida
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D003071:Cognition / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007189:Indans / Q000008:administration & dosage*; D008297:Male; D023421:Models, Animal; D018697:Nootropic Agents / Q000008:administration & dosage*; D010775:Photic Stimulation; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D012201:Reward
D001549:Benzamides; D002800:Cholinesterase Inhibitors; D007189:Indans; C507659:N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil